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University of Groningen
Continuous intraperitoneal insulin infusion in the treatment of type 1 diabetes mellitusvan Dijk, Peter R.
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Continuous intraperitoneal insulin infusion in the treatment of type 1 diabetes mellitus
Glycaemia and beyond
p.r. van dijk
Continuous intraperitoneal insulin infusion in the treatment of type 1 diabetes mellitus
Glycaemia and beyond
p.r. van dijk
© P.R. van Dijk, 2014
All rights are reserved. No part of this publication may be
reproduced, stored in a retrieval system, or transmitted in any
form or by any other means without the written permission of
the author.
Financial support for printing this thesis was kindly provided by
University of Groningen, University Medical Center Groningen,
Stichting Zwols Wetenschapsfonds Isala Klinieken and
Sanofi-Aventis The Netherlands b.v.
The studies presented in this thesis were kindly supported by
Stichting Zwols Wetenschapsfonds Isala Klinieken,
Sanofi-Aventis The Netherlands b.v., Medtronic International
Trading Sarl and Bayer Diabetes.
Design & layout: Hello Handsome
Printed by: Gildeprint
isbn 978-90-367-7520-5
isbn Electronic version 978-90-367-7521-2
Continuous intraperitoneal insulin infusion in the
treatment of type 1 diabetes mellitus
Glycaemia and beyond
Proefschrift
ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen op gezag van de rector magnificus prof. dr.
E. Sterken en volgens besluit van het College voor Promoties.
De openbare verdediging zal plaatsvinden op woensdag 21 januari 2015 om 16.15 uur
door
Peter Ruben van Dijk
geboren op 7 oktober 1986 te Zwolle
© P.R. van Dijk, 2014
All rights are reserved. No part of this publication may be
reproduced, stored in a retrieval system, or transmitted in any
form or by any other means without the written permission of
the author.
Financial support for printing this thesis was kindly provided by
University of Groningen, University Medical Center Groningen,
Stichting Zwols Wetenschapsfonds Isala Klinieken and
Sanofi-Aventis The Netherlands b.v.
The studies presented in this thesis were kindly supported by
Stichting Zwols Wetenschapsfonds Isala Klinieken,
Sanofi-Aventis The Netherlands b.v., Medtronic International
Trading Sarl and Bayer Diabetes.
Design & layout: Hello Handsome
Printed by: Gildeprint
isbn 978-90-367-7520-5
isbn Electronic version 978-90-367-7521-2
Continuous intraperitoneal insulin infusion in the
treatment of type 1 diabetes mellitus
Glycaemia and beyond
Proefschrift
ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen op gezag van de rector magnificus prof. dr.
E. Sterken en volgens besluit van het College voor Promoties.
De openbare verdediging zal plaatsvinden op woensdag 21 januari 2015 om 16.15 uur
door
Peter Ruben van Dijk
geboren op 7 oktober 1986 te Zwolle
6 7
promotores
copromotores
beoordelingscommissie
paranimfenProf. dr. H.J.G. Bilo
Prof. dr. R.O.B. Gans
Dr. N. Kleefstra
Dr. S.J.J. Logtenberg
Prof. dr. B.H.R. Wolffenbuttel
Prof. dr. E.J.P. de Koning
Prof. dr. H.J. Arnqvist
W.J. Meenhorst, BSc
Ing. W. Kanning
6 7
promotores
copromotores
beoordelingscommissie
paranimfenProf. dr. H.J.G. Bilo
Prof. dr. R.O.B. Gans
Dr. N. Kleefstra
Dr. S.J.J. Logtenberg
Prof. dr. B.H.R. Wolffenbuttel
Prof. dr. E.J.P. de Koning
Prof. dr. H.J. Arnqvist
W.J. Meenhorst, BSc
Ing. W. Kanning
8 9
table of content table of content
chapter 1 Introduction
part i : complications of cipii therapy using an implantable pump
chapter 2 Complications of continuous intraperitoneal insulin infusion
with an implantable pump in type 1 diabetes
part ii : effects of intraperitoneal insulin therapy - glycaemia, quality of life and treatment satisfaction
chapter 3 Glycaemic control, quality of life and treatment satisfaction
after 6 years intraperitoneal insulin infusion with an
implantable pump
chapter 4 A long-term comparison between continuous intraperitoneal
insulin infusion and subcutaneous insulin therapy among
patients with poorly controlled T1DM: a 7 year case-control study
chapter 5 Intraperitoneal insulin infusion is non-inferior to
subcutaneous insulin infusion in the treatment of type 1
diabetes: a prospective matched-control study
chapter 6 Quality of life and treatment satisfaction among type 1
diabetes mellitus patients treated with continuous intra-
peritoneal insulin infusion or subcutaneous insulin:
a prospective observational study
chapter 7 Continuous intraperitoneal insulin infusion versus sub-
cutaneous insulin therapy in the treatment of type 1 diabetes:
positive effects on glycaemic variability
part iii : effects of intraperitoneal insulin therapy - beyond glycaemia
chapter 8 Effect of intraperitoneal insulin administration on IGF1 and
IGFBP1 in type 1 diabetes
chapter 9 After 6 years of intraperitoneal insulin administration
IGF1 concentrations in T1DM patients are at low-normal level
chapter 10 Different effects of intraperitoneal and subcutaneous insulin
administration on the growth-hormone - insulin-like growth
factor-1 axis in type 1 diabetes
chapter 11 Discussion and perspectives
chapter 12 Summary in Dutch
Acknowledgements (in Dutch)
Curriculum Vitae
Publications
Previous dissertations
124
126
138
148
162
182
189194 195198
8
26
28
40
42
56
76
96
110
8 9
table of content table of content
chapter 1 Introduction
part i : complications of cipii therapy using an implantable pump
chapter 2 Complications of continuous intraperitoneal insulin infusion
with an implantable pump in type 1 diabetes
part ii : effects of intraperitoneal insulin therapy - glycaemia, quality of life and treatment satisfaction
chapter 3 Glycaemic control, quality of life and treatment satisfaction
after 6 years intraperitoneal insulin infusion with an
implantable pump
chapter 4 A long-term comparison between continuous intraperitoneal
insulin infusion and subcutaneous insulin therapy among
patients with poorly controlled T1DM: a 7 year case-control study
chapter 5 Intraperitoneal insulin infusion is non-inferior to
subcutaneous insulin infusion in the treatment of type 1
diabetes: a prospective matched-control study
chapter 6 Quality of life and treatment satisfaction among type 1
diabetes mellitus patients treated with continuous intra-
peritoneal insulin infusion or subcutaneous insulin:
a prospective observational study
chapter 7 Continuous intraperitoneal insulin infusion versus sub-
cutaneous insulin therapy in the treatment of type 1 diabetes:
positive effects on glycaemic variability
part iii : effects of intraperitoneal insulin therapy - beyond glycaemia
chapter 8 Effect of intraperitoneal insulin administration on IGF1 and
IGFBP1 in type 1 diabetes
chapter 9 After 6 years of intraperitoneal insulin administration
IGF1 concentrations in T1DM patients are at low-normal level
chapter 10 Different effects of intraperitoneal and subcutaneous insulin
administration on the growth-hormone - insulin-like growth
factor-1 axis in type 1 diabetes
chapter 11 Discussion and perspectives
chapter 12 Summary in Dutch
Acknowledgements (in Dutch)
Curriculum Vitae
Publications
Previous dissertations
124
126
138
148
162
182
189194 195198
8
26
28
40
42
56
76
96
110
10 11
Van Dijk PR, Logtenberg SJJ, Gans ROB, Bilo HJG, Kleefstra N.
Intraperitoneal insulin infusion: treatment option for type
1 diabetes resulting in beneficial endocrine effects beyond
glycaemia. Clin Endocrinol (Oxf) 2014; 81: 488-97.
chapter 1 Diabetes Mellitus
In healthy subjects, the concentration of glucose in plasma is remained within a narrow range
(3.5-7.0 mmol/l) despite fluctuations in nutritional intake, physical exercise and other (physical
or psychological) influences. One of the major determinants of this stable plasma glucose is
the action of the blood-glucose lowering hormone insulin.
Insulin secretion consists of 2 components: a continuous low basal rate and short-lived bursts
in response to stimuli. Basal insulin secretion occurs in the fasting state to inhibit hepatic
glycogenolysis, ketogenesis and gluconeogenesis and accounts for approximately 40% of the
total daily insulin output. Insulin secretion on top of basal secretion occurs when plasma
glucose level exceeds 4.4-5.6 mmol/l to restore euglycaemia by promoting peripheral
glucose uptake and storage. Through these mechanisms, plasma glucose rises to a peak in
30-60 minutes after eating and returns to basal concentrations within 2-3 hours. In healthy
individuals, basal insulin secretion together with the reactivity of insulin secretion in response
to various stimuli are key factors in ensuring glucose homeostasis, permitting stability and
reproducibility of blood glucose 1,2.
Diabetes mellitus refers to a group of metabolic disorders that share the phenotype of
hyperglycaemia. This hyperglycaemia results from defects in insulin secretion, insulin action or
both. Several distinct types of diabetes mellitus, caused by a complex interaction of genetic and
environmental factors, exist. The vast majority of individuals with diabetes mellitus fall into
two broad etiopathogenetic categories: type 1 diabetes mellitus (T1DM) and type 2 diabetes
mellitus (T2DM), accounting for ~5-10% and ~90-95% of all cases, respectively 3. T2DM is
characterized by hyperglycaemia and often combined with insulin resistance, with a relative
impairment in insulin secretion. In a minority of T2DM cases, a relative impairment in insulin
secretion exists without insulin resistance, while in T1DM there is an absolute impairment of
insulin secretion. In this thesis, the focus will be on individuals with T1DM.
Type 1 diabetes mellitus
In T1DM there is an (almost) absent secretion of insulin due to various (auto-immune)
mechanisms, which would lead without exogenous insulin administration to ketoacidosis
and ultimately death 4–6. T1DM is characterized by hyperglycaemia with the eventual
development of micro- and macrovascular complications. In individuals with T1DM,
parts of this chapter were published as
Introduction
chapter 1introduction
10 11
Van Dijk PR, Logtenberg SJJ, Gans ROB, Bilo HJG, Kleefstra N.
Intraperitoneal insulin infusion: treatment option for type
1 diabetes resulting in beneficial endocrine effects beyond
glycaemia. Clin Endocrinol (Oxf) 2014; 81: 488-97.
chapter 1 Diabetes Mellitus
In healthy subjects, the concentration of glucose in plasma is remained within a narrow range
(3.5-7.0 mmol/l) despite fluctuations in nutritional intake, physical exercise and other (physical
or psychological) influences. One of the major determinants of this stable plasma glucose is
the action of the blood-glucose lowering hormone insulin.
Insulin secretion consists of 2 components: a continuous low basal rate and short-lived bursts
in response to stimuli. Basal insulin secretion occurs in the fasting state to inhibit hepatic
glycogenolysis, ketogenesis and gluconeogenesis and accounts for approximately 40% of the
total daily insulin output. Insulin secretion on top of basal secretion occurs when plasma
glucose level exceeds 4.4-5.6 mmol/l to restore euglycaemia by promoting peripheral
glucose uptake and storage. Through these mechanisms, plasma glucose rises to a peak in
30-60 minutes after eating and returns to basal concentrations within 2-3 hours. In healthy
individuals, basal insulin secretion together with the reactivity of insulin secretion in response
to various stimuli are key factors in ensuring glucose homeostasis, permitting stability and
reproducibility of blood glucose 1,2.
Diabetes mellitus refers to a group of metabolic disorders that share the phenotype of
hyperglycaemia. This hyperglycaemia results from defects in insulin secretion, insulin action or
both. Several distinct types of diabetes mellitus, caused by a complex interaction of genetic and
environmental factors, exist. The vast majority of individuals with diabetes mellitus fall into
two broad etiopathogenetic categories: type 1 diabetes mellitus (T1DM) and type 2 diabetes
mellitus (T2DM), accounting for ~5-10% and ~90-95% of all cases, respectively 3. T2DM is
characterized by hyperglycaemia and often combined with insulin resistance, with a relative
impairment in insulin secretion. In a minority of T2DM cases, a relative impairment in insulin
secretion exists without insulin resistance, while in T1DM there is an absolute impairment of
insulin secretion. In this thesis, the focus will be on individuals with T1DM.
Type 1 diabetes mellitus
In T1DM there is an (almost) absent secretion of insulin due to various (auto-immune)
mechanisms, which would lead without exogenous insulin administration to ketoacidosis
and ultimately death 4–6. T1DM is characterized by hyperglycaemia with the eventual
development of micro- and macrovascular complications. In individuals with T1DM,
parts of this chapter were published as
Introduction
chapter 1introduction
12 13
it has been unambiguously proven that the development of micro- and macrovascular
complications amongst others is linked to the duration and severity of hyperglycaemia and
can be either prevented or delayed by intensive insulin therapy 7,8. Therefore, efforts are
made to achieve blood glucose levels as close to physiologic as possible while balancing
the risk of hypoglycaemia. Apart from lifestyle interventions, e.g. regular exercise, a healthy
diet and non-smoking habits, and treatment of associated conditions, e.g. hypertension,
dyslipidemia and/or obesity, the mainstay of current T1DM treatment is insulin replacement
therapy.
Insulin replacement therapy
An ideal insulin replacement regimen should achieve blood glucose levels as close to the
physiological state as possible and thus be able to accurately reproduce both the basal
and ‘burst’ (bolus) component of normal insulin secretion. This is the aim of the two most
common insulin replacement modalities in T1DM: multiple daily injections (MDI) of insulin
in the subcutaneous (SC) tissue and continuous subcutaneous insulin infusion (CSII) with an
externally placed pump (see Figure 1).
In general, the MDI treatment regimen consists of a combination of a basal (intermediate-
or long-acting) insulin, injected (mostly) once daily, and a bolus (short-acting) insulin
injected with meals, in order to mimic the physiologic insulin profile. For this purpose
the insulin analogues, introduced in the late 1980’s, are used. Insulin analogues can be
subdivided in rapid-acting (insulin lispro, aspart and glusine) and long-acting (insulin
glargine, detemir and degludec). These preparations differ from the previously used human
insulin by amino-acid substitutions or addition of myristic acid, leading to changes in their
ability to self-associate 9. Compared to human soluble insulin, insulin analogues are believed
to be characterized by less variability in absorption and shorter (or longer for the long-acting
analogues) duration of action and thus more rapid onset and less postprandial glucose
fluctuations 10,11.
CSII with a portable, externally placed, pump was introduced in the 1970’s. The first available
device (the Mill Hill infuser) delivered insulin through a subcutaneously placed cannula
by a miniature pump, carrying a 2ml syringe, at two rates: a slow basal (47 μl/hour) and an
eightfold higher rate 12. Although the present external insulin pumps are more sophisticated
than the initial model, the rationale is identical: insulin is administered at a slow basal
rate, 24 hours a day, through a cannula inserted in the SC tissue. Furthermore, patients can
administer insulin boosts (boluses).
Compared to MDI, CSII seems to improve glycaemic regulation in adult patients. Although
outcomes of individual studies vary, meta-analyses that compared MDI with CSII have
reported slightly lower HbA1c levels with CSII, with a mean difference of about 3.3-6.7 mmol/
mol (0.3-0.6%), and a similar rate of severe hypoglycaemic events 13–16. CSII offers patients
the use of pre-programmable basal insulin rates, a bolus function (with bolus calculator)
and linkage to external devices such as a personal computer or mobile telephone. With
these functions, increased flexibility with respect to diabetes management in activities of
daily living can also improve treatment satisfaction as compared to MDI 15,17,18.
Drawbacks of SC insulin therapy
With MDI and CSII deviations from the normal response occur due to pharmacokinetic and
pharmacodynamic properties of SC administered insulin. For example, the lagtime to insulin
action after SC injection varies between 5-15 minutes for the rapid-acting insulin analogues
with an effective duration between 4-6 hours 19. Partly due to tissue properties, and partly due
to the tendency of insulin molecules to aggregate, the rate of SC absorption of insulin varies
within and between individuals. Factors that contribute to the inconsistent pharmacokinetics
of insulin are related to the insulin preparation (volume, concentration, additives), differences
between injection sites (anatomical region, depth of injection, degree of fibrosis, injection
infiltrates) or changes to the injection site (local blood flow (temperature), other substances
applied). These combined factors may lead to a pronounced variability of the appearance of
introduction chapter 1
Subcutaneous modes of insulin administration: continuous subcutaneous insulin infusion with an externally placed pump (left) and injections of insulin (right).
figure 1
12 13
it has been unambiguously proven that the development of micro- and macrovascular
complications amongst others is linked to the duration and severity of hyperglycaemia and
can be either prevented or delayed by intensive insulin therapy 7,8. Therefore, efforts are
made to achieve blood glucose levels as close to physiologic as possible while balancing
the risk of hypoglycaemia. Apart from lifestyle interventions, e.g. regular exercise, a healthy
diet and non-smoking habits, and treatment of associated conditions, e.g. hypertension,
dyslipidemia and/or obesity, the mainstay of current T1DM treatment is insulin replacement
therapy.
Insulin replacement therapy
An ideal insulin replacement regimen should achieve blood glucose levels as close to the
physiological state as possible and thus be able to accurately reproduce both the basal
and ‘burst’ (bolus) component of normal insulin secretion. This is the aim of the two most
common insulin replacement modalities in T1DM: multiple daily injections (MDI) of insulin
in the subcutaneous (SC) tissue and continuous subcutaneous insulin infusion (CSII) with an
externally placed pump (see Figure 1).
In general, the MDI treatment regimen consists of a combination of a basal (intermediate-
or long-acting) insulin, injected (mostly) once daily, and a bolus (short-acting) insulin
injected with meals, in order to mimic the physiologic insulin profile. For this purpose
the insulin analogues, introduced in the late 1980’s, are used. Insulin analogues can be
subdivided in rapid-acting (insulin lispro, aspart and glusine) and long-acting (insulin
glargine, detemir and degludec). These preparations differ from the previously used human
insulin by amino-acid substitutions or addition of myristic acid, leading to changes in their
ability to self-associate 9. Compared to human soluble insulin, insulin analogues are believed
to be characterized by less variability in absorption and shorter (or longer for the long-acting
analogues) duration of action and thus more rapid onset and less postprandial glucose
fluctuations 10,11.
CSII with a portable, externally placed, pump was introduced in the 1970’s. The first available
device (the Mill Hill infuser) delivered insulin through a subcutaneously placed cannula
by a miniature pump, carrying a 2ml syringe, at two rates: a slow basal (47 μl/hour) and an
eightfold higher rate 12. Although the present external insulin pumps are more sophisticated
than the initial model, the rationale is identical: insulin is administered at a slow basal
rate, 24 hours a day, through a cannula inserted in the SC tissue. Furthermore, patients can
administer insulin boosts (boluses).
Compared to MDI, CSII seems to improve glycaemic regulation in adult patients. Although
outcomes of individual studies vary, meta-analyses that compared MDI with CSII have
reported slightly lower HbA1c levels with CSII, with a mean difference of about 3.3-6.7 mmol/
mol (0.3-0.6%), and a similar rate of severe hypoglycaemic events 13–16. CSII offers patients
the use of pre-programmable basal insulin rates, a bolus function (with bolus calculator)
and linkage to external devices such as a personal computer or mobile telephone. With
these functions, increased flexibility with respect to diabetes management in activities of
daily living can also improve treatment satisfaction as compared to MDI 15,17,18.
Drawbacks of SC insulin therapy
With MDI and CSII deviations from the normal response occur due to pharmacokinetic and
pharmacodynamic properties of SC administered insulin. For example, the lagtime to insulin
action after SC injection varies between 5-15 minutes for the rapid-acting insulin analogues
with an effective duration between 4-6 hours 19. Partly due to tissue properties, and partly due
to the tendency of insulin molecules to aggregate, the rate of SC absorption of insulin varies
within and between individuals. Factors that contribute to the inconsistent pharmacokinetics
of insulin are related to the insulin preparation (volume, concentration, additives), differences
between injection sites (anatomical region, depth of injection, degree of fibrosis, injection
infiltrates) or changes to the injection site (local blood flow (temperature), other substances
applied). These combined factors may lead to a pronounced variability of the appearance of
introduction chapter 1
Subcutaneous modes of insulin administration: continuous subcutaneous insulin infusion with an externally placed pump (left) and injections of insulin (right).
figure 1
14 15
insulin in the circulation of up to 35% 20. Furthermore, the variability in insulin sensitivity adds
to the variance in absorption and is also a determinant of insulin pharmacodynamics.
As a consequence, SC insulin administration may lead to unpredictable fluctuations in blood
glucose concentrations. These fluctuations in themselves are associated with elevated HbA1c
levels and hypoglycaemic episodes with subsequent stress, anxiety, impaired well-being and
reduced quality of life (QoL). This unpredictability is also illustrated by the fact that, despite
all efforts, approximately 15-25% of T1DM patients achieve the recommended HbA1c level
of less than 53 mmol/mol (7.0%) and the average patient suffers from two symptomatic
hypoglycaemic episodes per week 21,22. Thus, the current challenge of insulin therapy is to
improve glycaemic control with more time in normoglycaemia, without increasing the
incidence of hypoglycaemia and a minimal negative impact on QoL, which would eventually
translate in a reduction of complications. Despite all efforts of patients and health care
providers, in part of the patients this challenge remains difficult to achieve using the SC route
of insulin administration. Therefore, alternatives have been developed; one such alternative is
continuous intraperitoneal (IP) insulin infusion (CIPII) using an implantable pump.
Continuous intraperitoneal insulin infusion
a brief history The first trials with IP insulin infusion were performed in the early 1980’s, using externally
placed portable pumps connected to a catheter that had the distal end located in the IP space 23–26. Although the results of these studies demonstrated that IP insulin infusion stabilizes
plasma glucose and normalizes plasma free insulin levels, complications associated with the
combination of an external pump and an indwelling catheter, such as infections, imposed a
tremendous burden. Consequently, CIPII using an implantable pump came into focus.
The first implantable pumps available for daily care were used in the late 1980s for short-
term IP insulin treatment. Again, near-normalization of blood glucose profiles without
peripheral hyperinsulinaemia was established 27–30. From three initial investigational models
of implantable insulin pumps (Infusaid, model 1000, Strato/Infusaid, Norwood, Ms, USA;
Minimed Implantable Pump (MIP) 2001, Minimed Technologies, Sylmar, CA, USA; Siemens
ID3, Siemens-Elema, Solna, Sweden), only the MIP 2001 model persisted and succeeded in
obtaining the European Community approval in 1994.
However, several problems with the implantable pump system occurred. After some years of
reasonable results, a high incidence of insulin underdelivery was detected which was related
to modifications of the insulin used in the implanted pump 31. In order to comply with the
European regulations, slight modifications were made in the insulin preparation in 1993 which
resulted in impaired chemical stability in the MIP 2001 model. In 1997, this was resolved by
the use of a new 21PH ETP insulin variant (U-400 HOE 21PH, semi synthetic human insulin of
porcine origin, trade name: Insuplant® Hoechst, Frankfurt, Germany, nowadays Sanofi-Aventis)
with improved stability 32. After changing the insulin there was also a decrease in the number
of catheter obstructions due to tissue overgrowth at the catheter tip, which was possibly due to
a decrease in immune-inflammatory reactions against insulin deposits in the peritoneal space 28–30,33,34. The MIP 2001 model was also equipped with a side-port, allowing transcutaneous
flushes or rinse procedures (using NaOH) in case of suspected catheter obstructions 31.
Nevertheless, insulin underdelivery still occurred due to the fact that the lumen of the
catheter was unable to absorb the forward stroke volume of the pump piston. Modifications
of the catheter side-port, in order to accumulate the initial pressure impact, were necessary
to overcome this problem. Together, the improvements of the insulin, pump and catheter
resulted in a safe and reliable insulin delivery with the MIP 2001 model from 1998 onwards 35.
Another problem that occurred was the increased production of anti-insulin antibodies
seen in some patients treated with CIPII 36,37. Although the exact cause remains unknown, it
has been suggested that the increased anti-insulin antibodies concentrations may be due
to insulin modifications occurring during storage in the implantable pump or due to the
inadvertent formation of insulin aggregates which are known to be more antigenic 38. These
anti-insulin antibodies associate with insulin, in particular post-prandial and can theoretically
lead to higher postprandial blood glucose and an increased risk of delayed hypoglycaemia 39.
Nevertheless, this increased immunogenicity did not induce metabolic consequences, change
insulin requirements or the number of hypoglycaemic episodes 40. In addition, the increased
anti-insulin antibodies did not seem to correlate with the presence or absence of other
autoimmune diseases 41.
Although many issues were resolved and experience with CIPII increased over time, further
development was delayed and the widespread use of CIPII was impaired due to persistent
concerns regarding safety and cost(-effectiveness).
physiological propertiesWith CIPII, insulin is directly infused in the IP space. Speed of insulin absorption from the
peritoneal space depends on injected volume, concentration of insulin solution and duration
of injection, but the insulin is to a large extent directly absorbed into the portal system, where
chapter 1introduction
14 15
insulin in the circulation of up to 35% 20. Furthermore, the variability in insulin sensitivity adds
to the variance in absorption and is also a determinant of insulin pharmacodynamics.
As a consequence, SC insulin administration may lead to unpredictable fluctuations in blood
glucose concentrations. These fluctuations in themselves are associated with elevated HbA1c
levels and hypoglycaemic episodes with subsequent stress, anxiety, impaired well-being and
reduced quality of life (QoL). This unpredictability is also illustrated by the fact that, despite
all efforts, approximately 15-25% of T1DM patients achieve the recommended HbA1c level
of less than 53 mmol/mol (7.0%) and the average patient suffers from two symptomatic
hypoglycaemic episodes per week 21,22. Thus, the current challenge of insulin therapy is to
improve glycaemic control with more time in normoglycaemia, without increasing the
incidence of hypoglycaemia and a minimal negative impact on QoL, which would eventually
translate in a reduction of complications. Despite all efforts of patients and health care
providers, in part of the patients this challenge remains difficult to achieve using the SC route
of insulin administration. Therefore, alternatives have been developed; one such alternative is
continuous intraperitoneal (IP) insulin infusion (CIPII) using an implantable pump.
Continuous intraperitoneal insulin infusion
a brief history The first trials with IP insulin infusion were performed in the early 1980’s, using externally
placed portable pumps connected to a catheter that had the distal end located in the IP space 23–26. Although the results of these studies demonstrated that IP insulin infusion stabilizes
plasma glucose and normalizes plasma free insulin levels, complications associated with the
combination of an external pump and an indwelling catheter, such as infections, imposed a
tremendous burden. Consequently, CIPII using an implantable pump came into focus.
The first implantable pumps available for daily care were used in the late 1980s for short-
term IP insulin treatment. Again, near-normalization of blood glucose profiles without
peripheral hyperinsulinaemia was established 27–30. From three initial investigational models
of implantable insulin pumps (Infusaid, model 1000, Strato/Infusaid, Norwood, Ms, USA;
Minimed Implantable Pump (MIP) 2001, Minimed Technologies, Sylmar, CA, USA; Siemens
ID3, Siemens-Elema, Solna, Sweden), only the MIP 2001 model persisted and succeeded in
obtaining the European Community approval in 1994.
However, several problems with the implantable pump system occurred. After some years of
reasonable results, a high incidence of insulin underdelivery was detected which was related
to modifications of the insulin used in the implanted pump 31. In order to comply with the
European regulations, slight modifications were made in the insulin preparation in 1993 which
resulted in impaired chemical stability in the MIP 2001 model. In 1997, this was resolved by
the use of a new 21PH ETP insulin variant (U-400 HOE 21PH, semi synthetic human insulin of
porcine origin, trade name: Insuplant® Hoechst, Frankfurt, Germany, nowadays Sanofi-Aventis)
with improved stability 32. After changing the insulin there was also a decrease in the number
of catheter obstructions due to tissue overgrowth at the catheter tip, which was possibly due to
a decrease in immune-inflammatory reactions against insulin deposits in the peritoneal space 28–30,33,34. The MIP 2001 model was also equipped with a side-port, allowing transcutaneous
flushes or rinse procedures (using NaOH) in case of suspected catheter obstructions 31.
Nevertheless, insulin underdelivery still occurred due to the fact that the lumen of the
catheter was unable to absorb the forward stroke volume of the pump piston. Modifications
of the catheter side-port, in order to accumulate the initial pressure impact, were necessary
to overcome this problem. Together, the improvements of the insulin, pump and catheter
resulted in a safe and reliable insulin delivery with the MIP 2001 model from 1998 onwards 35.
Another problem that occurred was the increased production of anti-insulin antibodies
seen in some patients treated with CIPII 36,37. Although the exact cause remains unknown, it
has been suggested that the increased anti-insulin antibodies concentrations may be due
to insulin modifications occurring during storage in the implantable pump or due to the
inadvertent formation of insulin aggregates which are known to be more antigenic 38. These
anti-insulin antibodies associate with insulin, in particular post-prandial and can theoretically
lead to higher postprandial blood glucose and an increased risk of delayed hypoglycaemia 39.
Nevertheless, this increased immunogenicity did not induce metabolic consequences, change
insulin requirements or the number of hypoglycaemic episodes 40. In addition, the increased
anti-insulin antibodies did not seem to correlate with the presence or absence of other
autoimmune diseases 41.
Although many issues were resolved and experience with CIPII increased over time, further
development was delayed and the widespread use of CIPII was impaired due to persistent
concerns regarding safety and cost(-effectiveness).
physiological propertiesWith CIPII, insulin is directly infused in the IP space. Speed of insulin absorption from the
peritoneal space depends on injected volume, concentration of insulin solution and duration
of injection, but the insulin is to a large extent directly absorbed into the portal system, where
chapter 1introduction
16 17
it is detectable within 1 minute after administration 42,43. Because of the absorption by the
portal system there is a higher hepatic uptake of insulin, with the first-passage hepatic insulin
extraction being directly after absorption, and an alleviation of peripheral plasma insulin
concentrations is reached as compared to SC insulin administration 44–48. IP administered
insulin takes approximately 15 minutes to reach its peak effect and allows blood glucose
values to return to baseline values more rapidly with reproducible and more predictable
insulin profiles compared with SC injections of insulin 44,49–51. Thus, the IP route of insulin
administration mimics the physiological state more than the SC route. Other possible positive
effects of IP insulin infusion include improvement of the impaired glucagon secretion, also
during exercise, and enhanced hepatic glucose production in response to hypoglycaemia 47,52–55. Although the exact mechanisms behind these two phenomena are unknown it has been
hypothesized that lower peripheral plasma insulin concentrations with CIPII may (partly)
restore glucagon release or that CIPII increases hepatic sensitivity to glucagon or hepatic
glucose utilization during hypoglycaemia 47,55.
effects on glycaemic controlThree randomized studies have compared the effects of CIPII, using an implantable pump,
on glycaemic control with SC insulin therapy in patients with T1DM. The main results of these
studies are depicted in Table 1. Haardt et al. found improvements in both HbA1c and the
frequency of hypoglycaemic events during CIPII as compared to MDI treatment 56. Although
Selam et al. found a decline of HbA1c levels after 4 months in both the CIPII and SC treatment
group, there were no inter-group differences between CIPII or intensive SC treatment 57. In
2008, a randomized cross-over study performed by Logtenberg et al. compared the effects of
CIPII and SC insulin in 24 patients with poorly regulated T1DM. Glycaemic control improved
with CIPII as compared to SC treatment, with a mean difference in HbA1c of 8.4 mmol/mol
(0.76%) in favour of CIPII without an increase in hypoglycaemic events 58.
Several observational studies were in concordance with these results by showing a decrease in
HbA1c and a lower incidence of hypoglycaemic events with CIPII treatment 30,34,59–62. However,
it should be mentioned that all of these studies were non-blinded and performed in small and
selected T1DM populations.
In addition to HbA1c several studies assessed glycaemic variability, another facet of glycaemic
regulation and suggested to help predict hypoglycaemia and diabetes related complications 63,64.
Although performed before the era of rapid-acting insulin analogues and continuous glucose
measurement (CGM), these studies demonstrated less glycaemic variability (expressed as the
standard deviation of capillary glucose concentration) during CIPII as compared to SC therapy 56,57,62.
chapter 1introduction
tabl
e 1
Pros
pect
ive,
rand
omize
d st
udie
s com
parin
g CI
PII w
ith SC
(bot
h M
DI a
nd C
SII)
insu
lin ad
min
istra
tion
in T
1DM
, con
cern
ing
HbA
1c an
d hy
pogl
ycae
mic
even
ts.
tabl
e 1
a Cro
ss-o
ver t
rial, b N
umbe
r of h
ypog
lyca
emic
episo
de <
4.0
mm
ol/m
ol p
er w
eek,
C Num
ber o
f hyp
ogly
caem
ic ep
isode
<4.
0 m
mol
/mol
per
wee
k, d H
ypog
lyca
emic
episo
des p
er m
onth
, e Defi
ned
as th
e sd
of ca
pilla
ry g
luco
se va
lues
f No
exac
t val
ues m
entio
ned,
pre
sent
ed d
ata i
s ext
ract
ed fr
om g
raph
. Abb
revi
atio
ns: c
ipii,
cont
inuo
us in
trape
riton
eal i
nsul
in in
fusio
n; sc
, sub
cuta
neou
s; m
di, m
ultip
le d
aily
in
ject
ions
; csi
i, con
tinuo
us su
bcut
aneo
us in
sulin
infu
sion;
t1dm
, typ
e 1 d
iabe
tes m
ellit
us; n
r, n
ot re
porte
d; yr
; yea
r(s).
Stud
y 1st
auth
or,
year
; co
untr
y
Stud
y gro
up
Perio
d (m
onth
s)
Stud
y arm
Endp
oint
Re
sults
Pa
tient
s (%
fem
ale,
diab
etes
du
ratio
n, ag
e)
Num
ber
(I/C)
In
terv
entio
n
Cont
rol
Inte
rven
tion
(%)
Cont
rol
(%)
Diffe
renc
e in
terv
entio
n vs.
cont
rol
Logt
enbe
rg,
2009
; the
N
ethe
rland
s a
54, 2
3±11
yr, 4
4±12
yr
24/2
4 16
CI
PII (
Min
iMed
, 20
07C)
SC (M
DI
and
CSII)
H
bA1c
70 →
58
70 →
70
-8.4
(-15
.6, -
1.2) *
Hyp
ogly
caem
ia,
Grad
e 1b
4.0
→ 3.
5 4.
0 →
4.0
-.50
(-1.16
, 0.17
)
Hyp
ogly
acem
ia,
Grad
e 2 c
2.7 →
2.3
2.7 →
2.7
-0
.43 (
-0.8
9, 0
.04)
Sela
m, 1
992;
US
A 48
, NR,
38±3
N
R/N
R (2
1 in
tota
l)
9 CI
PII (
Infu
said
, m
odel
1000
)
SC (M
DI
and
CSII)
H
bA1c
f 80
→ 6
8 70
→ 6
5 N
R H
ypog
lyca
emia
N
R N
R N
R
Haa
rdt,
1994
; Fr
ance
a 20
, 13±
10 yr
, 39
±5 yr
10
/10
12
CIPI
I (In
fusa
id,
mod
el 10
00
and
Min
iMed
)
SC (M
DI)
HbA
1c
59 →
55
64 →
69
NR
Hyp
ogly
caem
ia d
NR
→ 5.
7 10
N
R
-0.5
(-1.2
, 0.2
)
-0.4
(-0.
9, 0
.04
16 17
it is detectable within 1 minute after administration 42,43. Because of the absorption by the
portal system there is a higher hepatic uptake of insulin, with the first-passage hepatic insulin
extraction being directly after absorption, and an alleviation of peripheral plasma insulin
concentrations is reached as compared to SC insulin administration 44–48. IP administered
insulin takes approximately 15 minutes to reach its peak effect and allows blood glucose
values to return to baseline values more rapidly with reproducible and more predictable
insulin profiles compared with SC injections of insulin 44,49–51. Thus, the IP route of insulin
administration mimics the physiological state more than the SC route. Other possible positive
effects of IP insulin infusion include improvement of the impaired glucagon secretion, also
during exercise, and enhanced hepatic glucose production in response to hypoglycaemia 47,52–55. Although the exact mechanisms behind these two phenomena are unknown it has been
hypothesized that lower peripheral plasma insulin concentrations with CIPII may (partly)
restore glucagon release or that CIPII increases hepatic sensitivity to glucagon or hepatic
glucose utilization during hypoglycaemia 47,55.
effects on glycaemic controlThree randomized studies have compared the effects of CIPII, using an implantable pump,
on glycaemic control with SC insulin therapy in patients with T1DM. The main results of these
studies are depicted in Table 1. Haardt et al. found improvements in both HbA1c and the
frequency of hypoglycaemic events during CIPII as compared to MDI treatment 56. Although
Selam et al. found a decline of HbA1c levels after 4 months in both the CIPII and SC treatment
group, there were no inter-group differences between CIPII or intensive SC treatment 57. In
2008, a randomized cross-over study performed by Logtenberg et al. compared the effects of
CIPII and SC insulin in 24 patients with poorly regulated T1DM. Glycaemic control improved
with CIPII as compared to SC treatment, with a mean difference in HbA1c of 8.4 mmol/mol
(0.76%) in favour of CIPII without an increase in hypoglycaemic events 58.
Several observational studies were in concordance with these results by showing a decrease in
HbA1c and a lower incidence of hypoglycaemic events with CIPII treatment 30,34,59–62. However,
it should be mentioned that all of these studies were non-blinded and performed in small and
selected T1DM populations.
In addition to HbA1c several studies assessed glycaemic variability, another facet of glycaemic
regulation and suggested to help predict hypoglycaemia and diabetes related complications 63,64.
Although performed before the era of rapid-acting insulin analogues and continuous glucose
measurement (CGM), these studies demonstrated less glycaemic variability (expressed as the
standard deviation of capillary glucose concentration) during CIPII as compared to SC therapy 56,57,62.
chapter 1introduction
tabl
e 1
Pros
pect
ive,
rand
omize
d st
udie
s com
parin
g CI
PII w
ith SC
(bot
h M
DI a
nd C
SII)
insu
lin ad
min
istra
tion
in T
1DM
, con
cern
ing
HbA
1c an
d hy
pogl
ycae
mic
even
ts.
tabl
e 1
a Cro
ss-o
ver t
rial, b N
umbe
r of h
ypog
lyca
emic
episo
de <
4.0
mm
ol/m
ol p
er w
eek,
C Num
ber o
f hyp
ogly
caem
ic ep
isode
<4.
0 m
mol
/mol
per
wee
k, d H
ypog
lyca
emic
episo
des p
er m
onth
, e Defi
ned
as th
e sd
of ca
pilla
ry g
luco
se va
lues
f No
exac
t val
ues m
entio
ned,
pre
sent
ed d
ata i
s ext
ract
ed fr
om g
raph
. Abb
revi
atio
ns: c
ipii,
cont
inuo
us in
trape
riton
eal i
nsul
in in
fusio
n; sc
, sub
cuta
neou
s; m
di, m
ultip
le d
aily
in
ject
ions
; csi
i, con
tinuo
us su
bcut
aneo
us in
sulin
infu
sion;
t1dm
, typ
e 1 d
iabe
tes m
ellit
us; n
r, n
ot re
porte
d; yr
; yea
r(s).
Stud
y 1st
auth
or,
year
; co
untr
y
Stud
y gro
up
Perio
d (m
onth
s)
Stud
y arm
Endp
oint
Re
sults
Pa
tient
s (%
fem
ale,
diab
etes
du
ratio
n, ag
e)
Num
ber
(I/C)
In
terv
entio
n
Cont
rol
Inte
rven
tion
(%)
Cont
rol
(%)
Diffe
renc
e in
terv
entio
n vs.
cont
rol
Logt
enbe
rg,
2009
; the
N
ethe
rland
s a
54, 2
3±11
yr, 4
4±12
yr
24/2
4 16
CI
PII (
Min
iMed
, 20
07C)
SC (M
DI
and
CSII)
H
bA1c
70 →
58
70 →
70
-8.4
(-15
.6, -
1.2) *
Hyp
ogly
caem
ia,
Grad
e 1b
4.0
→ 3.
5 4.
0 →
4.0
-.50
(-1.16
, 0.17
)
Hyp
ogly
acem
ia,
Grad
e 2 c
2.7 →
2.3
2.7 →
2.7
-0
.43 (
-0.8
9, 0
.04)
Sela
m, 1
992;
US
A 48
, NR,
38±3
N
R/N
R (2
1 in
tota
l)
9 CI
PII (
Infu
said
, m
odel
1000
)
SC (M
DI
and
CSII)
H
bA1c
f 80
→ 6
8 70
→ 6
5 N
R H
ypog
lyca
emia
N
R N
R N
R
Haa
rdt,
1994
; Fr
ance
a 20
, 13±
10 yr
, 39
±5 yr
10
/10
12
CIPI
I (In
fusa
id,
mod
el 10
00
and
Min
iMed
)
SC (M
DI)
HbA
1c
59 →
55
64 →
69
NR
Hyp
ogly
caem
ia d
NR
→ 5.
7 10
N
R
-0.5
(-1.2
, 0.2
)
-0.4
(-0.
9, 0
.04
18 19
effects on quality of lifeApart from glycaemic control, CIPII positively affects QoL. In the cross-over trial by Logtenberg
et al. the self-reported general QoL on the SF-36 questionnaire improved significantly during
CIPII therapy as compared to SC insulin therapy 65. Next to QoL, treatment satisfaction also
increased with CIPII as compared to SC insulin 65. An increase in diabetes specific QoL was
reported in the randomized trial by Selam et al. 29. Comparable findings were found in a French
cross-sectional study in which better treatment satisfaction and less ‘diabetes worry’ was found 66.
Nevertheless, baseline QoL seems to be rather poor in this group of patients. This is illustrated
by a Dutch observational study in which DeVries et al. found scores on the subscales
‘physical functioning’ and ‘mental health’ of the self-reported general QoL, using the SF-36
questionnaire, among patients using CIPII to be similar to patients with a serious medical
condition such as symptomatic chronic heart failure, post myocardial infarction with persistent
symptoms, or hypertension with severe heart failure symptomatology or a history of stroke.
For the subscales ‘general health’, ‘pain’ and ’social functioning’ the SF-36 scores even resembled
those of persons with a serious chronic medical disorder and current depressive symptoms 67.
In addition, there was a high number of CIPII patients with psychiatric symptoms and scores
on the diabetes specific DQOL questionnaire were significantly worse for patients using CIPII
as compared to patients with T1DM without CIPII 67.
effects beyond glycaemic control Insulin does not only affects glycaemia but influences a wide range of processes. Because
IP insulin is absorbed to a large extent in the portal vein catchment area, the insulin
concentration in the portal vein and the peripheral plasma insulin concentrations are more
physiological compared to SC administered insulin 44–47. This has consequences for other
endocrine systems, e.g. the growth hormone (GH) - insulin-like growth factor-1 (IGF1) axis. In
healthy subjects, circulating IGF1 is synthesized in the liver after stimulation of the GH-receptor
and plays a central role in cell metabolism and growth regulation 68–70. Insulin is suggested
to increase the sensitivity of the liver to GH by up regulating GH receptor expression, and
thereby augmenting IGF1 production 71. Insulin also seems to increases IGF1 bioactivity
by down regulating hepatic production of the IGF binding protein-1 (IGFBP1) at the
transcriptional level 68,72.
In patients with T1DM, low concentrations of total IGF1 and IGFBP3 and high concentrations
of IGFBP1 and GH are present probably due to insufficient insulinization of the liver secondary
to a lack of endogenous insulin in the portal vein (see Figure 2 for an overview of the suggested
relationships of portal insulin concentrations and the GH-IGF1 axis in T1DM) 73. Low IGF1
concentrations have been suggested to influence IGF1 sensitive tissues such as the vasculature,
bone and muscle and to contribute to increased insulin resistance and an increased risk of
long-term diabetes complications 74,75. Although these abnormalities in the GH-IGF1 axis
have been described in situations of poor glycaemic control, SC insulin administration and
improvements in glycaemic control only seem to attenuate these disturbances but do not
completely reverse them 76–79. The hypothesis that higher portal insulin concentrations
achieved with CIPII could have a beneficial effect on the impaired GH-IGF1 axis has been tested
in a few studies. Shishko et al. studied the effects of IP insulin infusion among newly diagnosed
T1DM patients and observed that IP insulin but not SC insulin therapy normalized IGF1 and
IGFBP1 concentrations 80. However, this study lacked data about endogenous insulin secretion.
Among C-peptide negative T1DM patients, a longitudinal study by Hanaire-Broutin et al.
showed that IGF1 concentrations were higher with CIPII therapy than during prior intensive SC
therapy 81. Furthermore, IGF1 concentrations tended to rise to a to a low-normal level one year
after initiating CIPII, despite a lack of improvement in HbA1c. Further evidence for the concept
that IP insulin influences the IGF1 was provided by Hedman et al. by finding, in addition to
higher IGF1 concentrations, increased IGF1 bioactivity during CIPII when compared with CSII
among T1DM patients 82. Further research needs to be performed in a larger population and
over a longer period to test the hypothesis that CIPII could alter the dysregulated GH-IGF1 axis
in T1DM.
chapter 1introduction
Alterations in GH-IGF1 system in T1DM and suggested role of insulin concentrations in the portal vein.figure 2
The (+) and (-) indicate positive and negative correlations, respectively. The (<arriba>), (<abajo>) and (=) indicate increases, decreases and unaltered concentrations as found in studies towards IP insulin administration, respectively 73,76,78,88–92. Abbreviations: GH, growth hormone; IGF1, insulin; like growth factor-1, IGFBP-1/-3, insulin like growth factor binding protein -1/-3.
18 19
effects on quality of lifeApart from glycaemic control, CIPII positively affects QoL. In the cross-over trial by Logtenberg
et al. the self-reported general QoL on the SF-36 questionnaire improved significantly during
CIPII therapy as compared to SC insulin therapy 65. Next to QoL, treatment satisfaction also
increased with CIPII as compared to SC insulin 65. An increase in diabetes specific QoL was
reported in the randomized trial by Selam et al. 29. Comparable findings were found in a French
cross-sectional study in which better treatment satisfaction and less ‘diabetes worry’ was found 66.
Nevertheless, baseline QoL seems to be rather poor in this group of patients. This is illustrated
by a Dutch observational study in which DeVries et al. found scores on the subscales
‘physical functioning’ and ‘mental health’ of the self-reported general QoL, using the SF-36
questionnaire, among patients using CIPII to be similar to patients with a serious medical
condition such as symptomatic chronic heart failure, post myocardial infarction with persistent
symptoms, or hypertension with severe heart failure symptomatology or a history of stroke.
For the subscales ‘general health’, ‘pain’ and ’social functioning’ the SF-36 scores even resembled
those of persons with a serious chronic medical disorder and current depressive symptoms 67.
In addition, there was a high number of CIPII patients with psychiatric symptoms and scores
on the diabetes specific DQOL questionnaire were significantly worse for patients using CIPII
as compared to patients with T1DM without CIPII 67.
effects beyond glycaemic control Insulin does not only affects glycaemia but influences a wide range of processes. Because
IP insulin is absorbed to a large extent in the portal vein catchment area, the insulin
concentration in the portal vein and the peripheral plasma insulin concentrations are more
physiological compared to SC administered insulin 44–47. This has consequences for other
endocrine systems, e.g. the growth hormone (GH) - insulin-like growth factor-1 (IGF1) axis. In
healthy subjects, circulating IGF1 is synthesized in the liver after stimulation of the GH-receptor
and plays a central role in cell metabolism and growth regulation 68–70. Insulin is suggested
to increase the sensitivity of the liver to GH by up regulating GH receptor expression, and
thereby augmenting IGF1 production 71. Insulin also seems to increases IGF1 bioactivity
by down regulating hepatic production of the IGF binding protein-1 (IGFBP1) at the
transcriptional level 68,72.
In patients with T1DM, low concentrations of total IGF1 and IGFBP3 and high concentrations
of IGFBP1 and GH are present probably due to insufficient insulinization of the liver secondary
to a lack of endogenous insulin in the portal vein (see Figure 2 for an overview of the suggested
relationships of portal insulin concentrations and the GH-IGF1 axis in T1DM) 73. Low IGF1
concentrations have been suggested to influence IGF1 sensitive tissues such as the vasculature,
bone and muscle and to contribute to increased insulin resistance and an increased risk of
long-term diabetes complications 74,75. Although these abnormalities in the GH-IGF1 axis
have been described in situations of poor glycaemic control, SC insulin administration and
improvements in glycaemic control only seem to attenuate these disturbances but do not
completely reverse them 76–79. The hypothesis that higher portal insulin concentrations
achieved with CIPII could have a beneficial effect on the impaired GH-IGF1 axis has been tested
in a few studies. Shishko et al. studied the effects of IP insulin infusion among newly diagnosed
T1DM patients and observed that IP insulin but not SC insulin therapy normalized IGF1 and
IGFBP1 concentrations 80. However, this study lacked data about endogenous insulin secretion.
Among C-peptide negative T1DM patients, a longitudinal study by Hanaire-Broutin et al.
showed that IGF1 concentrations were higher with CIPII therapy than during prior intensive SC
therapy 81. Furthermore, IGF1 concentrations tended to rise to a to a low-normal level one year
after initiating CIPII, despite a lack of improvement in HbA1c. Further evidence for the concept
that IP insulin influences the IGF1 was provided by Hedman et al. by finding, in addition to
higher IGF1 concentrations, increased IGF1 bioactivity during CIPII when compared with CSII
among T1DM patients 82. Further research needs to be performed in a larger population and
over a longer period to test the hypothesis that CIPII could alter the dysregulated GH-IGF1 axis
in T1DM.
chapter 1introduction
Alterations in GH-IGF1 system in T1DM and suggested role of insulin concentrations in the portal vein.figure 2
The (+) and (-) indicate positive and negative correlations, respectively. The (<arriba>), (<abajo>) and (=) indicate increases, decreases and unaltered concentrations as found in studies towards IP insulin administration, respectively 73,76,78,88–92. Abbreviations: GH, growth hormone; IGF1, insulin; like growth factor-1, IGFBP-1/-3, insulin like growth factor binding protein -1/-3.
20 21
complications and costs In one study, 80% of the patient who used CIPII did not experience any pump related
complication during a 15-year period. Among the patients that did experience complications,
local infection and pain were the most frequent complications 83. The current average
operation free period, ideally 1 procedure every 7 years to replace the pump when the battery
has been depleted, was 4.5 years 83. No CIPII related mortality has ever been reported.
An important issue of CIPII therapy is the high costs. In 1994, Haardt et al. estimated the costs
of CIPII to be 2.6 fold higher as compared to MDI 56. In 2010, direct pump- and procedures (such
as regular filling and rinsing procedures) related costs for CIPII were estimated to be 30.901
Euros in the first year and 7.579 Euros in the following 6 years 84. The annual costs of CIPII are
estimated to be 6.000 Euros higher on average than CSII 84. It should be noticed however that
none of these costs-effectiveness analyses took into account the influence of CIPII on the
hospital duration, which is reported to decrease from 45 days in the year before implantation
to 13 days in the year after implantation 67. At present, the costs of the MIP 2007D implantable
pump are approximately 34.000 Euros and an ampoule of insulin (approximately 2 ampoules
are needed per 6-week refill procedure) costs 500 Euros.
current use of CIPIIDue to limited evidence, risk of complications and high costs on the one hand and the further
development of alternatives (e.g. glucose sensor-augmented pump therapy) on the other
hand, CIPII is currently used only in a small number of T1DM patients. The current indications
for CIPII therapy are based on data from available studies, that demonstrated benefits of
the use of CIPII on glucose control in selected groups of patients, including: patients with
documented SC defects of insulin absorption (e.g. due to skin reactions due to SC insulin
administration, allergies, lipohypertrophy and/or lipoatrophy or SC insulin resistance), patients
with recurrent bouts of severe hypoglycaemia (especially combined with hypoglycaemia
unawareness) and patients showing sustained poor glucose control (HbA1c >58 mmol/mol
(7.5%)) despite intensive SC insulin therapy that results in recurrent hospitalizations, very poor
QoL and advanced diabetes complications 58,61,84–87. Still, it should be acknowledged, that more
evidence supporting these indications is needed.
The use of CIPII is largely restricted to Europe, especially Belgium, France, Sweden and
the Netherlands. Besides the externally placed DiaPort system there is only one type of
implantable pump (MIP 2007D, Medtronic/Minimed, Northridge, CA, USA) available for use
in patients. This model has a reservoir which can contain 15 ml of insulin and has a battery
with 7 years longevity. A silicone catheter is attached to the side port of the pump, through
which insulin is delivered directly into the peritoneal cavity (see Figure 3 and 4). The pump
can be remotely controlled with a pocket-sized personal pump communicator. Implantation
of the pump is performed under general anaesthesia and, usually, the pump is inserted in
a subcutaneous pocket in a lower abdominal quadrant (see Figure 4). From this pocket, the
peritoneum is opened and the tip of the catheter is carefully inserted and directed towards the
liver. After implantation, the pump reservoir is refilled transcutaneously with insulin at the
outpatient clinic at least every 3 months, depending on the individual insulin requirement.
From 2010 onwards a new human recombinant insulin (400 IU/ml; human insulin of E. Coli
origin, trade name: Insuman Implantable®, Sanofi-Aventis) was used since no batches were left
of the U-400 HOE 21PH insulin.
General aims and outline of this thesis
The general aim of this thesis was to study different aspects of CIPII using an implantable
pump in patients with T1DM, in particular the effects of long-term use, in order to provide a
more comprehensive and balanced view on the use of this therapy.
chapter 1introduction
The MIP 2007D implantable pump system and patients-pump communicator.
Illustration of the implantable pump system (left) and a the pump in situ (right) 83.
figure 3
figure 4
20 21
complications and costs In one study, 80% of the patient who used CIPII did not experience any pump related
complication during a 15-year period. Among the patients that did experience complications,
local infection and pain were the most frequent complications 83. The current average
operation free period, ideally 1 procedure every 7 years to replace the pump when the battery
has been depleted, was 4.5 years 83. No CIPII related mortality has ever been reported.
An important issue of CIPII therapy is the high costs. In 1994, Haardt et al. estimated the costs
of CIPII to be 2.6 fold higher as compared to MDI 56. In 2010, direct pump- and procedures (such
as regular filling and rinsing procedures) related costs for CIPII were estimated to be 30.901
Euros in the first year and 7.579 Euros in the following 6 years 84. The annual costs of CIPII are
estimated to be 6.000 Euros higher on average than CSII 84. It should be noticed however that
none of these costs-effectiveness analyses took into account the influence of CIPII on the
hospital duration, which is reported to decrease from 45 days in the year before implantation
to 13 days in the year after implantation 67. At present, the costs of the MIP 2007D implantable
pump are approximately 34.000 Euros and an ampoule of insulin (approximately 2 ampoules
are needed per 6-week refill procedure) costs 500 Euros.
current use of CIPIIDue to limited evidence, risk of complications and high costs on the one hand and the further
development of alternatives (e.g. glucose sensor-augmented pump therapy) on the other
hand, CIPII is currently used only in a small number of T1DM patients. The current indications
for CIPII therapy are based on data from available studies, that demonstrated benefits of
the use of CIPII on glucose control in selected groups of patients, including: patients with
documented SC defects of insulin absorption (e.g. due to skin reactions due to SC insulin
administration, allergies, lipohypertrophy and/or lipoatrophy or SC insulin resistance), patients
with recurrent bouts of severe hypoglycaemia (especially combined with hypoglycaemia
unawareness) and patients showing sustained poor glucose control (HbA1c >58 mmol/mol
(7.5%)) despite intensive SC insulin therapy that results in recurrent hospitalizations, very poor
QoL and advanced diabetes complications 58,61,84–87. Still, it should be acknowledged, that more
evidence supporting these indications is needed.
The use of CIPII is largely restricted to Europe, especially Belgium, France, Sweden and
the Netherlands. Besides the externally placed DiaPort system there is only one type of
implantable pump (MIP 2007D, Medtronic/Minimed, Northridge, CA, USA) available for use
in patients. This model has a reservoir which can contain 15 ml of insulin and has a battery
with 7 years longevity. A silicone catheter is attached to the side port of the pump, through
which insulin is delivered directly into the peritoneal cavity (see Figure 3 and 4). The pump
can be remotely controlled with a pocket-sized personal pump communicator. Implantation
of the pump is performed under general anaesthesia and, usually, the pump is inserted in
a subcutaneous pocket in a lower abdominal quadrant (see Figure 4). From this pocket, the
peritoneum is opened and the tip of the catheter is carefully inserted and directed towards the
liver. After implantation, the pump reservoir is refilled transcutaneously with insulin at the
outpatient clinic at least every 3 months, depending on the individual insulin requirement.
From 2010 onwards a new human recombinant insulin (400 IU/ml; human insulin of E. Coli
origin, trade name: Insuman Implantable®, Sanofi-Aventis) was used since no batches were left
of the U-400 HOE 21PH insulin.
General aims and outline of this thesis
The general aim of this thesis was to study different aspects of CIPII using an implantable
pump in patients with T1DM, in particular the effects of long-term use, in order to provide a
more comprehensive and balanced view on the use of this therapy.
chapter 1introduction
The MIP 2007D implantable pump system and patients-pump communicator.
Illustration of the implantable pump system (left) and a the pump in situ (right) 83.
figure 3
figure 4
22 23
part i. complications of CIPII therapy using an implantable pump Chapter 2 focusses on the complications related to CIPII therapy. As complications occurred
frequently in the past and influence the outcomes of CIPII therapy, it is of importance to
monitor the course of complications related to CIPII. In this chapter the nature, consequences
and course of complications of CIPII among patients with T1DM are described.
part ii. effects of intraperitoneal insulin therapy - glycaemia, quality of life and treatment satisfactionChapter 3 describes the long-term course of glycaemic regulation, general QoL and treatment
satisfaction among CIPII treated patients. All patients described in this chapter initiated CIPII
therapy during a cross-over trial in 2006, which allowed additional comparisons with both the
initial effects of CIPII insulin and previous SC insulin therapy.
In Chapter 4 the long-term effects of CIPII and SC insulin administration among T1DM patients
with inadequate glycaemic control are described. Outcomes included the change of glycaemic
control, clinical parameters and QoL within and between the two groups over a period of 7 years.
In order to compare patients on long-term CIPII with a matched group of patients using SC
insulin therapy, a 26-week prospective cohort study in a large population of T1DM patients was
performed. Chapter 5, 6 and 7 describe the results of this study with respect to glycaemic control
and clinical parameters, glycaemic variability, general and diabetes specific QoL, treatment
satisfaction, self-care and distress.
Part iii. Effects of intraperitoneal insulin therapy - beyond glycaemiaIn Chapter 8 the hypothesis that the IP route of insulin administration would increase IGF1
concentrations as compared to SC insulin was tested using samples derived from a previous
cross-over trial comparing SC and IP insulin therapy. Chapter 9 describes the course of IGF1
concentrations after this cross-over trial, over a period of 6 years during CIPII therapy. Further
testing and reporting on the effects of IP insulin, as compared to SC insulin administration,
on the GH-IGF1 axis is performed in Chapter 10. As most studies towards this topic had a relative
short duration and were performed in small populations, the effects of CIPII as compared to SC
insulin administration on the GH-IGF1 axis were studied in a large population of T1DM patients
who have been on their current mode of therapy for more than 4 years.
Finally, in Chapter 11 (Chapter 12 in Dutch) a summary of this thesis is given, together with
a discussion of the results, recommendations for the clinical practice and future research
directions.
1 Service FJ, Nelson RL. Characteristics of glycemic stability. Diabetes Care 1980; 3: 58–62.
2 Guerci B, Sauvanet JP. Subcutaneous insulin: pharmacokinetic variability and glycemic variability. Diabetes Metab
2005; 31: 4S7–4S24.
3 American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2008; 31 Suppl 1:
S55–60.
4 Roep BO, Peakman M. Surrogate end points in the design of immunotherapy trials: emerging lessons from
type 1 diabetes. Nat Rev Immunol 2010; 10: 145–52.
5 Coppieters KT, Dotta F, Amirian N, et al. Demonstration of islet-autoreactive CD8 T cells in insulitic lesions from recent
onset and long-term type 1 diabetes patients. J Exp Med 2012; 209: 51–60.
6 Willcox A, Richardson SJ, Bone AJ, Foulis AK, Morgan NG. Analysis of islet inflammation in human type 1 diabetes.
Clin Exp Immunol 2009; 155: 173–81.
7 The effect of intensive treatment of diabetes on the development and progression of long-term complications in
insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group.
N Engl J Med 1993; 329: 977–86.
8 Nathan DM, Cleary PA, Backlund J-YC, et al. Intensive diabetes treatment and cardiovascular disease in patients with
type 1 diabetes. N Engl J Med 2005; 353: 2643–53.
9 Brange J, Ribel U, Hansen JF, et al. Monomeric insulins obtained by protein engineering and their medical implications.
Nature 1988; 333: 679–82.
10 Hirsch IB. Insulin analogues. N Engl J Med 2005; 352: 174–83.
11 Rave K, Klein O, Frick AD, Becker RHA. Advantage of premeal-injected insulin glulisine compared with regular human
insulin in subjects with type 1 diabetes. Diabetes Care 2006; 29: 1812–7.
12 Pickup JC, Viberti GC, Keen H, Parsons JA, Alberti KG. Clinical application of pre-programmed insulin infusion:
continuous subcutaneous insulin therapy with a portable infusion system. Horm Metab Res Suppl 1979; : 202–4.
13 Pickup JC, Sutton AJ. Severe hypoglycaemia and glycaemic control in Type 1 diabetes: meta-analysis of multiple daily
insulin injections compared with continuous subcutaneous insulin infusion. Diabet Med 2008; 25: 765–74.
14 Weissberg-Benchell J, Antisdel-Lomaglio J, Seshadri R. Insulin pump therapy: a meta-analysis. Diabetes Care 2003;
26: 1079–87.
15 Yeh H-C, Brown TT, Maruthur N, et al. Comparative Effectiveness and Safety of Methods of Insulin Delivery and
Glucose Monitoring for Diabetes Mellitus: A Systematic Review and Meta-analysis. Annals of internal medicine 2012;
E–508.
16 Fatourechi MM, Kudva YC, Murad MH, Elamin MB, Tabini CC, Montori VM. Clinical review: Hypoglycemia with
intensive insulin therapy: a systematic review and meta-analyses of randomized trials of continuous subcutaneous
insulin infusion versus multiple daily injections. J Clin Endocrinol Metab 2009; 94: 729–40.
17 Bruttomesso D, Crazzolara D, Maran A, et al. In Type 1 diabetic patients with good glycaemic control, blood glucose
variability is lower during continuous subcutaneous insulin infusion than during multiple daily injections with insulin
glargine. Diabet Med 2008; 25: 326–32.
18 Nicolucci A, Maione A, Franciosi M, et al. Quality of life and treatment satisfaction in adults with Type 1 diabetes:
a comparison between continuous subcutaneous insulin infusion and multiple daily injections.
Diabet Med 2008; 25: 213–20.
19 DeWitt DE, Hirsch IB. Outpatient insulin therapy in type 1 and type 2 diabetes mellitus: scientific review. JAMA 2003;
289: 2254–64.
20 Bilo HJ, Heine RJ, Sikkenk AC, van der Meer J, van der Veen EA. Absorption kinetics and action profiles after sequential
subcutaneous administration of human soluble and lente insulin through one needle. Diabetes Care 1987; 10: 466–9.
chapter 1introduction
references
22 23
part i. complications of CIPII therapy using an implantable pump Chapter 2 focusses on the complications related to CIPII therapy. As complications occurred
frequently in the past and influence the outcomes of CIPII therapy, it is of importance to
monitor the course of complications related to CIPII. In this chapter the nature, consequences
and course of complications of CIPII among patients with T1DM are described.
part ii. effects of intraperitoneal insulin therapy - glycaemia, quality of life and treatment satisfactionChapter 3 describes the long-term course of glycaemic regulation, general QoL and treatment
satisfaction among CIPII treated patients. All patients described in this chapter initiated CIPII
therapy during a cross-over trial in 2006, which allowed additional comparisons with both the
initial effects of CIPII insulin and previous SC insulin therapy.
In Chapter 4 the long-term effects of CIPII and SC insulin administration among T1DM patients
with inadequate glycaemic control are described. Outcomes included the change of glycaemic
control, clinical parameters and QoL within and between the two groups over a period of 7 years.
In order to compare patients on long-term CIPII with a matched group of patients using SC
insulin therapy, a 26-week prospective cohort study in a large population of T1DM patients was
performed. Chapter 5, 6 and 7 describe the results of this study with respect to glycaemic control
and clinical parameters, glycaemic variability, general and diabetes specific QoL, treatment
satisfaction, self-care and distress.
Part iii. Effects of intraperitoneal insulin therapy - beyond glycaemiaIn Chapter 8 the hypothesis that the IP route of insulin administration would increase IGF1
concentrations as compared to SC insulin was tested using samples derived from a previous
cross-over trial comparing SC and IP insulin therapy. Chapter 9 describes the course of IGF1
concentrations after this cross-over trial, over a period of 6 years during CIPII therapy. Further
testing and reporting on the effects of IP insulin, as compared to SC insulin administration,
on the GH-IGF1 axis is performed in Chapter 10. As most studies towards this topic had a relative
short duration and were performed in small populations, the effects of CIPII as compared to SC
insulin administration on the GH-IGF1 axis were studied in a large population of T1DM patients
who have been on their current mode of therapy for more than 4 years.
Finally, in Chapter 11 (Chapter 12 in Dutch) a summary of this thesis is given, together with
a discussion of the results, recommendations for the clinical practice and future research
directions.
1 Service FJ, Nelson RL. Characteristics of glycemic stability. Diabetes Care 1980; 3: 58–62.
2 Guerci B, Sauvanet JP. Subcutaneous insulin: pharmacokinetic variability and glycemic variability. Diabetes Metab
2005; 31: 4S7–4S24.
3 American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2008; 31 Suppl 1:
S55–60.
4 Roep BO, Peakman M. Surrogate end points in the design of immunotherapy trials: emerging lessons from
type 1 diabetes. Nat Rev Immunol 2010; 10: 145–52.
5 Coppieters KT, Dotta F, Amirian N, et al. Demonstration of islet-autoreactive CD8 T cells in insulitic lesions from recent
onset and long-term type 1 diabetes patients. J Exp Med 2012; 209: 51–60.
6 Willcox A, Richardson SJ, Bone AJ, Foulis AK, Morgan NG. Analysis of islet inflammation in human type 1 diabetes.
Clin Exp Immunol 2009; 155: 173–81.
7 The effect of intensive treatment of diabetes on the development and progression of long-term complications in
insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group.
N Engl J Med 1993; 329: 977–86.
8 Nathan DM, Cleary PA, Backlund J-YC, et al. Intensive diabetes treatment and cardiovascular disease in patients with
type 1 diabetes. N Engl J Med 2005; 353: 2643–53.
9 Brange J, Ribel U, Hansen JF, et al. Monomeric insulins obtained by protein engineering and their medical implications.
Nature 1988; 333: 679–82.
10 Hirsch IB. Insulin analogues. N Engl J Med 2005; 352: 174–83.
11 Rave K, Klein O, Frick AD, Becker RHA. Advantage of premeal-injected insulin glulisine compared with regular human
insulin in subjects with type 1 diabetes. Diabetes Care 2006; 29: 1812–7.
12 Pickup JC, Viberti GC, Keen H, Parsons JA, Alberti KG. Clinical application of pre-programmed insulin infusion:
continuous subcutaneous insulin therapy with a portable infusion system. Horm Metab Res Suppl 1979; : 202–4.
13 Pickup JC, Sutton AJ. Severe hypoglycaemia and glycaemic control in Type 1 diabetes: meta-analysis of multiple daily
insulin injections compared with continuous subcutaneous insulin infusion. Diabet Med 2008; 25: 765–74.
14 Weissberg-Benchell J, Antisdel-Lomaglio J, Seshadri R. Insulin pump therapy: a meta-analysis. Diabetes Care 2003;
26: 1079–87.
15 Yeh H-C, Brown TT, Maruthur N, et al. Comparative Effectiveness and Safety of Methods of Insulin Delivery and
Glucose Monitoring for Diabetes Mellitus: A Systematic Review and Meta-analysis. Annals of internal medicine 2012;
E–508.
16 Fatourechi MM, Kudva YC, Murad MH, Elamin MB, Tabini CC, Montori VM. Clinical review: Hypoglycemia with
intensive insulin therapy: a systematic review and meta-analyses of randomized trials of continuous subcutaneous
insulin infusion versus multiple daily injections. J Clin Endocrinol Metab 2009; 94: 729–40.
17 Bruttomesso D, Crazzolara D, Maran A, et al. In Type 1 diabetic patients with good glycaemic control, blood glucose
variability is lower during continuous subcutaneous insulin infusion than during multiple daily injections with insulin
glargine. Diabet Med 2008; 25: 326–32.
18 Nicolucci A, Maione A, Franciosi M, et al. Quality of life and treatment satisfaction in adults with Type 1 diabetes:
a comparison between continuous subcutaneous insulin infusion and multiple daily injections.
Diabet Med 2008; 25: 213–20.
19 DeWitt DE, Hirsch IB. Outpatient insulin therapy in type 1 and type 2 diabetes mellitus: scientific review. JAMA 2003;
289: 2254–64.
20 Bilo HJ, Heine RJ, Sikkenk AC, van der Meer J, van der Veen EA. Absorption kinetics and action profiles after sequential
subcutaneous administration of human soluble and lente insulin through one needle. Diabetes Care 1987; 10: 466–9.
chapter 1introduction
references
24 25
21 Bryant W, Greenfield JR, Chisholm DJ, Campbell LV. Diabetes guidelines: easier to preach than to practise?
Med J Aust 2006; 185: 305–9.
22 Govan L, Wu O, Briggs A, et al. Achieved levels of HbA1c and likelihood of hospital admission in people with type 1
diabetes in the Scottish population: a study from the Scottish Diabetes Research Network Epidemiology Group.
Diabetes Care 2011; 34: 1992–7.
23 Selam JL, Slingeneyer A, Hedon B, Mares P, Beraud JJ, Mirouze J. Long-term ambulatory peritoneal insulin infusion of
brittle diabetes with portable pumps: comparison with intravenous and subcutaneous routes. Diabetes Care 1983;
6: 105–11.
24 Irsigler K, Kritz H. Alternate routes of insulin delivery. Diabetes Care 1980; 3: 219–28.
25 Eaton RP, Friedman NM, Spencerr WJ. Intraperitoneal delivery of insulin by a portable microinfusion pump. Metab Clin
Exp 1980; 29: 699–702.
26 Schade DS, Eaton RP, Friedman NM, Spencer WJ, Standefer JC. Five-day programmed intraperitoneal insulin delivery
in insulin-dependent diabetic man. J Clin Endocrinol Metab 1981; 52: 1165–70.
27 Multicentre trial of a programmable implantable insulin pump in type I diabetes. The Point Study II Group. Int J Artif
Organs 1995; 18: 322–5.
28 Saudek CD, Selam JL, Pitt HA, et al. A preliminary trial of the programmable implantable medication system for
insulin delivery. N Engl J Med 1989; 321: 574–9.
29 Selam JL, Micossi P, Dunn FL, Nathan DM. Clinical trial of programmable implantable insulin pump for type I diabetes.
Diabetes Care 1992; 15: 877–85.
30 Broussolle C, Jeandidier N, Hanaire-Broutin H. French multicentre experience of implantable insulin pumps.
The EVADIAC Study Group. Evaluation of Active Implants in Diabetes Society. Lancet 1994; 343: 514–5.
31 Renard E, Bouteleau S, Jacques-Apostol D, et al. Insulin underdelivery from implanted pumps using peritoneal route.
Determinant role of insulin pump compatibility. Diabetes Care 1996; 19: 812–7.
32 Boivin S, Belicar P, Melki V. Assessment of in vivo stability of a new insulin preparation for implantable insulin pumps.
A randomized multicenter prospective trial. EVADIAC Group. Evaluation Dans le diabète du Traitement par Implants
Actifs. Diabetes Care 1999; 22: 2089–90.
33 Renard E, Baldet P, Picot MC, et al. Catheter complications associated with implantable systems for peritoneal insulin
delivery. An analysis of frequency, predisposing factors, and obstructing materials. Diabetes Care 1995; 18: 300–6.
34 Gin H, Renard E, Melki V, et al. Combined improvements in implantable pump technology and insulin stability allow
safe and effective long term intraperitoneal insulin delivery in type 1 diabetic patients: the EVADIAC experience.
Diabetes Metab 2003; 29: 602–7.
35 Gin H, Melki V, Guerci B, Catargi B, Evaluation dans le Diabete du Traitement par Implants Actifs Study Group.
Clinical evaluation of a newly designed compliant side port catheter for an insulin implantable pump:
the EVADIAC experience. Evaluation dans le Diabete du Traitement par Implants Actifs. Diabetes Care 2001; 24: 175.
36 Olsen CL, Chan E, Turner DS, et al. Insulin antibody responses after long-term intraperitoneal insulin administration
via implantable programmable insulin delivery systems. Diabetes Care 1994; 17: 169–76.
37 Jeandidier N, Boivin S, Sapin R, et al. Immunogenicity of intraperitoneal insulin infusion using programmable
implantable devices. Diabetologia 1995; 38: 577–84.
38 Jeandidier N, Boullu S, Delatte E, et al. High antigenicity of intraperitoneal insulin infusion via implantable devices:
preliminary rat studies. Horm Metab Res 2001; 33: 34–8.
39 Lassmann-Vague V, Belicar P, Alessis C, Raccah D, Vialettes B, Vague P. Insulin kinetics in type I diabetic patients treated
by continuous intraperitoneal insulin infusion: influence of anti-insulin antibodies. Diabet Med 1996; 13: 1051–5.
40 Lassmann-Vague V, Belicar P, Raccah D, Vialettes B, Sodoyez JC, Vague P. Immunogenicity of long-term intraperitoneal
insulin administration with implantable programmable pumps. Metabolic consequences. Diabetes Care 1995; 18: 498–503.
41 Dufaitre-Patouraux L, Riveline JP, Renard E, et al. Continuous intraperitoneal insulin infusion does not increase the risk
of organ-specific autoimmune disease in type 1 diabetic patients: results of a multicentric, comparative study.
Diabetes Metab 2006; 32: 427–32.
42 Schade DS, Eaton RP, Davis T, et al. The kinetics of peritoneal insulin absorption. Metab Clin Exp 1981; 30: 149–55.
43 Radziuk J, Pye S, Seigler DE, Skyler JS, Offord R, Davies G. Splanchnic and systemic absorption of intraperitoneal insulin
using a new double-tracer method. Am J Physiol 1994; 266: E750–759.
44 Nathan DM, Dunn FL, Bruch J, et al. Postprandial insulin profiles with implantable pump therapy may explain
decreased frequency of severe hypoglycemia, compared with intensive subcutaneous regimens, in insulin-dependent
diabetes mellitus patients. Am J Med 1996; 100: 412–7.
45 Selam JL, Bergman RN, Raccah D, Jean-Didier N, Lozano J, Charles MA. Determination of portal insulin absorption
from peritoneum via novel nonisotopic method. Diabetes 1990; 39: 1361–5.
46 Giacca A, Caumo A, Galimberti G, et al. Peritoneal and subcutaneous absorption of insulin in type I diabetic subjects.
J Clin Endocrinol Metab 1993; 77: 738–42.
47 Oskarsson PR, Lins PE, Backman L, Adamson UC. Continuous intraperitoneal insulin infusion partly restores the
glucagon response to hypoglycaemia in type 1 diabetic patients. Diabetes Metab 2000; 26: 118–24.
48 Bratusch-Marrain PR, Waldhäusl WK, Gasić S, Hofer A. Hepatic disposal of biosynthetic human insulin and porcine
C-peptide in humans. Metab Clin Exp 1984; 33: 151–7.
49 Schade DS, Eaton RP, Spencer W, Goldman R, Corbett WT. The peritoneal absorption of insulin in diabetic man:
a potential site for a mechanical insulin delivery system. Metab Clin Exp 1979; 28: 195–7.
50 Micossi P, Cristallo M, Librenti MC, et al. Free-insulin profiles after intraperitoneal, intramuscular, and subcutaneous
insulin administration. Diabetes Care 1986; 9: 575–8.
51 Schaepelynck Bélicar P, Vague P, Lassmann-Vague V. Reproducibility of plasma insulin kinetics during intraperitoneal
insulin treatment by programmable pumps. Diabetes Metab 2003; 29: 344–8.
52 Wan CK, Giacca A, Matsuhisa M, et al. Increased responses of glucagon and glucose production to hypoglycemia with
intraperitoneal versus subcutaneous insulin treatment. Metab Clin Exp 2000; 49: 984–9.
53 Mason TM, Gupta N, Goh T, et al. Chronic intraperitoneal insulin delivery, as compared with subcutaneous delivery,
improves hepatic glucose metabolism in streptozotocin diabetic rats. Metab Clin Exp 2000; 49: 1411–6.
54 Oskarsson PR, Lins PE, Wallberg Henriksson H, Adamson UC. Metabolic and hormonal responses to exercise in
type 1 diabetic patients during continuous subcutaneous, as compared to continuous intraperitoneal, insulin infusion.
Diabetes Metab 1999; 25: 491–7.
55 Selam JL, Medlej R, M’bemba J, et al. Symptoms, hormones, and glucose fluxes during a gradual hypoglycaemia
induced by intraperitoneal vs venous insulin infusion in Type I diabetes. Diabet Med 1995; 12: 1102–9.
56 Haardt MJ, Selam JL, Slama G, et al. A cost-benefit comparison of intensive diabetes management with implantable
pumps versus multiple subcutaneous injections in patients with type I diabetes. Diabetes Care 1994; 17: 847–51.
57 Selam JL, Raccah D, Jean-Didier N, Lozano JL, Waxman K, Charles MA. Randomized comparison of metabolic control
achieved by intraperitoneal insulin infusion with implantable pumps versus intensive subcutaneous insulin therapy in
type I diabetic patients. Diabetes Care 1992; 15: 53–8.
58 Logtenberg SJ, Kleefstra N, Houweling ST, et al. Improved glycemic control with intraperitoneal versus subcutaneous
insulin in type 1 diabetes: a randomized controlled trial. Diabetes Care 2009; 32: 1372–7.
59 Schaepelynck P, Renard E, Jeandidier N, et al. A recent survey confirms the efficacy and the safety of implanted insulin
pumps during long-term use in poorly controlled type 1 diabetes patients. Diabetes Technol Ther 2011; 13: 657–60.
60 Hanaire-Broutin H, Broussolle C, Jeandidier N, et al. Feasibility of intraperitoneal insulin therapy with programmable
implantable pumps in IDDM. A multicenter study. The EVADIAC Study Group. Evaluation dans le Diabète du Traitement
par Implants Actifs. Diabetes Care 1995; 18: 388–92.
61 DeVries JH, Eskes SA, Snoek FJ, et al. Continuous intraperitoneal insulin infusion in patients with ‘brittle’ diabetes:
favourable effects on glycaemic control and hospital stay. Diabet Med 2002; 19: 496–501.
chapter 1introduction
24 25
21 Bryant W, Greenfield JR, Chisholm DJ, Campbell LV. Diabetes guidelines: easier to preach than to practise?
Med J Aust 2006; 185: 305–9.
22 Govan L, Wu O, Briggs A, et al. Achieved levels of HbA1c and likelihood of hospital admission in people with type 1
diabetes in the Scottish population: a study from the Scottish Diabetes Research Network Epidemiology Group.
Diabetes Care 2011; 34: 1992–7.
23 Selam JL, Slingeneyer A, Hedon B, Mares P, Beraud JJ, Mirouze J. Long-term ambulatory peritoneal insulin infusion of
brittle diabetes with portable pumps: comparison with intravenous and subcutaneous routes. Diabetes Care 1983;
6: 105–11.
24 Irsigler K, Kritz H. Alternate routes of insulin delivery. Diabetes Care 1980; 3: 219–28.
25 Eaton RP, Friedman NM, Spencerr WJ. Intraperitoneal delivery of insulin by a portable microinfusion pump. Metab Clin
Exp 1980; 29: 699–702.
26 Schade DS, Eaton RP, Friedman NM, Spencer WJ, Standefer JC. Five-day programmed intraperitoneal insulin delivery
in insulin-dependent diabetic man. J Clin Endocrinol Metab 1981; 52: 1165–70.
27 Multicentre trial of a programmable implantable insulin pump in type I diabetes. The Point Study II Group. Int J Artif
Organs 1995; 18: 322–5.
28 Saudek CD, Selam JL, Pitt HA, et al. A preliminary trial of the programmable implantable medication system for
insulin delivery. N Engl J Med 1989; 321: 574–9.
29 Selam JL, Micossi P, Dunn FL, Nathan DM. Clinical trial of programmable implantable insulin pump for type I diabetes.
Diabetes Care 1992; 15: 877–85.
30 Broussolle C, Jeandidier N, Hanaire-Broutin H. French multicentre experience of implantable insulin pumps.
The EVADIAC Study Group. Evaluation of Active Implants in Diabetes Society. Lancet 1994; 343: 514–5.
31 Renard E, Bouteleau S, Jacques-Apostol D, et al. Insulin underdelivery from implanted pumps using peritoneal route.
Determinant role of insulin pump compatibility. Diabetes Care 1996; 19: 812–7.
32 Boivin S, Belicar P, Melki V. Assessment of in vivo stability of a new insulin preparation for implantable insulin pumps.
A randomized multicenter prospective trial. EVADIAC Group. Evaluation Dans le diabète du Traitement par Implants
Actifs. Diabetes Care 1999; 22: 2089–90.
33 Renard E, Baldet P, Picot MC, et al. Catheter complications associated with implantable systems for peritoneal insulin
delivery. An analysis of frequency, predisposing factors, and obstructing materials. Diabetes Care 1995; 18: 300–6.
34 Gin H, Renard E, Melki V, et al. Combined improvements in implantable pump technology and insulin stability allow
safe and effective long term intraperitoneal insulin delivery in type 1 diabetic patients: the EVADIAC experience.
Diabetes Metab 2003; 29: 602–7.
35 Gin H, Melki V, Guerci B, Catargi B, Evaluation dans le Diabete du Traitement par Implants Actifs Study Group.
Clinical evaluation of a newly designed compliant side port catheter for an insulin implantable pump:
the EVADIAC experience. Evaluation dans le Diabete du Traitement par Implants Actifs. Diabetes Care 2001; 24: 175.
36 Olsen CL, Chan E, Turner DS, et al. Insulin antibody responses after long-term intraperitoneal insulin administration
via implantable programmable insulin delivery systems. Diabetes Care 1994; 17: 169–76.
37 Jeandidier N, Boivin S, Sapin R, et al. Immunogenicity of intraperitoneal insulin infusion using programmable
implantable devices. Diabetologia 1995; 38: 577–84.
38 Jeandidier N, Boullu S, Delatte E, et al. High antigenicity of intraperitoneal insulin infusion via implantable devices:
preliminary rat studies. Horm Metab Res 2001; 33: 34–8.
39 Lassmann-Vague V, Belicar P, Alessis C, Raccah D, Vialettes B, Vague P. Insulin kinetics in type I diabetic patients treated
by continuous intraperitoneal insulin infusion: influence of anti-insulin antibodies. Diabet Med 1996; 13: 1051–5.
40 Lassmann-Vague V, Belicar P, Raccah D, Vialettes B, Sodoyez JC, Vague P. Immunogenicity of long-term intraperitoneal
insulin administration with implantable programmable pumps. Metabolic consequences. Diabetes Care 1995; 18: 498–503.
41 Dufaitre-Patouraux L, Riveline JP, Renard E, et al. Continuous intraperitoneal insulin infusion does not increase the risk
of organ-specific autoimmune disease in type 1 diabetic patients: results of a multicentric, comparative study.
Diabetes Metab 2006; 32: 427–32.
42 Schade DS, Eaton RP, Davis T, et al. The kinetics of peritoneal insulin absorption. Metab Clin Exp 1981; 30: 149–55.
43 Radziuk J, Pye S, Seigler DE, Skyler JS, Offord R, Davies G. Splanchnic and systemic absorption of intraperitoneal insulin
using a new double-tracer method. Am J Physiol 1994; 266: E750–759.
44 Nathan DM, Dunn FL, Bruch J, et al. Postprandial insulin profiles with implantable pump therapy may explain
decreased frequency of severe hypoglycemia, compared with intensive subcutaneous regimens, in insulin-dependent
diabetes mellitus patients. Am J Med 1996; 100: 412–7.
45 Selam JL, Bergman RN, Raccah D, Jean-Didier N, Lozano J, Charles MA. Determination of portal insulin absorption
from peritoneum via novel nonisotopic method. Diabetes 1990; 39: 1361–5.
46 Giacca A, Caumo A, Galimberti G, et al. Peritoneal and subcutaneous absorption of insulin in type I diabetic subjects.
J Clin Endocrinol Metab 1993; 77: 738–42.
47 Oskarsson PR, Lins PE, Backman L, Adamson UC. Continuous intraperitoneal insulin infusion partly restores the
glucagon response to hypoglycaemia in type 1 diabetic patients. Diabetes Metab 2000; 26: 118–24.
48 Bratusch-Marrain PR, Waldhäusl WK, Gasić S, Hofer A. Hepatic disposal of biosynthetic human insulin and porcine
C-peptide in humans. Metab Clin Exp 1984; 33: 151–7.
49 Schade DS, Eaton RP, Spencer W, Goldman R, Corbett WT. The peritoneal absorption of insulin in diabetic man:
a potential site for a mechanical insulin delivery system. Metab Clin Exp 1979; 28: 195–7.
50 Micossi P, Cristallo M, Librenti MC, et al. Free-insulin profiles after intraperitoneal, intramuscular, and subcutaneous
insulin administration. Diabetes Care 1986; 9: 575–8.
51 Schaepelynck Bélicar P, Vague P, Lassmann-Vague V. Reproducibility of plasma insulin kinetics during intraperitoneal
insulin treatment by programmable pumps. Diabetes Metab 2003; 29: 344–8.
52 Wan CK, Giacca A, Matsuhisa M, et al. Increased responses of glucagon and glucose production to hypoglycemia with
intraperitoneal versus subcutaneous insulin treatment. Metab Clin Exp 2000; 49: 984–9.
53 Mason TM, Gupta N, Goh T, et al. Chronic intraperitoneal insulin delivery, as compared with subcutaneous delivery,
improves hepatic glucose metabolism in streptozotocin diabetic rats. Metab Clin Exp 2000; 49: 1411–6.
54 Oskarsson PR, Lins PE, Wallberg Henriksson H, Adamson UC. Metabolic and hormonal responses to exercise in
type 1 diabetic patients during continuous subcutaneous, as compared to continuous intraperitoneal, insulin infusion.
Diabetes Metab 1999; 25: 491–7.
55 Selam JL, Medlej R, M’bemba J, et al. Symptoms, hormones, and glucose fluxes during a gradual hypoglycaemia
induced by intraperitoneal vs venous insulin infusion in Type I diabetes. Diabet Med 1995; 12: 1102–9.
56 Haardt MJ, Selam JL, Slama G, et al. A cost-benefit comparison of intensive diabetes management with implantable
pumps versus multiple subcutaneous injections in patients with type I diabetes. Diabetes Care 1994; 17: 847–51.
57 Selam JL, Raccah D, Jean-Didier N, Lozano JL, Waxman K, Charles MA. Randomized comparison of metabolic control
achieved by intraperitoneal insulin infusion with implantable pumps versus intensive subcutaneous insulin therapy in
type I diabetic patients. Diabetes Care 1992; 15: 53–8.
58 Logtenberg SJ, Kleefstra N, Houweling ST, et al. Improved glycemic control with intraperitoneal versus subcutaneous
insulin in type 1 diabetes: a randomized controlled trial. Diabetes Care 2009; 32: 1372–7.
59 Schaepelynck P, Renard E, Jeandidier N, et al. A recent survey confirms the efficacy and the safety of implanted insulin
pumps during long-term use in poorly controlled type 1 diabetes patients. Diabetes Technol Ther 2011; 13: 657–60.
60 Hanaire-Broutin H, Broussolle C, Jeandidier N, et al. Feasibility of intraperitoneal insulin therapy with programmable
implantable pumps in IDDM. A multicenter study. The EVADIAC Study Group. Evaluation dans le Diabète du Traitement
par Implants Actifs. Diabetes Care 1995; 18: 388–92.
61 DeVries JH, Eskes SA, Snoek FJ, et al. Continuous intraperitoneal insulin infusion in patients with ‘brittle’ diabetes:
favourable effects on glycaemic control and hospital stay. Diabet Med 2002; 19: 496–501.
chapter 1introduction
26 27
62 Catargi B, Meyer L, Melki V, Renard E, Jeandidier N. Comparison of blood glucose stability and HbA1C between implan-
table insulin pumps using U400 HOE 21PH insulin and external pumps using lispro in type 1 diabetic patients:
a pilot study. Diabetes Metab 2002; 28: 133–7.
63 Cox DJ, Kovatchev BP, Julian DM, et al. Frequency of severe hypoglycemia in insulin-dependent diabetes mellitus can
be predicted from self-monitoring blood glucose data. J Clin Endocrinol Metab 1994; 79: 1659–62.
64 Kilpatrick ES, Rigby AS, Goode K, Atkin SL. Relating mean blood glucose and glucose variability to the risk of multiple
episodes of hypoglycaemia in type 1 diabetes. Diabetologia 2007; 50: 2553–61.
65 Logtenberg SJJ, van Ballegooie E, Israêl-Bultman H, van Linde A, Bilo HJG. Glycaemic control, health status and
treatment satisfaction with continuous intraperitoneal insulin infusion. Neth J Med 2007; 65: 65–70.
66 Renard E, Apostol D, Lauton D, Boulet F, Bringer J. Quality of life in diabetic patients treated by insulinpumps.
QoL newsletter 2002; : 11–3.
67 DeVries JH, Eskes SA, Snoek FJ, et al. Continuous intraperitoneal insulin infusion in patients with ‘brittle’ diabetes:
favourable effects on glycaemic control and hospital stay. Diabet Med 2002; 19: 496–501.
68 Frystyk J. Free insulin-like growth factors -- measurements and relationships to growth hormone secretion and glucose
homeostasis. Growth Horm IGF Res 2004; 14: 337–75.
69 LeRoith D, Yakar S. Mechanisms of disease: metabolic effects of growth hormone and insulin-like growth factor 1.
Nat Clin Pract Endocrinol Metab 2007; 3: 302–10.
70 Kim JJ, Accili D. Signalling through IGF-I and insulin receptors: where is the specificity? Growth Horm IGF Res 2002; 12: 84–90.
71 Leung KC, Doyle N, Ballesteros M, Waters MJ, Ho KK. Insulin regulation of human hepatic growth hormone receptors:
divergent effects on biosynthesis and surface translocation. J Clin Endocrinol Metab 2000; 85: 4712–20.
72 Brismar K, Fernqvist-Forbes E, Wahren J, Hall K. Effect of insulin on the hepatic production of insulin-like growth factor-
binding protein-1 (IGFBP-1), IGFBP-3, and IGF-I in insulin-dependent diabetes. J Clin Endocrinol Metab 1994; 79: 872–8.
73 Bereket A, Lang CH, Wilson TA. Alterations in the growth hormone-insulin-like growth factor axis in insulin dependent
diabetes mellitus. Horm Metab Res 1999; 31: 172–81.
74 Arnqvist HJ. The role of IGF-system in vascular insulin resistance. Horm Metab Res 2008; 40: 588–92.
75 Clemmons DR. Modifying IGF1 activity: an approach to treat endocrine disorders, atherosclerosis and cancer.
Nat Rev Drug Discov 2007; 6: 821–33.
76 Ekman B, Nyström F, Arnqvist HJ. Circulating IGF-I concentrations are low and not correlated to glycaemic control in
adults with type 1 diabetes. Eur J Endocrinol 2000; 143: 505–10.
77 Hedman CA, Orre-Pettersson AC, Lindström T, Arnqvist HJ. Treatment with insulin lispro changes the insulin profile but
does not affect the plasma concentrations of IGF-I and IGFBP-1 in type 1 diabetes. Clin Endocrinol (Oxf) 2001; 55: 107–12.
78 Hedman CA, Frystyk J, Lindström T, et al. Residual beta-cell function more than glycemic control determines abnormal-
ities of the insulin-like growth factor system in type 1 diabetes. J Clin Endocrinol Metab 2004; 89: 6305–9.
79 Hanaire-Broutin H, Sallerin-Caute B, Poncet MF, et al. Insulin therapy and GH-IGF-I axis disorders in diabetes:
impact of glycaemic control and hepatic insulinization. Diabetes Metab 1996; 22: 245–50.
80 Shishko PI, Dreval AV, Abugova IA, Zajarny IU, Goncharov VC. Insulin-like growth factors and binding proteins in
patients with recent-onset type 1 (insulin-dependent) diabetes mellitus: influence of diabetes control and intraportal
insulin infusion. Diabetes Res Clin Pract 1994; 25: 1–12.
81 Hanaire-Broutin H, Sallerin-Caute B, Poncet MF, et al. Effect of intraperitoneal insulin delivery on growth hormone
binding protein, insulin-like growth factor (IGF)-I, and IGF-binding protein-3 in IDDM. Diabetologia 1996; 39: 1498–504.
82 Hedman CA, Frystyk J, Lindström T, Oskarsson P, Arnqvist HJ. Intraperitoneal insulin delivery to patients with
type 1 diabetes results in higher serum IGF-I bioactivity than continuous subcutaneous insulin infusion.
Clin Endocrinol (Oxf) 2013. doi:10.1111/cen.12296.
83 Haveman JW, Logtenberg SJJ, Kleefstra N, Groenier KH, Bilo HJG, Blomme AM. Surgical aspects and complications of
continuous intraperitoneal insulin infusion with an implantable pump. Langenbecks Arch Surg 2010; 395: 65–71.
introduction
84 Logtenberg SJ, Kleefstra N, Houweling ST, Groenier KH, Gans RO, Bilo HJ. Health-related quality of life, treatment
satisfaction, and costs associated with intraperitoneal versus subcutaneous insulin administration in type 1 diabetes:
a randomized controlled trial. Diabetes Care 2010; 33: 1169–72.
85 Riveline JP, Vantyghem MC, Fermon C, et al. Subcutaneous insulin resistance successfully circumvented on long term
by peritoneal insulin delivery from an implantable pump in four diabetic patients. Diabetes Metab 2005; 31: 496–8.
86 Jeandidier N, Selam JL, Renard E, et al. Decreased severe hypoglycemia frequency during intraperitoneal insulin
infusion using programmable implantable pumps. Evadiac Study Group. Diabetes Care 1996; 19: 780.
87 Baillot-Rudoni S, Apostol D, Vaillant G, Brun J-M, Renard E, EVADIAC Study Group. Implantable pump therapy restores
metabolic control and quality of life in type 1 diabetic patients with Buschke’s nonsystemic scleroderma.
Diabetes Care 2006; 29: 1710.
88 Hansen AP, Johansen K. Diurnal patterns of blood glucose, serum free fatty acids, insulin, glucagon and growth hormone
in normals and juvenile diabetics. Diabetologia 1970; 6: 27–33.
89 Merimee TJ, Gardner DF, Zapf J, Froesch ER. Effect of glycemic control on serum insulin-like growth factors in diabetes
mellitus. Diabetes 1984; 33: 790–3.
90 Amiel SA, Sherwin RS, Hintz RL, Gertner JM, Press CM, Tamborlane WV. Effect of diabetes and its control on insulin-like
growth factors in the young subject with type I diabetes. Diabetes 1984; 33: 1175–9.
91 Tan K, Baxter RC. Serum insulin-like growth factor I levels in adult diabetic patients: the effect of age.
J Clin Endocrinol Metab 1986; 63: 651–5.
92 Jehle PM, Jehle DR, Mohan S, Böhm BO. Serum levels of insulin-like growth factor system components and relationship
to bone metabolism in Type 1 and Type 2 diabetes mellitus patients. J Endocrinol 1998; 159: 297–306.
chapter 1
26 27
62 Catargi B, Meyer L, Melki V, Renard E, Jeandidier N. Comparison of blood glucose stability and HbA1C between implan-
table insulin pumps using U400 HOE 21PH insulin and external pumps using lispro in type 1 diabetic patients:
a pilot study. Diabetes Metab 2002; 28: 133–7.
63 Cox DJ, Kovatchev BP, Julian DM, et al. Frequency of severe hypoglycemia in insulin-dependent diabetes mellitus can
be predicted from self-monitoring blood glucose data. J Clin Endocrinol Metab 1994; 79: 1659–62.
64 Kilpatrick ES, Rigby AS, Goode K, Atkin SL. Relating mean blood glucose and glucose variability to the risk of multiple
episodes of hypoglycaemia in type 1 diabetes. Diabetologia 2007; 50: 2553–61.
65 Logtenberg SJJ, van Ballegooie E, Israêl-Bultman H, van Linde A, Bilo HJG. Glycaemic control, health status and
treatment satisfaction with continuous intraperitoneal insulin infusion. Neth J Med 2007; 65: 65–70.
66 Renard E, Apostol D, Lauton D, Boulet F, Bringer J. Quality of life in diabetic patients treated by insulinpumps.
QoL newsletter 2002; : 11–3.
67 DeVries JH, Eskes SA, Snoek FJ, et al. Continuous intraperitoneal insulin infusion in patients with ‘brittle’ diabetes:
favourable effects on glycaemic control and hospital stay. Diabet Med 2002; 19: 496–501.
68 Frystyk J. Free insulin-like growth factors -- measurements and relationships to growth hormone secretion and glucose
homeostasis. Growth Horm IGF Res 2004; 14: 337–75.
69 LeRoith D, Yakar S. Mechanisms of disease: metabolic effects of growth hormone and insulin-like growth factor 1.
Nat Clin Pract Endocrinol Metab 2007; 3: 302–10.
70 Kim JJ, Accili D. Signalling through IGF-I and insulin receptors: where is the specificity? Growth Horm IGF Res 2002; 12: 84–90.
71 Leung KC, Doyle N, Ballesteros M, Waters MJ, Ho KK. Insulin regulation of human hepatic growth hormone receptors:
divergent effects on biosynthesis and surface translocation. J Clin Endocrinol Metab 2000; 85: 4712–20.
72 Brismar K, Fernqvist-Forbes E, Wahren J, Hall K. Effect of insulin on the hepatic production of insulin-like growth factor-
binding protein-1 (IGFBP-1), IGFBP-3, and IGF-I in insulin-dependent diabetes. J Clin Endocrinol Metab 1994; 79: 872–8.
73 Bereket A, Lang CH, Wilson TA. Alterations in the growth hormone-insulin-like growth factor axis in insulin dependent
diabetes mellitus. Horm Metab Res 1999; 31: 172–81.
74 Arnqvist HJ. The role of IGF-system in vascular insulin resistance. Horm Metab Res 2008; 40: 588–92.
75 Clemmons DR. Modifying IGF1 activity: an approach to treat endocrine disorders, atherosclerosis and cancer.
Nat Rev Drug Discov 2007; 6: 821–33.
76 Ekman B, Nyström F, Arnqvist HJ. Circulating IGF-I concentrations are low and not correlated to glycaemic control in
adults with type 1 diabetes. Eur J Endocrinol 2000; 143: 505–10.
77 Hedman CA, Orre-Pettersson AC, Lindström T, Arnqvist HJ. Treatment with insulin lispro changes the insulin profile but
does not affect the plasma concentrations of IGF-I and IGFBP-1 in type 1 diabetes. Clin Endocrinol (Oxf) 2001; 55: 107–12.
78 Hedman CA, Frystyk J, Lindström T, et al. Residual beta-cell function more than glycemic control determines abnormal-
ities of the insulin-like growth factor system in type 1 diabetes. J Clin Endocrinol Metab 2004; 89: 6305–9.
79 Hanaire-Broutin H, Sallerin-Caute B, Poncet MF, et al. Insulin therapy and GH-IGF-I axis disorders in diabetes:
impact of glycaemic control and hepatic insulinization. Diabetes Metab 1996; 22: 245–50.
80 Shishko PI, Dreval AV, Abugova IA, Zajarny IU, Goncharov VC. Insulin-like growth factors and binding proteins in
patients with recent-onset type 1 (insulin-dependent) diabetes mellitus: influence of diabetes control and intraportal
insulin infusion. Diabetes Res Clin Pract 1994; 25: 1–12.
81 Hanaire-Broutin H, Sallerin-Caute B, Poncet MF, et al. Effect of intraperitoneal insulin delivery on growth hormone
binding protein, insulin-like growth factor (IGF)-I, and IGF-binding protein-3 in IDDM. Diabetologia 1996; 39: 1498–504.
82 Hedman CA, Frystyk J, Lindström T, Oskarsson P, Arnqvist HJ. Intraperitoneal insulin delivery to patients with
type 1 diabetes results in higher serum IGF-I bioactivity than continuous subcutaneous insulin infusion.
Clin Endocrinol (Oxf) 2013. doi:10.1111/cen.12296.
83 Haveman JW, Logtenberg SJJ, Kleefstra N, Groenier KH, Bilo HJG, Blomme AM. Surgical aspects and complications of
continuous intraperitoneal insulin infusion with an implantable pump. Langenbecks Arch Surg 2010; 395: 65–71.
introduction
84 Logtenberg SJ, Kleefstra N, Houweling ST, Groenier KH, Gans RO, Bilo HJ. Health-related quality of life, treatment
satisfaction, and costs associated with intraperitoneal versus subcutaneous insulin administration in type 1 diabetes:
a randomized controlled trial. Diabetes Care 2010; 33: 1169–72.
85 Riveline JP, Vantyghem MC, Fermon C, et al. Subcutaneous insulin resistance successfully circumvented on long term
by peritoneal insulin delivery from an implantable pump in four diabetic patients. Diabetes Metab 2005; 31: 496–8.
86 Jeandidier N, Selam JL, Renard E, et al. Decreased severe hypoglycemia frequency during intraperitoneal insulin
infusion using programmable implantable pumps. Evadiac Study Group. Diabetes Care 1996; 19: 780.
87 Baillot-Rudoni S, Apostol D, Vaillant G, Brun J-M, Renard E, EVADIAC Study Group. Implantable pump therapy restores
metabolic control and quality of life in type 1 diabetic patients with Buschke’s nonsystemic scleroderma.
Diabetes Care 2006; 29: 1710.
88 Hansen AP, Johansen K. Diurnal patterns of blood glucose, serum free fatty acids, insulin, glucagon and growth hormone
in normals and juvenile diabetics. Diabetologia 1970; 6: 27–33.
89 Merimee TJ, Gardner DF, Zapf J, Froesch ER. Effect of glycemic control on serum insulin-like growth factors in diabetes
mellitus. Diabetes 1984; 33: 790–3.
90 Amiel SA, Sherwin RS, Hintz RL, Gertner JM, Press CM, Tamborlane WV. Effect of diabetes and its control on insulin-like
growth factors in the young subject with type I diabetes. Diabetes 1984; 33: 1175–9.
91 Tan K, Baxter RC. Serum insulin-like growth factor I levels in adult diabetic patients: the effect of age.
J Clin Endocrinol Metab 1986; 63: 651–5.
92 Jehle PM, Jehle DR, Mohan S, Böhm BO. Serum levels of insulin-like growth factor system components and relationship
to bone metabolism in Type 1 and Type 2 diabetes mellitus patients. J Endocrinol 1998; 159: 297–306.
chapter 1
28 29
Complications of continuous intraperitoneal insulin infusion
with an implantable pump in type 1 diabetes
chapter 2
part i
Complications of CIPII therapy using an implantable pump
28 29
Complications of continuous intraperitoneal insulin infusion
with an implantable pump in type 1 diabetes
chapter 2
part i
Complications of CIPII therapy using an implantable pump
30 31
Van Dijk PR, Logtenberg SJ, Groenier KH, Haveman JW,
Kleefstra N, Bilo HJ.
Complications of continuous intraperitoneal insulin infusion
with an implantable pump. World J Diabetes 2012; 3: 142-8.
chapter 2 Abstract
introductionContinuous intraperitoneal insulin infusion (CIPII) with an implantable pump is a last-resort
treatment option for patients with type 1 diabetes (T1DM). In order to monitor the course and
to gain more detailed insight in the complications, we performed a follow-up study.
patients and methods A retrospective, longitudinal observational cohort study in patients with T1DM that started
CIPII between January 1st 2000 and June 1st 2011 was performed. Outcomes were defined
as operation free period (OFP), rate and type of complications. Comparisons were made
between patients starting CIPII from 2000 and 2007 and from 2007 onwards.
results In 56 patients, 70 complications occurred during 283 patient years. Catheter occlusion (33%),
pump dysfunction (17%), pain at the pump site (16%) and infections (10%) were the most
frequent complications. This resulted in a median OFP of 4.5 years (95% confidence interval
4.1, 4.8) without a difference between the time periods. Fifty re-operations were performed
due to complications, one per 5.6 patient years, with a decrease in pump dysfunction
(from 4.9 to 1.8 events per 100 patient years, p=0.04) and pump explantations (from 6.6 to
3.5 events per 100 patient years, p=0.02) after 2007. In total, there were 69 hospital re-
admissions, with a median duration of 6 days. No CIPII related mortality was reported.
conclusionsA significant decrease in pump dysfunction and explantation was seen after 2007 compared
to the period 2000-2007. The OFP during the last decade is stable. No CIPII related mortality
was reported. CIPII remains a safe treatment modality for specific patient groups
published as
Complications of con-tinuous intraperitoneal insulin infusion with an implantable pump in type 1 diabetes
chapter 2part i
30 31
Van Dijk PR, Logtenberg SJ, Groenier KH, Haveman JW,
Kleefstra N, Bilo HJ.
Complications of continuous intraperitoneal insulin infusion
with an implantable pump. World J Diabetes 2012; 3: 142-8.
chapter 2 Abstract
introductionContinuous intraperitoneal insulin infusion (CIPII) with an implantable pump is a last-resort
treatment option for patients with type 1 diabetes (T1DM). In order to monitor the course and
to gain more detailed insight in the complications, we performed a follow-up study.
patients and methods A retrospective, longitudinal observational cohort study in patients with T1DM that started
CIPII between January 1st 2000 and June 1st 2011 was performed. Outcomes were defined
as operation free period (OFP), rate and type of complications. Comparisons were made
between patients starting CIPII from 2000 and 2007 and from 2007 onwards.
results In 56 patients, 70 complications occurred during 283 patient years. Catheter occlusion (33%),
pump dysfunction (17%), pain at the pump site (16%) and infections (10%) were the most
frequent complications. This resulted in a median OFP of 4.5 years (95% confidence interval
4.1, 4.8) without a difference between the time periods. Fifty re-operations were performed
due to complications, one per 5.6 patient years, with a decrease in pump dysfunction
(from 4.9 to 1.8 events per 100 patient years, p=0.04) and pump explantations (from 6.6 to
3.5 events per 100 patient years, p=0.02) after 2007. In total, there were 69 hospital re-
admissions, with a median duration of 6 days. No CIPII related mortality was reported.
conclusionsA significant decrease in pump dysfunction and explantation was seen after 2007 compared
to the period 2000-2007. The OFP during the last decade is stable. No CIPII related mortality
was reported. CIPII remains a safe treatment modality for specific patient groups
published as
Complications of con-tinuous intraperitoneal insulin infusion with an implantable pump in type 1 diabetes
chapter 2part i
32 33
Introduction
Continuous intraperitoneal insulin infusion (CIPII) with an implantable pump is a treatment
option for patients with diabetes since the 1980s. Nowadays this treatment modality is
mainly used in patients with so called ’brittle diabetes’, i.e. failure to reach adequate glycaemic
control despite intensive insulin therapy with multiple daily injections (MDI) or continuous
subcutaneous insulin infusion (CSII) and/or having frequent hypoglycaemic episodes, or
subcutaneous insulin resistance 1,2.
Although the long-term feasibility and positive metabolic benefits of CIPII are established
by several clinical studies, reports on the drawbacks of CIPII are relatively scarce 3,4. Obviously,
complications interfere with treatment outcome with respect to glycaemic control, costs and,
most importantly, quality of life 5,6. Furthermore, technical problems prevented widespread
use of CIPII in the past, but modifications of both the catheter attached to the pump and the
insulin have reduced the incidence of insulin aggregates blocking the insulin delivery; one of
the major problems some years ago 7.
Haveman et al. underlined this development by studying the complications of CIPII in patients
that started with CIPII before 2007 in our hospital (Isala, Zwolle, the Netherlands) 8. After
introduction of a new battery and a change in insulin solution in 2000, the operation free
period (OFP) was estimated to increase from 21 to 78 months. The incidence of complications
such as pump site infections and catheter related problems decreased, which is in accordance
with other studies on CIPII 5,6. However, ongoing monitoring is necessary to observe the
course of this decrease. Moreover, to gather accurate results on what the OFP really is after the
changes in 2000, as only limited number of patients at the time of the previous evaluation
(follow-up until 2007) had reached a 78 month follow-up. Thus it is essential to extend our
former study including the period from 2007 onwards.
Aim of the current study is to describe the complications of CIPII in patients with type 1
diabetes mellitus (T1DM) in the period from 2000 until 2011 in which we will also study in
more detail the origin and consequences of both pump- and/or catheter related problems and
complications.
Patients and methods
patientsIn the Netherlands, the following indications for CIPII have been formulated: subcutaneous
insulin resistance, brittle diabetes, hypoglycaemia unawareness, delayed insulin absorption,
allergies, lipohypertrophy and/or lipoatrophy, very lean subjects, needle phobia, severe
skin scarring or chronic dermatological problems 9. Patients were selected for CIPII after
consultation with diabetes professionals well acquainted with CIPII, with as a minimum
the participation of an internist and a diabetes specialist nurse in the decision making.
Implantation was always combined with intensive education and, on indication, assessment
by a psychologist.
All patients with T1DM who were treated with CIPII in the period of January 1st 2000 until
June 1st 2011 were included in the current analysis. All of these patients were referred to and
treated in the Isala. For all patients, detailed clinical data regarding surgical placement of the
pump, short- and long-term complications and consequences were collected retrospectively by
reviewing hospital charts, operation- and microbiology reports. Data were collected by use of
standardized case record forms.
proceduresInsulin pump, implantation and post-operative treatment and refill procedures have been
described previously 8. In brief, MiniMed MIP model 2007 CIPII devices (Medtronic-MiniMed,
Northridge, CA, USA) were implanted in our clinic from 2000 onwards. This model has a
reservoir which can contain 15 ml of special solution of U400 insulin and has a battery with 7
years longevity.
An outpatient rinse procedure with NaOH was performed every 9 months or in case of
insulin underdelivery. Insulin underdelivery is present when after the pump reservoir is
totally emptied, the ratio between programmed and actually infused insulin volume upon
programmed insulin, denominated as % error, was calculated. If the % error was higher than
20, or a clinically significant difference between the % error calculated at previous refill was
found, a rinse procedure would be performed. In addition, inspection of the patient-pump-
communicator for hardware or electronic failure was performed. If these procedures failed
to restore normal insulin infusion a catheter flushing and/or catheter x-ray investigation was
also performed. In case of signs of intractable occlusion, despite all of these actions, surgical
examination of the catheter to discover possible blockages with a post-surgical rinse of the
pump was deemed necessary.
chapter 2part i
32 33
Introduction
Continuous intraperitoneal insulin infusion (CIPII) with an implantable pump is a treatment
option for patients with diabetes since the 1980s. Nowadays this treatment modality is
mainly used in patients with so called ’brittle diabetes’, i.e. failure to reach adequate glycaemic
control despite intensive insulin therapy with multiple daily injections (MDI) or continuous
subcutaneous insulin infusion (CSII) and/or having frequent hypoglycaemic episodes, or
subcutaneous insulin resistance 1,2.
Although the long-term feasibility and positive metabolic benefits of CIPII are established
by several clinical studies, reports on the drawbacks of CIPII are relatively scarce 3,4. Obviously,
complications interfere with treatment outcome with respect to glycaemic control, costs and,
most importantly, quality of life 5,6. Furthermore, technical problems prevented widespread
use of CIPII in the past, but modifications of both the catheter attached to the pump and the
insulin have reduced the incidence of insulin aggregates blocking the insulin delivery; one of
the major problems some years ago 7.
Haveman et al. underlined this development by studying the complications of CIPII in patients
that started with CIPII before 2007 in our hospital (Isala, Zwolle, the Netherlands) 8. After
introduction of a new battery and a change in insulin solution in 2000, the operation free
period (OFP) was estimated to increase from 21 to 78 months. The incidence of complications
such as pump site infections and catheter related problems decreased, which is in accordance
with other studies on CIPII 5,6. However, ongoing monitoring is necessary to observe the
course of this decrease. Moreover, to gather accurate results on what the OFP really is after the
changes in 2000, as only limited number of patients at the time of the previous evaluation
(follow-up until 2007) had reached a 78 month follow-up. Thus it is essential to extend our
former study including the period from 2007 onwards.
Aim of the current study is to describe the complications of CIPII in patients with type 1
diabetes mellitus (T1DM) in the period from 2000 until 2011 in which we will also study in
more detail the origin and consequences of both pump- and/or catheter related problems and
complications.
Patients and methods
patientsIn the Netherlands, the following indications for CIPII have been formulated: subcutaneous
insulin resistance, brittle diabetes, hypoglycaemia unawareness, delayed insulin absorption,
allergies, lipohypertrophy and/or lipoatrophy, very lean subjects, needle phobia, severe
skin scarring or chronic dermatological problems 9. Patients were selected for CIPII after
consultation with diabetes professionals well acquainted with CIPII, with as a minimum
the participation of an internist and a diabetes specialist nurse in the decision making.
Implantation was always combined with intensive education and, on indication, assessment
by a psychologist.
All patients with T1DM who were treated with CIPII in the period of January 1st 2000 until
June 1st 2011 were included in the current analysis. All of these patients were referred to and
treated in the Isala. For all patients, detailed clinical data regarding surgical placement of the
pump, short- and long-term complications and consequences were collected retrospectively by
reviewing hospital charts, operation- and microbiology reports. Data were collected by use of
standardized case record forms.
proceduresInsulin pump, implantation and post-operative treatment and refill procedures have been
described previously 8. In brief, MiniMed MIP model 2007 CIPII devices (Medtronic-MiniMed,
Northridge, CA, USA) were implanted in our clinic from 2000 onwards. This model has a
reservoir which can contain 15 ml of special solution of U400 insulin and has a battery with 7
years longevity.
An outpatient rinse procedure with NaOH was performed every 9 months or in case of
insulin underdelivery. Insulin underdelivery is present when after the pump reservoir is
totally emptied, the ratio between programmed and actually infused insulin volume upon
programmed insulin, denominated as % error, was calculated. If the % error was higher than
20, or a clinically significant difference between the % error calculated at previous refill was
found, a rinse procedure would be performed. In addition, inspection of the patient-pump-
communicator for hardware or electronic failure was performed. If these procedures failed
to restore normal insulin infusion a catheter flushing and/or catheter x-ray investigation was
also performed. In case of signs of intractable occlusion, despite all of these actions, surgical
examination of the catheter to discover possible blockages with a post-surgical rinse of the
pump was deemed necessary.
chapter 2part i
34 35
complicationsPump site infection was defined as a culture proven infection in the subcutaneous pocket of
the insulin pump. Prolonged device related pain was defined as pain at the pump site which
lasted for more than 6 weeks after surgery and necessitated use of analgesics. Cutaneous
erosion of the skin was defined as redness with signs of (imminent) perforation of the overlying
skin at the pump site. Post-operative haematoma was defined as a swelling at the pump
site caused by bleeding. Pump dislocation was defined as migration or rotation of the pump
relative to the initial place of implantation. Catheter occlusion was defined as blockage of the
catheter by fibrin clots or an intrinsic catheter defect. Encapsulation in the peritoneal cavity
was defined as encapsulation of the catheter tip, which is positioned in the peritoneal cavity,
by the omentum as diagnosed by catheter x-ray investigation or during surgical inspection.
Hardware problems were defined as demonstrated hardware failure of the pump. Premature
battery end of life was defined as battery end of life within 3.5 years of implantation. Pump
dysfunction was defined as acute or chronic dysfunction of the pump after excluding of other
causes e.g. battery end of life or hardware failure.
statistical analysisAll statistical analysis were performed with SPSS software (IBM SPSS Statistics for Windows,
Version 20.0. Armonk, NY: IBM Corp.). Descriptive statistics include number (percentage),
mean (standard deviation (SD)) and median (interquartile range [IQR]). Data were compared
with the Fisher’s exact test in case of categorical data. In case of continuous data, Student’s
t-test or Mann-Whitney U test were used if the data was distributed normally or skewed,
respectively. Q-Q plots and histograms were used to determine if the tested variable had a
normal distribution or not. The OFP was calculated as the time from initial implantation to the
date of first documented re-operation. If patients had not experienced an operation, they were
censored at the date of last follow-up or time of death. Kaplan-Meier curves were constructed
to visualize the OFP. In order to further analyse the course of the complications, subanalyses
were made between patients starting CIPII from 2000 and 2007, the end of the previous study,
and from 2007 onwards. Differences in time until occurrence of complications and the OFP
rates were assessed for statistical significance using the log-rank test. A Cox regression analysis
was performed to study the influence of possible confounders (age, sex, body mass index
(BMI)), duration of diabetes) on the OFP. A (two-sided) p-value of less than 0.05 was considered
statistically significant.
Results
patients and implantation proceduresA total of 57 patients with T1DM were treated with CIPII. One patient with self-induced
complications was excluded from analysis; the remaining 56 patients are subject of this study.
Patient characteristics are depicted in Table 1. Two hundred eighty-three patient years of
follow-up were observed, with a median duration of 4.7 [3.7, 7.3] years. In total, 80 pumps were
implanted; 20 (35.7%) patients had a second pump and 4 (7.1%) patients had a third pump
implanted.
operation free periodAfter starting CIPII, 33 patients underwent re-operation; 6 due to expected battery end of life,
24 due to complications and 3 due to other reasons. As presented in Figure 1, the median OFP
between initial implantation and the first re-operation for all patients was 4.5 years (95%
confidence interval (CI) 4.1, 4.8). After excluding operations for pump replacement for expected
battery end of life or other reasons (n=9) the median OFP was 4.5 years (95% CI 3.9, 5.0).
complicationsA total of 70 complications occurred during the follow-up; see Table 2. Catheter occlusion
(32.9%), pump dysfunction (17.1%) and pain at the pump site (15.7%) were the most frequent
chapter 2part i
All patients Implantation period 2000 - 2011 (n=56)
2000 - 2007 (n=37)
2007 - 2011 (n=19)
Age (years) 37.6 (14.5) 38.0 (14.4) 36.6 (15.1)
Female sex (n) 38 (68) 28 (76) 10 (53)
Smokers (n) 12 (21) 7 (19) 5 (26)
Previous abdominal operation (n) 9 (16) 7 (19) 2 (11)
BMI (kg/m2) 25.4 (4.4) 26.3 (4.2) 23.7 (4.3)
Duration of diabetes (years) 16.7 [9.7, 26.3] 15.9 [9.8, 26.8] 19.1 [9.6, 26.3]
Retinopathy (n) 13 (23) 9 (24) 4 (21)
Neuropathy (n) 17 (30) 12 (32) 5 (26)
Nephropathy (n) 4 (7) 3 (8) 1 (5)
Baseline characteristics of patients starting CIPII.table 1
Data are presented as n (%), mean (SD) or median [IQR]. Abbreviations: BMI, body mass index; CIPII, continuous intraperitoneal insulin infusion.
34 35
complicationsPump site infection was defined as a culture proven infection in the subcutaneous pocket of
the insulin pump. Prolonged device related pain was defined as pain at the pump site which
lasted for more than 6 weeks after surgery and necessitated use of analgesics. Cutaneous
erosion of the skin was defined as redness with signs of (imminent) perforation of the overlying
skin at the pump site. Post-operative haematoma was defined as a swelling at the pump
site caused by bleeding. Pump dislocation was defined as migration or rotation of the pump
relative to the initial place of implantation. Catheter occlusion was defined as blockage of the
catheter by fibrin clots or an intrinsic catheter defect. Encapsulation in the peritoneal cavity
was defined as encapsulation of the catheter tip, which is positioned in the peritoneal cavity,
by the omentum as diagnosed by catheter x-ray investigation or during surgical inspection.
Hardware problems were defined as demonstrated hardware failure of the pump. Premature
battery end of life was defined as battery end of life within 3.5 years of implantation. Pump
dysfunction was defined as acute or chronic dysfunction of the pump after excluding of other
causes e.g. battery end of life or hardware failure.
statistical analysisAll statistical analysis were performed with SPSS software (IBM SPSS Statistics for Windows,
Version 20.0. Armonk, NY: IBM Corp.). Descriptive statistics include number (percentage),
mean (standard deviation (SD)) and median (interquartile range [IQR]). Data were compared
with the Fisher’s exact test in case of categorical data. In case of continuous data, Student’s
t-test or Mann-Whitney U test were used if the data was distributed normally or skewed,
respectively. Q-Q plots and histograms were used to determine if the tested variable had a
normal distribution or not. The OFP was calculated as the time from initial implantation to the
date of first documented re-operation. If patients had not experienced an operation, they were
censored at the date of last follow-up or time of death. Kaplan-Meier curves were constructed
to visualize the OFP. In order to further analyse the course of the complications, subanalyses
were made between patients starting CIPII from 2000 and 2007, the end of the previous study,
and from 2007 onwards. Differences in time until occurrence of complications and the OFP
rates were assessed for statistical significance using the log-rank test. A Cox regression analysis
was performed to study the influence of possible confounders (age, sex, body mass index
(BMI)), duration of diabetes) on the OFP. A (two-sided) p-value of less than 0.05 was considered
statistically significant.
Results
patients and implantation proceduresA total of 57 patients with T1DM were treated with CIPII. One patient with self-induced
complications was excluded from analysis; the remaining 56 patients are subject of this study.
Patient characteristics are depicted in Table 1. Two hundred eighty-three patient years of
follow-up were observed, with a median duration of 4.7 [3.7, 7.3] years. In total, 80 pumps were
implanted; 20 (35.7%) patients had a second pump and 4 (7.1%) patients had a third pump
implanted.
operation free periodAfter starting CIPII, 33 patients underwent re-operation; 6 due to expected battery end of life,
24 due to complications and 3 due to other reasons. As presented in Figure 1, the median OFP
between initial implantation and the first re-operation for all patients was 4.5 years (95%
confidence interval (CI) 4.1, 4.8). After excluding operations for pump replacement for expected
battery end of life or other reasons (n=9) the median OFP was 4.5 years (95% CI 3.9, 5.0).
complicationsA total of 70 complications occurred during the follow-up; see Table 2. Catheter occlusion
(32.9%), pump dysfunction (17.1%) and pain at the pump site (15.7%) were the most frequent
chapter 2part i
All patients Implantation period 2000 - 2011 (n=56)
2000 - 2007 (n=37)
2007 - 2011 (n=19)
Age (years) 37.6 (14.5) 38.0 (14.4) 36.6 (15.1)
Female sex (n) 38 (68) 28 (76) 10 (53)
Smokers (n) 12 (21) 7 (19) 5 (26)
Previous abdominal operation (n) 9 (16) 7 (19) 2 (11)
BMI (kg/m2) 25.4 (4.4) 26.3 (4.2) 23.7 (4.3)
Duration of diabetes (years) 16.7 [9.7, 26.3] 15.9 [9.8, 26.8] 19.1 [9.6, 26.3]
Retinopathy (n) 13 (23) 9 (24) 4 (21)
Neuropathy (n) 17 (30) 12 (32) 5 (26)
Nephropathy (n) 4 (7) 3 (8) 1 (5)
Baseline characteristics of patients starting CIPII.table 1
Data are presented as n (%), mean (SD) or median [IQR]. Abbreviations: BMI, body mass index; CIPII, continuous intraperitoneal insulin infusion.
36 37
chapter 2part i
Complications of CIPII during follow-up.
Re-operations due to complications of CIPII during follow-up.
table 2
table 3
Abbreviations: BMI, body mass index; CIPII, continuous intraperitoneal insulin infusion; PY, patient years.* p=0.04.
Abbreviations: BMI, body mass index; CIPII, continuous intraperitoneal insulin infusion; PY, patient years.* p=0.02.
Time between initial implantation and first re-operation, only for complications.
All patients Implantation period 2000 - 2011 2000 - 2007 2007 - 2011 (n=56) (n=37) (n=19) n % Per 100PY n % Per 100PY n % Per 100PY
Haematoma 3 4.3 1.1 2 3.8 0.9 1 5.9 1.8 Infection 7 10.0 2.5 4 7.5 1.8 3 17.6 5.3 Pain 11 15.7 3.9 8 15.1 3.5 3 17.6 5.3 Cutaneous erosion 2 2.9 0.7 2 3.8 0.9 0 0.0 0.0 Dislocation 3 4.3 1.1 2 3.8 0.9 1 5.9 1.8 Hardware failure 0 0.0 0.0 0 0.0 0.0 0 0.0 0.0 Premature battery end of life 0 0.0 0.0 0 0.0 0.0 0 0.0 0.0
Insulin aggregate 4 5.7 1.4 4 7.5 1.8 0 0.0 0.0 Catheter occlusion 23 32.9 8.1 16 30.2 7.1 7 41.2 12.3 Encapsulation of the catheter tip 3 4.3 1.1 3 5.7 1.3 0 0.0 0.0
Peritonitis 1 1.4 0.4 1 1.9 0.4 0 0.0 0.0 Pump dysfunction 12 17.1 4.2 11* 20.8 4.9 1* 5.9 1.8 Other 1 1.4 0.4 0 0.0 0.0 1 5.9 1.8 All 70 100.0 24.8 53 100.0 23.5 17 100.0 29.9
All patients Implantation date 2000 - 2011 2000 - 2007 2007 - 2011 (n=56) (n=37) (n=19) n % Per 100PY n % Per 100PY n % Per 100PY
Catheter inspection 2 4.0 0.7 2 5.3 0.9 0 0.0 0.0 Catheter replacement 13 26.0 4.6 8 21.1 3.5 5 41.7 8.8 Explantation of pump and catheter
17 34.0 6.0 15* 39.5 6.6 2* 16.7 3.5
Repositioning of pump 2 4.0 0.7 2 5.3 0.9 0 0.0 0.0 Fixation of pump 2 4.0 0.7 1 2.6 0.4 1 8.3 1.8 Cutaneous problem 0 0.0 0.0 0 0.0 0.0 0 0.0 0.0 Intra-abdominal problem
1 2.0 0.4 1 2.6 0.4 0 0.0 0.0
Remove clot at tip of catheter/ Flush catheter
7 14.0 2.5 4 10.5 1.8 3 25.0 5.3
Haematoma 1 2.0 0.4 1 2.6 0.4 0 0.0 0.0 Reposition of catheter 3 6.0 1.1 3 7.9 1.3 0 0.0 0.0 Infection 2 4.0 0.7 1 2.6 1.2 1 8.3 1.8 All 50 100.0 17.7 38 100.0 44.3 12 100.0 21.1
figure 2
Time between initial implantation and first re-operation, for all reasons.figure 1
The dotted blue line represents all patients. The red line and green line represents the patients who started CIPII between 2000 and 2007 and between 2007 and 2011, respectively (log-rank test for differences p=0.80). Abbreviations: CIPII, continuous intraperitoneal insulin infusion.
0 1 2 3 4 5 6 7 8
complications. Fifty-seven complications occurred with the first implanted pump in situ, 11 with
the second and 2 with the third. Twenty-one patients did not experience any complication, 15
patients experienced 1 complication, 11 patients 2 complications, 7 patients 3, 1 patient 4 and
1 patient 8 complications. The latter patient had recurrent infections and peritonitis, after a
catheter replacement procedure. The median time from implantation of the first pump until
occurrence of the first complication (excluding battery end of life) was 3.6 years (95% CI 2.2, 5.0).
consequences of complicationsDue to complications, 50 re-operations were performed, one per 5.6 year of follow-up;
see Table 3. Explantation of the pump and catheter (34.0%, 6.0 per 100 patient years) and
catheter replacement (26.0%, 4.6 per 100 patient years) were the most frequently performed
The dotted blue line represents all patients. The red line and green line represents the patients who started CIPII between 2000 and 2007 and between 2007 and 2011, respectively (log-rank test for differences p=0.72). Abbreviations: CIPII, continuous intraperitoneal insulin infusion.
36 37
chapter 2part i
Complications of CIPII during follow-up.
Re-operations due to complications of CIPII during follow-up.
table 2
table 3
Abbreviations: BMI, body mass index; CIPII, continuous intraperitoneal insulin infusion; PY, patient years.* p=0.04.
Abbreviations: BMI, body mass index; CIPII, continuous intraperitoneal insulin infusion; PY, patient years.* p=0.02.
Time between initial implantation and first re-operation, only for complications.
All patients Implantation period 2000 - 2011 2000 - 2007 2007 - 2011 (n=56) (n=37) (n=19) n % Per 100PY n % Per 100PY n % Per 100PY
Haematoma 3 4.3 1.1 2 3.8 0.9 1 5.9 1.8 Infection 7 10.0 2.5 4 7.5 1.8 3 17.6 5.3 Pain 11 15.7 3.9 8 15.1 3.5 3 17.6 5.3 Cutaneous erosion 2 2.9 0.7 2 3.8 0.9 0 0.0 0.0 Dislocation 3 4.3 1.1 2 3.8 0.9 1 5.9 1.8 Hardware failure 0 0.0 0.0 0 0.0 0.0 0 0.0 0.0 Premature battery end of life 0 0.0 0.0 0 0.0 0.0 0 0.0 0.0
Insulin aggregate 4 5.7 1.4 4 7.5 1.8 0 0.0 0.0 Catheter occlusion 23 32.9 8.1 16 30.2 7.1 7 41.2 12.3 Encapsulation of the catheter tip 3 4.3 1.1 3 5.7 1.3 0 0.0 0.0
Peritonitis 1 1.4 0.4 1 1.9 0.4 0 0.0 0.0 Pump dysfunction 12 17.1 4.2 11* 20.8 4.9 1* 5.9 1.8 Other 1 1.4 0.4 0 0.0 0.0 1 5.9 1.8 All 70 100.0 24.8 53 100.0 23.5 17 100.0 29.9
All patients Implantation date 2000 - 2011 2000 - 2007 2007 - 2011 (n=56) (n=37) (n=19) n % Per 100PY n % Per 100PY n % Per 100PY
Catheter inspection 2 4.0 0.7 2 5.3 0.9 0 0.0 0.0 Catheter replacement 13 26.0 4.6 8 21.1 3.5 5 41.7 8.8 Explantation of pump and catheter
17 34.0 6.0 15* 39.5 6.6 2* 16.7 3.5
Repositioning of pump 2 4.0 0.7 2 5.3 0.9 0 0.0 0.0 Fixation of pump 2 4.0 0.7 1 2.6 0.4 1 8.3 1.8 Cutaneous problem 0 0.0 0.0 0 0.0 0.0 0 0.0 0.0 Intra-abdominal problem
1 2.0 0.4 1 2.6 0.4 0 0.0 0.0
Remove clot at tip of catheter/ Flush catheter
7 14.0 2.5 4 10.5 1.8 3 25.0 5.3
Haematoma 1 2.0 0.4 1 2.6 0.4 0 0.0 0.0 Reposition of catheter 3 6.0 1.1 3 7.9 1.3 0 0.0 0.0 Infection 2 4.0 0.7 1 2.6 1.2 1 8.3 1.8 All 50 100.0 17.7 38 100.0 44.3 12 100.0 21.1
figure 2
Time between initial implantation and first re-operation, for all reasons.figure 1
The dotted blue line represents all patients. The red line and green line represents the patients who started CIPII between 2000 and 2007 and between 2007 and 2011, respectively (log-rank test for differences p=0.80). Abbreviations: CIPII, continuous intraperitoneal insulin infusion.
0 1 2 3 4 5 6 7 8
complications. Fifty-seven complications occurred with the first implanted pump in situ, 11 with
the second and 2 with the third. Twenty-one patients did not experience any complication, 15
patients experienced 1 complication, 11 patients 2 complications, 7 patients 3, 1 patient 4 and
1 patient 8 complications. The latter patient had recurrent infections and peritonitis, after a
catheter replacement procedure. The median time from implantation of the first pump until
occurrence of the first complication (excluding battery end of life) was 3.6 years (95% CI 2.2, 5.0).
consequences of complicationsDue to complications, 50 re-operations were performed, one per 5.6 year of follow-up;
see Table 3. Explantation of the pump and catheter (34.0%, 6.0 per 100 patient years) and
catheter replacement (26.0%, 4.6 per 100 patient years) were the most frequently performed
The dotted blue line represents all patients. The red line and green line represents the patients who started CIPII between 2000 and 2007 and between 2007 and 2011, respectively (log-rank test for differences p=0.72). Abbreviations: CIPII, continuous intraperitoneal insulin infusion.
38 39
re-operations. Nine episodes of ketoacidosis occurred during follow-up, in 8 due to pump
dysfunction and 1 due to catheter occlusion. Sixty-nine episodes of hospital re-admissions were
caused by complications. The median duration of re-admission was 6 [3.0, 12.8] days.
course of complicationsBetween 2000 and 2007, 37 (median follow-up 5.3 [4.7, 6.7] years) patients received a pump
and 19 (median follow-up 3.7 [1.4, 4.3] years) patients received a pump between 2007 and 2011.
The clinical characteristics of patients in the two different timeframes were comparable and
also showed no differences in median OFP (log-rank: p=0.80), even when excluding operations
for expected battery end of life and other reasons than complications (log-rank: p= 0.72); see
Figures 1 and 2. The number of pump dysfunctions among patients who started CIPII after
2007 was significant lower compared to the group of patients who started CIPII before 2007
(p=0.04); see Table 2. As shown in Table 3, from 2007 onwards there were significant less
re-operations for pump and catheter explantation due to complications (p=0.02). The Cox
regression analysis showed a non-significant hazard ratio of 1.12 (95% CI 0.46, 2.75, p=0.52)
for patients implanted after 2007 compared to those who were implanted between 2000 and
2007. None of the confounders had a significant relation with time to first re-intervention.
mortality and cessation of CIPII therapy During the follow-up period, one patient died due to heart failure whilst treated with CIPII. In
5 patients, CIPII was stopped and the pump removed. In two patients the pump was removed
because of recurrent infections. In the other cases because of pain (n=1), inadequate glycaemic
control (n=1) or at own choice (n=1). The remaining 50 patients are still treated with CIPII.
Discussion
The current study describes the incidence of complications in 56 T1DM patients treated with
CIPII with an implanted insulin pump during the last decade. During 283 patient years of
follow-up, 70 complications occurred, i.e. one complication per 4.0 patient years. Catheter
occlusion (32.9%), pump dysfunction (17.1%), pain (15.7%) and infections (10.0%) were the
most frequent complications. A significant decrease in pump dysfunction and the need
of premature explantation of the pump was seen since 2007 as compared to before 2007.
There was a non-significant but potentially relevant increase in infections, catheter related
complications and re-operations since 2007, which did not affect the OFP during the last
decade, however.
The incidence of infections in the present study, 2.5 per 100 patient years, is comparable
to previous studies on CIPII and other implanted devices 5,6,8,10–13. Apparently, this rate has
increased in patients operated after 2007 to a number of 5.3 infections per 100 patient years.
However, all infections appeared in one patient. Due to combined improvements in pump
technology, insulin stability and frequent rinse procedures the high incidence of catheter
blockage (between 7.8 and 57.3 per 100 patient years) in the past has been substantially
reduced 4,14–19. In 2003, Gin et al. reported an incidence of 3.7 catheter obstructions with need
of surgical intervention, per 100 patient years 6. Though we found no difference in the course,
compared to the scarce recent literature on this topic, the incidence of catheter occlusions and
re-operation for catheter replacement (12.3 respectively 8.8 per 100 patient years) since 2007
are rather high compared to the findings of Gin et al.
Besides the number of re-operations, the impact of complications are illustrated by the
number of ketoacidosis occurrences (n=9) and the hospital re-admissions (n=69 with a
median duration of 6 days) due to complications. DeVries et al. showed that initiation of CIPII
diminishes the median duration hospital stay for patients with poorly regulated diabetes from
45 days in the year before implantation to 13 days in the year after implantation, the latter
mostly due to implantation of the pump 1. As far as we know, the present study is the first to
report on the number of hospital re-admissions due to complications. This number is needed
to strengthen future analysis of cost-effectiveness and quality of life of CIPII.
This study has limitations. First, since the follow-up of the study performed by Haveman et al.
ended at January 1st 2007 we decided to use this point in time as cut-off for our subanalyses
for the course of the complications in time 8. Although this date is arbitrary and the numbers
of patients are small, it can aid to get insight in changes of complications, positively and
negatively, specific for a timeframe, that would need attention for present care of these
patients. Second, the exact cause of catheter or pump dysfunction could not always be
retrieved; therefore the rate of e.g. insulin aggregates that have led to pump dysfunction may
be underestimated.
Conclusion
The median OFP for patients treated by CIPII with an implantable pump has been stable over
the last decade: 4.5 years. Catheter occlusion (32.9%), pump dysfunction (17.1%), pain at the
pump site (15.7%) and infections (10.0%) were the most frequent complications. There was
chapter 2part i
38 39
re-operations. Nine episodes of ketoacidosis occurred during follow-up, in 8 due to pump
dysfunction and 1 due to catheter occlusion. Sixty-nine episodes of hospital re-admissions were
caused by complications. The median duration of re-admission was 6 [3.0, 12.8] days.
course of complicationsBetween 2000 and 2007, 37 (median follow-up 5.3 [4.7, 6.7] years) patients received a pump
and 19 (median follow-up 3.7 [1.4, 4.3] years) patients received a pump between 2007 and 2011.
The clinical characteristics of patients in the two different timeframes were comparable and
also showed no differences in median OFP (log-rank: p=0.80), even when excluding operations
for expected battery end of life and other reasons than complications (log-rank: p= 0.72); see
Figures 1 and 2. The number of pump dysfunctions among patients who started CIPII after
2007 was significant lower compared to the group of patients who started CIPII before 2007
(p=0.04); see Table 2. As shown in Table 3, from 2007 onwards there were significant less
re-operations for pump and catheter explantation due to complications (p=0.02). The Cox
regression analysis showed a non-significant hazard ratio of 1.12 (95% CI 0.46, 2.75, p=0.52)
for patients implanted after 2007 compared to those who were implanted between 2000 and
2007. None of the confounders had a significant relation with time to first re-intervention.
mortality and cessation of CIPII therapy During the follow-up period, one patient died due to heart failure whilst treated with CIPII. In
5 patients, CIPII was stopped and the pump removed. In two patients the pump was removed
because of recurrent infections. In the other cases because of pain (n=1), inadequate glycaemic
control (n=1) or at own choice (n=1). The remaining 50 patients are still treated with CIPII.
Discussion
The current study describes the incidence of complications in 56 T1DM patients treated with
CIPII with an implanted insulin pump during the last decade. During 283 patient years of
follow-up, 70 complications occurred, i.e. one complication per 4.0 patient years. Catheter
occlusion (32.9%), pump dysfunction (17.1%), pain (15.7%) and infections (10.0%) were the
most frequent complications. A significant decrease in pump dysfunction and the need
of premature explantation of the pump was seen since 2007 as compared to before 2007.
There was a non-significant but potentially relevant increase in infections, catheter related
complications and re-operations since 2007, which did not affect the OFP during the last
decade, however.
The incidence of infections in the present study, 2.5 per 100 patient years, is comparable
to previous studies on CIPII and other implanted devices 5,6,8,10–13. Apparently, this rate has
increased in patients operated after 2007 to a number of 5.3 infections per 100 patient years.
However, all infections appeared in one patient. Due to combined improvements in pump
technology, insulin stability and frequent rinse procedures the high incidence of catheter
blockage (between 7.8 and 57.3 per 100 patient years) in the past has been substantially
reduced 4,14–19. In 2003, Gin et al. reported an incidence of 3.7 catheter obstructions with need
of surgical intervention, per 100 patient years 6. Though we found no difference in the course,
compared to the scarce recent literature on this topic, the incidence of catheter occlusions and
re-operation for catheter replacement (12.3 respectively 8.8 per 100 patient years) since 2007
are rather high compared to the findings of Gin et al.
Besides the number of re-operations, the impact of complications are illustrated by the
number of ketoacidosis occurrences (n=9) and the hospital re-admissions (n=69 with a
median duration of 6 days) due to complications. DeVries et al. showed that initiation of CIPII
diminishes the median duration hospital stay for patients with poorly regulated diabetes from
45 days in the year before implantation to 13 days in the year after implantation, the latter
mostly due to implantation of the pump 1. As far as we know, the present study is the first to
report on the number of hospital re-admissions due to complications. This number is needed
to strengthen future analysis of cost-effectiveness and quality of life of CIPII.
This study has limitations. First, since the follow-up of the study performed by Haveman et al.
ended at January 1st 2007 we decided to use this point in time as cut-off for our subanalyses
for the course of the complications in time 8. Although this date is arbitrary and the numbers
of patients are small, it can aid to get insight in changes of complications, positively and
negatively, specific for a timeframe, that would need attention for present care of these
patients. Second, the exact cause of catheter or pump dysfunction could not always be
retrieved; therefore the rate of e.g. insulin aggregates that have led to pump dysfunction may
be underestimated.
Conclusion
The median OFP for patients treated by CIPII with an implantable pump has been stable over
the last decade: 4.5 years. Catheter occlusion (32.9%), pump dysfunction (17.1%), pain at the
pump site (15.7%) and infections (10.0%) were the most frequent complications. There was
chapter 2part i
40 41
1 DeVries JH, Eskes SA, Snoek FJ, et al. Continuous intraperitoneal insulin infusion in patients with ‘brittle’ diabetes: favourable effects on glycaemic control and hospital stay. Diabet Med J Br Diabet Assoc 2002; 19: 496–501.2 Renard E, Schaepelynck-Bélicar P, EVADIAC Group. Implantable insulin pumps. A position statement about their clinical use. Diabetes Metab 2007; 33: 158–66.3 Logtenberg SJJ, van Ballegooie E, Israêl-Bultman H, van Linde A, Bilo HJG. Glycaemic control, health status and treatment satisfaction with continuous intraperitoneal insulin infusion. Neth J Med 2007; 65: 65–70.4 Broussolle C, Jeandidier N, Hanaire-Broutin H. French multicentre experience of implantable insulin pumps. The EVADIAC Study Group. Evaluation of Active Implants in Diabetes Society. Lancet 1994; 343: 514–5.5 Renard E, Bouteleau S, Jacques-Apostol D, et al. Insulin underdelivery from implanted pumps using peritoneal route. Determinant role of insulin pump compatibility. Diabetes Care 1996; 19: 812–7.6 Gin H, Renard E, Melki V, et al. Combined improvements in implantable pump technology and insulin stability allow safe and effective long term intraperitoneal insulin delivery in type 1 diabetic patients: the EVADIAC experience. Diabetes Metab 2003; 29: 602–7.7 Gin H, Melki V, Guerci B, Catargi B, Evaluation dans le Diabete du Traitement par Implants Actifs Study Group. Clinical evaluation of a newly designed compliant side port catheter for an insulin implantable pump: the EVADIAC experience. Evaluation dans le Diabete du Traitement par Implants Actifs. Diabetes Care 2001; 24: 175.8 Haveman JW, Logtenberg SJJ, Kleefstra N, Groenier KH, Bilo HJG, Blomme AM. Surgical aspects and complications of continuous intraperitoneal insulin infusion with an implantable pump. Langenbecks Arch Surg Dtsch Ges Für Chir 2010; 395: 65–71.9 Nederlandse Internisten Vereniging: Statement concerning indications for continuous intraperitoneal insulin infusion, 2007. 10 Bélicar P, Lassmann-Vague V. Local adverse events associated with long-term treatment by implantable insulin pumps. The French EVADIAC Study Group experience. Evaluation dans le Diabète du Traitement par Implants Actifs. Diabetes Care 1998; 21: 325–6.11 Renard E, Rostane T, Carriere C, et al. Implantable insulin pumps: infections most likely due to seeding from skin flora determine severe outcomes of pump-pocket seromas. Diabetes Metab 2001; 27: 62–5.12 Udelsman R, Chen H, Loman K, Pitt HA, Saudek CD. Implanted programmable insulin pumps: one hundred fifty-three patient years of surgical experience. Surgery 1997; 122: 1005–11.13 Darouiche RO. Treatment of infections associated with surgical implants. N Engl J Med 2004; 350: 1422–9.14 One-year trial of a remote-controlled implantable insulin infusion system in type I diabetic patients. Point Study Group. Lancet 1988; 2: 866–9.15 Saudek CD, Selam JL, Pitt HA, et al. A preliminary trial of the programmable implantable medication system for insulin delivery. N Engl J Med 1989; 321: 574–9.16 Selam JL, Micossi P, Dunn FL, Nathan DM. Clinical trial of programmable implantable insulin pump for type I diabetes. Diabetes Care 1992; 15: 877–85.17 Hanaire-Broutin H, Broussolle C, Jeandidier N, et al. Feasibility of intraperitoneal insulin therapy with programmable implantable pumps in IDDM. A multicenter study. The EVADIAC Study Group. Evaluation dans le Diabète du Traitement par Implants Actifs. Diabetes Care 1995; 18: 388–92.18 Scavini M, Galli L, Reich S, Eaton RP, Charles MA, Dunn FL. Catheter survival during long-term insulin therapy with an implanted programmable pump. The Implantable Insulin Pump Trial Study Group. Diabetes Care 1997; 20: 610–3.19 Renard E, Baldet P, Picot MC, et al. Catheter complications associated with implantable systems for peritoneal insulin delivery. An analysis of frequency, predisposing factors, and obstructing materials. Diabetes Care 1995; 18: 300–6.
part i
referencesa significant decrease in the number of pump dysfunctions and pump explantations and no
significant alterations in the course of complications between the period from 2000 until 2007
and from 2007 onwards. However, the former group had a longer follow-up period. This may
mask a transition or possible future increase of complications and re-operations, thus yielding
a relative stable OFP among patients. It will require ongoing investigation and thorough
monitoring during the upcoming years.
In addition, since a new intraperitoneal insulin formulation had to be introduced in 2011 since
there are no batches of the original insulin formulation left, the findings of the present study
should be taken into account when evaluating the effects associated with the use of the new
insulin formulation. No CIPII related mortality was reported. CIPII remains a safe treatment
modality for specific patient groups.
chapter 2
40 41
1 DeVries JH, Eskes SA, Snoek FJ, et al. Continuous intraperitoneal insulin infusion in patients with ‘brittle’ diabetes: favourable effects on glycaemic control and hospital stay. Diabet Med J Br Diabet Assoc 2002; 19: 496–501.2 Renard E, Schaepelynck-Bélicar P, EVADIAC Group. Implantable insulin pumps. A position statement about their clinical use. Diabetes Metab 2007; 33: 158–66.3 Logtenberg SJJ, van Ballegooie E, Israêl-Bultman H, van Linde A, Bilo HJG. Glycaemic control, health status and treatment satisfaction with continuous intraperitoneal insulin infusion. Neth J Med 2007; 65: 65–70.4 Broussolle C, Jeandidier N, Hanaire-Broutin H. French multicentre experience of implantable insulin pumps. The EVADIAC Study Group. Evaluation of Active Implants in Diabetes Society. Lancet 1994; 343: 514–5.5 Renard E, Bouteleau S, Jacques-Apostol D, et al. Insulin underdelivery from implanted pumps using peritoneal route. Determinant role of insulin pump compatibility. Diabetes Care 1996; 19: 812–7.6 Gin H, Renard E, Melki V, et al. Combined improvements in implantable pump technology and insulin stability allow safe and effective long term intraperitoneal insulin delivery in type 1 diabetic patients: the EVADIAC experience. Diabetes Metab 2003; 29: 602–7.7 Gin H, Melki V, Guerci B, Catargi B, Evaluation dans le Diabete du Traitement par Implants Actifs Study Group. Clinical evaluation of a newly designed compliant side port catheter for an insulin implantable pump: the EVADIAC experience. Evaluation dans le Diabete du Traitement par Implants Actifs. Diabetes Care 2001; 24: 175.8 Haveman JW, Logtenberg SJJ, Kleefstra N, Groenier KH, Bilo HJG, Blomme AM. Surgical aspects and complications of continuous intraperitoneal insulin infusion with an implantable pump. Langenbecks Arch Surg Dtsch Ges Für Chir 2010; 395: 65–71.9 Nederlandse Internisten Vereniging: Statement concerning indications for continuous intraperitoneal insulin infusion, 2007. 10 Bélicar P, Lassmann-Vague V. Local adverse events associated with long-term treatment by implantable insulin pumps. The French EVADIAC Study Group experience. Evaluation dans le Diabète du Traitement par Implants Actifs. Diabetes Care 1998; 21: 325–6.11 Renard E, Rostane T, Carriere C, et al. Implantable insulin pumps: infections most likely due to seeding from skin flora determine severe outcomes of pump-pocket seromas. Diabetes Metab 2001; 27: 62–5.12 Udelsman R, Chen H, Loman K, Pitt HA, Saudek CD. Implanted programmable insulin pumps: one hundred fifty-three patient years of surgical experience. Surgery 1997; 122: 1005–11.13 Darouiche RO. Treatment of infections associated with surgical implants. N Engl J Med 2004; 350: 1422–9.14 One-year trial of a remote-controlled implantable insulin infusion system in type I diabetic patients. Point Study Group. Lancet 1988; 2: 866–9.15 Saudek CD, Selam JL, Pitt HA, et al. A preliminary trial of the programmable implantable medication system for insulin delivery. N Engl J Med 1989; 321: 574–9.16 Selam JL, Micossi P, Dunn FL, Nathan DM. Clinical trial of programmable implantable insulin pump for type I diabetes. Diabetes Care 1992; 15: 877–85.17 Hanaire-Broutin H, Broussolle C, Jeandidier N, et al. Feasibility of intraperitoneal insulin therapy with programmable implantable pumps in IDDM. A multicenter study. The EVADIAC Study Group. Evaluation dans le Diabète du Traitement par Implants Actifs. Diabetes Care 1995; 18: 388–92.18 Scavini M, Galli L, Reich S, Eaton RP, Charles MA, Dunn FL. Catheter survival during long-term insulin therapy with an implanted programmable pump. The Implantable Insulin Pump Trial Study Group. Diabetes Care 1997; 20: 610–3.19 Renard E, Baldet P, Picot MC, et al. Catheter complications associated with implantable systems for peritoneal insulin delivery. An analysis of frequency, predisposing factors, and obstructing materials. Diabetes Care 1995; 18: 300–6.
part i
referencesa significant decrease in the number of pump dysfunctions and pump explantations and no
significant alterations in the course of complications between the period from 2000 until 2007
and from 2007 onwards. However, the former group had a longer follow-up period. This may
mask a transition or possible future increase of complications and re-operations, thus yielding
a relative stable OFP among patients. It will require ongoing investigation and thorough
monitoring during the upcoming years.
In addition, since a new intraperitoneal insulin formulation had to be introduced in 2011 since
there are no batches of the original insulin formulation left, the findings of the present study
should be taken into account when evaluating the effects associated with the use of the new
insulin formulation. No CIPII related mortality was reported. CIPII remains a safe treatment
modality for specific patient groups.
chapter 2
42 43
Glycaemic control, quality of life and treatment satisfaction
after 6 years intraperitoneal insulin infusion with an implan-
table pump
A long-term comparison between continuous intraperitoneal
insulin infusion and subcutaneous insulin therapy among
patients with poorly controlled T1DM: a 7 year case-control study
Intraperitoneal insulin infusion is non-inferior to subcutaneous
insulin infusion in the treatment of type 1 diabetes:
a prospective matched-control study
Quality of life and treatment satisfaction among type 1 diabetes
mellitus patients treated with continuous intraperitoneal insulin
infusion or subcutaneous insulin: a prospective observational
study
Continuous intraperitoneal insulin infusion versus sub-
cutaneous insulin therapy in the treatment of type 1 diabetes:
positive effects on glycaemic variability
chapter 3
chapter 4
chapter 5
chapter 6
chapter 7
part ii
Effects of intraperitoneal insulin therapy - glycaemia, quality of life and treatment satisfaction
42 43
Glycaemic control, quality of life and treatment satisfaction
after 6 years intraperitoneal insulin infusion with an implan-
table pump
A long-term comparison between continuous intraperitoneal
insulin infusion and subcutaneous insulin therapy among
patients with poorly controlled T1DM: a 7 year case-control study
Intraperitoneal insulin infusion is non-inferior to subcutaneous
insulin infusion in the treatment of type 1 diabetes:
a prospective matched-control study
Quality of life and treatment satisfaction among type 1 diabetes
mellitus patients treated with continuous intraperitoneal insulin
infusion or subcutaneous insulin: a prospective observational
study
Continuous intraperitoneal insulin infusion versus sub-
cutaneous insulin therapy in the treatment of type 1 diabetes:
positive effects on glycaemic variability
chapter 3
chapter 4
chapter 5
chapter 6
chapter 7
part ii
Effects of intraperitoneal insulin therapy - glycaemia, quality of life and treatment satisfaction
44 45
Van Dijk PR, Logtenberg SJ, Groenier KH, Gans RO, Kleefstra
N, Bilo HJ.
Continuous intraperitoneal insulin infusion in type 1 diabetes:
a 6-year post-trial follow-up. BMC Endocr Disord 2014; 14: 30.
chapter 3 Abstract
introductionContinuous intraperitoneal insulin infusion (CIPII) with an implantable pump is a treatment
option for selected patients with type 1 diabetes mellitus (T1DM). Aim of the present study was
to describe the long-term course of glycaemic control, complications, quality of life (QoL) and
treatment satisfaction among T1DM patients treated with CIPII.
patients and methods Nineteen patients that participated in a randomized cross-over trial comparing CIPII and
subcutaneous (SC) therapy in 2006 were followed until 2012. Laboratory, continuous glucose
monitoring, QoL and treatment satisfaction measurements were performed at the start of
the study, the end of the SC-, the end of the CIPII treatment phase in 2006 and during CIPII
therapy in 2012. Linear mixed models were used to calculate estimated values and to test
differences between the moments in time.
results In 2012, more time was spent in hyperglycaemia than after the CIPII treatment phase in 2006:
37% (95% confidence interval (CI) 29, 44) versus 55% (95% CI 48, 63) with a mean difference
of 19.8% (95% CI 3.0, 36.6). HbA1c was 65 mmol/mol (95% CI 60, 71) at the end of the SC
treatment phase in 2006, 58 mmol/mol (95% CI 53, 64) at the end of the CIPII treatment
phase and 65 mmol/mol (95% CI 60, 71) in 2012, respectively (p>0.05). In 2012, the median
number of grade 2 hypoglycaemic events per week (1 (95% CI 0, 2)) was still significantly
lower than during prior SC therapy (3 (95% CI 2, 4)): mean change -1.8 (95% CI -3.4, -0.4).
Treatment satisfaction with CIPII was better than with SC insulin therapy and QoL remained
stable. Pump or catheter dysfunction of the necessitated re-operation in 7 patients. No
mortality was reported.
conclusionsAfter 6 years of CIPII treatment, glycaemic regulation is stable and the number of hypo-
glycaemic events decreased as compared to prior SC insulin therapy. Treatment satisfaction
with CIPII is superior to SC insulin therapy, QoL is stable and complications are scarce. CIPII is
a safe and effective treatment option for selected patients with T1DM, also on longer term.published as
Glycaemic control, quality of life and treat-ment satisfaction after 6 years intraperitoneal insulin infusion with an implantable pump
chapter 3part 2
44 45
Van Dijk PR, Logtenberg SJ, Groenier KH, Gans RO, Kleefstra
N, Bilo HJ.
Continuous intraperitoneal insulin infusion in type 1 diabetes:
a 6-year post-trial follow-up. BMC Endocr Disord 2014; 14: 30.
chapter 3 Abstract
introductionContinuous intraperitoneal insulin infusion (CIPII) with an implantable pump is a treatment
option for selected patients with type 1 diabetes mellitus (T1DM). Aim of the present study was
to describe the long-term course of glycaemic control, complications, quality of life (QoL) and
treatment satisfaction among T1DM patients treated with CIPII.
patients and methods Nineteen patients that participated in a randomized cross-over trial comparing CIPII and
subcutaneous (SC) therapy in 2006 were followed until 2012. Laboratory, continuous glucose
monitoring, QoL and treatment satisfaction measurements were performed at the start of
the study, the end of the SC-, the end of the CIPII treatment phase in 2006 and during CIPII
therapy in 2012. Linear mixed models were used to calculate estimated values and to test
differences between the moments in time.
results In 2012, more time was spent in hyperglycaemia than after the CIPII treatment phase in 2006:
37% (95% confidence interval (CI) 29, 44) versus 55% (95% CI 48, 63) with a mean difference
of 19.8% (95% CI 3.0, 36.6). HbA1c was 65 mmol/mol (95% CI 60, 71) at the end of the SC
treatment phase in 2006, 58 mmol/mol (95% CI 53, 64) at the end of the CIPII treatment
phase and 65 mmol/mol (95% CI 60, 71) in 2012, respectively (p>0.05). In 2012, the median
number of grade 2 hypoglycaemic events per week (1 (95% CI 0, 2)) was still significantly
lower than during prior SC therapy (3 (95% CI 2, 4)): mean change -1.8 (95% CI -3.4, -0.4).
Treatment satisfaction with CIPII was better than with SC insulin therapy and QoL remained
stable. Pump or catheter dysfunction of the necessitated re-operation in 7 patients. No
mortality was reported.
conclusionsAfter 6 years of CIPII treatment, glycaemic regulation is stable and the number of hypo-
glycaemic events decreased as compared to prior SC insulin therapy. Treatment satisfaction
with CIPII is superior to SC insulin therapy, QoL is stable and complications are scarce. CIPII is
a safe and effective treatment option for selected patients with T1DM, also on longer term.published as
Glycaemic control, quality of life and treat-ment satisfaction after 6 years intraperitoneal insulin infusion with an implantable pump
chapter 3part 2
46 47
Introduction
The mainstay of type 1 diabetes mellitus (T1DM) treatment consists of subcutaneous (SC)
insulin administration using multiple daily injections (MDI) or continuous subcutaneous
insulin infusion (CSII) with an externally placed pump. Although most patients achieve
acceptable glycaemic control using MDI or CSII, a relatively small group of patients fails to
reach adequate glycaemic control, have frequent hypoglycaemic episodes or SC insulin
resistance, despite intensive SC insulin therapy. For these patients, continuous intraperitoneal
insulin infusion (CIPII) with an implantable pump is a treatment option 1.
With intraperitoneal administration, insulin is better absorbed and allows blood glucose levels
to return to baseline values more rapidly with more predictable insulin profiles compared to SC
insulin administration 2,3. The higher hepatic uptake of insulin with CIPII mitigates peripheral
plasma insulin concentrations compared to SC administration 3,4. Other possible effects
include improvement of the impaired glucagon and hepatic glucose production in response to
hypoglycaemia through alleviation of peripheral hyperinsulinaemia 5.
In 2006, a randomized, cross-over study was performed at our centre to investigate the effects
of CIPII on the risk of hypoglycaemia, compared to intensive SC insulin treatment, both for a
six-month period. Glycaemic control, quality of life (QoL) and treatment satisfaction improved
during CIPII treatment as compared to SC insulin administration and there was no reduction or
increase in hypoglycaemic events 6,7. After the study all participants chose to continue CIPII.
Aim of the current analysis is to investigate long-term glycaemic control, QoL, treatment
satisfaction and complications among these patients with T1DM, treated with CIPII.
Patients and methods
study population Twenty three patients with T1DM, low fasting C-peptide concentrations (<0.2 nmol/l) and
intermediate or poor glycaemic control, defined as HbA1c ≥58 mmol/mol and/or ≥5 incidents
of hypoglycaemia (<4.0 mmol/l) per week, who were aged 18–70 years and treated with SC
insulin, were included in the cross-over study in 2006. The exclusion criteria were: impaired
renal function (plasma creatinine ≥150 µmol/l or glomerular filtration rate ≤50ml/min),
cardiac problems (unstable angina or myocardial infarction within the previous 12 months
or New York Heart Association class III or IV congestive heart failure), cognitive impairment,
current or past psychiatric treatment for schizophrenia, cognitive or bipolar disorder, current
use or oral corticosteroids or suffering from a condition which necessitated oral or systemic
corticosteroids use more than once in the previous 12 months, substance abuse, other than
nicotine, current pregnancy or plans to become pregnant during the trial, plans to engage in
activities that require going >25 feet below sea level. After the cross-over study all patients
chose to continue CIPII with an implantable pump (Minimed Insulin Pump).
study designThe previous study (NCT00286962) started in 2006, had an open-label, randomized cross-
over design and was performed at Isala (Zwolle, the Netherlands). The study consisted of 4
phases: the qualification phase, the first treatment phase, the crossover phase, and the second
treatment phase. After a 3-month qualification phase, patients were randomly allocated to
one of two groups, which differed only in the sequence of the two therapies. Between both
treatment phases of 6 months, a crossover phase of 4 weeks was instituted to minimize the
carryover effects of CIPII. The results of this study were reported previously and showed a
significant decrease in HbA1c, with more time spent in euglycaemia and without a change
in hypoglycaemic events with CIPII as compared to SC insulin therapy. In addition, QoL and
treatment satisfaction improved with CIPII 6,7. Follow-up measurements for the present
analysis were performed in December 2012 until March 2013.
procedures and methodsAt the start of the 2006 cross-over study, 3 patients were on MDI and 20 on CSII. During the SC
treatment phase in the 2006 study, SC insulin was delivered with either MDI or CSII, according
to what was used prior to the study. Patients treated with MDI continued to use their own
insulin regime, i.e. rapid-acting insulin analogues before meals and a daily dose of long-acting
insulin. Patients treated with CSII used rapid acting insulin analogues. During the crossover
phase insulin was administered SC. If the subject was using more than 40 IU of SC insulin per
day prior to starting the CIPII phase of the study, his or her starting dose was set at 90% of the
prior SC dose. Subjects using less than 40 IU of SC insulin received a starting dose of 80% of
the prior SC dose. Initially the dose was equally divided between a basal rate (50%) and a bolus
before meals 8.
In 2006-2007, the CIPII pump was implanted under general anaesthesia at the start of the
CIPII phase in all subjects. Insulin (U-400 HOE 21PH, semi synthetic human insulin of porcine
origin, trade name: Insuplant® Hoechst, Frankfurt, Germany, nowadays Sanofi-Aventis) was
chapter 3part 2
46 47
Introduction
The mainstay of type 1 diabetes mellitus (T1DM) treatment consists of subcutaneous (SC)
insulin administration using multiple daily injections (MDI) or continuous subcutaneous
insulin infusion (CSII) with an externally placed pump. Although most patients achieve
acceptable glycaemic control using MDI or CSII, a relatively small group of patients fails to
reach adequate glycaemic control, have frequent hypoglycaemic episodes or SC insulin
resistance, despite intensive SC insulin therapy. For these patients, continuous intraperitoneal
insulin infusion (CIPII) with an implantable pump is a treatment option 1.
With intraperitoneal administration, insulin is better absorbed and allows blood glucose levels
to return to baseline values more rapidly with more predictable insulin profiles compared to SC
insulin administration 2,3. The higher hepatic uptake of insulin with CIPII mitigates peripheral
plasma insulin concentrations compared to SC administration 3,4. Other possible effects
include improvement of the impaired glucagon and hepatic glucose production in response to
hypoglycaemia through alleviation of peripheral hyperinsulinaemia 5.
In 2006, a randomized, cross-over study was performed at our centre to investigate the effects
of CIPII on the risk of hypoglycaemia, compared to intensive SC insulin treatment, both for a
six-month period. Glycaemic control, quality of life (QoL) and treatment satisfaction improved
during CIPII treatment as compared to SC insulin administration and there was no reduction or
increase in hypoglycaemic events 6,7. After the study all participants chose to continue CIPII.
Aim of the current analysis is to investigate long-term glycaemic control, QoL, treatment
satisfaction and complications among these patients with T1DM, treated with CIPII.
Patients and methods
study population Twenty three patients with T1DM, low fasting C-peptide concentrations (<0.2 nmol/l) and
intermediate or poor glycaemic control, defined as HbA1c ≥58 mmol/mol and/or ≥5 incidents
of hypoglycaemia (<4.0 mmol/l) per week, who were aged 18–70 years and treated with SC
insulin, were included in the cross-over study in 2006. The exclusion criteria were: impaired
renal function (plasma creatinine ≥150 µmol/l or glomerular filtration rate ≤50ml/min),
cardiac problems (unstable angina or myocardial infarction within the previous 12 months
or New York Heart Association class III or IV congestive heart failure), cognitive impairment,
current or past psychiatric treatment for schizophrenia, cognitive or bipolar disorder, current
use or oral corticosteroids or suffering from a condition which necessitated oral or systemic
corticosteroids use more than once in the previous 12 months, substance abuse, other than
nicotine, current pregnancy or plans to become pregnant during the trial, plans to engage in
activities that require going >25 feet below sea level. After the cross-over study all patients
chose to continue CIPII with an implantable pump (Minimed Insulin Pump).
study designThe previous study (NCT00286962) started in 2006, had an open-label, randomized cross-
over design and was performed at Isala (Zwolle, the Netherlands). The study consisted of 4
phases: the qualification phase, the first treatment phase, the crossover phase, and the second
treatment phase. After a 3-month qualification phase, patients were randomly allocated to
one of two groups, which differed only in the sequence of the two therapies. Between both
treatment phases of 6 months, a crossover phase of 4 weeks was instituted to minimize the
carryover effects of CIPII. The results of this study were reported previously and showed a
significant decrease in HbA1c, with more time spent in euglycaemia and without a change
in hypoglycaemic events with CIPII as compared to SC insulin therapy. In addition, QoL and
treatment satisfaction improved with CIPII 6,7. Follow-up measurements for the present
analysis were performed in December 2012 until March 2013.
procedures and methodsAt the start of the 2006 cross-over study, 3 patients were on MDI and 20 on CSII. During the SC
treatment phase in the 2006 study, SC insulin was delivered with either MDI or CSII, according
to what was used prior to the study. Patients treated with MDI continued to use their own
insulin regime, i.e. rapid-acting insulin analogues before meals and a daily dose of long-acting
insulin. Patients treated with CSII used rapid acting insulin analogues. During the crossover
phase insulin was administered SC. If the subject was using more than 40 IU of SC insulin per
day prior to starting the CIPII phase of the study, his or her starting dose was set at 90% of the
prior SC dose. Subjects using less than 40 IU of SC insulin received a starting dose of 80% of
the prior SC dose. Initially the dose was equally divided between a basal rate (50%) and a bolus
before meals 8.
In 2006-2007, the CIPII pump was implanted under general anaesthesia at the start of the
CIPII phase in all subjects. Insulin (U-400 HOE 21PH, semi synthetic human insulin of porcine
origin, trade name: Insuplant® Hoechst, Frankfurt, Germany, nowadays Sanofi-Aventis) was
chapter 3part 2
48 49
administered with the implantable pump. Since there were no batches left of the U400 semi
synthetic human insulin, a new human recombinant insulin (400 IU/ml; human insulin of
E. Coli origin, trade name: Insuman Implantable®, Sanofi-Aventis) was used from 2010
onwards. Between 2006 and 2012, all patients received standard care at our outpatient clinic
which consisted of insulin refills every 6-12 weeks and a rinse procedure with NaOH was
performed every 9 months or in case of insulin underdelivery. The insulin pump, implantation,
insulin dosage and refill procedures have been described in more detail previously 8,9.
measurementsIn order to yield information about the long-term impact of CIPII on glycaemic control in
comparison to that on SC insulin therapy, we compared data derived from the measurements
in 2012/2013 (referred to as “2012 study”) with data from the start of the 2006 study, the end of
the SC- , the end of the CIPII phase of the 2006 cross-over study.
Demographic and clinical parameters included smoking and alcohol habits, year of diagnosis
of diabetes, presence of complications, any comorbidity, height and weight, daily insulin dose,
number of self-reported hypoglycaemic events grade 1 (<4.0 mmol/l) and grade 2 (<3.5 mmol/l)
during the last 7 days. The HbA1c level was measured with a Primus Ultra2 system using high-
performance liquid chromatography (reference value 20-42 mmol/mol). In addition, 5- to 7-day
24-hours interstitial glucose profiles were recorded with a continuous glucose monitoring
(CGM) system (iPro2, Medtronic, Northridge, CA, USA). Time spent in the hypoglycaemic range
was defined as the percentage of CGM recordings <4.0 mmol/l, time spent in euglycaemic
range was defined as the percentage of CGM recordings from 4.0 to 10.0 mmol/l, and time
spent in hyperglycaemic range was defined as the percentage of CGM recordings >10.0 mmol/l.
For QoL assessment, the 36-item short-form health survey (SF-36) and the World Health
Organization-Five Well-Being Index (WHO-5) questionnaires were used. The SF-36 is a widely
used, generic questionnaire with 36 items involving eight subscales and a physical and mental
component summary (PCS and MCS, respectively). Scale scores range from 0 to 100, with higher
scores indicating better QoL 10,11. The WHO-5 is designed to measure positive well-being and is
reported to be better in identifying depression than the MCS 12,13. It consists of five items with a
total score ranging from 0 to 100. A total score below 50 or an answer of “0 or 1” on a single item
suggests poor emotional well-being 14. Treatment satisfaction was measured with the Diabetes
Treatment Satisfaction Questionnaire (DTSQ). All eight items are scored on a 7-point scale. Two
items assess perceived frequency of hyperglycaemia and hypoglycaemia, and six items comprise
the treatment satisfaction scale, with higher scores indicating higher satisfaction (range 0 to 36) 15.
statistical analysisDescriptive summaries included the mean with standard deviation (SD) for normally
distributed variables and the median with the interquartile range [25th-75th percentile]
for other variables. Q-Q plots were used to determine if the tested variable had a normal
distribution or not. Time variables, such as times spent in the different glycaemic states, are
presented as absolute values. Linear mixed models with Bonferroni correction were used
to calculate and to test differences in time. Estimated values and estimated differences,
calculated with linear mixed models, are reported. All observed values are presented in
Appendix 1. All statistical analysis were performed with SPSS software (IBM SPSS Statistics for
Windows, Version 20.0. Armonk, NY: IBM Corp.). A two-sided significance level of 0.05 was
considered statistically significant.
ethical considerationsStudies were performed in accordance with the Declaration of Helsinki. For this study,
informed consent was obtained from all patients in 2006 as well as in 2012. Approval by the
medical ethics committee of the Isala (Zwolle, the Netherlands) was given for the crossover
study in 2006 and the follow-up measurements in 2012.
Results
patientsOf 23 patients who participated in the previous cross-over study, 22 were still treated with CIPII
in 2012. One patient stopped CIPII treatment due to neuropathic pains. The patient believed
the implanted pump caused this pain. Two female patients were excluded from the current
analysis: 1 due to chronic prednisolone use for myasthenia gravis and 1 due to participation
in an in vitro fertilization program. One patient refused participation. Therefore, 19 patients
(53% male) are included in the present analysis, with a mean age of 45 (10) years and a diabetes
duration 23 [16, 33] years at the start of the 2006 study. Four of these patients are current
smokers.
clinical parametersThe estimated values of the clinical parameters and comparisons between the start of the 2006
study, the end of the SC- , the end of the CIPII treatment phase and the start of the present 2012
study, 6 (0.4) years later, are presented in Table 1. Systolic blood pressure, BMI, cholesterol and
the insulin dose remained stable over time. Two patients were diagnosed with neuropathy, one
chapter 3part 2
48 49
administered with the implantable pump. Since there were no batches left of the U400 semi
synthetic human insulin, a new human recombinant insulin (400 IU/ml; human insulin of
E. Coli origin, trade name: Insuman Implantable®, Sanofi-Aventis) was used from 2010
onwards. Between 2006 and 2012, all patients received standard care at our outpatient clinic
which consisted of insulin refills every 6-12 weeks and a rinse procedure with NaOH was
performed every 9 months or in case of insulin underdelivery. The insulin pump, implantation,
insulin dosage and refill procedures have been described in more detail previously 8,9.
measurementsIn order to yield information about the long-term impact of CIPII on glycaemic control in
comparison to that on SC insulin therapy, we compared data derived from the measurements
in 2012/2013 (referred to as “2012 study”) with data from the start of the 2006 study, the end of
the SC- , the end of the CIPII phase of the 2006 cross-over study.
Demographic and clinical parameters included smoking and alcohol habits, year of diagnosis
of diabetes, presence of complications, any comorbidity, height and weight, daily insulin dose,
number of self-reported hypoglycaemic events grade 1 (<4.0 mmol/l) and grade 2 (<3.5 mmol/l)
during the last 7 days. The HbA1c level was measured with a Primus Ultra2 system using high-
performance liquid chromatography (reference value 20-42 mmol/mol). In addition, 5- to 7-day
24-hours interstitial glucose profiles were recorded with a continuous glucose monitoring
(CGM) system (iPro2, Medtronic, Northridge, CA, USA). Time spent in the hypoglycaemic range
was defined as the percentage of CGM recordings <4.0 mmol/l, time spent in euglycaemic
range was defined as the percentage of CGM recordings from 4.0 to 10.0 mmol/l, and time
spent in hyperglycaemic range was defined as the percentage of CGM recordings >10.0 mmol/l.
For QoL assessment, the 36-item short-form health survey (SF-36) and the World Health
Organization-Five Well-Being Index (WHO-5) questionnaires were used. The SF-36 is a widely
used, generic questionnaire with 36 items involving eight subscales and a physical and mental
component summary (PCS and MCS, respectively). Scale scores range from 0 to 100, with higher
scores indicating better QoL 10,11. The WHO-5 is designed to measure positive well-being and is
reported to be better in identifying depression than the MCS 12,13. It consists of five items with a
total score ranging from 0 to 100. A total score below 50 or an answer of “0 or 1” on a single item
suggests poor emotional well-being 14. Treatment satisfaction was measured with the Diabetes
Treatment Satisfaction Questionnaire (DTSQ). All eight items are scored on a 7-point scale. Two
items assess perceived frequency of hyperglycaemia and hypoglycaemia, and six items comprise
the treatment satisfaction scale, with higher scores indicating higher satisfaction (range 0 to 36) 15.
statistical analysisDescriptive summaries included the mean with standard deviation (SD) for normally
distributed variables and the median with the interquartile range [25th-75th percentile]
for other variables. Q-Q plots were used to determine if the tested variable had a normal
distribution or not. Time variables, such as times spent in the different glycaemic states, are
presented as absolute values. Linear mixed models with Bonferroni correction were used
to calculate and to test differences in time. Estimated values and estimated differences,
calculated with linear mixed models, are reported. All observed values are presented in
Appendix 1. All statistical analysis were performed with SPSS software (IBM SPSS Statistics for
Windows, Version 20.0. Armonk, NY: IBM Corp.). A two-sided significance level of 0.05 was
considered statistically significant.
ethical considerationsStudies were performed in accordance with the Declaration of Helsinki. For this study,
informed consent was obtained from all patients in 2006 as well as in 2012. Approval by the
medical ethics committee of the Isala (Zwolle, the Netherlands) was given for the crossover
study in 2006 and the follow-up measurements in 2012.
Results
patientsOf 23 patients who participated in the previous cross-over study, 22 were still treated with CIPII
in 2012. One patient stopped CIPII treatment due to neuropathic pains. The patient believed
the implanted pump caused this pain. Two female patients were excluded from the current
analysis: 1 due to chronic prednisolone use for myasthenia gravis and 1 due to participation
in an in vitro fertilization program. One patient refused participation. Therefore, 19 patients
(53% male) are included in the present analysis, with a mean age of 45 (10) years and a diabetes
duration 23 [16, 33] years at the start of the 2006 study. Four of these patients are current
smokers.
clinical parametersThe estimated values of the clinical parameters and comparisons between the start of the 2006
study, the end of the SC- , the end of the CIPII treatment phase and the start of the present 2012
study, 6 (0.4) years later, are presented in Table 1. Systolic blood pressure, BMI, cholesterol and
the insulin dose remained stable over time. Two patients were diagnosed with neuropathy, one
chapter 3part 2
50 51
chapter 3part 2
Discussion
After 6 years of treatment with CIPII, HbA1c leveled with the value these T1DM patients
had during intensive SC therapy, prior to starting CIPII. Nevertheless, patients experienced
significant less grade 2 hypoglycaemic events and remained much more satisfied with CIPII
compared to the SC treatment.
During the previous cross-over trial in which CIPII was commenced there was a significant
decrease in HbA1c compared to the SC treatment phase from 70 to 58 mmol/mol. Compared
to the SC treatment phase, the decrease in that study was significantly greater with CIPII with
a mean difference of 8.4 mmol/mol. During the follow-up period described in the present
study HbA1c stabilized at a level of 65 mmol/mol, which was not different to the levels prior
and shortly after starting CIPII 6 years before. Several studies have described the effect of
CIPII, as compared to SC insulin therapy, on glycaemic control. In all 3 short-term randomized
studies, HbA1c improved with CIPII 6,16,17. In contrast to the findings in the present study,
HbA1c improvement persisted over the years in subsequent long-term observational studies.
Nevertheless, follow-up duration (45 days to 7.3 years) varied substantially between studies
and, importantly, not all patients in those studies had intermediately or poorly controlled
T1DM (HbA1c ranging from 63 to 83 mmol/mol) 18–24.
In accordance with previous studies, the number of grade 2 hypoglycaemic events decreased
during CIPII in the present cohort as compared to prior SC therapy 16,20,25. This may well be
the result of a slightly more hyperglycaemic profile. Although speculative, the restoration of
the portal to peripheral insulin gradient with CIPII treatment, known to improve glucagon
secretion and hepatic glucose production in response to hypoglycaemia, may also help to
explain this finding 5,26.
The HbA1c course in the current cohort may be partly explained by the effect of being under
strict study conditions during the cross-over study, which diminishes after the end of the study.
Several other explanations may be taken into account. First, complications of CIPII may also
have a negative influence on glycaemic regulation. Second, it should be mentioned that from
2010 onwards all CIPII patients switched to another insulin (Insuman® Implantable 400 IU/mL)
because the previous insulin batch (U-400 HOE 21PH , Insuplant ® 400 IU/mL) was no longer
available. The effect of the change in insulin formulation remains to be determined from an
on-going study (clinical trials identifier NCT01194882).
with retinopathy and one with a macrovascular complication (occlusion of the femoral artery).
There were no new cases of nephropathy.
glycaemic parametersAs shown in Table 1, the mean estimated HbA1c in 2012 was 65 (95% confidence interval (CI)
60, 71) mmol/mol and was not significantly different from the HbA1c at the start of the 2006
study: 70 (95% CI 64, 75) mmol/mol, with a mean estimated change of -4.5 mmol/mol
(95% CI -14.9, 5.9). Although there was a tendency to rise, the HbA1c in 2012 did not differ
significantly from the HbA1c at the end of the SC phase (-0.1 mmol/mol 95% CI -10.5, 10.3) and
the end of the CIPII phase (7.1 mmol/mol 95% CI -3.3, 17.5) of the 2006 study.
The number of grade 2 hypoglycaemic events per week decreased from 3 (95% CI 2, 4), at the
start and at the end of the SC therapy phase of the 2006 study, to 1 (95% CI 0, 2) event per week
in 2012. In 2012, compared with the start of the 2006 study the mean change was -1.8 events
per week (95% CI -3.4, -0.4) and compared with the end of SC therapy phase the mean change
was -1.9 (95% CI -3.5, -0.4). More time was spent in hyperglycaemia during CGM measurements
in 2012 than at the end of the CIPII phase in 2006: mean change 19.8 (95% CI 3.0, 36.6).
Percentage time spent in euglycaemia with CIPII in 2012 was less than at the end of the CIPII
phase of the 2006 study: mean change -18.7% (95% CI -33.3, -4.1).
qol and treatment satisfactionAs shown in Table 2, none of the SF-36 subscales and component scores changed over time.
The WHO-5 scores in 2012 remained stable over the years with CIPII. In 2012, 8 patients had a
poor emotional well-being according to the WHO-5 questionnaire, compared to 9 at the end
of the SC phase and 2 at the end of the CIPII study phase. The treatment satisfaction remained
significantly higher with CIPII than with SC insulin: the mean difference between 2012 and the
start of the 2006 study was 8.3 (95% CI 2.3, 14.3) and between 2012 and the end of the SC phase
was 8.4 (95% CI 2.4, 14.3). The perceived hyperglycaemia score of the DTSQ was higher in 2012
than at the end of the 2006 CIPII therapy phase with a difference of 1.5 (95% CI 0.2, 2.7).
device complicationsAfter a mean duration of 5 (1) years, 3 cases of pump dysfunction and 3 cases of (expected)
battery end-of-life necessitated replacement of the pump. In 3 patients a laparoscopic
procedure was performed to replace the catheter and in 1 patient a laparoscopic operation was
necessary to remove a fibrin plug from the tip of the catheter. The mean duration of hospital
admission for the 10 patients who experienced any pump related issue (including planned
replacement due to battery end-of-life) was 0.6 [0, 1] days per year. No mortality was reported.
50 51
chapter 3part 2
Discussion
After 6 years of treatment with CIPII, HbA1c leveled with the value these T1DM patients
had during intensive SC therapy, prior to starting CIPII. Nevertheless, patients experienced
significant less grade 2 hypoglycaemic events and remained much more satisfied with CIPII
compared to the SC treatment.
During the previous cross-over trial in which CIPII was commenced there was a significant
decrease in HbA1c compared to the SC treatment phase from 70 to 58 mmol/mol. Compared
to the SC treatment phase, the decrease in that study was significantly greater with CIPII with
a mean difference of 8.4 mmol/mol. During the follow-up period described in the present
study HbA1c stabilized at a level of 65 mmol/mol, which was not different to the levels prior
and shortly after starting CIPII 6 years before. Several studies have described the effect of
CIPII, as compared to SC insulin therapy, on glycaemic control. In all 3 short-term randomized
studies, HbA1c improved with CIPII 6,16,17. In contrast to the findings in the present study,
HbA1c improvement persisted over the years in subsequent long-term observational studies.
Nevertheless, follow-up duration (45 days to 7.3 years) varied substantially between studies
and, importantly, not all patients in those studies had intermediately or poorly controlled
T1DM (HbA1c ranging from 63 to 83 mmol/mol) 18–24.
In accordance with previous studies, the number of grade 2 hypoglycaemic events decreased
during CIPII in the present cohort as compared to prior SC therapy 16,20,25. This may well be
the result of a slightly more hyperglycaemic profile. Although speculative, the restoration of
the portal to peripheral insulin gradient with CIPII treatment, known to improve glucagon
secretion and hepatic glucose production in response to hypoglycaemia, may also help to
explain this finding 5,26.
The HbA1c course in the current cohort may be partly explained by the effect of being under
strict study conditions during the cross-over study, which diminishes after the end of the study.
Several other explanations may be taken into account. First, complications of CIPII may also
have a negative influence on glycaemic regulation. Second, it should be mentioned that from
2010 onwards all CIPII patients switched to another insulin (Insuman® Implantable 400 IU/mL)
because the previous insulin batch (U-400 HOE 21PH , Insuplant ® 400 IU/mL) was no longer
available. The effect of the change in insulin formulation remains to be determined from an
on-going study (clinical trials identifier NCT01194882).
with retinopathy and one with a macrovascular complication (occlusion of the femoral artery).
There were no new cases of nephropathy.
glycaemic parametersAs shown in Table 1, the mean estimated HbA1c in 2012 was 65 (95% confidence interval (CI)
60, 71) mmol/mol and was not significantly different from the HbA1c at the start of the 2006
study: 70 (95% CI 64, 75) mmol/mol, with a mean estimated change of -4.5 mmol/mol
(95% CI -14.9, 5.9). Although there was a tendency to rise, the HbA1c in 2012 did not differ
significantly from the HbA1c at the end of the SC phase (-0.1 mmol/mol 95% CI -10.5, 10.3) and
the end of the CIPII phase (7.1 mmol/mol 95% CI -3.3, 17.5) of the 2006 study.
The number of grade 2 hypoglycaemic events per week decreased from 3 (95% CI 2, 4), at the
start and at the end of the SC therapy phase of the 2006 study, to 1 (95% CI 0, 2) event per week
in 2012. In 2012, compared with the start of the 2006 study the mean change was -1.8 events
per week (95% CI -3.4, -0.4) and compared with the end of SC therapy phase the mean change
was -1.9 (95% CI -3.5, -0.4). More time was spent in hyperglycaemia during CGM measurements
in 2012 than at the end of the CIPII phase in 2006: mean change 19.8 (95% CI 3.0, 36.6).
Percentage time spent in euglycaemia with CIPII in 2012 was less than at the end of the CIPII
phase of the 2006 study: mean change -18.7% (95% CI -33.3, -4.1).
qol and treatment satisfactionAs shown in Table 2, none of the SF-36 subscales and component scores changed over time.
The WHO-5 scores in 2012 remained stable over the years with CIPII. In 2012, 8 patients had a
poor emotional well-being according to the WHO-5 questionnaire, compared to 9 at the end
of the SC phase and 2 at the end of the CIPII study phase. The treatment satisfaction remained
significantly higher with CIPII than with SC insulin: the mean difference between 2012 and the
start of the 2006 study was 8.3 (95% CI 2.3, 14.3) and between 2012 and the end of the SC phase
was 8.4 (95% CI 2.4, 14.3). The perceived hyperglycaemia score of the DTSQ was higher in 2012
than at the end of the 2006 CIPII therapy phase with a difference of 1.5 (95% CI 0.2, 2.7).
device complicationsAfter a mean duration of 5 (1) years, 3 cases of pump dysfunction and 3 cases of (expected)
battery end-of-life necessitated replacement of the pump. In 3 patients a laparoscopic
procedure was performed to replace the catheter and in 1 patient a laparoscopic operation was
necessary to remove a fibrin plug from the tip of the catheter. The mean duration of hospital
admission for the 10 patients who experienced any pump related issue (including planned
replacement due to battery end-of-life) was 0.6 [0, 1] days per year. No mortality was reported.
52 53
chapter 3part 2
Clin
ical a
nd gl
ycae
mic
para
met
ers.
tabl
e 1
Estim
ated
valu
es an
d di
ffere
nces
are r
epor
ted.
Dat
a are
pre
sent
ed as
estim
ated
mea
n (9
5% C
I) or
mea
n ch
ange
(95%
CI).
Num
bers
may
not
add
up d
ue to
roun
ding
. Abb
revi
atio
ns B
MI;
body
mas
s ind
ex,
CIPI
I; co
ntin
uous
intra
perit
onea
l ins
ulin
infu
sion,
SBP;
syst
olic
bloo
d pr
essu
re, S
C; su
bcut
aneo
us. †
Defi
ned
as th
e num
ber o
f blo
od g
luco
se va
lues
<4.
0 m
mol
/l pe
r wee
k. ‡
Defi
ned
as th
e num
ber o
f blo
od
gluc
ose v
alue
s <3.
5 mm
ol/l
per w
eek.
*p<0
.05.
St
art 2
006
stud
y (A)
En
d SC
pha
se (B
) En
d CI
PII p
hase
(C)
2012
stud
y (D
) D
vs. A
D
vs. B
D
vs. C
Cl
inica
l par
amet
ers
SB
P (m
mH
g)
141 (
133,
150)
13
5 (12
6, 14
3)
139
(130
, 147
) 14
0 (1
31, 1
49)
-1. -
1.1 (-
17.6
, 15.
5)
5.5 (
-11.0
, 22.
0)
1.3 (-
15.2
, 17.
9)
BMI (
kg/m
2 ) 26
(24,
29)
27 (2
4, 29
) 28
(25,
30)
26 (2
4, 29
) -0
.4 (-
4.9,
4.1)
-0
.2 (-
5.3,
4.9
) -1
.2 (-
6.1,
3.7)
To
tal c
hole
ster
ol
4.8
(4.5
, 5.2
) 4.
7 (4.
3, 5.
1)
4.5 (
4.1,
4.9)
4.
8 (4
.4, 5
.2)
-0.1
(-0.9
, 0.7
) 0.
0 (-0
.7, 0
.8)
-0.2
(-0.
5, 1.
0)
HD
L cho
lest
erol
1.8
(1.6
, 2.0
) 1.8
(1.5
, 2.0
) 1.6
(1.3
, 1.8
) 1.7
(1.4
, 1.9
) -0
.1 (-0
.6, 0
.3)
-0.1
(-0.6
, 0.4
) 0.
1 (-0
.3, 0
.6)
LDL c
hole
ster
ol
2.6
(2.3
, 3.0
) 2.
5 (2.
2, 2.
8)
2.4
(2.1,
2.7)
2.
8 (2
.5, 3
.1)
0.2 (
-0.4
, 0.8
) 0.
3 (-0
.3, 0
.9)
0.4
(-0.2
, 1.1)
Tr
igly
cerid
es
0.9
(0.7
, 1.2
) 1.1
(0.8
, 1.3
) 1.3
(1.0
, 1.5
) 1.0
(0.7
, 1.3
) -0
.1 (-0
.5, 0
.6)
-0.1
(-0.6
, 0.5
) -0
.3 (-
0.8,
0.3
) To
tal i
nsul
in d
ose (
IU/d
ay)
19 (1
3, 24
) 25
(20,
31)
20 (1
5, 25
) 20
(15,
26)
8.2 (
-18.
3, 34
.7)
8.2 (
-17.
6, 33
.9)
6.1 (
-19.
7, 31
.8)
Basa
l ins
ulin
dos
e (IU
/day
) 35
(24,
45)
32
(22,
43)
35
(25,
46)
44
(34,
55)
9.6
(-10.
6, 29
.8)
12.0
(-8.
1, 32
.2)
8.5 (
-11.7
, 28.
7)
Bolu
s ins
ulin
dos
e (IU
/day
) 54
(40,
67)
58
(44,
71)
56 (4
2, 6
9)
65 (5
1, 78
) 1.4
(-8.
9, 11
.7)
-5.1
(-15.
3, 5.
2)
0.4
(-9.9
, 10.
7)
Glyc
aem
ic pa
ram
eter
s
HbA
1c (m
mol
/mol
) 70
(64,
75)
65 (6
0, 71
) 58
(53,
64)
65
(60,
71)
-4.5
(-14
.9, 5
.9)
-0.1
(-10.
5,10
.3)
7.1 (
-3.3
, 17.
5)
Hyp
ogly
caem
ia g
rade
1 † 4
(3, 6
) 4
(3, 6
) 4
(2, 5
) 3 (
1, 4)
-1
.8 (-
4.2,
0.7
) -1
.7 (-
4.2,
0.8
) -1
.1 (-3
.6, 1
.4)
Hyp
ogly
caem
ia g
rade
2 ‡ 3 (
2, 4
) 3 (
2, 4
) 2 (
2, 3)
1 (
0, 2)
-1
.8 (-
3.4,
-0.4
)*
-1.9
(-3.
5, -0
.4)*
-1
.4 (-
3.0,
0.1)
Ti
me s
pent
in h
ypog
lyca
emia
(%)
8 (5
, 11)
8
(5, 1
1)
6 (3
, 9)
5 (2,
7)
-3.7
(-9.
3, 1.
9)
-3.6
(-9.
2, 2.
0)
-1.1
(-6.7
, 4.5
) Ti
me s
pent
in h
yper
glyc
aem
ia (%
) 45
(36,
54)
47 (3
8, 56
) 39
(30,
48)
59
(50,
68)
13
.7 (-
3.1,
30.5
) 12
.0 (-
4.8,
28.8
) 19
.8 (3
.0, 3
6.6)
* Ti
me s
pent
in eu
glyc
aem
ia (%
) 47
(39,
54)
45 (3
8, 53
) 55
(48,
63)
37
(29,
44)
-1
0.0
(-24.
6, 4
.6)
-8.4
(-23
.0, 6
.2)
-18.
7 (-3
3.3,
-4.1)
*
QoL a
nd tr
eatm
ent s
atisf
actio
n.ta
ble 2
Estim
ated
valu
es an
d di
ffere
nces
are r
epor
ted.
Dat
a are
pre
sent
ed as
estim
ated
mea
n (9
5% C
I) or
mea
n ch
ange
(95%
CI).
Num
bers
may
not
add
up d
ue to
roun
ding
. Abb
revi
atio
ns D
TSQ;
dia
bete
s tre
atm
ent
satis
fact
ion
ques
tionn
aire
, CIP
II; co
ntin
uous
intra
perit
onea
l insu
lin in
fusio
n, SC
; sub
cuta
neou
s, SF
-36;
36-it
em sh
ort-f
orm
hea
lth su
rvey
, WH
O-5;
wor
ld h
ealth
org
aniza
tion-
five w
ell-b
eing
inde
x. *p
<0.0
5.
St
art 2
006
stud
y (A)
En
d SC
pha
se (B
) En
d CI
PII p
hase
(C)
2012
stud
y (D
) D
vs. A
D
vs. B
D
vs. C
SF
-36 s
ubsc
ales
Phys
ical f
unct
ioni
ng
76 (6
6, 8
6)
69 (5
9, 79
) 81
(71,
91)
76 (6
5, 8
6)
-0.3
(-19
.7, 1
9.1)
7.
4 (-1
2.1,
26.8
) -5
.3 (-
24.7
, 14.
1)
Socia
l fun
ctio
ning
68
(53,
76)
65 (5
3, 76
) 77
(66,
88)
74
(63,
85)
6.
6 (-1
4.7,
27.8
) 9.
9 (-1
1.4, 3
1.2)
-2.6
(-32
.9, 1
8.6)
Ro
le li
mita
tions
-phy
sical
38
(17,
59)
42 (2
1, 63
) 66
(45,
87)
57
(36,
78)
18.4
(-22
.0, 5
8.8)
14
.5 (-
26.0
, 54.
9)
-9.2
(-49
.6, 3
1.2)
Role
lim
itatio
ns-e
mot
iona
l 68
(50,
87)
68
(50,
87)
86
(67,
100)
77
(58,
96)
8.
8 (-2
7.3,
44.
8)
8.8
(-27.
3, 4
4.8)
-8
.8 (-
44.8
, 27.
3)
Men
tal h
ealth
70
(60,
79)
67 (5
8, 77
) 77
(68,
87)
79
(70,
89)
9.
6 (-8
.1, 27
.4)
12.0
(-5.
8, 29
.7)
2.1 (
-15.
7, 19
.8)
Vita
lity
48 (3
9, 58
) 43
(34,
71)
62 (5
2, 71
) 58
(49,
67)
9.
5 (-7
.9, 2
6.9)
15
.3 (-
2.2,
32.7
) -4
.5 (-
32.9
, 12.
8)
Bodi
ly p
ain
64 (5
2, 75
) 64
(53,
76)
66 (5
4, 77
) 67
(56,
78)
3.3 (
-18.
5, 25
.0)
2.6
(-19.
2, 24
.3)
1.4 (-
20.4
, 23.
1)
Gene
ral h
ealth
41
(32,
50)
46 (3
7, 54
) 56
(47,
64)
48
(38,
56)
6.5 (
-10.
1, 23
.1)
1.7 (-
14.9
, 18.
3)
-8.0
(-24
.7, 8
.6)
SF-3
6 com
pone
nt sc
ores
Men
tal c
ompo
nent
scor
e 59
(50,
68)
58
(49,
67)
72
(63,
81)
67
(58,
76)
8.2 (
-9.1,
25.5
) 9.
5 (-7
.7, 2
6.8)
-4
.4 (-
21.6
, 12.
9)
Phys
ical c
ompo
nent
scor
e 56
(46,
65)
55
(45,
64)
68
(58,
77)
63 (5
4, 73
) 7.
3 (-1
0.9,
25.6
) 8.
5 (-9
.7, 2
6.8)
-4
.7 (-
23.0
, 13.
5)
WH
O-5 s
core
49
(39,
59)
47 (3
7, 57
) 69
(59,
79)
60 (5
0, 70
) 10
.5 (-
9.0,
30.0
) 12
.6 (-
6.9,
32.1)
-9
.2 (-
28.8
, 10.
2)
DTS
Q
Perc
eive
d hy
perg
lyca
emia
scor
e 3 (
2, 4
) 4
(3, 5
) 3 (
2, 3)
3 (
2, 4
) -1
.1 (-2
.4, 0
.1)
-0.9
(-2.
1, 0.
3)
1.5 (0
.2, 2
.7)*
Pe
rcei
ved
hypo
glyc
aem
ia sc
ore
5 (4,
6)
5 (4,
5)
2 (2,
3)
4 (3
, 5)
-0.4
(-2.
0, 1.
2)
-0.8
(-2.
4, 0
.8)
0.3 (
-1.3
, 1.9
) To
tal s
core
24
(21,
27)
24 (2
1, 27
) 33
(30,
36)
33 (2
9, 36
) 8.
3 (2.
3, 14
.3)*
8.
4 (2
.4,14
.3)*
-0
.3 (-
6.3,
5.7)
52 53
chapter 3part 2
Clin
ical a
nd gl
ycae
mic
para
met
ers.
tabl
e 1
Estim
ated
valu
es an
d di
ffere
nces
are r
epor
ted.
Dat
a are
pre
sent
ed as
estim
ated
mea
n (9
5% C
I) or
mea
n ch
ange
(95%
CI).
Num
bers
may
not
add
up d
ue to
roun
ding
. Abb
revi
atio
ns B
MI;
body
mas
s ind
ex,
CIPI
I; co
ntin
uous
intra
perit
onea
l ins
ulin
infu
sion,
SBP;
syst
olic
bloo
d pr
essu
re, S
C; su
bcut
aneo
us. †
Defi
ned
as th
e num
ber o
f blo
od g
luco
se va
lues
<4.
0 m
mol
/l pe
r wee
k. ‡
Defi
ned
as th
e num
ber o
f blo
od
gluc
ose v
alue
s <3.
5 mm
ol/l
per w
eek.
*p<0
.05.
St
art 2
006
stud
y (A)
En
d SC
pha
se (B
) En
d CI
PII p
hase
(C)
2012
stud
y (D
) D
vs. A
D
vs. B
D
vs. C
Cl
inica
l par
amet
ers
SB
P (m
mH
g)
141 (
133,
150)
13
5 (12
6, 14
3)
139
(130
, 147
) 14
0 (1
31, 1
49)
-1. -
1.1 (-
17.6
, 15.
5)
5.5 (
-11.0
, 22.
0)
1.3 (-
15.2
, 17.
9)
BMI (
kg/m
2 ) 26
(24,
29)
27 (2
4, 29
) 28
(25,
30)
26 (2
4, 29
) -0
.4 (-
4.9,
4.1)
-0
.2 (-
5.3,
4.9
) -1
.2 (-
6.1,
3.7)
To
tal c
hole
ster
ol
4.8
(4.5
, 5.2
) 4.
7 (4.
3, 5.
1)
4.5 (
4.1,
4.9)
4.
8 (4
.4, 5
.2)
-0.1
(-0.9
, 0.7
) 0.
0 (-0
.7, 0
.8)
-0.2
(-0.
5, 1.
0)
HD
L cho
lest
erol
1.8
(1.6
, 2.0
) 1.8
(1.5
, 2.0
) 1.6
(1.3
, 1.8
) 1.7
(1.4
, 1.9
) -0
.1 (-0
.6, 0
.3)
-0.1
(-0.6
, 0.4
) 0.
1 (-0
.3, 0
.6)
LDL c
hole
ster
ol
2.6
(2.3
, 3.0
) 2.
5 (2.
2, 2.
8)
2.4
(2.1,
2.7)
2.
8 (2
.5, 3
.1)
0.2 (
-0.4
, 0.8
) 0.
3 (-0
.3, 0
.9)
0.4
(-0.2
, 1.1)
Tr
igly
cerid
es
0.9
(0.7
, 1.2
) 1.1
(0.8
, 1.3
) 1.3
(1.0
, 1.5
) 1.0
(0.7
, 1.3
) -0
.1 (-0
.5, 0
.6)
-0.1
(-0.6
, 0.5
) -0
.3 (-
0.8,
0.3
) To
tal i
nsul
in d
ose (
IU/d
ay)
19 (1
3, 24
) 25
(20,
31)
20 (1
5, 25
) 20
(15,
26)
8.2 (
-18.
3, 34
.7)
8.2 (
-17.
6, 33
.9)
6.1 (
-19.
7, 31
.8)
Basa
l ins
ulin
dos
e (IU
/day
) 35
(24,
45)
32
(22,
43)
35
(25,
46)
44
(34,
55)
9.6
(-10.
6, 29
.8)
12.0
(-8.
1, 32
.2)
8.5 (
-11.7
, 28.
7)
Bolu
s ins
ulin
dos
e (IU
/day
) 54
(40,
67)
58
(44,
71)
56 (4
2, 6
9)
65 (5
1, 78
) 1.4
(-8.
9, 11
.7)
-5.1
(-15.
3, 5.
2)
0.4
(-9.9
, 10.
7)
Glyc
aem
ic pa
ram
eter
s
HbA
1c (m
mol
/mol
) 70
(64,
75)
65 (6
0, 71
) 58
(53,
64)
65
(60,
71)
-4.5
(-14
.9, 5
.9)
-0.1
(-10.
5,10
.3)
7.1 (
-3.3
, 17.
5)
Hyp
ogly
caem
ia g
rade
1 † 4
(3, 6
) 4
(3, 6
) 4
(2, 5
) 3 (
1, 4)
-1
.8 (-
4.2,
0.7
) -1
.7 (-
4.2,
0.8
) -1
.1 (-3
.6, 1
.4)
Hyp
ogly
caem
ia g
rade
2 ‡ 3 (
2, 4
) 3 (
2, 4
) 2 (
2, 3)
1 (
0, 2)
-1
.8 (-
3.4,
-0.4
)*
-1.9
(-3.
5, -0
.4)*
-1
.4 (-
3.0,
0.1)
Ti
me s
pent
in h
ypog
lyca
emia
(%)
8 (5
, 11)
8
(5, 1
1)
6 (3
, 9)
5 (2,
7)
-3.7
(-9.
3, 1.
9)
-3.6
(-9.
2, 2.
0)
-1.1
(-6.7
, 4.5
) Ti
me s
pent
in h
yper
glyc
aem
ia (%
) 45
(36,
54)
47 (3
8, 56
) 39
(30,
48)
59
(50,
68)
13
.7 (-
3.1,
30.5
) 12
.0 (-
4.8,
28.8
) 19
.8 (3
.0, 3
6.6)
* Ti
me s
pent
in eu
glyc
aem
ia (%
) 47
(39,
54)
45 (3
8, 53
) 55
(48,
63)
37
(29,
44)
-1
0.0
(-24.
6, 4
.6)
-8.4
(-23
.0, 6
.2)
-18.
7 (-3
3.3,
-4.1)
*
QoL a
nd tr
eatm
ent s
atisf
actio
n.ta
ble 2
Estim
ated
valu
es an
d di
ffere
nces
are r
epor
ted.
Dat
a are
pre
sent
ed as
estim
ated
mea
n (9
5% C
I) or
mea
n ch
ange
(95%
CI).
Num
bers
may
not
add
up d
ue to
roun
ding
. Abb
revi
atio
ns D
TSQ;
dia
bete
s tre
atm
ent
satis
fact
ion
ques
tionn
aire
, CIP
II; co
ntin
uous
intra
perit
onea
l insu
lin in
fusio
n, SC
; sub
cuta
neou
s, SF
-36;
36-it
em sh
ort-f
orm
hea
lth su
rvey
, WH
O-5;
wor
ld h
ealth
org
aniza
tion-
five w
ell-b
eing
inde
x. *p
<0.0
5.
St
art 2
006
stud
y (A)
En
d SC
pha
se (B
) En
d CI
PII p
hase
(C)
2012
stud
y (D
) D
vs. A
D
vs. B
D
vs. C
SF
-36 s
ubsc
ales
Phys
ical f
unct
ioni
ng
76 (6
6, 8
6)
69 (5
9, 79
) 81
(71,
91)
76 (6
5, 8
6)
-0.3
(-19
.7, 1
9.1)
7.
4 (-1
2.1,
26.8
) -5
.3 (-
24.7
, 14.
1)
Socia
l fun
ctio
ning
68
(53,
76)
65 (5
3, 76
) 77
(66,
88)
74
(63,
85)
6.
6 (-1
4.7,
27.8
) 9.
9 (-1
1.4, 3
1.2)
-2.6
(-32
.9, 1
8.6)
Ro
le li
mita
tions
-phy
sical
38
(17,
59)
42 (2
1, 63
) 66
(45,
87)
57
(36,
78)
18.4
(-22
.0, 5
8.8)
14
.5 (-
26.0
, 54.
9)
-9.2
(-49
.6, 3
1.2)
Role
lim
itatio
ns-e
mot
iona
l 68
(50,
87)
68
(50,
87)
86
(67,
100)
77
(58,
96)
8.
8 (-2
7.3,
44.
8)
8.8
(-27.
3, 4
4.8)
-8
.8 (-
44.8
, 27.
3)
Men
tal h
ealth
70
(60,
79)
67 (5
8, 77
) 77
(68,
87)
79
(70,
89)
9.
6 (-8
.1, 27
.4)
12.0
(-5.
8, 29
.7)
2.1 (
-15.
7, 19
.8)
Vita
lity
48 (3
9, 58
) 43
(34,
71)
62 (5
2, 71
) 58
(49,
67)
9.
5 (-7
.9, 2
6.9)
15
.3 (-
2.2,
32.7
) -4
.5 (-
32.9
, 12.
8)
Bodi
ly p
ain
64 (5
2, 75
) 64
(53,
76)
66 (5
4, 77
) 67
(56,
78)
3.3 (
-18.
5, 25
.0)
2.6
(-19.
2, 24
.3)
1.4 (-
20.4
, 23.
1)
Gene
ral h
ealth
41
(32,
50)
46 (3
7, 54
) 56
(47,
64)
48
(38,
56)
6.5 (
-10.
1, 23
.1)
1.7 (-
14.9
, 18.
3)
-8.0
(-24
.7, 8
.6)
SF-3
6 com
pone
nt sc
ores
Men
tal c
ompo
nent
scor
e 59
(50,
68)
58
(49,
67)
72
(63,
81)
67
(58,
76)
8.2 (
-9.1,
25.5
) 9.
5 (-7
.7, 2
6.8)
-4
.4 (-
21.6
, 12.
9)
Phys
ical c
ompo
nent
scor
e 56
(46,
65)
55
(45,
64)
68
(58,
77)
63 (5
4, 73
) 7.
3 (-1
0.9,
25.6
) 8.
5 (-9
.7, 2
6.8)
-4
.7 (-
23.0
, 13.
5)
WH
O-5 s
core
49
(39,
59)
47 (3
7, 57
) 69
(59,
79)
60 (5
0, 70
) 10
.5 (-
9.0,
30.0
) 12
.6 (-
6.9,
32.1)
-9
.2 (-
28.8
, 10.
2)
DTS
Q
Perc
eive
d hy
perg
lyca
emia
scor
e 3 (
2, 4
) 4
(3, 5
) 3 (
2, 3)
3 (
2, 4
) -1
.1 (-2
.4, 0
.1)
-0.9
(-2.
1, 0.
3)
1.5 (0
.2, 2
.7)*
Pe
rcei
ved
hypo
glyc
aem
ia sc
ore
5 (4,
6)
5 (4,
5)
2 (2,
3)
4 (3
, 5)
-0.4
(-2.
0, 1.
2)
-0.8
(-2.
4, 0
.8)
0.3 (
-1.3
, 1.9
) To
tal s
core
24
(21,
27)
24 (2
1, 27
) 33
(30,
36)
33 (2
9, 36
) 8.
3 (2.
3, 14
.3)*
8.
4 (2
.4,14
.3)*
-0
.3 (-
6.3,
5.7)
54 55
1 Renard E, Schaepelynck-Bélicar P, EVADIAC Group. Implantable insulin pumps. A position statement about their clinical use. Diabetes Metab 2007; 33: 158–66.2 Schade DS, Eaton RP, Davis T, et al. The kinetics of peritoneal insulin absorption. Metabolism 1981; 30: 149–55.3 Nathan DM, Dunn FL, Bruch J, et al. Postprandial insulin profiles with implantable pump therapy may explain decreased frequency of severe hypoglycemia, compared with intensive subcutaneous regimens, in insulin-dependent diabetes mellitus patients. Am J Med 1996; 100: 412–7.4 Selam JL, Bergman RN, Raccah D, Jean-Didier N, Lozano J, Charles MA. Determination of portal insulin absorption from peritoneum via novel nonisotopic method. Diabetes 1990; 39: 1361–5.5 Wan CK, Giacca A, Matsuhisa M, et al. Increased responses of glucagon and glucose production to hypoglycemia with intraperitoneal versus subcutaneous insulin treatment. Metabolism 2000; 49: 984–9.6 Logtenberg SJ, Kleefstra N, Houweling ST, et al. Improved glycemic control with intraperitoneal versus subcutaneous insulin in type 1 diabetes: a randomized controlled trial. Diabetes Care 2009; 32: 1372–7.7 Logtenberg SJ, Kleefstra N, Houweling ST, Groenier KH, Gans RO, Bilo HJ. Health-related quality of life, treatment satisfaction, and costs associated with intraperitoneal versus subcutaneous insulin administration in type 1 diabetes: a randomized controlled trial. Diabetes Care 2010; 33: 1169–72.8 Van Dijk PR, Logtenberg SJJ, Groenier KH, Kleefstra N, Bilo H, Arnqvist H. Effect of intraperitoneal insulin administration on IGF1 and IGFBP1 in type 1 diabetes. Endocr Connect 2013. doi:10.1530/EC-13-0089.9 Haveman JW, Logtenberg SJJ, Kleefstra N, Groenier KH, Bilo HJG, Blomme AM. Surgical aspects and complications of continuous intraperitoneal insulin infusion with an implantable pump. Langenbecks Arch Surg Dtsch Ges Für Chir 2010; 395: 65–71.10 Ware J, Snow K, Kosinski M Gandek: SF-36 Health Survey: Manual and Interpretation Guide. Boston, The Health Institute, New England Medical Center; 1993.11 Ware JE, Kosinski M, Keller SD. SF-36 Physical and Mental Health Summary Scales: A User’s Manual. Boston, The Health Institute, New England Medical Center; 1994.12 World Health Organization, Regional Office for Europe Wellbeing measures in primary health care: the Depcare Project. Report on a WHO Meeting. 1998.13 Bech P, Olsen LR, Kjoller M, Rasmussen NK. Measuring well-being rather than the absence of distress symptoms: a comparison of the SF-36 Mental Health subscale and the WHO-Five Well-Being Scale. Int J Methods Psychiatr Res 2003; 12: 85–91.14 Löwe B, Spitzer RL, Gräfe K, et al. Comparative validity of three screening questionnaires for DSM-IV depressive disorders and physicians’ diagnoses. J Affect Disord 2004; 78: 131–40.15 Bradley C. The Diabetes Treatment Satisfaction Questionnaire: DTSQ. Handbook of Psychology and Diabetes: a guide to psychological measurement in diabetes research and practice Chur: Harwood Academic Publishers, 1994:111-3216 Haardt MJ, Selam JL, Slama G, et al. A cost-benefit comparison of intensive diabetes management with implantable pumps versus multiple subcutaneous injections in patients with type I diabetes. Diabetes Care 1994; 17: 847–51.17 Selam JL, Raccah D, Jean-Didier N, Lozano JL, Waxman K, Charles MA. Randomized comparison of metabolic control achieved by intraperitoneal insulin infusion with implantable pumps versus intensive subcutaneous insulin therapy in type I diabetic patients. Diabetes Care 1992; 15: 53–8.18 Logtenberg SJJ, van Ballegooie E, Israêl-Bultman H, van Linde A, Bilo HJG. Glycaemic control, health status and treat- ment satisfaction with continuous intraperitoneal insulin infusion. Neth J Med 2007; 65: 65–70.19 DeVries JH, Eskes SA, Snoek FJ, et al. Continuous intraperitoneal insulin infusion in patients with ‘brittle’ diabetes: favourable effects on glycaemic control and hospital stay. Diabet Med J Br Diabet Assoc 2002; 19: 496–501.20 Selam JL, Micossi P, Dunn FL, Nathan DM. Clinical trial of programmable implantable insulin pump for type I diabetes. Diabetes Care 1992; 15: 877–85.21 Schaepelynck P, Renard E, Jeandidier N, et al. A recent survey confirms the efficacy and the safety of implanted insulin pumps during long-term use in poorly controlled type 1 diabetes patients. Diabetes Technol Ther 2011; 13: 657–60.
chapter 3part 2
referencesThe switch from SC insulin to CIPII increases QoL, which stabilizes over time 7,20. In the present
study the level of QoL among CIPII treated subjects perpetuated. Nevertheless, as found
in other studies and emphasized by the fact that 42% of all patients had a WHO-5 score
indicating poor emotional well-being, the QoL of these individuals remains poor 1,19,20.
We found the SF-36 subscales role-physical and vitality to be comparable to patients with
a minor (uncomplicated) chronic disease and the other subscales similar to patients with
complicated diabetes or complicated coronary artery disease 27. Still, it is likely that the short
duration of hospital admissions found in the present study (<1 day per year), compared to
45 days per year before implantation of the pump previously described in a similar population,
positively influence QoL and treatment satisfaction 19.
Since CIPII is used as a last treatment option in the Netherlands, the population in the present
study is complex, strictly selected and has a small size. On the other hand, this limitation
reflects general practice nowadays where CIPII is limited to a small number of patients in a
small number of centers. Furthermore, when interpreting the comparisons between CIPII and
previous SC therapy made in this study one should take differences in treatment periods
(e.g.a duration of 6 months of the SC phase during a controlled study versus 6.4 years of
subsequent CIPII therapy) into account. Prospective, long-term and large-scale studies with
respect to glycaemic control, QoL and cost-effectiveness to compare CIPII and SC therapy for
T1DM are imperative.
Conclusions
Taken together, the stable QoL, increased treatment satisfaction, little time spent in hospital
and stable HbA1c combined with a decrease in grade 2 hypoglycaemic events as compared
to previous SC therapy underlines the clinical observation that CIPII is a valuable treatment
option for selected patients with T1DM, also on longer term.
54 55
1 Renard E, Schaepelynck-Bélicar P, EVADIAC Group. Implantable insulin pumps. A position statement about their clinical use. Diabetes Metab 2007; 33: 158–66.2 Schade DS, Eaton RP, Davis T, et al. The kinetics of peritoneal insulin absorption. Metabolism 1981; 30: 149–55.3 Nathan DM, Dunn FL, Bruch J, et al. Postprandial insulin profiles with implantable pump therapy may explain decreased frequency of severe hypoglycemia, compared with intensive subcutaneous regimens, in insulin-dependent diabetes mellitus patients. Am J Med 1996; 100: 412–7.4 Selam JL, Bergman RN, Raccah D, Jean-Didier N, Lozano J, Charles MA. Determination of portal insulin absorption from peritoneum via novel nonisotopic method. Diabetes 1990; 39: 1361–5.5 Wan CK, Giacca A, Matsuhisa M, et al. Increased responses of glucagon and glucose production to hypoglycemia with intraperitoneal versus subcutaneous insulin treatment. Metabolism 2000; 49: 984–9.6 Logtenberg SJ, Kleefstra N, Houweling ST, et al. Improved glycemic control with intraperitoneal versus subcutaneous insulin in type 1 diabetes: a randomized controlled trial. Diabetes Care 2009; 32: 1372–7.7 Logtenberg SJ, Kleefstra N, Houweling ST, Groenier KH, Gans RO, Bilo HJ. Health-related quality of life, treatment satisfaction, and costs associated with intraperitoneal versus subcutaneous insulin administration in type 1 diabetes: a randomized controlled trial. Diabetes Care 2010; 33: 1169–72.8 Van Dijk PR, Logtenberg SJJ, Groenier KH, Kleefstra N, Bilo H, Arnqvist H. Effect of intraperitoneal insulin administration on IGF1 and IGFBP1 in type 1 diabetes. Endocr Connect 2013. doi:10.1530/EC-13-0089.9 Haveman JW, Logtenberg SJJ, Kleefstra N, Groenier KH, Bilo HJG, Blomme AM. Surgical aspects and complications of continuous intraperitoneal insulin infusion with an implantable pump. Langenbecks Arch Surg Dtsch Ges Für Chir 2010; 395: 65–71.10 Ware J, Snow K, Kosinski M Gandek: SF-36 Health Survey: Manual and Interpretation Guide. Boston, The Health Institute, New England Medical Center; 1993.11 Ware JE, Kosinski M, Keller SD. SF-36 Physical and Mental Health Summary Scales: A User’s Manual. Boston, The Health Institute, New England Medical Center; 1994.12 World Health Organization, Regional Office for Europe Wellbeing measures in primary health care: the Depcare Project. Report on a WHO Meeting. 1998.13 Bech P, Olsen LR, Kjoller M, Rasmussen NK. Measuring well-being rather than the absence of distress symptoms: a comparison of the SF-36 Mental Health subscale and the WHO-Five Well-Being Scale. Int J Methods Psychiatr Res 2003; 12: 85–91.14 Löwe B, Spitzer RL, Gräfe K, et al. Comparative validity of three screening questionnaires for DSM-IV depressive disorders and physicians’ diagnoses. J Affect Disord 2004; 78: 131–40.15 Bradley C. The Diabetes Treatment Satisfaction Questionnaire: DTSQ. Handbook of Psychology and Diabetes: a guide to psychological measurement in diabetes research and practice Chur: Harwood Academic Publishers, 1994:111-3216 Haardt MJ, Selam JL, Slama G, et al. A cost-benefit comparison of intensive diabetes management with implantable pumps versus multiple subcutaneous injections in patients with type I diabetes. Diabetes Care 1994; 17: 847–51.17 Selam JL, Raccah D, Jean-Didier N, Lozano JL, Waxman K, Charles MA. Randomized comparison of metabolic control achieved by intraperitoneal insulin infusion with implantable pumps versus intensive subcutaneous insulin therapy in type I diabetic patients. Diabetes Care 1992; 15: 53–8.18 Logtenberg SJJ, van Ballegooie E, Israêl-Bultman H, van Linde A, Bilo HJG. Glycaemic control, health status and treat- ment satisfaction with continuous intraperitoneal insulin infusion. Neth J Med 2007; 65: 65–70.19 DeVries JH, Eskes SA, Snoek FJ, et al. Continuous intraperitoneal insulin infusion in patients with ‘brittle’ diabetes: favourable effects on glycaemic control and hospital stay. Diabet Med J Br Diabet Assoc 2002; 19: 496–501.20 Selam JL, Micossi P, Dunn FL, Nathan DM. Clinical trial of programmable implantable insulin pump for type I diabetes. Diabetes Care 1992; 15: 877–85.21 Schaepelynck P, Renard E, Jeandidier N, et al. A recent survey confirms the efficacy and the safety of implanted insulin pumps during long-term use in poorly controlled type 1 diabetes patients. Diabetes Technol Ther 2011; 13: 657–60.
chapter 3part 2
referencesThe switch from SC insulin to CIPII increases QoL, which stabilizes over time 7,20. In the present
study the level of QoL among CIPII treated subjects perpetuated. Nevertheless, as found
in other studies and emphasized by the fact that 42% of all patients had a WHO-5 score
indicating poor emotional well-being, the QoL of these individuals remains poor 1,19,20.
We found the SF-36 subscales role-physical and vitality to be comparable to patients with
a minor (uncomplicated) chronic disease and the other subscales similar to patients with
complicated diabetes or complicated coronary artery disease 27. Still, it is likely that the short
duration of hospital admissions found in the present study (<1 day per year), compared to
45 days per year before implantation of the pump previously described in a similar population,
positively influence QoL and treatment satisfaction 19.
Since CIPII is used as a last treatment option in the Netherlands, the population in the present
study is complex, strictly selected and has a small size. On the other hand, this limitation
reflects general practice nowadays where CIPII is limited to a small number of patients in a
small number of centers. Furthermore, when interpreting the comparisons between CIPII and
previous SC therapy made in this study one should take differences in treatment periods
(e.g.a duration of 6 months of the SC phase during a controlled study versus 6.4 years of
subsequent CIPII therapy) into account. Prospective, long-term and large-scale studies with
respect to glycaemic control, QoL and cost-effectiveness to compare CIPII and SC therapy for
T1DM are imperative.
Conclusions
Taken together, the stable QoL, increased treatment satisfaction, little time spent in hospital
and stable HbA1c combined with a decrease in grade 2 hypoglycaemic events as compared
to previous SC therapy underlines the clinical observation that CIPII is a valuable treatment
option for selected patients with T1DM, also on longer term.
56 57
part 2
22 Catargi B, Meyer L, Melki V, Renard E, Jeandidier N, EVADIAC Study Group. Comparison of blood glucose stability and HbA1C between implantable insulin pumps using U400 HOE 21PH insulin and external pumps using lispro in type 1 diabetic patients: a pilot study. Diabetes Metab 2002; 28: 133–7.23 Gin H, Renard E, Melki V, et al. Combined improvements in implantable pump technology and insulin stability allow safe and effective long term intraperitoneal insulin delivery in type 1 diabetic patients: the EVADIAC experience. Diabetes Metab 2003; 29: 602–7.24 Hanaire-Broutin H, Broussolle C, Jeandidier N, et al. Feasibility of intraperitoneal insulin therapy with programmable implantable pumps in IDDM. A multicenter study. The EVADIAC Study Group. Evaluation dans le Diabète du Traitement par Implants Actifs. Diabetes Care 1995; 18: 388–92.25 Broussolle C, Jeandidier N, Hanaire-Broutin H. French multicentre experience of implantable insulin pumps. The EVADIAC Study Group. Evaluation of Active Implants in Diabetes Society. Lancet 1994; 343: 514–5.26 Oskarsson PR, Lins PE, Backman L, Adamson UC. Continuous intraperitoneal insulin infusion partly restores the glucagon response to hypoglycaemia in type 1 diabetic patients. Diabetes Metab 2000; 26: 118–24.27 McHorney CA, Ware JE Jr, Raczek AE. The MOS 36-Item Short-Form Health Survey (SF-36): II. Psychometric and clinical tests of validity in measuring physical and mental health constructs. Med Care 1993; 31: 247–63.
Observed values at the different moments in time.appendix 1
Data are presented as mean (SD), median [IQR]. Observed values are reported. Abbreviations BMI; body mass index, CIPII; continuous intra-peritoneal insulin infusion, SBP; systolic blood pressure, SC; subcutaneous. *p<0.05. † Defined as a number of blood glucose value <4.0 mmol/l per week. ‡ Defined as a number of blood glucose value <3.5 mmol/l per week.
Start 2006 study End SC phase End CIPII phase 2012 study Clinical parameters SBP (mmHg) 141 (21) 135 (18) 139 (19) 140 (17) BMI (kg/m2) 26.6 (5.2) 26.5 (4.8) 27.5 (5.2) 27.5 (4.5) Total cholesterol 4.8 (0.8) 4.7 (0.9) 4.5 (0.9) 4.8 (1.0) HDL cholesterol 1.8 (0.5) 1.7 (0.5) 1.6 (0.5) 1.7 (0.6) LDL cholesterol 2.7 (0.7) 2.5 (0.7) 2.4 (0.6) 2.8 (0.8) Triglycerides 0.9 (0.4) 1.1 (0.6) 1.2 (0.8) 1.0 (0.5) Total insulin dose [IU/day] 50 [35, 75] 50 [40, 68] 49 [35, 70] 57 [46, 74] Basal insulin dose [IU/day] 28 [22, 31] 26 [13,37] 30 [20, 52] 37 [26, 60] Bolus insulin dose [IU/day] 16 [10, 25] 21 [13,37] 16 [13, 30] 17 [13, 28] Glycaemic parameters HbA1c (mmol/mol) 70 (12) 65 (13) 58 (9) 65 (13) Hypoglycaemia grade 1 † 4 (2, 5) 4 (1, 7) 3 (2, 5) 2 (0, 3) Hypoglycaemia grade 2 ‡ 3 (1, 4) 3 (1, 4) 2 (1, 3) 1 (0, 2) Time in hypoglycaemia (%) 8 (7) 8 (8) 6 (6) 5 (5) Time in hyperglycaemia (%) 45 (16) 47 (20) 39 (19) 59 (20) Time in euglycaemia (%) 47 (12) 45 (16) 55 (18) 36 (19) SF-36 Physical functioning 76 (20) 69 (24) 81 (21) 76 (23) Social functioning 68 (21) 65 (29) 77 (25) 74 (21) Role limitations-physical 38 (11) 42 (11) 66 (11) 57 (11) Role limitations-emotional 68 (10) 68 (9) 86 (9) 77 (9) Mental health 70 (24) 67 (22) 77 (17) 79 (17) Vitality 48 (22) 43 (21) 62 (19) 58 (18) Bodily pain 64 (25) 64 (29) 66 (23) 67 (21) General health 41 (18) 46 (21) 56 (19) 48 (17) Physical component score 56 (18) 55 (24) 69 (20) 63 (21) Mental component score 59 (20) 58 (22) 72 (19) 67 (17) WHO-5-score 50 (21) 48 (25) 70 (21) 60 (22) DSTQ Total score 24 (8) 23 (9) 33 (4) 32 (3) Perceived hypoglycaemia score 3 (2) 4 (2) 3 (2) 3 (1) Perceived hyperglycaemia score 5 (1) 5 (1) 2 (2) 4 (2)
chapter 3
56 57
part 2
22 Catargi B, Meyer L, Melki V, Renard E, Jeandidier N, EVADIAC Study Group. Comparison of blood glucose stability and HbA1C between implantable insulin pumps using U400 HOE 21PH insulin and external pumps using lispro in type 1 diabetic patients: a pilot study. Diabetes Metab 2002; 28: 133–7.23 Gin H, Renard E, Melki V, et al. Combined improvements in implantable pump technology and insulin stability allow safe and effective long term intraperitoneal insulin delivery in type 1 diabetic patients: the EVADIAC experience. Diabetes Metab 2003; 29: 602–7.24 Hanaire-Broutin H, Broussolle C, Jeandidier N, et al. Feasibility of intraperitoneal insulin therapy with programmable implantable pumps in IDDM. A multicenter study. The EVADIAC Study Group. Evaluation dans le Diabète du Traitement par Implants Actifs. Diabetes Care 1995; 18: 388–92.25 Broussolle C, Jeandidier N, Hanaire-Broutin H. French multicentre experience of implantable insulin pumps. The EVADIAC Study Group. Evaluation of Active Implants in Diabetes Society. Lancet 1994; 343: 514–5.26 Oskarsson PR, Lins PE, Backman L, Adamson UC. Continuous intraperitoneal insulin infusion partly restores the glucagon response to hypoglycaemia in type 1 diabetic patients. Diabetes Metab 2000; 26: 118–24.27 McHorney CA, Ware JE Jr, Raczek AE. The MOS 36-Item Short-Form Health Survey (SF-36): II. Psychometric and clinical tests of validity in measuring physical and mental health constructs. Med Care 1993; 31: 247–63.
Observed values at the different moments in time.appendix 1
Data are presented as mean (SD), median [IQR]. Observed values are reported. Abbreviations BMI; body mass index, CIPII; continuous intra-peritoneal insulin infusion, SBP; systolic blood pressure, SC; subcutaneous. *p<0.05. † Defined as a number of blood glucose value <4.0 mmol/l per week. ‡ Defined as a number of blood glucose value <3.5 mmol/l per week.
Start 2006 study End SC phase End CIPII phase 2012 study Clinical parameters SBP (mmHg) 141 (21) 135 (18) 139 (19) 140 (17) BMI (kg/m2) 26.6 (5.2) 26.5 (4.8) 27.5 (5.2) 27.5 (4.5) Total cholesterol 4.8 (0.8) 4.7 (0.9) 4.5 (0.9) 4.8 (1.0) HDL cholesterol 1.8 (0.5) 1.7 (0.5) 1.6 (0.5) 1.7 (0.6) LDL cholesterol 2.7 (0.7) 2.5 (0.7) 2.4 (0.6) 2.8 (0.8) Triglycerides 0.9 (0.4) 1.1 (0.6) 1.2 (0.8) 1.0 (0.5) Total insulin dose [IU/day] 50 [35, 75] 50 [40, 68] 49 [35, 70] 57 [46, 74] Basal insulin dose [IU/day] 28 [22, 31] 26 [13,37] 30 [20, 52] 37 [26, 60] Bolus insulin dose [IU/day] 16 [10, 25] 21 [13,37] 16 [13, 30] 17 [13, 28] Glycaemic parameters HbA1c (mmol/mol) 70 (12) 65 (13) 58 (9) 65 (13) Hypoglycaemia grade 1 † 4 (2, 5) 4 (1, 7) 3 (2, 5) 2 (0, 3) Hypoglycaemia grade 2 ‡ 3 (1, 4) 3 (1, 4) 2 (1, 3) 1 (0, 2) Time in hypoglycaemia (%) 8 (7) 8 (8) 6 (6) 5 (5) Time in hyperglycaemia (%) 45 (16) 47 (20) 39 (19) 59 (20) Time in euglycaemia (%) 47 (12) 45 (16) 55 (18) 36 (19) SF-36 Physical functioning 76 (20) 69 (24) 81 (21) 76 (23) Social functioning 68 (21) 65 (29) 77 (25) 74 (21) Role limitations-physical 38 (11) 42 (11) 66 (11) 57 (11) Role limitations-emotional 68 (10) 68 (9) 86 (9) 77 (9) Mental health 70 (24) 67 (22) 77 (17) 79 (17) Vitality 48 (22) 43 (21) 62 (19) 58 (18) Bodily pain 64 (25) 64 (29) 66 (23) 67 (21) General health 41 (18) 46 (21) 56 (19) 48 (17) Physical component score 56 (18) 55 (24) 69 (20) 63 (21) Mental component score 59 (20) 58 (22) 72 (19) 67 (17) WHO-5-score 50 (21) 48 (25) 70 (21) 60 (22) DSTQ Total score 24 (8) 23 (9) 33 (4) 32 (3) Perceived hypoglycaemia score 3 (2) 4 (2) 3 (2) 3 (1) Perceived hyperglycaemia score 5 (1) 5 (1) 2 (2) 4 (2)
chapter 3
58 59
Van Dijk PR, Logtenberg SJ, Groenier KH, Gans RO, Bilo HJ,
Kleefstra N.
Report of a 7 year case-control study of continuous intra-
peritoneal insulin infusion and subcutaneous insulin therapy
among patients with poorly controlled type 1 diabetes mellitus:
favourable effects on hypoglycaemic episodes. Diabetes Res
Clin Pract 2014
chapter 4 Abstract
introductionContinuous intraperitoneal insulin infusion (CIPII) is a last-resort treatment option for
patients with type 1 diabetes mellitus (T1DM) who fail to reach adequate glycaemic control
with subcutaneous (SC) insulin therapy. Aim of the present study was to compare the long-
term effects of CIPII and SC insulin therapy among patients with T1DM in poor glycaemic
control.
patients and methodsPatients in which CIPII was initiated in 2006 were compared with a control group of T1DM
patients who continued SC therapy. Linear mixed models were used to calculate differences
between the baseline (2006) and final (2013) measurements within and between groups.
resultsA total of 95 patients of which 21 were using CIPII and 74 using SC insulin were included.
Within the CIPII group, the number of hypoglycaemic episodes decreased with -5 (95%
confidence interval (CI) -8, -3) per 2 weeks while it remained stable among SC patients. Over
time, only the number of hypoglycaemic episodes decreased more with CIPII as compared
to SC insulin treatment (difference: -6 (95% CI -9, -4)). There were no differences between
treatment groups regarding HbA1c, clinical parameters and quality of life scores over time.
Pump or catheter dysfunction led to ketoacidosis in 6 patients: 2 using CIPII and 4 using SC
insulin therapy.
conclusionsAfter 7 years of follow-up, there is a persistent decline of hypoglycaemic events among CIPII
treated T1DM patients. Besides less hypoglycaemic episodes with CIPII therapy, there are no
differences between long-term CIPII and SC insulin therapy.
published as
A long-term comparison between continuous intraperitoneal insulin infusion and sub- cutaneous insulin therapy among patients with poorly controlled T1DM: a 7 year case-control study
chapter 4part 2
58 59
Van Dijk PR, Logtenberg SJ, Groenier KH, Gans RO, Bilo HJ,
Kleefstra N.
Report of a 7 year case-control study of continuous intra-
peritoneal insulin infusion and subcutaneous insulin therapy
among patients with poorly controlled type 1 diabetes mellitus:
favourable effects on hypoglycaemic episodes. Diabetes Res
Clin Pract 2014
chapter 4 Abstract
introductionContinuous intraperitoneal insulin infusion (CIPII) is a last-resort treatment option for
patients with type 1 diabetes mellitus (T1DM) who fail to reach adequate glycaemic control
with subcutaneous (SC) insulin therapy. Aim of the present study was to compare the long-
term effects of CIPII and SC insulin therapy among patients with T1DM in poor glycaemic
control.
patients and methodsPatients in which CIPII was initiated in 2006 were compared with a control group of T1DM
patients who continued SC therapy. Linear mixed models were used to calculate differences
between the baseline (2006) and final (2013) measurements within and between groups.
resultsA total of 95 patients of which 21 were using CIPII and 74 using SC insulin were included.
Within the CIPII group, the number of hypoglycaemic episodes decreased with -5 (95%
confidence interval (CI) -8, -3) per 2 weeks while it remained stable among SC patients. Over
time, only the number of hypoglycaemic episodes decreased more with CIPII as compared
to SC insulin treatment (difference: -6 (95% CI -9, -4)). There were no differences between
treatment groups regarding HbA1c, clinical parameters and quality of life scores over time.
Pump or catheter dysfunction led to ketoacidosis in 6 patients: 2 using CIPII and 4 using SC
insulin therapy.
conclusionsAfter 7 years of follow-up, there is a persistent decline of hypoglycaemic events among CIPII
treated T1DM patients. Besides less hypoglycaemic episodes with CIPII therapy, there are no
differences between long-term CIPII and SC insulin therapy.
published as
A long-term comparison between continuous intraperitoneal insulin infusion and sub- cutaneous insulin therapy among patients with poorly controlled T1DM: a 7 year case-control study
chapter 4part 2
60 61
Introduction
The mainstay of type 1 diabetes mellitus (T1DM) treatment consists of subcutaneous (SC)
insulin administration using multiple daily injections (MDI) or continuous subcutaneous
insulin infusion (CSII) with an external pump. Although most patients achieve acceptable
glycaemic control using MDI or CSII, a relatively small group of patients fails to reach adequate
glycaemic control, have high blood glucose variability, frequent hypoglycaemic episodes
(often with hypoglycaemia unawareness) or SC insulin resistance, despite intensive SC insulin
therapy.
One alternative treatment option for this group of patients is continuous intraperitoneal
insulin infusion (CIPII) using an implanted pump. With CIPII the SC compartment is bypassed
and the physiological route of insulin is largely mimicked as intraperitoneally administered
insulin diffuses predominantly through the portal vein flow bed, which results in higher
hepatic insulin uptake, alleviation of peripheral plasma insulin concentrations and a more
rapid and predictable insulin action 1–4.
The 3 randomized clinical studies that compared CIPII with SC insulin treatment in T1DM
patients reported improved glycaemic control without an increase in hypoglycaemic episodes 5–7. In addition, quality of life (QoL) and treatment satisfaction improved during CIPII treatment 8. However, the duration of these studies was rather short (6 months) and available long-term
observational studies lack a control group of patients treated with SC therapy 9,10.
In order to compare the long-term effects of CIPII and SC insulin administration, we performed
a case-control study among patients with T1DM and poor glycaemic control.
Patients and methods
study designThis is a retrospective case-control study in the period 2006 to 2013 performed in a single
centre (Isala, Zwolle, the Netherlands). In the present study, cases and controls were derived
from 2 different cohorts of T1DM patients. Cases, using CIPII therapy, were derived from a
cohort which initiated CIPII therapy in 2006 and controls, using SC insulin therapy, were
selected from another T1DM cohort in the Isala.
study populationCases were derived from a previous randomized, cross-over study in 2006 in which CIPII was
initiated 5. Primary aim of that 16-month study was to investigate the effects of CIPII compared
to intensive SC insulin treatment. In brief, patients with T1DM in poor glycaemic control,
defined as HbA1c ≥7.5% (58 mmol/mol) and/or ≥5 incidents of hypoglycaemia (<4.0 mmol/l)
per week, who were aged 18-70 years and treated with SC insulin, were included.
Control patients were selected from a prospective T1DM cohort study, initiated in 1995 at
the Isala. The full study design has been published in detail previously 11. In brief, from 1995
onwards all patients were examined (both physical and biochemical) annually at the same
diabetes outpatient clinic and completed questionnaires, all according to standardized
protocol. Patients were selected as controls for the present study if (1) they would have been
eligible to participate in the 2006 cross-over study according to abovementioned criteria but
(2) did not participate and instead continued SC insulin (both MDI and CSII) treatment over
time and (3) completed participation in the prospective cohort study from 2006 until 2013.
Exclusion criteria were identical for cases and controls and included: impaired renal function
(plasma creatinine ≥150 µmol/l or estimated glomerular filtration rate ≤50ml/min/1,73m²),
cardiac problems (unstable angina or myocardial infarction within the previous 12 months
or New York Heart Association class III or IV congestive heart failure), cognitive dysfunction,
current or past psychiatric treatment for schizophrenia, cognitive or bipolar disorder, current
use or oral corticosteroids or suffering from a condition which necessitated oral or systemic
corticosteroids use more than once in the previous 12 months, substance abuse other than
nicotine, current pregnancy or plans to become pregnant during the trial and plans to engage
in activities that require going >25 feet below sea level 5,8.
After completion of the 2006 cross-over study all CIPII treated patients chose to continue with
CIPII. Between 2006 and 2013, all patients received standard care at our outpatient clinic which
consisted of insulin refills every 6-12 weeks and an rinse procedure with NaOH was performed
every 9 months or in case of insulin underdelivery. Insulin (U-400 HOE 21PH, semi synthetic
human insulin of porcine origin, trade name: Insuplant® Hoechst, Frankfurt, Germany,
nowadays Sanofi-Aventis) was administered with the implantable pump. Since there were
no batches left of the U400 semi synthetic human insulin, a new human recombinant insulin
(400 IU/ml; human insulin of E. Coli origin, trade name: Insuman Implantable®, Sanofi-Aventis)
was used from 2010 onwards. Details about the implantable pump and CIPII treatment (e.g.
insulin dosage and refill procedures) have been described in detail previously 12,13.
chapter 4part 2
60 61
Introduction
The mainstay of type 1 diabetes mellitus (T1DM) treatment consists of subcutaneous (SC)
insulin administration using multiple daily injections (MDI) or continuous subcutaneous
insulin infusion (CSII) with an external pump. Although most patients achieve acceptable
glycaemic control using MDI or CSII, a relatively small group of patients fails to reach adequate
glycaemic control, have high blood glucose variability, frequent hypoglycaemic episodes
(often with hypoglycaemia unawareness) or SC insulin resistance, despite intensive SC insulin
therapy.
One alternative treatment option for this group of patients is continuous intraperitoneal
insulin infusion (CIPII) using an implanted pump. With CIPII the SC compartment is bypassed
and the physiological route of insulin is largely mimicked as intraperitoneally administered
insulin diffuses predominantly through the portal vein flow bed, which results in higher
hepatic insulin uptake, alleviation of peripheral plasma insulin concentrations and a more
rapid and predictable insulin action 1–4.
The 3 randomized clinical studies that compared CIPII with SC insulin treatment in T1DM
patients reported improved glycaemic control without an increase in hypoglycaemic episodes 5–7. In addition, quality of life (QoL) and treatment satisfaction improved during CIPII treatment 8. However, the duration of these studies was rather short (6 months) and available long-term
observational studies lack a control group of patients treated with SC therapy 9,10.
In order to compare the long-term effects of CIPII and SC insulin administration, we performed
a case-control study among patients with T1DM and poor glycaemic control.
Patients and methods
study designThis is a retrospective case-control study in the period 2006 to 2013 performed in a single
centre (Isala, Zwolle, the Netherlands). In the present study, cases and controls were derived
from 2 different cohorts of T1DM patients. Cases, using CIPII therapy, were derived from a
cohort which initiated CIPII therapy in 2006 and controls, using SC insulin therapy, were
selected from another T1DM cohort in the Isala.
study populationCases were derived from a previous randomized, cross-over study in 2006 in which CIPII was
initiated 5. Primary aim of that 16-month study was to investigate the effects of CIPII compared
to intensive SC insulin treatment. In brief, patients with T1DM in poor glycaemic control,
defined as HbA1c ≥7.5% (58 mmol/mol) and/or ≥5 incidents of hypoglycaemia (<4.0 mmol/l)
per week, who were aged 18-70 years and treated with SC insulin, were included.
Control patients were selected from a prospective T1DM cohort study, initiated in 1995 at
the Isala. The full study design has been published in detail previously 11. In brief, from 1995
onwards all patients were examined (both physical and biochemical) annually at the same
diabetes outpatient clinic and completed questionnaires, all according to standardized
protocol. Patients were selected as controls for the present study if (1) they would have been
eligible to participate in the 2006 cross-over study according to abovementioned criteria but
(2) did not participate and instead continued SC insulin (both MDI and CSII) treatment over
time and (3) completed participation in the prospective cohort study from 2006 until 2013.
Exclusion criteria were identical for cases and controls and included: impaired renal function
(plasma creatinine ≥150 µmol/l or estimated glomerular filtration rate ≤50ml/min/1,73m²),
cardiac problems (unstable angina or myocardial infarction within the previous 12 months
or New York Heart Association class III or IV congestive heart failure), cognitive dysfunction,
current or past psychiatric treatment for schizophrenia, cognitive or bipolar disorder, current
use or oral corticosteroids or suffering from a condition which necessitated oral or systemic
corticosteroids use more than once in the previous 12 months, substance abuse other than
nicotine, current pregnancy or plans to become pregnant during the trial and plans to engage
in activities that require going >25 feet below sea level 5,8.
After completion of the 2006 cross-over study all CIPII treated patients chose to continue with
CIPII. Between 2006 and 2013, all patients received standard care at our outpatient clinic which
consisted of insulin refills every 6-12 weeks and an rinse procedure with NaOH was performed
every 9 months or in case of insulin underdelivery. Insulin (U-400 HOE 21PH, semi synthetic
human insulin of porcine origin, trade name: Insuplant® Hoechst, Frankfurt, Germany,
nowadays Sanofi-Aventis) was administered with the implantable pump. Since there were
no batches left of the U400 semi synthetic human insulin, a new human recombinant insulin
(400 IU/ml; human insulin of E. Coli origin, trade name: Insuman Implantable®, Sanofi-Aventis)
was used from 2010 onwards. Details about the implantable pump and CIPII treatment (e.g.
insulin dosage and refill procedures) have been described in detail previously 12,13.
chapter 4part 2
62 63
measurements For cases, measurements prior to pump implantation were used as baseline measurements
and the last available measurements in 2013 were used as final measurements. For controls,
the measurements during the annual check-up at the outpatient clinic in 2006 were used
as baseline measurements and the last available measurements in 2013 were used as final
measurements.
Clinical and biochemical parameters were collected from standardized electronic patient
charts and included: smoking (no or ever/current) and alcohol (yes/no) habits, married/
cohabiting (yes/no), date of diagnosis of diabetes, presence of microvascular- (nephropathy,
neuropathy or retinopathy) or macrovascular complications (angina pectoris, myocardial
infarction, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty,
stroke, transient ischaemic attack, peripheral artery disease), body mass index (BMI), daily
insulin dose, number of self-reported hypoglycaemic events <4.0 mmol/l and needing third
party help during the last 14 days, systolic blood pressure, total cholesterol, high density
lipoprotein (HDL) and low density lipoprotein (LDL), triglycerides and HbA1c. HbA1c level
was measured with a Primus Ultra2 system using high-performance liquid chromatography
(reference value 4.0-6.0% (20-42 mmol/mol)). For QoL assessment, the 36-item short-form
health survey (SF-36) questionnaire was used. The SF-36 is a widely used, generic questionnaire
with 36 items involving 8 subscales and a physical and mental component score. Scores range
from 0 to 100, with higher scores indicating better QoL 14,15.
outcomesPrimary outcome was the change in HbA1c from 2006 until 2013 between the patients treated
with CIPII or SC insulin. Secondary outcomes included HbA1c change within groups and
changes within and between groups in hypoglycaemic episodes, QoL, clinical and biochemical
parameters. Additionally, the between group differences for HbA1c and QoL measures were
corrected for the number of hypoglycaemic episodes (<4.0 mmol/l during the last 2 weeks) on
baseline, accordingly, the change in hypoglycaemic episodes between groups was corrected
for HbA1c. Furthermore, subanalysis were performed among patients with baseline HbA1c
≥7.5% (58 mmol/mol), ≥5 incidents of hypoglycaemia (<4.0 mmol/l) per week or both. Finally,
complications related to the mode of insulin administration (i.e. CIPII, MDI and CSII) were
analysed.
statistical analysisStatistical analyses were performed using SPSS (IBM SPSS Statistics for Windows, Version
20.0. Armonk, NY: IBM Corp.). Results are expressed as mean (with standard deviation (SD)) or
median (with interquartile range [IQR]) for normally distributed and non-normally distributed
data, respectively. Q-Q plots were used to determine if the tested variable had a normal
distribution or not. Where appropriate, paired parametric and non-parametric tests were used
to compare baseline data between groups. Linear mixed models (with Bonferroni correction
where applicable) were used to calculate and test estimated values and difference between the
2 moments in time and between patients treated with CIPII or SC (both MDI and CSII) insulin.
Both observed and estimated values are reported. A (two-sided) p-value of less than 0.05 was
considered statistically significant.
ethical considerationsBoth studies were performed in accordance with the Declaration of Helsinki. For both studies
informed consent was obtained from all patients. Both study protocols were approved by the
local medical ethics committee.
Results
patient selectionOf all 23 patients who started CIPII in 2006 and completed the randomized cross-over trial,
22 were still treated with CIPII in 2013. One patient stopped CIPII treatment after 2 years due
to neuropathic pains, for which the patient blamed the implanted pump. One female patient
was excluded from the current analysis due to chronic corticosteroid use for myasthenia gravis.
Therefore, 21 patients using CIPII were included as cases in the present analysis.
Concerning the control patients, of the 195 patients who were followed from 2006 onwards,
78 patients were not eligible for inclusion: 65 patients due to a mean HbA1c <7.5% (58 mmol/
mol) in 2006, 9 patients were aged over 70 years, 2 patients switched from CSII to CIPII during
follow-up, 1 patient had a C-peptide concentration of 0.4 nmol/l and 1 patient had a plasma
creatinine ≥150 µmol/l. Of the remaining 117 patients, 13 switched from MDI towards CSII and
30 patients were lost to follow-up. Therefore, 74 control patients who used SC insulin therapy
were included in the present analysis.
chapter 4part 2
62 63
measurements For cases, measurements prior to pump implantation were used as baseline measurements
and the last available measurements in 2013 were used as final measurements. For controls,
the measurements during the annual check-up at the outpatient clinic in 2006 were used
as baseline measurements and the last available measurements in 2013 were used as final
measurements.
Clinical and biochemical parameters were collected from standardized electronic patient
charts and included: smoking (no or ever/current) and alcohol (yes/no) habits, married/
cohabiting (yes/no), date of diagnosis of diabetes, presence of microvascular- (nephropathy,
neuropathy or retinopathy) or macrovascular complications (angina pectoris, myocardial
infarction, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty,
stroke, transient ischaemic attack, peripheral artery disease), body mass index (BMI), daily
insulin dose, number of self-reported hypoglycaemic events <4.0 mmol/l and needing third
party help during the last 14 days, systolic blood pressure, total cholesterol, high density
lipoprotein (HDL) and low density lipoprotein (LDL), triglycerides and HbA1c. HbA1c level
was measured with a Primus Ultra2 system using high-performance liquid chromatography
(reference value 4.0-6.0% (20-42 mmol/mol)). For QoL assessment, the 36-item short-form
health survey (SF-36) questionnaire was used. The SF-36 is a widely used, generic questionnaire
with 36 items involving 8 subscales and a physical and mental component score. Scores range
from 0 to 100, with higher scores indicating better QoL 14,15.
outcomesPrimary outcome was the change in HbA1c from 2006 until 2013 between the patients treated
with CIPII or SC insulin. Secondary outcomes included HbA1c change within groups and
changes within and between groups in hypoglycaemic episodes, QoL, clinical and biochemical
parameters. Additionally, the between group differences for HbA1c and QoL measures were
corrected for the number of hypoglycaemic episodes (<4.0 mmol/l during the last 2 weeks) on
baseline, accordingly, the change in hypoglycaemic episodes between groups was corrected
for HbA1c. Furthermore, subanalysis were performed among patients with baseline HbA1c
≥7.5% (58 mmol/mol), ≥5 incidents of hypoglycaemia (<4.0 mmol/l) per week or both. Finally,
complications related to the mode of insulin administration (i.e. CIPII, MDI and CSII) were
analysed.
statistical analysisStatistical analyses were performed using SPSS (IBM SPSS Statistics for Windows, Version
20.0. Armonk, NY: IBM Corp.). Results are expressed as mean (with standard deviation (SD)) or
median (with interquartile range [IQR]) for normally distributed and non-normally distributed
data, respectively. Q-Q plots were used to determine if the tested variable had a normal
distribution or not. Where appropriate, paired parametric and non-parametric tests were used
to compare baseline data between groups. Linear mixed models (with Bonferroni correction
where applicable) were used to calculate and test estimated values and difference between the
2 moments in time and between patients treated with CIPII or SC (both MDI and CSII) insulin.
Both observed and estimated values are reported. A (two-sided) p-value of less than 0.05 was
considered statistically significant.
ethical considerationsBoth studies were performed in accordance with the Declaration of Helsinki. For both studies
informed consent was obtained from all patients. Both study protocols were approved by the
local medical ethics committee.
Results
patient selectionOf all 23 patients who started CIPII in 2006 and completed the randomized cross-over trial,
22 were still treated with CIPII in 2013. One patient stopped CIPII treatment after 2 years due
to neuropathic pains, for which the patient blamed the implanted pump. One female patient
was excluded from the current analysis due to chronic corticosteroid use for myasthenia gravis.
Therefore, 21 patients using CIPII were included as cases in the present analysis.
Concerning the control patients, of the 195 patients who were followed from 2006 onwards,
78 patients were not eligible for inclusion: 65 patients due to a mean HbA1c <7.5% (58 mmol/
mol) in 2006, 9 patients were aged over 70 years, 2 patients switched from CSII to CIPII during
follow-up, 1 patient had a C-peptide concentration of 0.4 nmol/l and 1 patient had a plasma
creatinine ≥150 µmol/l. Of the remaining 117 patients, 13 switched from MDI towards CSII and
30 patients were lost to follow-up. Therefore, 74 control patients who used SC insulin therapy
were included in the present analysis.
chapter 4part 2
64 65
baseline patient characteristicsThe baseline characteristics of all patients (n=95), those initiating CIPII (n=21) and those
continuing SC insulin therapy (n=74) are presented in Table 1 (more detailed information
is available in Appendix 1). In the SC insulin group, 41 patients used MDI and 33 used CSII
throughout follow-up. Patients who initiated CIPII therapy in 2006 had more frequent
neuropathy and reported more hypoglycaemic episodes than those who continued SC insulin
therapy. Furthermore, patients who initiated CIPII had significantly lower scores on the SF-36
subscales physical functioning, social functioning, role limitations due to physical problems,
vitality, bodily pain, general health perception and on the mental component and physical
component scores as compared to patients who continued SC insulin therapy. Patients who
initiated CIPII had a higher systolic blood pressure and a lower LDL-cholesterol as compared
to patients who continued SC therapy with CSII. Within the SC group, there were no baseline
differences between patients on MDI or CSII (see Appendix 2).
changes during follow-up - HbA1cThe observed changes of HbA1c during the 7 (1) years follow-up are presented in Table 1 and in
Figure 1. The estimated differences within and between the treatment groups are presented in
Table 2. HbA1c decreased significantly from 8.7 to 8.1% (72 to 65 mmol/mol) with a difference
of -0.6% (95% CI -1.1, -0.1) (-7 mmol/mol (95% CI -12, -1)) among CIPII treated patients. For
patients on SC insulin therapy, HbA1c did not change. Over time, there was no significant
difference between the CIPII and SC insulin therapy group regarding the HbA1c (difference:
-0.5% (95% CI -1.0, 0.2)) (-5 mmol/mol (95% CI -11, 2)). After adjustment for hypoglycaemic
episodes at baseline the difference between treatment groups was -0.2% (95% CI -0.8, 0.4) (-2
mmol/mol (95% CI -9, 4)). In subanalysis among patients with a baseline HbA1c concentration
≥7.5% (58 mmol/mol) (n=92), there were also no differences in HbA1c over time between the
CIPII and SC insulin therapy present (see Appendix 3).
changes during follow-up - hypoglycaemic episodesThe number of hypoglycaemic episodes decreased from 9 to 3 episodes per 2 weeks with a
difference of -5 (95% CI -8, -3) among CIPII treated patients while it remained stable among
patients treated with SC insulin therapy (see Table 2). The difference over time between
the two treatment modalities was -6 (95% CI -9, -4) episodes per 2 weeks in favour of CIPII
treated patients, remained the same after adjustment for HbA1c and was also present when
comparing MDI and CSII treated patients with CIPII (see Appendix 4).
chapter 4part 2
Observed data at the start and end of follow-up for all-, CIPII- and SC insulin treated patients.tabel 1
Data are presented as n (%), mean (SD) or median [IQR]. Abbreviations: BMI; body mass index, CIPII; continuous intraperitoneal infusion, MCS; mental component score, PCS; physical component score, SC; subcutaneous. † Categories may not add up due to multiple complications per patient. ‡ Defined as the number of blood glucose value <4.0 mmol/l during the last 2 weeks. *p<0.05 as compared to CIPII, p-values are based on appropriate parametric and non-parametric tests. Additional clinical and biochemical variables are presented in Appendix 1.
All patients (n=95)
CIPII (n=21) Start
End
SC (n=74) Start
End
Clinical and biochemical Age (years) 47 (10) 44 (11) 47 (9) Female sex (n) 40 (42) 10 (48) 30 (41) Diabetes duration (years) 22 (10) 21 (9) 22 (10) BMI (kg/m2) 28 (5) 27 (5) 26 (5) 28 (4) 29 (5)* Systolic blood pressure (mmHg) 137 (16) 142 (21) 140 (16) 136 (14)* 129 (14) * Microvascular complication (n) † 44 (46) 9 (43) 12 (57) 35 (47) 49 (66)
Retinopathy (n) 39 (41) 5 (24) 6 (29) 34 (46) 52 (70)* Neuropathy (n) 14 (15) 9 (43) 10 (48) 5 (7) * 8 (11)* Nephropathy (n) 8 (8) 2 (10) 2 (10) 6 (8) 6 (8)
Macrovascular complication (n) 9 (9) 1 (5) 3 (14) 8 (11) 13 (18) Total cholesterol (mmol/l) 5.2 (1.0) 4.9 (0.8) 4.7 (0.9) 5.2 (1.0) 4.8 (0.9) LDL cholesterol (mmol/l) 2.9 (0.8) 2.7 (0.7) 2.5 (0.8) 3.0 (0.9) 2.6 (0.7) HbA1c (%) 8.4 (0.9) 8.7 (1.4) 8.1 (1.1) 8.4 (0.7) 8.2 (0.7) HbA1c (mmol/mol) 68 (10) 72 (15) 65 (12) 68 (8) 66 (8) Hypoglycaemic events‡ 2 [1, 4] 9 [4, 10] 2 [0, 5] 1 [0, 2]* 2 [1,4] Hypoglycaemic events needing help 0 [0, 0] 0 [0, 0] 0 [0, 0] 0 [0, 0] 0 [0, 0]
Total insulin dose (IU/day) 53 [42, 69] 50 [35, 70] 57 [46, 47] 56 [45, 69] 55 [43, 69] SF-36 subscales Physical functioning 95 [80, 100] 80 [61, 90] 85 [65, 95] 95 [85, 100]* 95 [ 85, 100] Social functioning 88 [62.5,100] 69 [50,75] 75 [63, 100] 88 [75, 100]* 88 [74, 100] Role limitations-physical 100 [50, 100] 25 [0, 75] 25 [0, 100] 100 [75, 100]* 100 [63, 100] Role limitations-emotional 100 [75, 100] 100 [8, 100] 100 [67, 100] 100 [100, 100] 100 [100, 100] Mental health 80 [64, 88] 74 [53, 88] 84 [72, 92] 84 [68, 88] 80 [71, 80] Vitality 60 [45, 80] 53 [30, 60] 55 [45, 75] 65 [50, 80]* 65 [55, 80] Bodily pain 84 [62, 100] 62 [41, 83] 72 [51, 84] 100 [62, 100]* 84 [64, 100] General health 62 [47, 73] 36 [25, 55] 42 [35, 57] 67 [50, 77]* 67 [52, 77] SF-36 component scores Mental 74 [58, 87] 60 [48, 72] 71 [62, 84] 77 [66, 88]* 81 [68, 88] Physical 77 [56, 88] 53 [43, 69] 56 [45, 82] 82 [68, 90] 84 [63, 89]
64 65
baseline patient characteristicsThe baseline characteristics of all patients (n=95), those initiating CIPII (n=21) and those
continuing SC insulin therapy (n=74) are presented in Table 1 (more detailed information
is available in Appendix 1). In the SC insulin group, 41 patients used MDI and 33 used CSII
throughout follow-up. Patients who initiated CIPII therapy in 2006 had more frequent
neuropathy and reported more hypoglycaemic episodes than those who continued SC insulin
therapy. Furthermore, patients who initiated CIPII had significantly lower scores on the SF-36
subscales physical functioning, social functioning, role limitations due to physical problems,
vitality, bodily pain, general health perception and on the mental component and physical
component scores as compared to patients who continued SC insulin therapy. Patients who
initiated CIPII had a higher systolic blood pressure and a lower LDL-cholesterol as compared
to patients who continued SC therapy with CSII. Within the SC group, there were no baseline
differences between patients on MDI or CSII (see Appendix 2).
changes during follow-up - HbA1cThe observed changes of HbA1c during the 7 (1) years follow-up are presented in Table 1 and in
Figure 1. The estimated differences within and between the treatment groups are presented in
Table 2. HbA1c decreased significantly from 8.7 to 8.1% (72 to 65 mmol/mol) with a difference
of -0.6% (95% CI -1.1, -0.1) (-7 mmol/mol (95% CI -12, -1)) among CIPII treated patients. For
patients on SC insulin therapy, HbA1c did not change. Over time, there was no significant
difference between the CIPII and SC insulin therapy group regarding the HbA1c (difference:
-0.5% (95% CI -1.0, 0.2)) (-5 mmol/mol (95% CI -11, 2)). After adjustment for hypoglycaemic
episodes at baseline the difference between treatment groups was -0.2% (95% CI -0.8, 0.4) (-2
mmol/mol (95% CI -9, 4)). In subanalysis among patients with a baseline HbA1c concentration
≥7.5% (58 mmol/mol) (n=92), there were also no differences in HbA1c over time between the
CIPII and SC insulin therapy present (see Appendix 3).
changes during follow-up - hypoglycaemic episodesThe number of hypoglycaemic episodes decreased from 9 to 3 episodes per 2 weeks with a
difference of -5 (95% CI -8, -3) among CIPII treated patients while it remained stable among
patients treated with SC insulin therapy (see Table 2). The difference over time between
the two treatment modalities was -6 (95% CI -9, -4) episodes per 2 weeks in favour of CIPII
treated patients, remained the same after adjustment for HbA1c and was also present when
comparing MDI and CSII treated patients with CIPII (see Appendix 4).
chapter 4part 2
Observed data at the start and end of follow-up for all-, CIPII- and SC insulin treated patients.tabel 1
Data are presented as n (%), mean (SD) or median [IQR]. Abbreviations: BMI; body mass index, CIPII; continuous intraperitoneal infusion, MCS; mental component score, PCS; physical component score, SC; subcutaneous. † Categories may not add up due to multiple complications per patient. ‡ Defined as the number of blood glucose value <4.0 mmol/l during the last 2 weeks. *p<0.05 as compared to CIPII, p-values are based on appropriate parametric and non-parametric tests. Additional clinical and biochemical variables are presented in Appendix 1.
All patients (n=95)
CIPII (n=21) Start
End
SC (n=74) Start
End
Clinical and biochemical Age (years) 47 (10) 44 (11) 47 (9) Female sex (n) 40 (42) 10 (48) 30 (41) Diabetes duration (years) 22 (10) 21 (9) 22 (10) BMI (kg/m2) 28 (5) 27 (5) 26 (5) 28 (4) 29 (5)* Systolic blood pressure (mmHg) 137 (16) 142 (21) 140 (16) 136 (14)* 129 (14) * Microvascular complication (n) † 44 (46) 9 (43) 12 (57) 35 (47) 49 (66)
Retinopathy (n) 39 (41) 5 (24) 6 (29) 34 (46) 52 (70)* Neuropathy (n) 14 (15) 9 (43) 10 (48) 5 (7) * 8 (11)* Nephropathy (n) 8 (8) 2 (10) 2 (10) 6 (8) 6 (8)
Macrovascular complication (n) 9 (9) 1 (5) 3 (14) 8 (11) 13 (18) Total cholesterol (mmol/l) 5.2 (1.0) 4.9 (0.8) 4.7 (0.9) 5.2 (1.0) 4.8 (0.9) LDL cholesterol (mmol/l) 2.9 (0.8) 2.7 (0.7) 2.5 (0.8) 3.0 (0.9) 2.6 (0.7) HbA1c (%) 8.4 (0.9) 8.7 (1.4) 8.1 (1.1) 8.4 (0.7) 8.2 (0.7) HbA1c (mmol/mol) 68 (10) 72 (15) 65 (12) 68 (8) 66 (8) Hypoglycaemic events‡ 2 [1, 4] 9 [4, 10] 2 [0, 5] 1 [0, 2]* 2 [1,4] Hypoglycaemic events needing help 0 [0, 0] 0 [0, 0] 0 [0, 0] 0 [0, 0] 0 [0, 0]
Total insulin dose (IU/day) 53 [42, 69] 50 [35, 70] 57 [46, 47] 56 [45, 69] 55 [43, 69] SF-36 subscales Physical functioning 95 [80, 100] 80 [61, 90] 85 [65, 95] 95 [85, 100]* 95 [ 85, 100] Social functioning 88 [62.5,100] 69 [50,75] 75 [63, 100] 88 [75, 100]* 88 [74, 100] Role limitations-physical 100 [50, 100] 25 [0, 75] 25 [0, 100] 100 [75, 100]* 100 [63, 100] Role limitations-emotional 100 [75, 100] 100 [8, 100] 100 [67, 100] 100 [100, 100] 100 [100, 100] Mental health 80 [64, 88] 74 [53, 88] 84 [72, 92] 84 [68, 88] 80 [71, 80] Vitality 60 [45, 80] 53 [30, 60] 55 [45, 75] 65 [50, 80]* 65 [55, 80] Bodily pain 84 [62, 100] 62 [41, 83] 72 [51, 84] 100 [62, 100]* 84 [64, 100] General health 62 [47, 73] 36 [25, 55] 42 [35, 57] 67 [50, 77]* 67 [52, 77] SF-36 component scores Mental 74 [58, 87] 60 [48, 72] 71 [62, 84] 77 [66, 88]* 81 [68, 88] Physical 77 [56, 88] 53 [43, 69] 56 [45, 82] 82 [68, 90] 84 [63, 89]
66 67
chapter 4part 2
Course of the HbA1c over time.
figure 1
Course of the HbA1c (estimated mean with 95% CI) in the period 2006 (baseline) and 2013 (end) among T1DM patients treated with CIPII (consecutive line) or SC (dotted line) insulin therapy.
The number of hypoglycaemic episodes needing help decreased among CIPII treated patients
(difference: -0.3 (95% CI -0.7, 0.0)). Because the number of hypoglycaemic episodes needing
help among SC patients remained the same the difference in the change over time between
treatment modes was the same as the decrease for CIPII patients (difference: -0.3 (95% CI -0.7,
0.0)) unadjusted as well as adjusted for baseline HbA1c. Subanalysis among patients with
≥5 incidents of hypoglycaemia per week at baseline (n=15) demonstrated that among patients
who started CIPII treatment, the number of hypoglycaemic episodes decreased from 11 to 4
episodes per 2 weeks with a difference of -7 (95%CI -12, -3) (see Appendix 3).
changes during follow-up - clinical and biochemical parameters and QoLAmong patients who started CIPII, clinical and biochemical parameters other than HbA1c and
hypoglycaemic episodes remained stable (see Table 2). For patients who continued SC insulin
therapy there was a decrease of the systolic blood pressure, from 135 to 129 mmHg with a
difference of -6 mmHg (95% CI -11, -1). Furthermore, among these patients the total cholesterol
decreased from 5.2 to 4.8 mmol/l in 2013 (difference: -0.4 (95% CI -0.7, -0.1)).
There were no changes in the SF-36 scores within and between the CIPII and SC group (see
Table 2). However, after adjustment for the number of hypoglycaemic episodes there was
significant change of the component scale ‘general health’ (difference: 12 (95% CI 4, 20) and
physical component score (difference: 10 (95% CI 3, 18) in favour of CIPII treated patients.
Estim
ated
dat
a and
chan
ges d
urin
g fol
low
-up
for C
IPII
and
SC in
sulin
trea
ted
patie
nts.
tabe
l 2
Dat
a are
pre
sent
ed as
estim
ated
mea
n (9
5% co
nfide
nce i
nter
val)
and
mea
n ch
ange
s (95
% co
nfide
nce i
nter
val )
with
line
ar m
ixed
mod
els.
Abbr
evia
tions
: BM
I; bo
dy m
ass i
ndex
, CIP
II; co
ntin
uous
in
trape
riton
eal i
nfus
ion,
MCS
; men
tal c
ompo
nent
scor
e, PC
S; p
hysic
al co
mpo
nent
scor
e SC;
subc
utan
eous
. * p
<0.0
5.
CI
PII
Star
t
End
With
in g
roup
Δ
SC
Star
t
End
With
in g
roup
Δ
Δ Be
twee
n CI
PII
and
SC
Clin
ical a
nd b
ioch
emica
l
Syst
olic
bloo
d pr
essu
re (m
mH
g)
142 (
134,
148)
14
0 (1
34, 1
46)
-2 (-
11, 8
) 13
5 (13
2, 13
9)
129
(127
, 133
) -6
(-11
, -1)
* 4
(-6, 1
4)
BMI (
kg/m
2 ) 27
(25,
28)
26 (2
4, 28
) -1
(-4,
2)
28 (2
7, 29
) 29
(28,
30)
1 (-1
, 2)
-1 (-
5, 2)
To
tal c
hole
ster
ol (m
mol
/l)
4.9
(4.5
, 5.4
) 4.
7 (4.
3, 5.
1)
-0.3
(-0.
8, 0
.3)
5.2 (
4.9,
5.4)
4.
8 (4
.6, 5
.0)
-0.4
(-0.
7, -0
.1)*
0.2 (
-0.5
, 0.8
) LD
L cho
lest
erol
(mm
ol/l)
2.
7 (2.
4, 3.
1)
2.6
(2.3
, 3.0
) -0
.1 (-0
.6, 0
.4)
3.1 (
2.8,
3.4)
3.
1 (2.
6, 3.
5)
0.0
(-1, 1
) -0
.1 (-0
.8, 0
.6)
HbA
1c (%
) 8.
7 (8.
3, 9
.1)
8.1 (
7.7,
8.5
) -0
.6 (-
1.1, -
0.1)
8.
4 (8
.1, 8
.6)
8.2 (
8.0,
8.4
) -0
.2 (-
0.5,
0.1)
-0
.5 (-
1.0, 0
.2)
HbA
1c (m
mol
/mol
) 72
(67,
76)
65 (6
1, 69
) -7
(-12
, -1)
* 68
(65,
70)
66 (6
4, 6
8)
-2 (-
5, 1)
-5
(-11
, 2)
Hyp
ogly
caem
ic ev
ents
‡
9 (7
, 10)
3 (
2, 5)
-5
(-8,
-3)
2 (1,
3)
3 (2,
3)
1 (-0
.3, 2
) -6
(-9,
-4)*
H
ypog
lyca
emic
even
ts n
eedi
ng h
elp
0.4
(0.1,
0.6
) 0.
1 (-0
.1, 0
.2)
-0.3
(-0.
7, -0
.0)*
0.
1 (0.
0, 0
.2)
0.1 (
0.0,
0.2
) 0.
0 (-0
.1, 0
.2)
-0.3
(-0.
7,-0
.0)*
To
tal i
nsul
in d
ose (
IU/d
ay)
54 (4
4, 6
3)
65 (5
1, 78
) 11
(-5,
27)
57 (5
1, 63
) 59
(51,
67)
2 (-8
, 12)
9
(-10,
28)
SF-3
6 sub
scal
es
Ph
ysica
l fun
ctio
ning
75
(67,
83)
76
(68,
84)
2 (
-9, 1
3)
89 (8
5, 9
3)
89 (8
4, 9
3)
-1 (-
7, 5)
2 (
-10,
15)
Socia
l fun
ctio
ning
66
(58,
75)
74 (6
6, 8
3)
8 (-4
, 20)
85
(81,
90)
85 (8
0, 8
9)
-1 (-
7, 6
) 9
(-5, 2
3)
Role
lim
itatio
ns-p
hysic
al
41 (2
6, 57
) 51
(34,
68)
10
(-13
, 33)
80
(73,
89)
80
(71,
89)
-1 (-
13, 1
1)
11 (-
14, 3
7)
Role
lim
itatio
ns-e
mot
iona
l 70
(55,
86)
77
(62,
93)
7 (
-15,
29)
85 (7
7, 9
3)
86 (7
8, 9
5)
1 (-1
0, 13
) 6
(-19,
31)
Men
tal h
ealth
69
(60,
78)
79 (6
6, 9
2)
11 (-
5, 26
) 77
(72,
81)
81
(74,
88)
5 (
-4, 1
3)
6 (-1
2, 24
) Vi
talit
y 48
(39,
57)
58 (4
9, 6
7)
10 (-
3, 22
) 65
(60,
70)
65 (6
0, 6
9)
0 (-7
, 7)
10 (-
4, 24
) Bo
dily
pai
n 62
(53,
72)
67 (5
6, 76
) 4
(-9, 1
8)
83 (7
8, 8
8)
83 (7
8, 8
7)
0 (-7
, 7)
5 (-1
0, 20
) Ge
nera
l hea
lth
41 (3
3, 4
9)
48 (3
8, 57
) 7 (
-5, 1
9)
64 (6
0, 6
9)
62 (5
8, 6
8)
-2 (-
8, 5)
8
(-5, 2
2)
SF-3
6 com
pone
nt sc
ores
MCS
59
(51,
67)
67 (5
8, 75
) 9
(-2, 1
9)
75 (7
1, 79
) 76
(71,
80)
1 (-5
, 7)
8 (-5
, 20)
PC
S 56
(49,
63)
63
(55,
70)
7 (-4
, 17)
78
(74,
82)
77
(73,
81)
-1
(-6,
5)
8 (-4
, 19)
66 67
chapter 4part 2
Course of the HbA1c over time.
figure 1
Course of the HbA1c (estimated mean with 95% CI) in the period 2006 (baseline) and 2013 (end) among T1DM patients treated with CIPII (consecutive line) or SC (dotted line) insulin therapy.
The number of hypoglycaemic episodes needing help decreased among CIPII treated patients
(difference: -0.3 (95% CI -0.7, 0.0)). Because the number of hypoglycaemic episodes needing
help among SC patients remained the same the difference in the change over time between
treatment modes was the same as the decrease for CIPII patients (difference: -0.3 (95% CI -0.7,
0.0)) unadjusted as well as adjusted for baseline HbA1c. Subanalysis among patients with
≥5 incidents of hypoglycaemia per week at baseline (n=15) demonstrated that among patients
who started CIPII treatment, the number of hypoglycaemic episodes decreased from 11 to 4
episodes per 2 weeks with a difference of -7 (95%CI -12, -3) (see Appendix 3).
changes during follow-up - clinical and biochemical parameters and QoLAmong patients who started CIPII, clinical and biochemical parameters other than HbA1c and
hypoglycaemic episodes remained stable (see Table 2). For patients who continued SC insulin
therapy there was a decrease of the systolic blood pressure, from 135 to 129 mmHg with a
difference of -6 mmHg (95% CI -11, -1). Furthermore, among these patients the total cholesterol
decreased from 5.2 to 4.8 mmol/l in 2013 (difference: -0.4 (95% CI -0.7, -0.1)).
There were no changes in the SF-36 scores within and between the CIPII and SC group (see
Table 2). However, after adjustment for the number of hypoglycaemic episodes there was
significant change of the component scale ‘general health’ (difference: 12 (95% CI 4, 20) and
physical component score (difference: 10 (95% CI 3, 18) in favour of CIPII treated patients.
Estim
ated
dat
a and
chan
ges d
urin
g fol
low
-up
for C
IPII
and
SC in
sulin
trea
ted
patie
nts.
tabe
l 2
Dat
a are
pre
sent
ed as
estim
ated
mea
n (9
5% co
nfide
nce i
nter
val)
and
mea
n ch
ange
s (95
% co
nfide
nce i
nter
val )
with
line
ar m
ixed
mod
els.
Abbr
evia
tions
: BM
I; bo
dy m
ass i
ndex
, CIP
II; co
ntin
uous
in
trape
riton
eal i
nfus
ion,
MCS
; men
tal c
ompo
nent
scor
e, PC
S; p
hysic
al co
mpo
nent
scor
e SC;
subc
utan
eous
. * p
<0.0
5.
CI
PII
Star
t
End
With
in g
roup
Δ
SC
Star
t
End
With
in g
roup
Δ
Δ Be
twee
n CI
PII
and
SC
Clin
ical a
nd b
ioch
emica
l
Syst
olic
bloo
d pr
essu
re (m
mH
g)
142 (
134,
148)
14
0 (1
34, 1
46)
-2 (-
11, 8
) 13
5 (13
2, 13
9)
129
(127
, 133
) -6
(-11
, -1)
* 4
(-6, 1
4)
BMI (
kg/m
2 ) 27
(25,
28)
26 (2
4, 28
) -1
(-4,
2)
28 (2
7, 29
) 29
(28,
30)
1 (-1
, 2)
-1 (-
5, 2)
To
tal c
hole
ster
ol (m
mol
/l)
4.9
(4.5
, 5.4
) 4.
7 (4.
3, 5.
1)
-0.3
(-0.
8, 0
.3)
5.2 (
4.9,
5.4)
4.
8 (4
.6, 5
.0)
-0.4
(-0.
7, -0
.1)*
0.2 (
-0.5
, 0.8
) LD
L cho
lest
erol
(mm
ol/l)
2.
7 (2.
4, 3.
1)
2.6
(2.3
, 3.0
) -0
.1 (-0
.6, 0
.4)
3.1 (
2.8,
3.4)
3.
1 (2.
6, 3.
5)
0.0
(-1, 1
) -0
.1 (-0
.8, 0
.6)
HbA
1c (%
) 8.
7 (8.
3, 9
.1)
8.1 (
7.7,
8.5
) -0
.6 (-
1.1, -
0.1)
8.
4 (8
.1, 8
.6)
8.2 (
8.0,
8.4
) -0
.2 (-
0.5,
0.1)
-0
.5 (-
1.0, 0
.2)
HbA
1c (m
mol
/mol
) 72
(67,
76)
65 (6
1, 69
) -7
(-12
, -1)
* 68
(65,
70)
66 (6
4, 6
8)
-2 (-
5, 1)
-5
(-11
, 2)
Hyp
ogly
caem
ic ev
ents
‡
9 (7
, 10)
3 (
2, 5)
-5
(-8,
-3)
2 (1,
3)
3 (2,
3)
1 (-0
.3, 2
) -6
(-9,
-4)*
H
ypog
lyca
emic
even
ts n
eedi
ng h
elp
0.4
(0.1,
0.6
) 0.
1 (-0
.1, 0
.2)
-0.3
(-0.
7, -0
.0)*
0.
1 (0.
0, 0
.2)
0.1 (
0.0,
0.2
) 0.
0 (-0
.1, 0
.2)
-0.3
(-0.
7,-0
.0)*
To
tal i
nsul
in d
ose (
IU/d
ay)
54 (4
4, 6
3)
65 (5
1, 78
) 11
(-5,
27)
57 (5
1, 63
) 59
(51,
67)
2 (-8
, 12)
9
(-10,
28)
SF-3
6 sub
scal
es
Ph
ysica
l fun
ctio
ning
75
(67,
83)
76
(68,
84)
2 (
-9, 1
3)
89 (8
5, 9
3)
89 (8
4, 9
3)
-1 (-
7, 5)
2 (
-10,
15)
Socia
l fun
ctio
ning
66
(58,
75)
74 (6
6, 8
3)
8 (-4
, 20)
85
(81,
90)
85 (8
0, 8
9)
-1 (-
7, 6
) 9
(-5, 2
3)
Role
lim
itatio
ns-p
hysic
al
41 (2
6, 57
) 51
(34,
68)
10
(-13
, 33)
80
(73,
89)
80
(71,
89)
-1 (-
13, 1
1)
11 (-
14, 3
7)
Role
lim
itatio
ns-e
mot
iona
l 70
(55,
86)
77
(62,
93)
7 (
-15,
29)
85 (7
7, 9
3)
86 (7
8, 9
5)
1 (-1
0, 13
) 6
(-19,
31)
Men
tal h
ealth
69
(60,
78)
79 (6
6, 9
2)
11 (-
5, 26
) 77
(72,
81)
81
(74,
88)
5 (
-4, 1
3)
6 (-1
2, 24
) Vi
talit
y 48
(39,
57)
58 (4
9, 6
7)
10 (-
3, 22
) 65
(60,
70)
65 (6
0, 6
9)
0 (-7
, 7)
10 (-
4, 24
) Bo
dily
pai
n 62
(53,
72)
67 (5
6, 76
) 4
(-9, 1
8)
83 (7
8, 8
8)
83 (7
8, 8
7)
0 (-7
, 7)
5 (-1
0, 20
) Ge
nera
l hea
lth
41 (3
3, 4
9)
48 (3
8, 57
) 7 (
-5, 1
9)
64 (6
0, 6
9)
62 (5
8, 6
8)
-2 (-
8, 5)
8
(-5, 2
2)
SF-3
6 com
pone
nt sc
ores
MCS
59
(51,
67)
67 (5
8, 75
) 9
(-2, 1
9)
75 (7
1, 79
) 76
(71,
80)
1 (-5
, 7)
8 (-5
, 20)
PC
S 56
(49,
63)
63
(55,
70)
7 (-4
, 17)
78
(74,
82)
77
(73,
81)
-1
(-6,
5)
8 (-4
, 19)
68 69
be explained by the pharmacodynamic and pharmacokinetic properties of IP administered
insulin 3,4,17,18. In addition, IP insulin is reported to improve the impaired glucagon secretion and
enhances hepatic glucose production in response to hypoglycemia 19–23.
At baseline, QoL measures were significantly worse for patients who started CIPII as compared
to patients who continued SC insulin therapy. This may indicate that CIPII is used as a last-
resort treatment and that for these patients the complexity of their diabetes, e.g. frequent
hypo- and hyperglycaemic episodes and hospital admissions, impose a great burden on their
(poor) QoL. And although all QoL scores improved over time among CIPII treated patients
these changes were not significant, also as compared to SC treated patients. Although a
reduction in the number of hypoglycaemic events could explain this finding, since there was
a significant difference in some QoL measures after adjustment for the baseline number of
hypoglycaemic events, other explanations should be considered as well.
Possibly, aforementioned study limitations are of concern. In a previous study, the presence
of psychiatric disorders was speculated to be a determinant of poor QoL among CIPII treated
patients 24. Since the presence of psychiatric disorders was an exclusion criteria for CIPII therapy
in the present study, we hypothesize the presence of other pre-existent but not measured
determinants of poor QoL such as poor coping skills, social functioning and support.
Since it is unlikely that a mode of insulin administration could alleviate the full burden of poor
QoL and glycaemic control, it should be acknowledged that our results are limited by the use
of a generic QoL questionnaire which is poorly sensitive to change and lack of data regarding
glycaemic variability. This study is also limited by the fact that the number of eligible patients
was low, which necessitated a non-random inclusion of all available patients. Furthermore,
as many SC controls were included due to a high HbA1c, and not due to a high frequency of
hypoglycaemic episodes, this may well have resulted in differences in baseline characteristics
between treatment groups and insufficient power to detect differences, in particular in the
subgroup analysis. Taken together, these limitations limit the generalizability of the present
study. Nevertheless, despite these limitations the present study gives an impression of the
course of CIPII, as compared to SC, treatment among selected T1DM patients.
chapter 4part 2
treatment related complicationsOver time, 2 cases of dysfunction and 3 cases of expected battery end-of-life necessitated
replacement of the implanted pump. In 2 patients a laparoscopic procedure was performed
to replace the catheter and in 3 patients a fibrin plug from the tip of the catheter had to be
removed. These complications resulted in 2 [0,4] days of hospital admission and 2 episodes
of ketoacidosis among CIPII treated patients. Among patients treated with CSII there were 4
episodes of ketoacidosis: 2 due to dysfunction of the external pump and 2 due to an unknown
cause (all among CSII treated patients). One patient treated with MDI was hospitalized due to
(accidentally) overdosing insulin. Median duration of hospital admission due to complications
in the SC group was 4 [2, 5] days. No mortality was reported.
Discussion
This is the first study to compare the long-term effects of CIPII and SC insulin administration
among inadequately controlled T1DM patients. Over a period of 7 years, there was a persistent
decline in the number of hypoglycaemic events among CIPII treated patients. As compared to
patients using SC insulin, only the number of hypoglycaemic decreased significantly more with
CIPII.
Previous randomized clinical studies that compared both insulin administration modes in
T1DM patients reported an improvement of HbA1c of ~0.7 to 1.0% (8 to 11 mmol/mol) during
CIPII as compared to SC therapy 5–7. Two long-term follow-up studies among T1DM patients
(one from our centre) confirmed the effectiveness of CIPII therapy by showing that HbA1c
levels are equal or better than previous SC insulin therapy after 6 years of CIPII treatment 9,16.
The present study extends these results by finding a sustained HbA1c improvement of 0.6% (7
mmol/mol) after a period of 7 years among all CIPII treated patients, which was not significant
as compared to the HbA1c course among patients treated with SC insulin. Several explanations
can account for this latter finding. First, it is likely that the small sample size of this study led
to relatively wide confidence intervals. Second, previous results were found under strict study
conditions while our findings reflect real-life clinical practice, meaning that outside of study
conditions, CIPII in daily practice has less beneficial effect on glycaemic control than during
study circumstances.
Of notice, there was a significant decrease of the number of hypoglycaemic events among
CIPII treated patients, also as compared to subjects treated with SC insulin. This finding could
68 69
be explained by the pharmacodynamic and pharmacokinetic properties of IP administered
insulin 3,4,17,18. In addition, IP insulin is reported to improve the impaired glucagon secretion and
enhances hepatic glucose production in response to hypoglycemia 19–23.
At baseline, QoL measures were significantly worse for patients who started CIPII as compared
to patients who continued SC insulin therapy. This may indicate that CIPII is used as a last-
resort treatment and that for these patients the complexity of their diabetes, e.g. frequent
hypo- and hyperglycaemic episodes and hospital admissions, impose a great burden on their
(poor) QoL. And although all QoL scores improved over time among CIPII treated patients
these changes were not significant, also as compared to SC treated patients. Although a
reduction in the number of hypoglycaemic events could explain this finding, since there was
a significant difference in some QoL measures after adjustment for the baseline number of
hypoglycaemic events, other explanations should be considered as well.
Possibly, aforementioned study limitations are of concern. In a previous study, the presence
of psychiatric disorders was speculated to be a determinant of poor QoL among CIPII treated
patients 24. Since the presence of psychiatric disorders was an exclusion criteria for CIPII therapy
in the present study, we hypothesize the presence of other pre-existent but not measured
determinants of poor QoL such as poor coping skills, social functioning and support.
Since it is unlikely that a mode of insulin administration could alleviate the full burden of poor
QoL and glycaemic control, it should be acknowledged that our results are limited by the use
of a generic QoL questionnaire which is poorly sensitive to change and lack of data regarding
glycaemic variability. This study is also limited by the fact that the number of eligible patients
was low, which necessitated a non-random inclusion of all available patients. Furthermore,
as many SC controls were included due to a high HbA1c, and not due to a high frequency of
hypoglycaemic episodes, this may well have resulted in differences in baseline characteristics
between treatment groups and insufficient power to detect differences, in particular in the
subgroup analysis. Taken together, these limitations limit the generalizability of the present
study. Nevertheless, despite these limitations the present study gives an impression of the
course of CIPII, as compared to SC, treatment among selected T1DM patients.
chapter 4part 2
treatment related complicationsOver time, 2 cases of dysfunction and 3 cases of expected battery end-of-life necessitated
replacement of the implanted pump. In 2 patients a laparoscopic procedure was performed
to replace the catheter and in 3 patients a fibrin plug from the tip of the catheter had to be
removed. These complications resulted in 2 [0,4] days of hospital admission and 2 episodes
of ketoacidosis among CIPII treated patients. Among patients treated with CSII there were 4
episodes of ketoacidosis: 2 due to dysfunction of the external pump and 2 due to an unknown
cause (all among CSII treated patients). One patient treated with MDI was hospitalized due to
(accidentally) overdosing insulin. Median duration of hospital admission due to complications
in the SC group was 4 [2, 5] days. No mortality was reported.
Discussion
This is the first study to compare the long-term effects of CIPII and SC insulin administration
among inadequately controlled T1DM patients. Over a period of 7 years, there was a persistent
decline in the number of hypoglycaemic events among CIPII treated patients. As compared to
patients using SC insulin, only the number of hypoglycaemic decreased significantly more with
CIPII.
Previous randomized clinical studies that compared both insulin administration modes in
T1DM patients reported an improvement of HbA1c of ~0.7 to 1.0% (8 to 11 mmol/mol) during
CIPII as compared to SC therapy 5–7. Two long-term follow-up studies among T1DM patients
(one from our centre) confirmed the effectiveness of CIPII therapy by showing that HbA1c
levels are equal or better than previous SC insulin therapy after 6 years of CIPII treatment 9,16.
The present study extends these results by finding a sustained HbA1c improvement of 0.6% (7
mmol/mol) after a period of 7 years among all CIPII treated patients, which was not significant
as compared to the HbA1c course among patients treated with SC insulin. Several explanations
can account for this latter finding. First, it is likely that the small sample size of this study led
to relatively wide confidence intervals. Second, previous results were found under strict study
conditions while our findings reflect real-life clinical practice, meaning that outside of study
conditions, CIPII in daily practice has less beneficial effect on glycaemic control than during
study circumstances.
Of notice, there was a significant decrease of the number of hypoglycaemic events among
CIPII treated patients, also as compared to subjects treated with SC insulin. This finding could
70 71
Conclusions
Over a period of 7 years, there was a persistent decline in the number of hypoglycaemic
events among CIPII treated patients. As compared to patients using SC insulin, the number of
hypoglycaemic decreased significantly more with CIPII while HbA1c, clinical parameters and
QoL remained stable. The results of this study support the effectiveness and current indications
of CIPII therapy as a last-resort treatment option for selected T1DM patients who experience
frequent hypoglycaemic episodes.
1 Giacca A, Caumo A, Galimberti G, et al. Peritoneal and subcutaneous absorption of insulin in type I diabetic subjects. J Clin Endocrinol Metab 1993; 77: 738–42.2 Bratusch-Marrain PR, Waldhäusl WK, Gasić S, Hofer A. Hepatic disposal of biosynthetic human insulin and porcine C-peptide in humans. Metabolism 1984; 33: 151–7.3 Nathan DM, Dunn FL, Bruch J, et al. Postprandial insulin profiles with implantable pump therapy may explain decreased frequency of severe hypoglycemia, compared with intensive subcutaneous regimens, in insulin-dependent diabetes mellitus patients. Am J Med 1996; 100: 412–7.4 Schaepelynck Bélicar P, Vague P, Lassmann-Vague V. Reproducibility of plasma insulin kinetics during intraperitoneal insulin treatment by programmable pumps. Diabetes Metab 2003; 29: 344–8.5 Logtenberg SJ, Kleefstra N, Houweling ST, et al. Improved glycemic control with intraperitoneal versus subcutaneous insulin in type 1 diabetes: a randomized controlled trial. Diabetes Care 2009; 32: 1372–7.6 Selam JL, Raccah D, Jean-Didier N, Lozano JL, Waxman K, Charles MA. Randomized comparison of metabolic control achieved by intraperitoneal insulin infusion with implantable pumps versus intensive subcutaneous insulin therapy in type I diabetic patients. Diabetes Care 1992; 15: 53–8.7 Haardt MJ, Selam JL, Slama G, et al. A cost-benefit comparison of intensive diabetes management with implantable pumps versus multiple subcutaneous injections in patients with type I diabetes. Diabetes Care 1994; 17: 847–51.8 Logtenberg SJ, Kleefstra N, Houweling ST, Groenier KH, Gans RO, Bilo HJ. Health-related quality of life, treatment satisfaction, and costs associated with intraperitoneal versus subcutaneous insulin administration in type 1 diabetes: a randomized controlled trial. Diabetes Care 2010; 33: 1169–72.9 Schaepelynck P, Renard E, Jeandidier N, et al. A recent survey confirms the efficacy and the safety of implanted insulin pumps during long-term use in poorly controlled type 1 diabetes patients. Diabetes Technol Ther 2011; 13: 657–60.10 Logtenberg SJJ, van Ballegooie E, Israêl-Bultman H, van Linde A, Bilo HJG. Glycaemic control, health status and treatment satisfaction with continuous intraperitoneal insulin infusion. Neth J Med 2007; 65: 65–70.11 Hart HE, Bilo HJG, Redekop WK, Stolk RP, Assink JH, Meyboom-de Jong B. Quality of life of patients with type I diabetes mellitus. Qual Life Res Int J Qual Life Asp Treat Care Rehabil 2003; 12: 1089–97.12 Haveman JW, Logtenberg SJJ, Kleefstra N, Groenier KH, Bilo HJG, Blomme AM. Surgical aspects and complications of continuous intraperitoneal insulin infusion with an implantable pump. Langenbecks Arch Surg Dtsch Ges Für Chir 2010; 395: 65–71.13 Van Dijk PR, Logtenberg SJJ, Groenier KH, Kleefstra N, Bilo HJG, Arnqvist HJ. Effect of i.p. insulin administration on IGF1 and IGFBP1 in type 1 diabetes. Endocr Connect 2014; 3: 17–23.14 Ware J, Snow K, Gandek KM: SF-36 Health Survey: Manual and Interpretation Guide. Boston: The Health Institute, New England Medical Center 1993.15 Ware JE, Kosinski M, Keller S: SF-36 Physical and Mental Health Summary Scales: A User’s Manual. Boston: The Health Institute, New England Medical Center 1994. 16 Van Dijk PR, Logtenberg SJ, Groenier KH, Gans RO, Kleefstra N, Bilo HJ. Continuous intraperitoneal insulin infusion in type 1 diabetes: a 6-year post-trial follow-up. BMC Endocr Disord 2014; 14: 30.17 Schade DS, Eaton RP, Spencer W, Goldman R, Corbett WT. The peritoneal absorption of insulin in diabetic man: a potential site for a mechanical insulin delivery system. Metabolism 1979; 28: 195–7.18 Micossi P, Cristallo M, Librenti MC, et al. Free-insulin profiles after intraperitoneal, intramuscular, and subcutaneous insulin administration. Diabetes Care 1986; 9: 575–8.19 Oskarsson PR, Lins PE, Backman L, Adamson UC. Continuous intraperitoneal insulin infusion partly restores the glucagon response to hypoglycaemia in type 1 diabetic patients. Diabetes Metab 2000; 26: 118–24.20 Wan CK, Giacca A, Matsuhisa M, et al. Increased responses of glucagon and glucose production to hypoglycemia with intraperitoneal versus subcutaneous insulin treatment. Metabolism 2000; 49: 984–9.21 Mason TM, Gupta N, Goh T, et al. Chronic intraperitoneal insulin delivery, as compared with subcutaneous delivery, improves hepatic glucose metabolism in streptozotocin diabetic rats. Metabolism 2000; 49: 1411–6.
chapter 4part 2
references
70 71
Conclusions
Over a period of 7 years, there was a persistent decline in the number of hypoglycaemic
events among CIPII treated patients. As compared to patients using SC insulin, the number of
hypoglycaemic decreased significantly more with CIPII while HbA1c, clinical parameters and
QoL remained stable. The results of this study support the effectiveness and current indications
of CIPII therapy as a last-resort treatment option for selected T1DM patients who experience
frequent hypoglycaemic episodes.
1 Giacca A, Caumo A, Galimberti G, et al. Peritoneal and subcutaneous absorption of insulin in type I diabetic subjects. J Clin Endocrinol Metab 1993; 77: 738–42.2 Bratusch-Marrain PR, Waldhäusl WK, Gasić S, Hofer A. Hepatic disposal of biosynthetic human insulin and porcine C-peptide in humans. Metabolism 1984; 33: 151–7.3 Nathan DM, Dunn FL, Bruch J, et al. Postprandial insulin profiles with implantable pump therapy may explain decreased frequency of severe hypoglycemia, compared with intensive subcutaneous regimens, in insulin-dependent diabetes mellitus patients. Am J Med 1996; 100: 412–7.4 Schaepelynck Bélicar P, Vague P, Lassmann-Vague V. Reproducibility of plasma insulin kinetics during intraperitoneal insulin treatment by programmable pumps. Diabetes Metab 2003; 29: 344–8.5 Logtenberg SJ, Kleefstra N, Houweling ST, et al. Improved glycemic control with intraperitoneal versus subcutaneous insulin in type 1 diabetes: a randomized controlled trial. Diabetes Care 2009; 32: 1372–7.6 Selam JL, Raccah D, Jean-Didier N, Lozano JL, Waxman K, Charles MA. Randomized comparison of metabolic control achieved by intraperitoneal insulin infusion with implantable pumps versus intensive subcutaneous insulin therapy in type I diabetic patients. Diabetes Care 1992; 15: 53–8.7 Haardt MJ, Selam JL, Slama G, et al. A cost-benefit comparison of intensive diabetes management with implantable pumps versus multiple subcutaneous injections in patients with type I diabetes. Diabetes Care 1994; 17: 847–51.8 Logtenberg SJ, Kleefstra N, Houweling ST, Groenier KH, Gans RO, Bilo HJ. Health-related quality of life, treatment satisfaction, and costs associated with intraperitoneal versus subcutaneous insulin administration in type 1 diabetes: a randomized controlled trial. Diabetes Care 2010; 33: 1169–72.9 Schaepelynck P, Renard E, Jeandidier N, et al. A recent survey confirms the efficacy and the safety of implanted insulin pumps during long-term use in poorly controlled type 1 diabetes patients. Diabetes Technol Ther 2011; 13: 657–60.10 Logtenberg SJJ, van Ballegooie E, Israêl-Bultman H, van Linde A, Bilo HJG. Glycaemic control, health status and treatment satisfaction with continuous intraperitoneal insulin infusion. Neth J Med 2007; 65: 65–70.11 Hart HE, Bilo HJG, Redekop WK, Stolk RP, Assink JH, Meyboom-de Jong B. Quality of life of patients with type I diabetes mellitus. Qual Life Res Int J Qual Life Asp Treat Care Rehabil 2003; 12: 1089–97.12 Haveman JW, Logtenberg SJJ, Kleefstra N, Groenier KH, Bilo HJG, Blomme AM. Surgical aspects and complications of continuous intraperitoneal insulin infusion with an implantable pump. Langenbecks Arch Surg Dtsch Ges Für Chir 2010; 395: 65–71.13 Van Dijk PR, Logtenberg SJJ, Groenier KH, Kleefstra N, Bilo HJG, Arnqvist HJ. Effect of i.p. insulin administration on IGF1 and IGFBP1 in type 1 diabetes. Endocr Connect 2014; 3: 17–23.14 Ware J, Snow K, Gandek KM: SF-36 Health Survey: Manual and Interpretation Guide. Boston: The Health Institute, New England Medical Center 1993.15 Ware JE, Kosinski M, Keller S: SF-36 Physical and Mental Health Summary Scales: A User’s Manual. Boston: The Health Institute, New England Medical Center 1994. 16 Van Dijk PR, Logtenberg SJ, Groenier KH, Gans RO, Kleefstra N, Bilo HJ. Continuous intraperitoneal insulin infusion in type 1 diabetes: a 6-year post-trial follow-up. BMC Endocr Disord 2014; 14: 30.17 Schade DS, Eaton RP, Spencer W, Goldman R, Corbett WT. The peritoneal absorption of insulin in diabetic man: a potential site for a mechanical insulin delivery system. Metabolism 1979; 28: 195–7.18 Micossi P, Cristallo M, Librenti MC, et al. Free-insulin profiles after intraperitoneal, intramuscular, and subcutaneous insulin administration. Diabetes Care 1986; 9: 575–8.19 Oskarsson PR, Lins PE, Backman L, Adamson UC. Continuous intraperitoneal insulin infusion partly restores the glucagon response to hypoglycaemia in type 1 diabetic patients. Diabetes Metab 2000; 26: 118–24.20 Wan CK, Giacca A, Matsuhisa M, et al. Increased responses of glucagon and glucose production to hypoglycemia with intraperitoneal versus subcutaneous insulin treatment. Metabolism 2000; 49: 984–9.21 Mason TM, Gupta N, Goh T, et al. Chronic intraperitoneal insulin delivery, as compared with subcutaneous delivery, improves hepatic glucose metabolism in streptozotocin diabetic rats. Metabolism 2000; 49: 1411–6.
chapter 4part 2
references
72 73
chapter 4part 2
Additional clinical and biochemical variables.appendix 1
Data are presented as n (%), mean (SD) or median [IQR]. † Categories may not add up due to multiple complications per patient. Abbreviations:, CIPII; continuous intraperitoneal infusion, SC; subcutaneous.
22 Oskarsson PR, Lins PE, Wallberg Henriksson H, Adamson UC. Metabolic and hormonal responses to exercise in type 1 diabetic patients during continuous subcutaneous, as compared to continuous intraperitoneal, insulin infusion. Diabetes Metab 1999; 25: 491–7.23 Selam JL, Medlej R, M’bemba J, et al. Symptoms, hormones, and glucose fluxes during a gradual hypoglycaemia induced by intraperitoneal vs venous insulin infusion in Type I diabetes. Diabet Med J Br Diabet Assoc 1995; 12: 1102–9.24 DeVries JH, Eskes SA, Snoek FJ, et al. Continuous intraperitoneal insulin infusion in patients with ‘brittle’ diabetes: favourable effects on glycaemic control and hospital stay. Diabet Med J Br Diabet Assoc 2002; 19: 496–501.
72 73
chapter 4part 2
Additional clinical and biochemical variables.appendix 1
Data are presented as n (%), mean (SD) or median [IQR]. † Categories may not add up due to multiple complications per patient. Abbreviations:, CIPII; continuous intraperitoneal infusion, SC; subcutaneous.
22 Oskarsson PR, Lins PE, Wallberg Henriksson H, Adamson UC. Metabolic and hormonal responses to exercise in type 1 diabetic patients during continuous subcutaneous, as compared to continuous intraperitoneal, insulin infusion. Diabetes Metab 1999; 25: 491–7.23 Selam JL, Medlej R, M’bemba J, et al. Symptoms, hormones, and glucose fluxes during a gradual hypoglycaemia induced by intraperitoneal vs venous insulin infusion in Type I diabetes. Diabet Med J Br Diabet Assoc 1995; 12: 1102–9.24 DeVries JH, Eskes SA, Snoek FJ, et al. Continuous intraperitoneal insulin infusion in patients with ‘brittle’ diabetes: favourable effects on glycaemic control and hospital stay. Diabet Med J Br Diabet Assoc 2002; 19: 496–501.
74 75
chapter 4part 2
appe
ndix
2Ob
serv
ed d
ata a
t sta
rt an
d en
d of
follo
w-u
p fo
r MDI
and
CSII
treat
ed p
atie
nts.
Dat
a are
pre
sent
ed as
n (%
), m
ean
(SD
) or m
edia
n [IQ
R]. †
Cat
egor
ies m
ay n
ot ad
d up
due
to m
ultip
le co
mpl
icatio
ns p
er p
atie
nt. ‡
Defi
ned
as th
e num
ber o
f blo
od g
luco
se va
lue <
4.0
mm
ol/l
durin
g th
e la
st 2
wee
ks. *
p<0.
05 as
com
pare
d to
CIP
II, p
-val
ues a
re b
ased
on
appr
opria
te p
aram
etric
and
non-
para
met
ric te
sts.
Abbr
evia
tions
: BM
I; bo
dy m
ass i
ndex
, CIP
II; co
ntin
uous
intra
perit
onea
l inf
usio
n, C
SII;
cont
inuo
us su
bcut
aneo
us in
sulin
infu
sion,
MCS
; men
tal c
ompo
nent
scor
e, M
DI;
mul
tiple
dai
ly in
ject
ions
, PCS
; phy
sical
com
pone
nt sc
ore.
appe
ndix
3aSu
bana
lysis
amon
g pat
ient
s with
bas
elin
e HbA
1c co
ncen
tratio
n ≥7
.5% (5
8 mm
ol/m
ol).
Amon
g pa
tient
s who
star
ted
CIPI
I the
rapy
in 20
06, 8
(38.
1%) p
atie
nts h
ad a
base
line H
bA1c
conc
entra
tion
≥7.5
% (5
8 mm
ol/m
ol),
2 (9.
5%) p
atie
nts h
ad ≥
5 inc
iden
ts of
hyp
ogly
caem
ia p
er w
eek a
nd in
11
(52.
4%) p
atie
nts b
oth
inclu
sion
crite
ria w
ere p
rese
nt. A
mon
g SC
trea
ted
patie
nts,
thes
e num
bers
wer
e 72 (
97.3
%),
1 (1.4
%) a
nd 1
(1.4%
) res
pect
ivel
y. D
ata a
re p
rese
nted
as es
timat
ed m
ean
(95%
confi
denc
e in
terv
al) a
nd m
ean
chan
ges (
95%
confi
denc
e int
erva
l ) w
ith li
near
mix
ed m
odel
s. *p
<0.0
5. Ab
brev
iatio
ns: B
MI;
Body
Mas
s Ind
ex, C
IPII;
cont
inuo
us in
trape
riton
eal i
nfus
ion,
MCS
; men
tal c
ompo
nent
scor
e, PC
S; p
hysic
al co
mpo
nent
scor
e SC;
subc
utan
eous
.
74 75
chapter 4part 2
appe
ndix
2Ob
serv
ed d
ata a
t sta
rt an
d en
d of
follo
w-u
p fo
r MDI
and
CSII
treat
ed p
atie
nts.
Dat
a are
pre
sent
ed as
n (%
), m
ean
(SD
) or m
edia
n [IQ
R]. †
Cat
egor
ies m
ay n
ot ad
d up
due
to m
ultip
le co
mpl
icatio
ns p
er p
atie
nt. ‡
Defi
ned
as th
e num
ber o
f blo
od g
luco
se va
lue <
4.0
mm
ol/l
durin
g th
e la
st 2
wee
ks. *
p<0.
05 as
com
pare
d to
CIP
II, p
-val
ues a
re b
ased
on
appr
opria
te p
aram
etric
and
non-
para
met
ric te
sts.
Abbr
evia
tions
: BM
I; bo
dy m
ass i
ndex
, CIP
II; co
ntin
uous
intra
perit
onea
l inf
usio
n, C
SII;
cont
inuo
us su
bcut
aneo
us in
sulin
infu
sion,
MCS
; men
tal c
ompo
nent
scor
e, M
DI;
mul
tiple
dai
ly in
ject
ions
, PCS
; phy
sical
com
pone
nt sc
ore.
appe
ndix
3aSu
bana
lysis
amon
g pat
ient
s with
bas
elin
e HbA
1c co
ncen
tratio
n ≥7
.5% (5
8 mm
ol/m
ol).
Amon
g pa
tient
s who
star
ted
CIPI
I the
rapy
in 20
06, 8
(38.
1%) p
atie
nts h
ad a
base
line H
bA1c
conc
entra
tion
≥7.5
% (5
8 mm
ol/m
ol),
2 (9.
5%) p
atie
nts h
ad ≥
5 inc
iden
ts of
hyp
ogly
caem
ia p
er w
eek a
nd in
11
(52.
4%) p
atie
nts b
oth
inclu
sion
crite
ria w
ere p
rese
nt. A
mon
g SC
trea
ted
patie
nts,
thes
e num
bers
wer
e 72 (
97.3
%),
1 (1.4
%) a
nd 1
(1.4%
) res
pect
ivel
y. D
ata a
re p
rese
nted
as es
timat
ed m
ean
(95%
confi
denc
e in
terv
al) a
nd m
ean
chan
ges (
95%
confi
denc
e int
erva
l ) w
ith li
near
mix
ed m
odel
s. *p
<0.0
5. Ab
brev
iatio
ns: B
MI;
Body
Mas
s Ind
ex, C
IPII;
cont
inuo
us in
trape
riton
eal i
nfus
ion,
MCS
; men
tal c
ompo
nent
scor
e, PC
S; p
hysic
al co
mpo
nent
scor
e SC;
subc
utan
eous
.
76 77
chapter 4part 2
appe
ndix
3bSu
bana
lysis
amon
g pat
ient
s with
≥5 in
ciden
ts of
hyp
ogly
caem
ia p
er w
eek a
t bas
elin
e †.
Amon
g pa
tient
s who
star
ted
CIPI
I the
rapy
in 20
06, 8
(38.
1%) p
atie
nts h
ad a
base
line H
bA1c
conc
entra
tion
≥7.5
% (5
8 mm
ol/m
ol),
2 (9.
5%) p
atie
nts h
ad ≥
5 inc
iden
ts of
hyp
ogly
caem
ia p
er w
eek a
nd in
11
(52.
4%) p
atie
nts b
oth
inclu
sion
crite
ria w
ere p
rese
nt. A
mon
g SC
trea
ted
patie
nts,
thes
e num
bers
wer
e 72 (
97.3
%),
1 (1.4
%) a
nd 1
(1.4%
) res
pect
ivel
y. †
As th
ere w
ere o
nly 2
pat
ient
s usin
g SC
insu
lin th
erap
y in
the c
ontro
l gro
up w
ith ≥
5 inc
iden
ts of
hyp
ogly
caem
ia p
er w
eek a
t bas
elin
e the
se o
utco
mes
coul
d no
t be c
alcu
late
d. D
ata a
re p
rese
nted
as es
timat
ed m
ean
(95%
confi
denc
e int
erva
l) an
d m
ean
chan
ges
(95%
confi
denc
e int
erva
l ) w
ith li
near
mix
ed m
odel
s. *p
<0.0
5. Ab
brev
iatio
ns: B
MI;
Body
Mas
s Ind
ex, C
IPII;
cont
inuo
us in
trape
riton
eal i
nfus
ion,
MCS
; men
tal c
ompo
nent
scor
e, PC
S; p
hysic
al co
mpo
nent
sc
ore,
SC; s
ubcu
tane
ous.
appe
ndix
4Es
timat
ed d
ata a
nd ch
ange
s dur
ing f
ollo
w-u
p fo
r CIP
II , M
DI an
d CS
II tre
ated
pat
ient
s.
Dat
a are
pre
sent
ed as
estim
ated
mea
n (9
5% co
nfide
nce i
nter
val)
and
mea
n ch
ange
s (95
% co
nfide
nce i
nter
val )
with
line
ar m
ixed
mod
els.
*p<0
.05.
Abbr
evia
tions
: BM
I; Bo
dy M
ass I
ndex
, CIP
II; co
ntin
uous
in
trape
riton
eal i
nfus
ion,
MCS
; men
tal c
ompo
nent
scor
e, PC
S; p
hysic
al co
mpo
nent
scor
e, SC
; sub
cuta
neou
s.
Clin
ical a
nd b
ioch
emica
l
76 77
chapter 4part 2
appe
ndix
3bSu
bana
lysis
amon
g pat
ient
s with
≥5 in
ciden
ts of
hyp
ogly
caem
ia p
er w
eek a
t bas
elin
e †.
Amon
g pa
tient
s who
star
ted
CIPI
I the
rapy
in 20
06, 8
(38.
1%) p
atie
nts h
ad a
base
line H
bA1c
conc
entra
tion
≥7.5
% (5
8 mm
ol/m
ol),
2 (9.
5%) p
atie
nts h
ad ≥
5 inc
iden
ts of
hyp
ogly
caem
ia p
er w
eek a
nd in
11
(52.
4%) p
atie
nts b
oth
inclu
sion
crite
ria w
ere p
rese
nt. A
mon
g SC
trea
ted
patie
nts,
thes
e num
bers
wer
e 72 (
97.3
%),
1 (1.4
%) a
nd 1
(1.4%
) res
pect
ivel
y. †
As th
ere w
ere o
nly 2
pat
ient
s usin
g SC
insu
lin th
erap
y in
the c
ontro
l gro
up w
ith ≥
5 inc
iden
ts of
hyp
ogly
caem
ia p
er w
eek a
t bas
elin
e the
se o
utco
mes
coul
d no
t be c
alcu
late
d. D
ata a
re p
rese
nted
as es
timat
ed m
ean
(95%
confi
denc
e int
erva
l) an
d m
ean
chan
ges
(95%
confi
denc
e int
erva
l ) w
ith li
near
mix
ed m
odel
s. *p
<0.0
5. Ab
brev
iatio
ns: B
MI;
Body
Mas
s Ind
ex, C
IPII;
cont
inuo
us in
trape
riton
eal i
nfus
ion,
MCS
; men
tal c
ompo
nent
scor
e, PC
S; p
hysic
al co
mpo
nent
sc
ore,
SC; s
ubcu
tane
ous.
appe
ndix
4Es
timat
ed d
ata a
nd ch
ange
s dur
ing f
ollo
w-u
p fo
r CIP
II , M
DI an
d CS
II tre
ated
pat
ient
s.
Dat
a are
pre
sent
ed as
estim
ated
mea
n (9
5% co
nfide
nce i
nter
val)
and
mea
n ch
ange
s (95
% co
nfide
nce i
nter
val )
with
line
ar m
ixed
mod
els.
*p<0
.05.
Abbr
evia
tions
: BM
I; Bo
dy M
ass I
ndex
, CIP
II; co
ntin
uous
in
trape
riton
eal i
nfus
ion,
MCS
; men
tal c
ompo
nent
scor
e, PC
S; p
hysic
al co
mpo
nent
scor
e, SC
; sub
cuta
neou
s.
Clin
ical a
nd b
ioch
emica
l
78 79
Van Dijk PR, Logtenberg SJ, Groenier KH, Feenstra J, Gans RO,
Bilo HJ, Kleefstra N.
Intraperitoneal insulin infusion is non-inferior to subcutaneous
insulin infusion in the treatment of type 1 diabetes: a prospec-
tive matched-control study.
chapter 5 Abstract
introductionContinuous intraperitoneal insulin infusion (CIPII) using an implantable pump is a last-
resort treatment option for patients with type 1 diabetes mellitus (T1DM) who fail to reach
glycaemic control with intensified subcutaneous (SC) insulin regimens. Aim of this study was
to compare the effects of CIPII with SC insulin therapy in T1DM.
patients and methodsProspective, observational matched-control study. Patients were eligible if they had been
treated with either CIPII or SC insulin for > 4 years and had a HbA1c of ≥ 7.0%. CIPII treated
cases were matched to SC treated controls regarding age and gender. Primary endpoint
was a non-inferiority assessment (pre-defined margin of -0.5%) of the difference in HbA1c
during a 26-week interval between both groups. Analysis were performed with ANCOVA,
taking baseline differences into account.
resultsDuring study, one patient withdrew consent. Subsequently 183 patients with a mean age
of 50 years (standard deviation (SD) 12) and a diabetes duration of 26 years (SD 13) were
analysed. Of these, 39 were treated with CIPII and 144 with SC insulin therapy. Age and
gender were well matched. HbA1c remained stable within the CIPII group while it decreased
with -0.09% (95% confidence interval (CI) -0.17, -0.01) in the SC group. The difference
between treatment groups was -0.27% (95% CI -0.46, -0.09) and met the predefined non-
inferiority criterion. During continuous glucose sensor use, patients using SC insulin therapy
spend less time in hyperglycaemia (-9.3%, 95% CI -15.8, -2.8%) and more in euglycaemia
(6.9%, 95% CI 1.2, 12.5%) as compared to patients using CIPII. Besides a difference in alanine
aminotransferase (ALT) concentrations between groups of 3.6 U/l (95% CI 1.2, 6.0), being
lower in the CIPII group, no other biochemical or clinical differences were present.
conclusionCIPII therapy is non-inferior to SC insulin therapy with respect to HbA1c in the treatment of
poorly controlled T1DM patients. Besides a lower ALT among CIPII treated patients within
the normal range, there are no differences in clinical and biochemical parameters. This study
supports the long-term use of CIPII therapy as last-resort treatment in T1DM.
submitted as
Intraperitoneal insulin infusion is non-inferior to subcutaneous insulin infusion in the treatment of type 1 diabetes: a prospective mached- control study
chapter 5part 2
78 79
Van Dijk PR, Logtenberg SJ, Groenier KH, Feenstra J, Gans RO,
Bilo HJ, Kleefstra N.
Intraperitoneal insulin infusion is non-inferior to subcutaneous
insulin infusion in the treatment of type 1 diabetes: a prospec-
tive matched-control study.
chapter 5 Abstract
introductionContinuous intraperitoneal insulin infusion (CIPII) using an implantable pump is a last-
resort treatment option for patients with type 1 diabetes mellitus (T1DM) who fail to reach
glycaemic control with intensified subcutaneous (SC) insulin regimens. Aim of this study was
to compare the effects of CIPII with SC insulin therapy in T1DM.
patients and methodsProspective, observational matched-control study. Patients were eligible if they had been
treated with either CIPII or SC insulin for > 4 years and had a HbA1c of ≥ 7.0%. CIPII treated
cases were matched to SC treated controls regarding age and gender. Primary endpoint
was a non-inferiority assessment (pre-defined margin of -0.5%) of the difference in HbA1c
during a 26-week interval between both groups. Analysis were performed with ANCOVA,
taking baseline differences into account.
resultsDuring study, one patient withdrew consent. Subsequently 183 patients with a mean age
of 50 years (standard deviation (SD) 12) and a diabetes duration of 26 years (SD 13) were
analysed. Of these, 39 were treated with CIPII and 144 with SC insulin therapy. Age and
gender were well matched. HbA1c remained stable within the CIPII group while it decreased
with -0.09% (95% confidence interval (CI) -0.17, -0.01) in the SC group. The difference
between treatment groups was -0.27% (95% CI -0.46, -0.09) and met the predefined non-
inferiority criterion. During continuous glucose sensor use, patients using SC insulin therapy
spend less time in hyperglycaemia (-9.3%, 95% CI -15.8, -2.8%) and more in euglycaemia
(6.9%, 95% CI 1.2, 12.5%) as compared to patients using CIPII. Besides a difference in alanine
aminotransferase (ALT) concentrations between groups of 3.6 U/l (95% CI 1.2, 6.0), being
lower in the CIPII group, no other biochemical or clinical differences were present.
conclusionCIPII therapy is non-inferior to SC insulin therapy with respect to HbA1c in the treatment of
poorly controlled T1DM patients. Besides a lower ALT among CIPII treated patients within
the normal range, there are no differences in clinical and biochemical parameters. This study
supports the long-term use of CIPII therapy as last-resort treatment in T1DM.
submitted as
Intraperitoneal insulin infusion is non-inferior to subcutaneous insulin infusion in the treatment of type 1 diabetes: a prospective mached- control study
chapter 5part 2
80 81
Introduction
Treatment of type 1 diabetes mellitus (T1DM) consists of insulin administration or pancreas
(islet cells) transplantation. In most patients, insulin is administered subcutaneously (SC) using
multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII) using an
external pump. Although most patients achieve acceptable glycaemic control using SC insulin
some patients fail to either reach adequate glycaemic control, some because of SC insulin
resistance, or have frequent hypoglycaemic episodes 1. Continuous intraperitoneal insulin
infusion (CIPII) with an implantable pump is a treatment option for such patients.
With CIPII, the SC environment is bypassed and the physiological route of insulin is mimicked
because intraperitoneal (IP) administered insulin diffuses into the portal vein catchment area.
Compared to SC insulin therapy, IP administered insulin results in higher hepatic insulin
uptake, alleviation of peripheral plasma insulin concentrations and a more rapid and
predictable insulin action 2–5. Of the three randomized clinical studies that compared CIPII with
SC insulin treatment in T1DM patients, two reported HbA1c improvements of 0.76% to 1.28%
without an increase in hypoglycaemic episodes and one did not find any differences between
therapies 6–8.
Since CIPII with an implantable pump is an invasive and costly treatment for selected patients,
there is a clear need for data regarding the long-term efficacy of CIPII as compared to SC insulin
therapy in order to justify the use of CIPII. However, available randomized studies have a short
duration and a small number of participants, and observational studies lack a control group 9,10.
Aim of this study was to compare the effects of long-term CIPII therapy with SC insulin therapy
among patients with poorly controlled T1DM.
Patients and methods
study designWe conducted an investigator initiated, prospective, observational matched-control study to
compare the effects on glycaemic control of CIPII versus SC insulin therapy. Patient recruitment
took place in two hospitals, the Isala (Zwolle, the Netherlands) and the Diaconessenhuis
hospital (Meppel, the Netherlands).
Since CIPII is as a last-resort treatment option for T1DM, CIPII treated patients are a highly
selected population with a rather complex background and disease history. In order to account
for this inequality between both treatment groups (CIPII versus SC insulin therapy), the
primary endpoint was a non-inferiority assessment of the difference in HbA1c during a
26-week period, taking possible baseline differences into account, between both groups.
patient selection Cases were subjects on CIPII therapy using an implanted insulin pump (MIP 2007D, Medtronic/
Minimed, Northridge, CA, USA) for the past 4 years without interruptions of >30 days, in order
to avoid effects related to initiating therapy. Inclusion criteria for cases were identical to those
of a prior study in our centre and have been described in detail previously 6. In brief, patients
with T1DM, aged 18 to 70 years with a HbA1c ≥ 7.5% and/or ≥ 5 incidents of hypoglycemia
glucose (< 4.0 mmol/l) per week, were eligible.
Controls using SC insulin therapy were selected from the outpatient clinic population.
Eligibility criteria were T1DM, MDI or CSII insulin as mode of insulin administration for the past
4 years without interruptions of >30 days, HbA1c ≥ 7.0% and proper knowledge of the Dutch
language.
Exclusion criteria for both cases and controls were: impaired renal function (plasma creatinine
≥150 µmol/l or glomerular filtration rate as estimated by the Cockcroft-Gault formula
≤50 ml/min, cardiac problems (unstable angina or myocardial infarction within the previous
12 months or New York Heart Association class III or IV congestive heart failure, cognitive
impairment, current or past psychiatric treatment for schizophrenia, cognitive or bipolar
disorder, current use of oral corticosteroids or suffering from a condition which necessitated
oral or systemic corticosteroids use more than once in the previous 12 months, substance
abuse, other than nicotine, current gravidity or plans to become pregnant during the study,
plans to engage in activities that require going >25 feet below sea level or any condition that
the investigator and/or coordinating investigator feels would interfere with study participation
or evaluation of results.
If patients were eligible to act as SC control, they were matched to the CIPII treated cases based
on gender and age. The SC control group consisted of both MDI and CSII users. The ratio of
participants on the different therapies (CIPII:MDI:CSII) was 1:2:2.
chapter 5part 2
80 81
Introduction
Treatment of type 1 diabetes mellitus (T1DM) consists of insulin administration or pancreas
(islet cells) transplantation. In most patients, insulin is administered subcutaneously (SC) using
multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII) using an
external pump. Although most patients achieve acceptable glycaemic control using SC insulin
some patients fail to either reach adequate glycaemic control, some because of SC insulin
resistance, or have frequent hypoglycaemic episodes 1. Continuous intraperitoneal insulin
infusion (CIPII) with an implantable pump is a treatment option for such patients.
With CIPII, the SC environment is bypassed and the physiological route of insulin is mimicked
because intraperitoneal (IP) administered insulin diffuses into the portal vein catchment area.
Compared to SC insulin therapy, IP administered insulin results in higher hepatic insulin
uptake, alleviation of peripheral plasma insulin concentrations and a more rapid and
predictable insulin action 2–5. Of the three randomized clinical studies that compared CIPII with
SC insulin treatment in T1DM patients, two reported HbA1c improvements of 0.76% to 1.28%
without an increase in hypoglycaemic episodes and one did not find any differences between
therapies 6–8.
Since CIPII with an implantable pump is an invasive and costly treatment for selected patients,
there is a clear need for data regarding the long-term efficacy of CIPII as compared to SC insulin
therapy in order to justify the use of CIPII. However, available randomized studies have a short
duration and a small number of participants, and observational studies lack a control group 9,10.
Aim of this study was to compare the effects of long-term CIPII therapy with SC insulin therapy
among patients with poorly controlled T1DM.
Patients and methods
study designWe conducted an investigator initiated, prospective, observational matched-control study to
compare the effects on glycaemic control of CIPII versus SC insulin therapy. Patient recruitment
took place in two hospitals, the Isala (Zwolle, the Netherlands) and the Diaconessenhuis
hospital (Meppel, the Netherlands).
Since CIPII is as a last-resort treatment option for T1DM, CIPII treated patients are a highly
selected population with a rather complex background and disease history. In order to account
for this inequality between both treatment groups (CIPII versus SC insulin therapy), the
primary endpoint was a non-inferiority assessment of the difference in HbA1c during a
26-week period, taking possible baseline differences into account, between both groups.
patient selection Cases were subjects on CIPII therapy using an implanted insulin pump (MIP 2007D, Medtronic/
Minimed, Northridge, CA, USA) for the past 4 years without interruptions of >30 days, in order
to avoid effects related to initiating therapy. Inclusion criteria for cases were identical to those
of a prior study in our centre and have been described in detail previously 6. In brief, patients
with T1DM, aged 18 to 70 years with a HbA1c ≥ 7.5% and/or ≥ 5 incidents of hypoglycemia
glucose (< 4.0 mmol/l) per week, were eligible.
Controls using SC insulin therapy were selected from the outpatient clinic population.
Eligibility criteria were T1DM, MDI or CSII insulin as mode of insulin administration for the past
4 years without interruptions of >30 days, HbA1c ≥ 7.0% and proper knowledge of the Dutch
language.
Exclusion criteria for both cases and controls were: impaired renal function (plasma creatinine
≥150 µmol/l or glomerular filtration rate as estimated by the Cockcroft-Gault formula
≤50 ml/min, cardiac problems (unstable angina or myocardial infarction within the previous
12 months or New York Heart Association class III or IV congestive heart failure, cognitive
impairment, current or past psychiatric treatment for schizophrenia, cognitive or bipolar
disorder, current use of oral corticosteroids or suffering from a condition which necessitated
oral or systemic corticosteroids use more than once in the previous 12 months, substance
abuse, other than nicotine, current gravidity or plans to become pregnant during the study,
plans to engage in activities that require going >25 feet below sea level or any condition that
the investigator and/or coordinating investigator feels would interfere with study participation
or evaluation of results.
If patients were eligible to act as SC control, they were matched to the CIPII treated cases based
on gender and age. The SC control group consisted of both MDI and CSII users. The ratio of
participants on the different therapies (CIPII:MDI:CSII) was 1:2:2.
chapter 5part 2
82 83
study proceduresThere were four study visits. During the first visit, baseline characteristics were collected using
a standardized case record form and a continuous glucose measurement (CGM) system was
inserted for a period of six days. During the second visit (five to seven days later) the CGM
system was removed and laboratory measurements were performed. During the third visit, 26
weeks after visit 1, clinical parameters were collected and again a CGM device was inserted for
a period of six days. During the fourth visit, five to seven days after the third visit, laboratory
measurements were performed and the CGM device was removed. During the study period all
patients received usual care.
measurementsDemographic and clinical parameters included: age, gender, weight, length, blood pressure,
smoking and alcohol habits, co-morbidities, medication use, year of diagnosis of diabetes,
presence of microvascular (nephropathy, neuropathy and/or retinopathy) or macrovascular
complications (angina pectoris, myocardial infarction, coronary artery bypass grafting,
percutaneous transluminal coronary angioplasty, stroke, transient ischemic attack, peripheral
artery disease), previous day insulin therapy (kind of insulin, dosage and, if applicable, the
number of daily injections) and the number of self-reported hypoglycaemic events grade 1
(<4.0 mmol/l), grade 2 (<3.5 mmol/l) and grade 3 (requiring third party help or losing
consciousness) during the last two weeks. Blood pressure was measured using a blood
pressure monitor (M6 comfort; OMRON Healthcare) using the highest mean of four
measurements (two on each arm). Laboratory measurements included hemoglobin (Hb),
creatinine, C-peptide, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides,
albumin, fibrinogen, aspartate aminotransferase (AST), alanine aminotransferase (ALT),
y-glutamyl transpeptidase (gamma-GT), alkaline phosphatase and urine albumin/creatinine
ratio and HbA1c. HbA1c was measured with a Primus Ultra2 system using high-performance
liquid chromatography (reference value 4.0-6.0%). The six-day 24-hours interstitial glucose
profiles were recorded using a blinded CGM device (iPro2, Medtronic, Northridge, CA, USA).
The CGM device was inserted in the periumbilical area, and in pump users contralateral to
the (implanted) insulin pump. Patients injecting insulin were asked not to inject insulin on
the same side of the sensor insertion side. Patients were instructed to perform a minimum
of 4 blood glucose self-measurements daily during the CGM period, using a validated blood
glucose meter (Contour XT; Bayer) to calibrate the sensor. Time spent in hypoglycemia was
defined as the percentage of CGM readings <4.0 mmol/l, time spent in euglycemia was defined
as the percentage of CGM readings from 4.0 to 10.0 mmol/l, and time spent in hyperglycemia
was defined as the percentage of CGM readings >10.0 mmol/l.
outcome measuresThe primary outcome measure was the difference in HbA1c over a period of 26 weeks between
cases and controls adjusted for baseline differences. Secondary outcomes included differences
in clinical aspects, CGM measures and laboratory measurements between groups.
statistical analysisThe study was designed to test the hypothesis that CIPII would be non-inferior to SC insulin
therapy in T1DM patients during a 26-week follow-up period with respect to the primary
outcome measure. The criteria for non-inferiority required that the upper limits of the 95%
confidence intervals (CI) were above the predefined margin for the difference in HbA1c.
Based on the results of previous randomized clinical trials and discussion with experts, a
non-inferiority margin (Δ) of -0.5% was chosen 6–8. According to pre-specified protocol, both
per protocol and intention-to-treat analysis were performed. A regression model based on
covariate analysis (ANCOVA) was applied in order to take possible baseline imbalance in
HbA1c into account. In the model the fixed factors CIPII and SC insulin therapy were used
as determinants. The difference in scores was determined based on the b-coefficient of the
particular (CIPII or SC, MDI or CSII) group. Significance of the b-coefficient was investigated
with the Wald test based on a p<0.05. The quantity of the b-coefficient, with a 95% CI, gives
the difference between both treatment modalities over the study period adjusted for baseline
differences.
With the use of a standard deviation (SD) of 0.9%, estimated from the previous cross-over
study, and a non-inferiority margin of -0.5%, we calculated that we would need to enrol 175
patients (35 CIPII, 140 SC insulin therapy) to show non-inferiority of CIPII therapy at a one-sided
alpha level of 0.025 6. In order to compensate for loss-to-follow-up, intended group sample
sizes were 40 and 150, respectively.
Statistical analyses were performed using SPSS (IBM SPSS Statistics for Windows, Version 20.0.
Armonk, NY: IBM Corp.) and STATA version 12 (Stata Corp., College Station, TX: StataCorp LP).
Results were expressed as mean (with SD) or median (with the interquartile range [IQR]) for
normally distributed and non-normally distributed data, respectively. A significance level of
5% was used.
The study protocol was registered prior to the start of the study at the appropriate local
(NL41037.075.12) and international registers (NCT01621308). The study protocol was approved
by the local medical ethics committee and all patients gave informed consent.
chapter 5part 2
82 83
study proceduresThere were four study visits. During the first visit, baseline characteristics were collected using
a standardized case record form and a continuous glucose measurement (CGM) system was
inserted for a period of six days. During the second visit (five to seven days later) the CGM
system was removed and laboratory measurements were performed. During the third visit, 26
weeks after visit 1, clinical parameters were collected and again a CGM device was inserted for
a period of six days. During the fourth visit, five to seven days after the third visit, laboratory
measurements were performed and the CGM device was removed. During the study period all
patients received usual care.
measurementsDemographic and clinical parameters included: age, gender, weight, length, blood pressure,
smoking and alcohol habits, co-morbidities, medication use, year of diagnosis of diabetes,
presence of microvascular (nephropathy, neuropathy and/or retinopathy) or macrovascular
complications (angina pectoris, myocardial infarction, coronary artery bypass grafting,
percutaneous transluminal coronary angioplasty, stroke, transient ischemic attack, peripheral
artery disease), previous day insulin therapy (kind of insulin, dosage and, if applicable, the
number of daily injections) and the number of self-reported hypoglycaemic events grade 1
(<4.0 mmol/l), grade 2 (<3.5 mmol/l) and grade 3 (requiring third party help or losing
consciousness) during the last two weeks. Blood pressure was measured using a blood
pressure monitor (M6 comfort; OMRON Healthcare) using the highest mean of four
measurements (two on each arm). Laboratory measurements included hemoglobin (Hb),
creatinine, C-peptide, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides,
albumin, fibrinogen, aspartate aminotransferase (AST), alanine aminotransferase (ALT),
y-glutamyl transpeptidase (gamma-GT), alkaline phosphatase and urine albumin/creatinine
ratio and HbA1c. HbA1c was measured with a Primus Ultra2 system using high-performance
liquid chromatography (reference value 4.0-6.0%). The six-day 24-hours interstitial glucose
profiles were recorded using a blinded CGM device (iPro2, Medtronic, Northridge, CA, USA).
The CGM device was inserted in the periumbilical area, and in pump users contralateral to
the (implanted) insulin pump. Patients injecting insulin were asked not to inject insulin on
the same side of the sensor insertion side. Patients were instructed to perform a minimum
of 4 blood glucose self-measurements daily during the CGM period, using a validated blood
glucose meter (Contour XT; Bayer) to calibrate the sensor. Time spent in hypoglycemia was
defined as the percentage of CGM readings <4.0 mmol/l, time spent in euglycemia was defined
as the percentage of CGM readings from 4.0 to 10.0 mmol/l, and time spent in hyperglycemia
was defined as the percentage of CGM readings >10.0 mmol/l.
outcome measuresThe primary outcome measure was the difference in HbA1c over a period of 26 weeks between
cases and controls adjusted for baseline differences. Secondary outcomes included differences
in clinical aspects, CGM measures and laboratory measurements between groups.
statistical analysisThe study was designed to test the hypothesis that CIPII would be non-inferior to SC insulin
therapy in T1DM patients during a 26-week follow-up period with respect to the primary
outcome measure. The criteria for non-inferiority required that the upper limits of the 95%
confidence intervals (CI) were above the predefined margin for the difference in HbA1c.
Based on the results of previous randomized clinical trials and discussion with experts, a
non-inferiority margin (Δ) of -0.5% was chosen 6–8. According to pre-specified protocol, both
per protocol and intention-to-treat analysis were performed. A regression model based on
covariate analysis (ANCOVA) was applied in order to take possible baseline imbalance in
HbA1c into account. In the model the fixed factors CIPII and SC insulin therapy were used
as determinants. The difference in scores was determined based on the b-coefficient of the
particular (CIPII or SC, MDI or CSII) group. Significance of the b-coefficient was investigated
with the Wald test based on a p<0.05. The quantity of the b-coefficient, with a 95% CI, gives
the difference between both treatment modalities over the study period adjusted for baseline
differences.
With the use of a standard deviation (SD) of 0.9%, estimated from the previous cross-over
study, and a non-inferiority margin of -0.5%, we calculated that we would need to enrol 175
patients (35 CIPII, 140 SC insulin therapy) to show non-inferiority of CIPII therapy at a one-sided
alpha level of 0.025 6. In order to compensate for loss-to-follow-up, intended group sample
sizes were 40 and 150, respectively.
Statistical analyses were performed using SPSS (IBM SPSS Statistics for Windows, Version 20.0.
Armonk, NY: IBM Corp.) and STATA version 12 (Stata Corp., College Station, TX: StataCorp LP).
Results were expressed as mean (with SD) or median (with the interquartile range [IQR]) for
normally distributed and non-normally distributed data, respectively. A significance level of
5% was used.
The study protocol was registered prior to the start of the study at the appropriate local
(NL41037.075.12) and international registers (NCT01621308). The study protocol was approved
by the local medical ethics committee and all patients gave informed consent.
chapter 5part 2
84 85
Results
patientsFrom December 2012 through August 2013, a total of 335 patients were screened and received
information about the study of which 190 agreed to participate. After baseline laboratory
measurements, six patients were excluded because of reasons presented in Figure 1.
Consequently, 184 patients were followed during the 26-week study period. After the first visit
one patient withdrew informed consent due to lack of interest. Therefore, 183 patients were
analysed.
Main baseline characteristics are presented in Table 1 and more detailed information is
provided in Appendix 1. Age and gender were well matched between groups. No grade 3
hypoglycaemic events were reported. Compared to patients using SC insulin therapy, CIPII
patients had a higher diastolic blood pressure, more microvascular complications, used
more units of insulin per day and spent less time in hypoglycaemic range and more time in
hyperglycaemic range during CGM recordings.
primary outcome - glycaemic controlWithin the group of CIPII treated patients, HbA1c did not significantly changed while it
decreased with -0.09% (95% CI -0.17, -0.01) among patients treated with SC insulin therapy
(see Table 2). Taking baseline differences into account, the difference between treatment
groups was -0.27% (95% CI -0.46, -0.09) and met the non-inferiority criterion of -0.5 % (see
Figure 2). The results of the intention-to treat analyses did not differ from the per-protocol
analysis (see Appendix 2). During study, the number of grade 1 hypoglycaemic episodes during
the last 2 weeks decreased with -1.2 (95% CI -1.7, -0.7) among patients with SC insulin. Patients
using SC insulin therapy spent less percentage of time in hyperglycemia (-9.3% (95% CI -15.8,
-2.8)) and more in euglycemia (6.9% (95% CI 1.2, 12.5) as compared to patients using CIPII.
secondary outcome - clinical and biochemical parametersDuring follow-up, three patients experienced a macrovascular complication: one patient
treated with CIPII had angina pectoris, one patient using MDI had a transient ischemic attack
and one patients using CSII had a myocardial infarction. In two patients a new microvascular
complication was diagnosed: one patient using MDI had nephropathy and patient using CSII
had retinopathy..There was a decrease in systolic blood pressure (-5.6 mmHg, 95% CI -11.0, -0.1)
and serum creatinin concentration (5.0 µmol/l, 95% CI 2.0, 7.5) over time among CIPII treated
patients. Among SC treated patients systolic blood pressure (-3.4 mmHg, 95% CI -6.5, -0.2)
decreased and BMI (0.2 kg/m2, 95% CI 0.0, 0.4) increased over time. Concentrations of ALT (2.6
U/l, 95% CI 1. 2, 4.0) and serum creatinine (3.2 µmol/l, 95% CI 2.2, 4.2) increased in SC treated
patients. Taking baseline differences into account, CIPII treated patients had significant lower
concentrations of ALT as compared to patients treated with SC insulin therapy: 3.6 U/l (95% CI
1.2, 6.0). The results of measurements of all clinical and biochemical parameters performed
at baseline and the end of the study and changes within and differences between groups are
presented in the Appendix 3.
chapter 5part 2
Patient flowchart.figure 1
eligible patients that received information (n=335)
included (n=190)
cipii therapy (n=40)sc insulin therapy (n=150)• mdi (n=75)• csii (n=75)
excluded after visit 2 (n=1)• egfr <40 ml/min
excluded after visit 2 (n=5)• c-peptide > 0.2 nmol/l (n=4)• egfr < 40 ml/min (n=1)
discontinued study (withdrew consent) (n=1)
completed study and included in analysis (n=144)• mdi (n=70)• csii (n=74)
completed study and included in analysis (n=39)
excluded (n=145)• not meeting inclusion criteria (n=11) - psychiatric illness (n=4) - hbA1c < 7.0% (n=3) - predison use (n=2) - non-compliant (n=1)• declined to participate (n=46)• not asked for participation due to logistic reasons (n=88)
84 85
Results
patientsFrom December 2012 through August 2013, a total of 335 patients were screened and received
information about the study of which 190 agreed to participate. After baseline laboratory
measurements, six patients were excluded because of reasons presented in Figure 1.
Consequently, 184 patients were followed during the 26-week study period. After the first visit
one patient withdrew informed consent due to lack of interest. Therefore, 183 patients were
analysed.
Main baseline characteristics are presented in Table 1 and more detailed information is
provided in Appendix 1. Age and gender were well matched between groups. No grade 3
hypoglycaemic events were reported. Compared to patients using SC insulin therapy, CIPII
patients had a higher diastolic blood pressure, more microvascular complications, used
more units of insulin per day and spent less time in hypoglycaemic range and more time in
hyperglycaemic range during CGM recordings.
primary outcome - glycaemic controlWithin the group of CIPII treated patients, HbA1c did not significantly changed while it
decreased with -0.09% (95% CI -0.17, -0.01) among patients treated with SC insulin therapy
(see Table 2). Taking baseline differences into account, the difference between treatment
groups was -0.27% (95% CI -0.46, -0.09) and met the non-inferiority criterion of -0.5 % (see
Figure 2). The results of the intention-to treat analyses did not differ from the per-protocol
analysis (see Appendix 2). During study, the number of grade 1 hypoglycaemic episodes during
the last 2 weeks decreased with -1.2 (95% CI -1.7, -0.7) among patients with SC insulin. Patients
using SC insulin therapy spent less percentage of time in hyperglycemia (-9.3% (95% CI -15.8,
-2.8)) and more in euglycemia (6.9% (95% CI 1.2, 12.5) as compared to patients using CIPII.
secondary outcome - clinical and biochemical parametersDuring follow-up, three patients experienced a macrovascular complication: one patient
treated with CIPII had angina pectoris, one patient using MDI had a transient ischemic attack
and one patients using CSII had a myocardial infarction. In two patients a new microvascular
complication was diagnosed: one patient using MDI had nephropathy and patient using CSII
had retinopathy..There was a decrease in systolic blood pressure (-5.6 mmHg, 95% CI -11.0, -0.1)
and serum creatinin concentration (5.0 µmol/l, 95% CI 2.0, 7.5) over time among CIPII treated
patients. Among SC treated patients systolic blood pressure (-3.4 mmHg, 95% CI -6.5, -0.2)
decreased and BMI (0.2 kg/m2, 95% CI 0.0, 0.4) increased over time. Concentrations of ALT (2.6
U/l, 95% CI 1. 2, 4.0) and serum creatinine (3.2 µmol/l, 95% CI 2.2, 4.2) increased in SC treated
patients. Taking baseline differences into account, CIPII treated patients had significant lower
concentrations of ALT as compared to patients treated with SC insulin therapy: 3.6 U/l (95% CI
1.2, 6.0). The results of measurements of all clinical and biochemical parameters performed
at baseline and the end of the study and changes within and differences between groups are
presented in the Appendix 3.
chapter 5part 2
Patient flowchart.figure 1
eligible patients that received information (n=335)
included (n=190)
cipii therapy (n=40)sc insulin therapy (n=150)• mdi (n=75)• csii (n=75)
excluded after visit 2 (n=1)• egfr <40 ml/min
excluded after visit 2 (n=5)• c-peptide > 0.2 nmol/l (n=4)• egfr < 40 ml/min (n=1)
discontinued study (withdrew consent) (n=1)
completed study and included in analysis (n=144)• mdi (n=70)• csii (n=74)
completed study and included in analysis (n=39)
excluded (n=145)• not meeting inclusion criteria (n=11) - psychiatric illness (n=4) - hbA1c < 7.0% (n=3) - predison use (n=2) - non-compliant (n=1)• declined to participate (n=46)• not asked for participation due to logistic reasons (n=88)
86 87
chapter 5part 2
Differences between treatment groups with 95%CI and the non-inferiority interval.figure 2
Error bars indicate the 2-sided 95% CI. The blue dashed line at x=Δ indicates the pre-defined non-inferiority margin for the difference between CIPII and SC insulin treated patients of -0.5%. A: mean difference (95% CI) between CIPII and SC.
Baseline characteristics.table 1
Data are presented as n (%), mean (SD) or median [IQR]. Variables may not add up because of rounding off. *p<0.05 as compared to CIPII, P-values are based on appropriate parametric and non-parametric tests. † Defined as the number of hypoglycaemic events < 4 (grade 1) and < 3.5 (grade 2) during the last 14 days. Abbreviations: ALT; alanine aminotransferase, BMI; Body Mass Index, CIPII; continuous intraperitoneal infusion, SC; subcutaneous. a based on n=32 (CIPII) and n=116 (SC).
Change in glycaemic parameters within- and difference between groups. table 2
Data are means (95% CI) differences within the groups and mean between the (SC vs CIPII insulin therapy) groups adjusted for baseline differences. *p<0.05. † Defined as the number of blood glucose value <4.0 mmol/l during the last 2 weeks ‡ Defined as the number of blood glucose value <3.5 mmol/l during the last 2 weeks. Abbreviations: CIPII; continuous intraperitoneal infusion, SC; subcutaneous. a based on n=36 (CIPII) and n=137 (SC).
MDI and CSII versus CIPIIIn comparison with the CIPII group, MDI and CSII users had a lower HbA1c (-0.29% (95% CI
-0.54, -0.04) for MDI users and -0.26% (95% CI -0.5, -0.01) for CSII users, respectively) and
spent less time in hyperglycemia (-10.3%, (95% CI -17.6, -3.0) for MDI users and -8.6% (95% CI
-15.5, -1.7) for CSII users, respectively) after adjustment for baseline differences. In addition,
MDI users spent 8.2% (95% CI 2.0, 14.5) more time in the euglycaemic range than CIPII treated
patients. Besides higher concentrations of ALT (4.0 U/l, 95% CI 0.8, 7.2 for MDI users and 3.2
U/l, 95% CI 0.1, 6.4 for CSII users, respectively) there were no other differences with respect to
clinical and biochemical parameters (see Appendix 4).
86 87
chapter 5part 2
Differences between treatment groups with 95%CI and the non-inferiority interval.figure 2
Error bars indicate the 2-sided 95% CI. The blue dashed line at x=Δ indicates the pre-defined non-inferiority margin for the difference between CIPII and SC insulin treated patients of -0.5%. A: mean difference (95% CI) between CIPII and SC.
Baseline characteristics.table 1
Data are presented as n (%), mean (SD) or median [IQR]. Variables may not add up because of rounding off. *p<0.05 as compared to CIPII, P-values are based on appropriate parametric and non-parametric tests. † Defined as the number of hypoglycaemic events < 4 (grade 1) and < 3.5 (grade 2) during the last 14 days. Abbreviations: ALT; alanine aminotransferase, BMI; Body Mass Index, CIPII; continuous intraperitoneal infusion, SC; subcutaneous. a based on n=32 (CIPII) and n=116 (SC).
Change in glycaemic parameters within- and difference between groups. table 2
Data are means (95% CI) differences within the groups and mean between the (SC vs CIPII insulin therapy) groups adjusted for baseline differences. *p<0.05. † Defined as the number of blood glucose value <4.0 mmol/l during the last 2 weeks ‡ Defined as the number of blood glucose value <3.5 mmol/l during the last 2 weeks. Abbreviations: CIPII; continuous intraperitoneal infusion, SC; subcutaneous. a based on n=36 (CIPII) and n=137 (SC).
MDI and CSII versus CIPIIIn comparison with the CIPII group, MDI and CSII users had a lower HbA1c (-0.29% (95% CI
-0.54, -0.04) for MDI users and -0.26% (95% CI -0.5, -0.01) for CSII users, respectively) and
spent less time in hyperglycemia (-10.3%, (95% CI -17.6, -3.0) for MDI users and -8.6% (95% CI
-15.5, -1.7) for CSII users, respectively) after adjustment for baseline differences. In addition,
MDI users spent 8.2% (95% CI 2.0, 14.5) more time in the euglycaemic range than CIPII treated
patients. Besides higher concentrations of ALT (4.0 U/l, 95% CI 0.8, 7.2 for MDI users and 3.2
U/l, 95% CI 0.1, 6.4 for CSII users, respectively) there were no other differences with respect to
clinical and biochemical parameters (see Appendix 4).
88 89
Discussion
CIPII is non-inferior to SC insulin therapy with respect to HbA1c among T1DM patients in poor
glycaemic control. CIPII treated patients spent more time in the hyperglycemia and less in
euglycemia as compared to patients using SC insulin therapy. Furthermore, besides lower ALT
concentrations among CIPII treated patients, there were no other differences in clinical and
biochemical parameters between T1DM patients treated with CIPII and SC insulin.
This is the first study to compare the effects of long-term CIPII and SC insulin administration in
a large population of poorly regulated T1DM patients receiving usual care. Since CIPII is a last-
resort treatment option for T1DM, the group of CIPII treated patients is considered selected
and more complex as compared to SC treated patients. This is emphasized by the higher
frequency of microvascular complications and more hyperglycaemic profile among CIPII
treated patients, as compared to SC treated patients, found at baseline in the current study.
Although groups were matched on age and gender, patients were on therapy for
>4 years, measurements were performed with a 26-week interval and outcomes were adjusted
for baseline differences: the non-randomized design remains a limitation of the present study.
In particular the complexity of the CIPII treated group, consisting of both patients with high
HbA1c as well as frequent hypoglycaemic episodes due to various causes, and the modest
number of available patients necessitated pragmatic measures in the study design. In order
to reflect the heterogeneous nature of the CIPII group, a lower HbA1c inclusion criterion for
SC treated patients was chosen. And although groups were well matched on age, gender,
HbA1c and hypoglycaemic episodes at baseline, differences between groups that are known
to influence glycaemic control, such as quality of life which is known to be lower among
CIPII treated patients, could still be present 11,12. Although hypothetical, the presence of such
(unmeasured) differences between groups may have caused a (slight) underestimation of the
effect of CIPII on glycaemic control. This would also be in line with the fact that superiority of
CIPII, above SC insulin, therapy was only found in previous studies with a cross-over design,
which minimize inter-patient variability and looks only at intra-patient changes, and not in
studies with a parallel design 6–8. While fully acknowledging these limitations, we feel that the
current design is the best available for the present study objective given the real-life, clinical
restrictions.
According to the study protocol, the HbA1c difference between both treatment groups was
assessed using a non-inferiority method. Although the HbA1c difference of -0.27% (95% CI
-0.46, -0.09) between CIPII and SC treated patients was negative, the 95% CI remained above
the predefined margin of -0.5%. Therefore it is concluded that CIPII is non-inferior to SC insulin
therapy with respect to HbA1c in the treatment of T1DM.
The present study expands current knowledge regarding CIPII as a treatment modality for
selected patients with T1DM. The effects of CIPII have been described previously in three
randomized studies. After 6 months of cross-over treatment with CIPII and SC insulin, Haardt
et al. reported a difference of 1.28% in favor of CIPII, with a reduction of glycaemic fluctuations
and hypoglycaemic episodes 8. In the 6-month parallel study by Selam et al. there were no
differences between the SC and CIPII study group 7. Among the 24 T1DM patients studied in a
cross-over by Logtenberg et al. there was a HbA1c decrease of 0.76%, with 11% more time spent
in euglycemia and without a change in hypoglycaemic events, in favor of CIPII 6. Subsequent
observational studies among CIPII treated patients found stabilisation of the HbA1c during
long-term follow-up at an equal or lower level than before initiation of CIPII 9,10,13,14.
Although ALT concentrations were still within the normal range and the other liver enzymes
were stable, this finding is remarkable. It might be hypothesized that, since IP insulin
administration results in higher hepatic insulin concentrations than SC insulin administration
this leads to altered hepatic metabolism secondary to higher insulinization 2,3,15.
At present, the costs of CIPII therapy seems to outweighs the advantages of CIPII with regard
to glycaemic regulation for the majority of patients and health care systems 12. Nevertheless,
based on the short-term positive effects found in previous studies, including HbA1c
improvements, less hypoglycaemic episodes and improved quality of life, and the findings
of the present study among long-term CIPII-treated patients we advocate that CIPII using an
implantable pump should be seen a valuable and feasible last-resort treatment option for selected
patients with T1DM who are unable to reach glycaemic control with SC insulin therapy 6,8,12,14.
Conclusions
For the long-term treatment of poorly regulated patients with T1DM, CIPII is non-inferior to
SC insulin therapy with respect to HbA1c. Except for lower ALT concentrations among CIPII
treated patients within the normal range, there are no differences in clinical and biochemical
parameters. This study supports the effectiveness of long-term CIPII therapy as last-resort
treatment in T1DM.
chapter 5part 2
88 89
Discussion
CIPII is non-inferior to SC insulin therapy with respect to HbA1c among T1DM patients in poor
glycaemic control. CIPII treated patients spent more time in the hyperglycemia and less in
euglycemia as compared to patients using SC insulin therapy. Furthermore, besides lower ALT
concentrations among CIPII treated patients, there were no other differences in clinical and
biochemical parameters between T1DM patients treated with CIPII and SC insulin.
This is the first study to compare the effects of long-term CIPII and SC insulin administration in
a large population of poorly regulated T1DM patients receiving usual care. Since CIPII is a last-
resort treatment option for T1DM, the group of CIPII treated patients is considered selected
and more complex as compared to SC treated patients. This is emphasized by the higher
frequency of microvascular complications and more hyperglycaemic profile among CIPII
treated patients, as compared to SC treated patients, found at baseline in the current study.
Although groups were matched on age and gender, patients were on therapy for
>4 years, measurements were performed with a 26-week interval and outcomes were adjusted
for baseline differences: the non-randomized design remains a limitation of the present study.
In particular the complexity of the CIPII treated group, consisting of both patients with high
HbA1c as well as frequent hypoglycaemic episodes due to various causes, and the modest
number of available patients necessitated pragmatic measures in the study design. In order
to reflect the heterogeneous nature of the CIPII group, a lower HbA1c inclusion criterion for
SC treated patients was chosen. And although groups were well matched on age, gender,
HbA1c and hypoglycaemic episodes at baseline, differences between groups that are known
to influence glycaemic control, such as quality of life which is known to be lower among
CIPII treated patients, could still be present 11,12. Although hypothetical, the presence of such
(unmeasured) differences between groups may have caused a (slight) underestimation of the
effect of CIPII on glycaemic control. This would also be in line with the fact that superiority of
CIPII, above SC insulin, therapy was only found in previous studies with a cross-over design,
which minimize inter-patient variability and looks only at intra-patient changes, and not in
studies with a parallel design 6–8. While fully acknowledging these limitations, we feel that the
current design is the best available for the present study objective given the real-life, clinical
restrictions.
According to the study protocol, the HbA1c difference between both treatment groups was
assessed using a non-inferiority method. Although the HbA1c difference of -0.27% (95% CI
-0.46, -0.09) between CIPII and SC treated patients was negative, the 95% CI remained above
the predefined margin of -0.5%. Therefore it is concluded that CIPII is non-inferior to SC insulin
therapy with respect to HbA1c in the treatment of T1DM.
The present study expands current knowledge regarding CIPII as a treatment modality for
selected patients with T1DM. The effects of CIPII have been described previously in three
randomized studies. After 6 months of cross-over treatment with CIPII and SC insulin, Haardt
et al. reported a difference of 1.28% in favor of CIPII, with a reduction of glycaemic fluctuations
and hypoglycaemic episodes 8. In the 6-month parallel study by Selam et al. there were no
differences between the SC and CIPII study group 7. Among the 24 T1DM patients studied in a
cross-over by Logtenberg et al. there was a HbA1c decrease of 0.76%, with 11% more time spent
in euglycemia and without a change in hypoglycaemic events, in favor of CIPII 6. Subsequent
observational studies among CIPII treated patients found stabilisation of the HbA1c during
long-term follow-up at an equal or lower level than before initiation of CIPII 9,10,13,14.
Although ALT concentrations were still within the normal range and the other liver enzymes
were stable, this finding is remarkable. It might be hypothesized that, since IP insulin
administration results in higher hepatic insulin concentrations than SC insulin administration
this leads to altered hepatic metabolism secondary to higher insulinization 2,3,15.
At present, the costs of CIPII therapy seems to outweighs the advantages of CIPII with regard
to glycaemic regulation for the majority of patients and health care systems 12. Nevertheless,
based on the short-term positive effects found in previous studies, including HbA1c
improvements, less hypoglycaemic episodes and improved quality of life, and the findings
of the present study among long-term CIPII-treated patients we advocate that CIPII using an
implantable pump should be seen a valuable and feasible last-resort treatment option for selected
patients with T1DM who are unable to reach glycaemic control with SC insulin therapy 6,8,12,14.
Conclusions
For the long-term treatment of poorly regulated patients with T1DM, CIPII is non-inferior to
SC insulin therapy with respect to HbA1c. Except for lower ALT concentrations among CIPII
treated patients within the normal range, there are no differences in clinical and biochemical
parameters. This study supports the effectiveness of long-term CIPII therapy as last-resort
treatment in T1DM.
chapter 5part 2
90 91
1 Renard E, Schaepelynck-Bélicar P, EVADIAC Group. Implantable insulin pumps. A position statement about their clinical use. Diabetes Metab 2007; 33: 158–66.2 Giacca A, Caumo A, Galimberti G, et al. Peritoneal and subcutaneous absorption of insulin in type I diabetic subjects. J Clin Endocrinol Metab 1993; 77: 738–42.3 Bratusch-Marrain PR, Waldhäusl WK, Gasić S, Hofer A. Hepatic disposal of biosynthetic human insulin and porcine C-peptide in humans. Metabolism 1984; 33: 151–7.4 Nathan DM, Dunn FL, Bruch J, et al. Postprandial insulin profiles with implantable pump therapy may explain decreased frequency of severe hypoglycemia, compared with intensive subcutaneous regimens, in insulin-dependent diabetes mellitus patients. Am J Med 1996; 100: 412–7.5 Schaepelynck Bélicar P, Vague P, Lassmann-Vague V. Reproducibility of plasma insulin kinetics during intraperitoneal insulin treatment by programmable pumps. Diabetes Metab 2003; 29: 344–8.6 Logtenberg SJ, Kleefstra N, Houweling ST, et al. Improved glycemic control with intraperitoneal versus subcutaneous insulin in type 1 diabetes: a randomized controlled trial. Diabetes Care 2009; 32: 1372–7.7 Selam JL, Raccah D, Jean-Didier N, Lozano JL, Waxman K, Charles MA. Randomized comparison of metabolic control achieved by intraperitoneal insulin infusion with implantable pumps versus intensive subcutaneous insulin therapy in type I diabetic patients. Diabetes Care 1992; 15: 53–8.8 Haardt MJ, Selam JL, Slama G, et al. A cost-benefit comparison of intensive diabetes management with implantable pumps versus multiple subcutaneous injections in patients with type I diabetes. Diabetes Care 1994; 17: 847–51.9 Schaepelynck P, Renard E, Jeandidier N, et al. A recent survey confirms the efficacy and the safety of implanted insulin pumps during long-term use in poorly controlled type 1 diabetes patients. Diabetes Technol Ther 2011; 13: 657–60.10 Logtenberg SJJ, van Ballegooie E, Israêl-Bultman H, van Linde A, Bilo HJG. Glycaemic control, health status and treat- ment satisfaction with continuous intraperitoneal insulin infusion. Neth J Med 2007; 65: 65–70.11 DeVries JH, Eskes SA, Snoek FJ, et al. Continuous intraperitoneal insulin infusion in patients with ‘brittle’ diabetes: favourable effects on glycaemic control and hospital stay. Diabet Med J Br Diabet Assoc 2002; 19: 496–501.12 Logtenberg SJ, Kleefstra N, Houweling ST, Groenier KH, Gans RO, Bilo HJ. Health-related quality of life, treatment satisfaction, and costs associated with intraperitoneal versus subcutaneous insulin administration in type 1 diabetes: a randomized controlled trial. Diabetes Care 2010; 33: 1169–72.13 Gin H, Renard E, Melki V, et al. Combined improvements in implantable pump technology and insulin stability allow safe and effective long term intraperitoneal insulin delivery in type 1 diabetic patients: the EVADIAC experience. Diabetes Metab 2003; 29: 602–7.14 Van Dijk PR, Logtenberg SJ, Groenier KH, Gans RO, Kleefstra N, Bilo HJ. Continuous intraperitoneal insulin infusion in type 1 diabetes: a 6-year post-trial follow-up. BMC Endocr Disord 2014; 14: 30.15 Selam JL, Bergman RN, Raccah D, Jean-Didier N, Lozano J, Charles MA. Determination of portal insulin absorption from peritoneum via novel nonisotopic method. Diabetes 1990; 39: 1361–5.
chapter 5part 2
references
90 91
1 Renard E, Schaepelynck-Bélicar P, EVADIAC Group. Implantable insulin pumps. A position statement about their clinical use. Diabetes Metab 2007; 33: 158–66.2 Giacca A, Caumo A, Galimberti G, et al. Peritoneal and subcutaneous absorption of insulin in type I diabetic subjects. J Clin Endocrinol Metab 1993; 77: 738–42.3 Bratusch-Marrain PR, Waldhäusl WK, Gasić S, Hofer A. Hepatic disposal of biosynthetic human insulin and porcine C-peptide in humans. Metabolism 1984; 33: 151–7.4 Nathan DM, Dunn FL, Bruch J, et al. Postprandial insulin profiles with implantable pump therapy may explain decreased frequency of severe hypoglycemia, compared with intensive subcutaneous regimens, in insulin-dependent diabetes mellitus patients. Am J Med 1996; 100: 412–7.5 Schaepelynck Bélicar P, Vague P, Lassmann-Vague V. Reproducibility of plasma insulin kinetics during intraperitoneal insulin treatment by programmable pumps. Diabetes Metab 2003; 29: 344–8.6 Logtenberg SJ, Kleefstra N, Houweling ST, et al. Improved glycemic control with intraperitoneal versus subcutaneous insulin in type 1 diabetes: a randomized controlled trial. Diabetes Care 2009; 32: 1372–7.7 Selam JL, Raccah D, Jean-Didier N, Lozano JL, Waxman K, Charles MA. Randomized comparison of metabolic control achieved by intraperitoneal insulin infusion with implantable pumps versus intensive subcutaneous insulin therapy in type I diabetic patients. Diabetes Care 1992; 15: 53–8.8 Haardt MJ, Selam JL, Slama G, et al. A cost-benefit comparison of intensive diabetes management with implantable pumps versus multiple subcutaneous injections in patients with type I diabetes. Diabetes Care 1994; 17: 847–51.9 Schaepelynck P, Renard E, Jeandidier N, et al. A recent survey confirms the efficacy and the safety of implanted insulin pumps during long-term use in poorly controlled type 1 diabetes patients. Diabetes Technol Ther 2011; 13: 657–60.10 Logtenberg SJJ, van Ballegooie E, Israêl-Bultman H, van Linde A, Bilo HJG. Glycaemic control, health status and treat- ment satisfaction with continuous intraperitoneal insulin infusion. Neth J Med 2007; 65: 65–70.11 DeVries JH, Eskes SA, Snoek FJ, et al. Continuous intraperitoneal insulin infusion in patients with ‘brittle’ diabetes: favourable effects on glycaemic control and hospital stay. Diabet Med J Br Diabet Assoc 2002; 19: 496–501.12 Logtenberg SJ, Kleefstra N, Houweling ST, Groenier KH, Gans RO, Bilo HJ. Health-related quality of life, treatment satisfaction, and costs associated with intraperitoneal versus subcutaneous insulin administration in type 1 diabetes: a randomized controlled trial. Diabetes Care 2010; 33: 1169–72.13 Gin H, Renard E, Melki V, et al. Combined improvements in implantable pump technology and insulin stability allow safe and effective long term intraperitoneal insulin delivery in type 1 diabetic patients: the EVADIAC experience. Diabetes Metab 2003; 29: 602–7.14 Van Dijk PR, Logtenberg SJ, Groenier KH, Gans RO, Kleefstra N, Bilo HJ. Continuous intraperitoneal insulin infusion in type 1 diabetes: a 6-year post-trial follow-up. BMC Endocr Disord 2014; 14: 30.15 Selam JL, Bergman RN, Raccah D, Jean-Didier N, Lozano J, Charles MA. Determination of portal insulin absorption from peritoneum via novel nonisotopic method. Diabetes 1990; 39: 1361–5.
chapter 5part 2
references
92 93
chapter 5part 2
appe
ndix
1Ba
selin
e cha
ract
erist
ics.
Dat
a are
pre
sent
ed as
n (%
), m
ean
(SD
) or m
edia
n [IQ
R]. *
p<0.
05 as
com
pare
d to
CIP
II, †
p<0
.05 f
or M
DI v
ersu
s CSI
I. P-v
alue
s are
bas
ed o
n ap
prop
riate
par
amet
ric an
d no
n-pa
ram
etric
test
s. Re
tinop
athy
, ne
urop
athy
and
neph
ropa
thy c
ateg
orie
s do
not a
dd u
p to
micr
ovas
cula
r cat
egor
y as p
rese
nted
in Ta
ble 1
. Abb
revi
atio
ns: A
LT; a
lani
ne am
inot
rans
fera
se, A
ST; a
spar
tate
amin
otra
nsfe
rase
, BM
I; bo
dy
mas
s ind
ex, C
SII;
cont
inuo
us in
trape
riton
eal i
nsul
in in
fusio
n, C
IPII;
cont
inuo
us in
trape
riton
eal i
nfus
ion,
Gam
ma-
GT; G
amm
a-gl
utam
yl tr
ansp
eptid
ase,
HD
L; h
igh
dens
ity li
popr
otei
n, LD
L; lo
w d
ensit
y lip
opro
tein
, MD
I; m
ultip
le d
aily
inje
ctio
ns, S
C; su
bcut
aneo
us. a b
ased
on
n=32
(CIP
II), n
=56 (
MD
I) an
d n=
69 (C
SII).
92 93
chapter 5part 2
appe
ndix
1Ba
selin
e cha
ract
erist
ics.
Dat
a are
pre
sent
ed as
n (%
), m
ean
(SD
) or m
edia
n [IQ
R]. *
p<0.
05 as
com
pare
d to
CIP
II, †
p<0
.05 f
or M
DI v
ersu
s CSI
I. P-v
alue
s are
bas
ed o
n ap
prop
riate
par
amet
ric an
d no
n-pa
ram
etric
test
s. Re
tinop
athy
, ne
urop
athy
and
neph
ropa
thy c
ateg
orie
s do
not a
dd u
p to
micr
ovas
cula
r cat
egor
y as p
rese
nted
in Ta
ble 1
. Abb
revi
atio
ns: A
LT; a
lani
ne am
inot
rans
fera
se, A
ST; a
spar
tate
amin
otra
nsfe
rase
, BM
I; bo
dy
mas
s ind
ex, C
SII;
cont
inuo
us in
trape
riton
eal i
nsul
in in
fusio
n, C
IPII;
cont
inuo
us in
trape
riton
eal i
nfus
ion,
Gam
ma-
GT; G
amm
a-gl
utam
yl tr
ansp
eptid
ase,
HD
L; h
igh
dens
ity li
popr
otei
n, LD
L; lo
w d
ensit
y lip
opro
tein
, MD
I; m
ultip
le d
aily
inje
ctio
ns, S
C; su
bcut
aneo
us. a b
ased
on
n=32
(CIP
II), n
=56 (
MD
I) an
d n=
69 (C
SII).
94 95
chapter 5part 2
Resu
lts of
the p
er p
roto
col a
nd in
tent
ion
to tr
eat a
naly
sis fo
r the
prim
ary o
utco
me.
appe
ndix
2
Dat
a are
mea
ns (S
D) a
nd d
iffer
ence
bet
wee
n m
eans
(95%
CI).
Dat
a are
mea
ns (S
D) a
nd d
iffer
ence
bet
wee
n m
eans
(95%
CI).
Inte
ntio
n to
trea
t ana
lysis
(n=1
84)
Per p
roto
col a
naly
sis (n
=183
)
appe
ndix
3Ou
tcom
es d
urin
g bas
elin
e and
fina
l visi
t, cha
nges
with
in- a
nd d
iffer
ence
s bet
wee
n gr
oups
.
Dat
a are
pre
sent
ed as
n (%
), m
ean
(SD
) or m
edia
n [IQ
R]. *
p<0.
05 a b
ased
on
n=11
6 and
n=3
2 b bas
ed o
n n=
137 a
nd n
=36.
† D
efine
d as
the n
umbe
r of b
lood
glu
cose
valu
e <4.
0 m
mol
/l du
ring
the l
ast 2
wee
ks
‡ D
efine
d as
the n
umbe
r of b
lood
glu
cose
valu
e <3.
5 mm
ol/l
durin
g th
e las
t 2 w
eeks
. ¥ D
efine
d as
the n
umbe
r of h
ypog
lyca
emic
episo
des r
equi
ring
third
par
ty h
elp
or lo
sing
cons
cious
ness
dur
ing
the l
ast
2 wee
ks. A
bbre
viat
ions
: ALT
; ala
nine
amin
otra
nsfe
rase
, AST
; asp
arta
te am
inot
rans
fera
se, B
MI;
body
mas
s ind
ex, C
IPII;
cont
inuo
us in
trape
riton
eal i
nfus
ion,
Gam
ma-
GT; G
amm
a-gl
utam
yl tr
ansp
eptid
ase,
HD
L; h
igh
dens
ity li
popr
otei
n, LD
L; lo
w d
ensit
y lip
opro
tein
, SC;
subc
utan
eous
. † D
efine
d as
a nu
mbe
r of b
lood
glu
cose
valu
e <4.
0 m
mol
/l du
ring
the l
ast 2
wee
ks.
94 95
chapter 5part 2
Resu
lts of
the p
er p
roto
col a
nd in
tent
ion
to tr
eat a
naly
sis fo
r the
prim
ary o
utco
me.
appe
ndix
2
Dat
a are
mea
ns (S
D) a
nd d
iffer
ence
bet
wee
n m
eans
(95%
CI).
Dat
a are
mea
ns (S
D) a
nd d
iffer
ence
bet
wee
n m
eans
(95%
CI).
Inte
ntio
n to
trea
t ana
lysis
(n=1
84)
Per p
roto
col a
naly
sis (n
=183
)
appe
ndix
3Ou
tcom
es d
urin
g bas
elin
e and
fina
l visi
t, cha
nges
with
in- a
nd d
iffer
ence
s bet
wee
n gr
oups
.
Dat
a are
pre
sent
ed as
n (%
), m
ean
(SD
) or m
edia
n [IQ
R]. *
p<0.
05 a b
ased
on
n=11
6 and
n=3
2 b bas
ed o
n n=
137 a
nd n
=36.
† D
efine
d as
the n
umbe
r of b
lood
glu
cose
valu
e <4.
0 m
mol
/l du
ring
the l
ast 2
wee
ks
‡ D
efine
d as
the n
umbe
r of b
lood
glu
cose
valu
e <3.
5 mm
ol/l
durin
g th
e las
t 2 w
eeks
. ¥ D
efine
d as
the n
umbe
r of h
ypog
lyca
emic
episo
des r
equi
ring
third
par
ty h
elp
or lo
sing
cons
cious
ness
dur
ing
the l
ast
2 wee
ks. A
bbre
viat
ions
: ALT
; ala
nine
amin
otra
nsfe
rase
, AST
; asp
arta
te am
inot
rans
fera
se, B
MI;
body
mas
s ind
ex, C
IPII;
cont
inuo
us in
trape
riton
eal i
nfus
ion,
Gam
ma-
GT; G
amm
a-gl
utam
yl tr
ansp
eptid
ase,
HD
L; h
igh
dens
ity li
popr
otei
n, LD
L; lo
w d
ensit
y lip
opro
tein
, SC;
subc
utan
eous
. † D
efine
d as
a nu
mbe
r of b
lood
glu
cose
valu
e <4.
0 m
mol
/l du
ring
the l
ast 2
wee
ks.
96 97
chapter 5part 2
appe
ndix
4Ou
tcom
es d
urin
g bas
elin
e and
fina
l visi
t, cha
nges
with
in th
e MDI
and
CSII
grou
ps an
d di
ffere
nces
with
the C
IPII
grou
p.
Dat
a are
pre
sent
ed as
n (%
), m
ean
(SD
) or m
edia
n [IQ
R]. *
p<0.
05 a b
ased
on
n=11
6 and
n=3
2 b bas
ed o
n n=
137 a
nd n
=36.
† D
efine
d as
the n
umbe
r of b
lood
glu
cose
valu
e <4.
0 m
mol
/l du
ring
the l
ast 2
wee
ks
‡ D
efine
d as
the n
umbe
r of b
lood
glu
cose
valu
e <3.
5 mm
ol/l
durin
g th
e las
t 2 w
eeks
. ¥ D
efine
d as
the n
umbe
r of h
ypog
lyca
emic
episo
des r
equi
ring
third
par
ty h
elp
or lo
sing
cons
cious
ness
dur
ing
the l
ast
2 wee
ks. A
bbre
viat
ions
: ALT
; ala
nine
amin
otra
nsfe
rase
, AST
; asp
arta
te am
inot
rans
fera
se, B
MI;
body
mas
s ind
ex, C
SII;
cont
inuo
us in
trape
riton
eal i
nsul
in in
fusio
n, C
IPII;
cont
inuo
us in
trape
riton
eal i
nfus
ion,
Ga
mm
a-GT
; Gam
ma-
glut
amyl
tran
spep
tidas
e, H
DL;
hig
h de
nsity
lipo
prot
ein,
LDL;
low
den
sity l
ipop
rote
in, M
DI;
mul
tiple
dai
ly in
ject
ions
.
96 97
chapter 5part 2
appe
ndix
4Ou
tcom
es d
urin
g bas
elin
e and
fina
l visi
t, cha
nges
with
in th
e MDI
and
CSII
grou
ps an
d di
ffere
nces
with
the C
IPII
grou
p.
Dat
a are
pre
sent
ed as
n (%
), m
ean
(SD
) or m
edia
n [IQ
R]. *
p<0.
05 a b
ased
on
n=11
6 and
n=3
2 b bas
ed o
n n=
137 a
nd n
=36.
† D
efine
d as
the n
umbe
r of b
lood
glu
cose
valu
e <4.
0 m
mol
/l du
ring
the l
ast 2
wee
ks
‡ D
efine
d as
the n
umbe
r of b
lood
glu
cose
valu
e <3.
5 mm
ol/l
durin
g th
e las
t 2 w
eeks
. ¥ D
efine
d as
the n
umbe
r of h
ypog
lyca
emic
episo
des r
equi
ring
third
par
ty h
elp
or lo
sing
cons
cious
ness
dur
ing
the l
ast
2 wee
ks. A
bbre
viat
ions
: ALT
; ala
nine
amin
otra
nsfe
rase
, AST
; asp
arta
te am
inot
rans
fera
se, B
MI;
body
mas
s ind
ex, C
SII;
cont
inuo
us in
trape
riton
eal i
nsul
in in
fusio
n, C
IPII;
cont
inuo
us in
trape
riton
eal i
nfus
ion,
Ga
mm
a-GT
; Gam
ma-
glut
amyl
tran
spep
tidas
e, H
DL;
hig
h de
nsity
lipo
prot
ein,
LDL;
low
den
sity l
ipop
rote
in, M
DI;
mul
tiple
dai
ly in
ject
ions
.
98 99
Van Dijk PR, Logtenberg SJ, Hendriks SH, Groenier KH, Gans
RO, Pouwer F, Bilo HJ, Kleefstra N.
Quality of life and treatment satisfaction among type 1 diabetes
mellitus patients treated with continuous intraperitoneal
insulin infusion or subcutaneous insulin: a prospective,
observational study.
chapter 6 Abstract
introductionAim of this study was to test whether patients using long-term continuous intraperitoneal
insulin infusion (CIPII), a last-resort treatment option for type 1 diabetes mellitus (T1DM),
or subcutaneous (SC) insulin therapy differed regarding their quality of life (QoL) and
treatment satisfaction.
patients and methodsIn this 26-week prospective, observational matched-control study the effects of CIPII and
SC insulin therapy were compared. Self-report questionnaires were used to assess health
status (SF-36), general- (WHO-5) and diabetes-related (DQOL and PAID) QoL and treatment
satisfaction (DTSQ). Analysis were performed with ANCOVA, taking baseline differences into
account.
resultsOne patient withdrew consent. Subsequently 183 patients with a mean age of 50 years
(standard deviation (SD) 12), diabetes duration of 26 years (SD 13) and a HbA1c of 64 mmol/
mol (11) were analysed. At baseline, scores of six out of the eight SF-36 subscales, both SF-36
component scores, the WHO-5 score and the DQOL ‘satisfaction’ and ‘impact’ scores were
lower, and treatment satisfaction was higher among CIPII treated patients as compared
to patients treated with SC insulin therapy. There were no changes within groups during
the study. After adjustment for baseline differences, scores of five out of the eight SF-36
subscales and both the mental (6.9, 95% CI 2.4, 11.3) and physical (9.6, 95% CI 4.2, 15.0) SF-36
component scores were lower with CIPII as compared to SC insulin therapy. Besides a lower
perceived hypoglycaemia score (0.7, 95% CI 0.1, 1.2) with CIPII, there were no differences in
outcomes after adjustment for baseline differences between CIPII and SC insulin therapy
concerning general and diabetes-related QoL and treatment satisfaction.
conclusionIn T1DM patients using CIPII, the perceived health status, general- and (parts of the)
diabetes-related QoL are rather poor and worse as compared to patients treated with
SC insulin therapy, while treatment satisfaction is higher. After adjustment for baseline
differences, differences in health status remained present but the perceived hypoglycaemia
score was better with CIPII and there were no differences in general- and diabetes-related
QoL and treatment satisfaction between treatments.
submitted as
Quality of life and treatment satisfaction among type 1 diabetes mellitus patients treated with continuous intra- peritoneal insulin in- fusion or subcutaneous insulin: a prospective, observational study
chapter 6part 2
98 99
Van Dijk PR, Logtenberg SJ, Hendriks SH, Groenier KH, Gans
RO, Pouwer F, Bilo HJ, Kleefstra N.
Quality of life and treatment satisfaction among type 1 diabetes
mellitus patients treated with continuous intraperitoneal
insulin infusion or subcutaneous insulin: a prospective,
observational study.
chapter 6 Abstract
introductionAim of this study was to test whether patients using long-term continuous intraperitoneal
insulin infusion (CIPII), a last-resort treatment option for type 1 diabetes mellitus (T1DM),
or subcutaneous (SC) insulin therapy differed regarding their quality of life (QoL) and
treatment satisfaction.
patients and methodsIn this 26-week prospective, observational matched-control study the effects of CIPII and
SC insulin therapy were compared. Self-report questionnaires were used to assess health
status (SF-36), general- (WHO-5) and diabetes-related (DQOL and PAID) QoL and treatment
satisfaction (DTSQ). Analysis were performed with ANCOVA, taking baseline differences into
account.
resultsOne patient withdrew consent. Subsequently 183 patients with a mean age of 50 years
(standard deviation (SD) 12), diabetes duration of 26 years (SD 13) and a HbA1c of 64 mmol/
mol (11) were analysed. At baseline, scores of six out of the eight SF-36 subscales, both SF-36
component scores, the WHO-5 score and the DQOL ‘satisfaction’ and ‘impact’ scores were
lower, and treatment satisfaction was higher among CIPII treated patients as compared
to patients treated with SC insulin therapy. There were no changes within groups during
the study. After adjustment for baseline differences, scores of five out of the eight SF-36
subscales and both the mental (6.9, 95% CI 2.4, 11.3) and physical (9.6, 95% CI 4.2, 15.0) SF-36
component scores were lower with CIPII as compared to SC insulin therapy. Besides a lower
perceived hypoglycaemia score (0.7, 95% CI 0.1, 1.2) with CIPII, there were no differences in
outcomes after adjustment for baseline differences between CIPII and SC insulin therapy
concerning general and diabetes-related QoL and treatment satisfaction.
conclusionIn T1DM patients using CIPII, the perceived health status, general- and (parts of the)
diabetes-related QoL are rather poor and worse as compared to patients treated with
SC insulin therapy, while treatment satisfaction is higher. After adjustment for baseline
differences, differences in health status remained present but the perceived hypoglycaemia
score was better with CIPII and there were no differences in general- and diabetes-related
QoL and treatment satisfaction between treatments.
submitted as
Quality of life and treatment satisfaction among type 1 diabetes mellitus patients treated with continuous intra- peritoneal insulin in- fusion or subcutaneous insulin: a prospective, observational study
chapter 6part 2
100 101
Introduction
Treatment of type 1 diabetes mellitus (T1DM) consists of exogenous insulin administration
or pancreas (islet cells) transplantation. In most patients, insulin is administered in a sub-
cutaneous (SC) manner using multiple daily injections (MDI) or continuous subcutaneous
insulin infusion (CSII). Although most patients achieve acceptable glycaemic control using SC
insulin, some patients have high HbA1c concentrations or experience frequent hypoglycaemic
episodes 1. For these patients continuous intraperitoneal insulin infusion (CIPII) therapy using
an implanted pump is a last-resort treatment option.
Intraperitoneal (IP) insulin administration results in more predictable insulin profiles and
improves hepatic glucose production in response to hypoglycaemia 2–4. Although providing
a different route for insulin administration, with positive effects on the number of
hypoglycaemic events, CIPII requires a surgical procedure to insert the implantable pump
in the SC tissue of the abdomen 5,6. In addition, every 6 weeks insulin refill procedures are
necessary 5. On the other hand, with CSII and MDI respectively, either infusion sets have to be
replaced by the patient every 2 to 3 days or SC injections often have to be administered at least
4 times daily 7. Using a device, either being for CSII or CIPII, offers the advantage of increased
flexibility in diet and activities but requires extensive involvement of both the patient and
diabetes professional. All these considerations may well influence quality of life (QoL),
diabetes-related distress and treatment satisfaction.
Previous literature demonstrated that prior to initiating CIPII the QoL and treatment
satisfaction are poor 7. Although treatment satisfaction increased significantly during CIPII
therapy, QoL remain poor among these CIPII treated patients during 5 to 6 years of therapy 5,8,9. As short-term comparisons between CIPII and SC insulin therapy demonstrated an
improvement of QoL during CIPII therapy, the effects of long-term CIPII versus SC insulin
therapy on QoL are unknown.
Aim of the current study was to test whether patients using long-term CIPII or SC insulin
therapy differed regarding their QoL and level of treatment satisfaction.
Patients and methods
study designThis investigator initiated study had a prospective, observational matched-controldesign.
Inclusion took place at the Isala (Zwolle, the Netherlands) and Diaconessenhuis hospital
(Meppel, the Netherlands). Primary aim was to compare the effects of CIPII to SC insulin
therapy, with respect to glycaemic control. As secondary outcome, and presented in this
chapter, QoL (including health status, general- and diabetes-related QoL and diabetes-related
distress) and treatment satisfaction were assessed.
patient selectionCases were subjects on CIPII therapy using an implanted insulin pump (MIP 2007D, Medtronic/
Minimed, Northridge, CA, USA) for the past 4 years without interruptions of >30 days, in order
to avoid effects related to initiating therapy. Inclusion criteria for cases were identical to those
of a prior study in our centre and have been described in detail previously 10. In brief, patients
with T1DM, aged 18 to 70 years with a HbA1c ≥ 58 mmol/mol (7.5%) and/or ≥ 5 incidents of
hypoglycaemia (glucose < 4.0 mmol/l) per week, were eligible.
The SC control group was age and gender matched to the cases and consisted of both MDI
and CSII users. Eligibility criteria for controls were T1DM, SC insulin as mode of insulin
administration for the past 4 years without interruptions of >30 days, HbA1c at time of
matching ≥ 53 mmol/mol (7.0%) and sufficient mastery of the Dutch language. Exclusion
criteria for both cases and controls included impaired renal function, cardiac problems and
current use or oral corticosteroids. Exclusion criteria were similar to the previous cross-over
study and have been described in detail previously 10. The ratio of participants on the different
therapies (CIPII:MDI:CSII) was 1:2:2.
study proceduresThere were 4 study visits. During the first visit, baseline characteristics were collected using a
standardized case record form, questionnaires were handed out and patients were asked to
fill in the questionnaires at home. During the second visit (5-7 days later) the questionnaires
were collected and laboratory measurements were performed. During the third visit, 26 weeks
after visit 1, clinical parameters were collected and again questionnaires were handed out
for the second measurement. During the fourth visit, 5-7 days after the third visit, laboratory
measurements were performed and again questionnaires were collected.
part 2 chapter 6
100 101
Introduction
Treatment of type 1 diabetes mellitus (T1DM) consists of exogenous insulin administration
or pancreas (islet cells) transplantation. In most patients, insulin is administered in a sub-
cutaneous (SC) manner using multiple daily injections (MDI) or continuous subcutaneous
insulin infusion (CSII). Although most patients achieve acceptable glycaemic control using SC
insulin, some patients have high HbA1c concentrations or experience frequent hypoglycaemic
episodes 1. For these patients continuous intraperitoneal insulin infusion (CIPII) therapy using
an implanted pump is a last-resort treatment option.
Intraperitoneal (IP) insulin administration results in more predictable insulin profiles and
improves hepatic glucose production in response to hypoglycaemia 2–4. Although providing
a different route for insulin administration, with positive effects on the number of
hypoglycaemic events, CIPII requires a surgical procedure to insert the implantable pump
in the SC tissue of the abdomen 5,6. In addition, every 6 weeks insulin refill procedures are
necessary 5. On the other hand, with CSII and MDI respectively, either infusion sets have to be
replaced by the patient every 2 to 3 days or SC injections often have to be administered at least
4 times daily 7. Using a device, either being for CSII or CIPII, offers the advantage of increased
flexibility in diet and activities but requires extensive involvement of both the patient and
diabetes professional. All these considerations may well influence quality of life (QoL),
diabetes-related distress and treatment satisfaction.
Previous literature demonstrated that prior to initiating CIPII the QoL and treatment
satisfaction are poor 7. Although treatment satisfaction increased significantly during CIPII
therapy, QoL remain poor among these CIPII treated patients during 5 to 6 years of therapy 5,8,9. As short-term comparisons between CIPII and SC insulin therapy demonstrated an
improvement of QoL during CIPII therapy, the effects of long-term CIPII versus SC insulin
therapy on QoL are unknown.
Aim of the current study was to test whether patients using long-term CIPII or SC insulin
therapy differed regarding their QoL and level of treatment satisfaction.
Patients and methods
study designThis investigator initiated study had a prospective, observational matched-controldesign.
Inclusion took place at the Isala (Zwolle, the Netherlands) and Diaconessenhuis hospital
(Meppel, the Netherlands). Primary aim was to compare the effects of CIPII to SC insulin
therapy, with respect to glycaemic control. As secondary outcome, and presented in this
chapter, QoL (including health status, general- and diabetes-related QoL and diabetes-related
distress) and treatment satisfaction were assessed.
patient selectionCases were subjects on CIPII therapy using an implanted insulin pump (MIP 2007D, Medtronic/
Minimed, Northridge, CA, USA) for the past 4 years without interruptions of >30 days, in order
to avoid effects related to initiating therapy. Inclusion criteria for cases were identical to those
of a prior study in our centre and have been described in detail previously 10. In brief, patients
with T1DM, aged 18 to 70 years with a HbA1c ≥ 58 mmol/mol (7.5%) and/or ≥ 5 incidents of
hypoglycaemia (glucose < 4.0 mmol/l) per week, were eligible.
The SC control group was age and gender matched to the cases and consisted of both MDI
and CSII users. Eligibility criteria for controls were T1DM, SC insulin as mode of insulin
administration for the past 4 years without interruptions of >30 days, HbA1c at time of
matching ≥ 53 mmol/mol (7.0%) and sufficient mastery of the Dutch language. Exclusion
criteria for both cases and controls included impaired renal function, cardiac problems and
current use or oral corticosteroids. Exclusion criteria were similar to the previous cross-over
study and have been described in detail previously 10. The ratio of participants on the different
therapies (CIPII:MDI:CSII) was 1:2:2.
study proceduresThere were 4 study visits. During the first visit, baseline characteristics were collected using a
standardized case record form, questionnaires were handed out and patients were asked to
fill in the questionnaires at home. During the second visit (5-7 days later) the questionnaires
were collected and laboratory measurements were performed. During the third visit, 26 weeks
after visit 1, clinical parameters were collected and again questionnaires were handed out
for the second measurement. During the fourth visit, 5-7 days after the third visit, laboratory
measurements were performed and again questionnaires were collected.
part 2 chapter 6
102 103
measurementsDemographic and clinical parameters included: age, gender, weight, length, blood pressure,
year of diagnosis of diabetes, presence of microvascular (nephropathy, neuropathy and/or
retinopathy) or macrovascular complications (angina pectoris, myocardial infarction, coronary
artery bypass grafting, percutaneous transluminal coronary angioplasty, stroke, transient
ischaemic attack, peripheral artery disease) and the number of self-reported hypoglycaemic
events grade 1 (glucose <4.0 mmol/l), grade 2 (glucose <3.5 mmol/l) and grade 3 (requiring
third party help or losing consciousness) during the last 14 days. Laboratory measurements
included, amongst others, HbA1c concentrations measured with a Primus Ultra2 system using
high-performance liquid chromatography (reference value 20–42 mmol/mol (4.0-6.0%)).
Perceived health status was assessed using the 36-item short-form health survey (SF-36).
The SF-36 is a widely used, self-administered generic questionnaire with 36 items involving 8
subscales: physical functioning, social functioning, role limitations due to physical problems,
role limitations due to emotional problems, mental health, vitality, bodily pain and general
health perception. Scale score range from 0 to 100, higher scores indicating better health
status. In addition, a mental and physical component summary (MCS and PCS) score can
be determined 11. General QoL was assessed using the WHO-5 questionnaire. The WHO-5 is
designed to measure positive well-being and is reported to be better in identifying depression
than the MCS of the SF-36 questionnaire 12,13. It consists of 5 items with a total score ranging
from 0 to100. A total score below 50 or an answer of “0 or 1” on a single item suggests poor
emotional well-being 14. Diabetes-related QoL was measured using the diabetes-related QoL
(DQOL) questionnaire. The DQOL contains 46 items, which the patients rank on a 5-point
scale. Scores are presented on a score range from 0 to 100: a score of 100 represents no impact
or worries and always satisfied and a score of 0 represents always affected, worried or never
satisfied 15,16. The measure has four scales: satisfaction with current mode of therapy, impact
of diabetes and treatment on living, diabetes worry and social/vocational worry 15. Diabetes-
related distress was measured using the problem areas in diabetes (PAID) questionnaire,
a 20-item questionnaire in which each item represents a unique area of diabetes-related
psychosocial distress. Scores were calculated using a five-point likert-scale with options ranging
from “0-not a problem” to “4-serious problem”. Summing all item scores and multiplying by
1.25 resulted in an overall PAID score of 0 to 100, with higher PAID scores indicating greater
emotional distress. Treatment satisfaction was measured with the diabetes treatment
satisfaction questionnaire (DTSQ). All 8 items are scored on a 7-point scale. Two items assess
perceived frequency of hyperglycaemia and hypoglycaemia, and six items comprise the
treatment satisfaction scale, with higher scores indicating higher satisfaction (range 0 to 36) 17.
statistical analysisResults were expressed as mean (with standard deviation (SD)) or median (with interquartile
range [IQR]) for normally distributed and non-normally distributed data, respectively.
A significance level of 5% (two-sided) was used. Normality was examined with Q-Q plots.
Analysis were performed in a intention to treat manner. A regression model based on covariate
analysis (ANCOVA) was applied in order to take possible baseline imbalance into account.
In the model the fixed factors CIPII and SC insulin therapy were used as determinants.
The difference in scores was determined based on the b-coefficient of the particular (CIPII
or SC) group. Significance of the b-coefficient was investigated with the Wald test based on
a p<0.05. The quantity of the b-coefficient, with a 95% CI, gives the difference between both
treatment modalities over the study period adjusted for baseline differences. Statistical
analyses were performed using SPSS (IBM SPSS Statistics for Windows, Version 20.0. Armonk,
NY: IBM Corp.) and STATA version 12 (Stata Corp., College Station, TX: StataCorp LP).
The study protocol was registered prior to the start of the study (identifiers: NL41037.075.12
and NCT01621308). The study protocol was approved by the local medical ethics committee,
and all patients gave informed consent.
Results
patientsFrom December 2012 through August 2013, a total of 335 patients were screened and received
information about the study, of which 190 (57%) agreed to participate. After baseline
laboratory measurements, 6 patients were excluded because of reasons presented in Figure 1.
(see Chapter 5, page 83) Consequently, 184 patients were followed during the 26-week study
period. After the first visit one patient withdrew informed consent due to lack of interest.
Therefore, 183 patients were analysed.
Baseline characteristics of these patients are presented in Table 1. Age and gender were well
matched between groups and no grade 3 hypoglycaemic events were reported. Compared
to patients using SC insulin therapy, CIPII patients had microvascular complications more
frequently. Baseline SF-36 health status scores for physical and social functioning, role
limitations due to physical limitations, vitality, bodily pain, general health, both component
scores and the WHO-5 score were significantly lower among CIPII treated patients as
compared to patients using SC insulin therapy (Table 2).
part 2 chapter 6
102 103
measurementsDemographic and clinical parameters included: age, gender, weight, length, blood pressure,
year of diagnosis of diabetes, presence of microvascular (nephropathy, neuropathy and/or
retinopathy) or macrovascular complications (angina pectoris, myocardial infarction, coronary
artery bypass grafting, percutaneous transluminal coronary angioplasty, stroke, transient
ischaemic attack, peripheral artery disease) and the number of self-reported hypoglycaemic
events grade 1 (glucose <4.0 mmol/l), grade 2 (glucose <3.5 mmol/l) and grade 3 (requiring
third party help or losing consciousness) during the last 14 days. Laboratory measurements
included, amongst others, HbA1c concentrations measured with a Primus Ultra2 system using
high-performance liquid chromatography (reference value 20–42 mmol/mol (4.0-6.0%)).
Perceived health status was assessed using the 36-item short-form health survey (SF-36).
The SF-36 is a widely used, self-administered generic questionnaire with 36 items involving 8
subscales: physical functioning, social functioning, role limitations due to physical problems,
role limitations due to emotional problems, mental health, vitality, bodily pain and general
health perception. Scale score range from 0 to 100, higher scores indicating better health
status. In addition, a mental and physical component summary (MCS and PCS) score can
be determined 11. General QoL was assessed using the WHO-5 questionnaire. The WHO-5 is
designed to measure positive well-being and is reported to be better in identifying depression
than the MCS of the SF-36 questionnaire 12,13. It consists of 5 items with a total score ranging
from 0 to100. A total score below 50 or an answer of “0 or 1” on a single item suggests poor
emotional well-being 14. Diabetes-related QoL was measured using the diabetes-related QoL
(DQOL) questionnaire. The DQOL contains 46 items, which the patients rank on a 5-point
scale. Scores are presented on a score range from 0 to 100: a score of 100 represents no impact
or worries and always satisfied and a score of 0 represents always affected, worried or never
satisfied 15,16. The measure has four scales: satisfaction with current mode of therapy, impact
of diabetes and treatment on living, diabetes worry and social/vocational worry 15. Diabetes-
related distress was measured using the problem areas in diabetes (PAID) questionnaire,
a 20-item questionnaire in which each item represents a unique area of diabetes-related
psychosocial distress. Scores were calculated using a five-point likert-scale with options ranging
from “0-not a problem” to “4-serious problem”. Summing all item scores and multiplying by
1.25 resulted in an overall PAID score of 0 to 100, with higher PAID scores indicating greater
emotional distress. Treatment satisfaction was measured with the diabetes treatment
satisfaction questionnaire (DTSQ). All 8 items are scored on a 7-point scale. Two items assess
perceived frequency of hyperglycaemia and hypoglycaemia, and six items comprise the
treatment satisfaction scale, with higher scores indicating higher satisfaction (range 0 to 36) 17.
statistical analysisResults were expressed as mean (with standard deviation (SD)) or median (with interquartile
range [IQR]) for normally distributed and non-normally distributed data, respectively.
A significance level of 5% (two-sided) was used. Normality was examined with Q-Q plots.
Analysis were performed in a intention to treat manner. A regression model based on covariate
analysis (ANCOVA) was applied in order to take possible baseline imbalance into account.
In the model the fixed factors CIPII and SC insulin therapy were used as determinants.
The difference in scores was determined based on the b-coefficient of the particular (CIPII
or SC) group. Significance of the b-coefficient was investigated with the Wald test based on
a p<0.05. The quantity of the b-coefficient, with a 95% CI, gives the difference between both
treatment modalities over the study period adjusted for baseline differences. Statistical
analyses were performed using SPSS (IBM SPSS Statistics for Windows, Version 20.0. Armonk,
NY: IBM Corp.) and STATA version 12 (Stata Corp., College Station, TX: StataCorp LP).
The study protocol was registered prior to the start of the study (identifiers: NL41037.075.12
and NCT01621308). The study protocol was approved by the local medical ethics committee,
and all patients gave informed consent.
Results
patientsFrom December 2012 through August 2013, a total of 335 patients were screened and received
information about the study, of which 190 (57%) agreed to participate. After baseline
laboratory measurements, 6 patients were excluded because of reasons presented in Figure 1.
(see Chapter 5, page 83) Consequently, 184 patients were followed during the 26-week study
period. After the first visit one patient withdrew informed consent due to lack of interest.
Therefore, 183 patients were analysed.
Baseline characteristics of these patients are presented in Table 1. Age and gender were well
matched between groups and no grade 3 hypoglycaemic events were reported. Compared
to patients using SC insulin therapy, CIPII patients had microvascular complications more
frequently. Baseline SF-36 health status scores for physical and social functioning, role
limitations due to physical limitations, vitality, bodily pain, general health, both component
scores and the WHO-5 score were significantly lower among CIPII treated patients as
compared to patients using SC insulin therapy (Table 2).
part 2 chapter 6
104 105
part 2 chapter 6
In addition, CIPII treated patients had worse scores for the DQOL satisfaction and impact
subscales and a higher treatment satisfaction score as compared to SC patients.
health status and general qolNo significant differences within both groups regarding change of health status and general
QoL were observed (Table 2). After adjustment for baseline differences, the SF-36 subscales
for social functioning (9.6, 95% CI 2.6, 16.6), role limitations due to physical functioning (23.8,
95% CI 10.0, 37.6), vitality (9.7, 95% CI 3.7, 15.6), bodily pain (15.2, 95% CI 7.7, 22.7) and general
health (7.3, 95% CI 2.1, 12.6) were significantly lower at the end of the study period among
patients treated with CIPII as compared to patients treated with SC insulin. In addition, both
the mental (6.9, 95% CI 2.4, 11.3) and physical (9.6, 95% CI 4.2, 15.0) component scores were
lower. After additional adjustment for baseline differences in microvascular complications
these differences remained present. After adjustment for baseline differences, the scores of the
WHO-5 questionnaire did not differ between the treatment groups. However, the percentage
of patients with a WHO-5 score indicative of a depression was significantly higher among CIPII
treated patients as compared to the SC treatment group: 37% vs. 28% at visit 1 and 47% vs.
24% at visit 2 (p<0.05 for both).
diabetes-related qol, diabetes-related distress and treatment satisfactionDuring the study period, no differences within both groups regarding diabetes-related QoL,
diabetes-related distress and treatment satisfaction were observed (Table 2). After adjustment
for baseline differences, CIPII treated patients reported the same diabetes-related QoL for
all 4 subscales of the DQOL questionnaire as compared to patients using SC insulin therapy.
Additionally, after adjustment for baseline differences, there were no differences in diabetes-
related distress between both treatment groups and subjects on CIPII perceived significantly
less hypoglycaemic events than subjects on SC insulin therapy: 0.7 (95% CI 0.1, 1.2).
MDI and CSII versus CIPIISubgroup analysis of patients using MDI (n=70) and CSII (n=74) as SC mode of insulin therapy
versus CIPII treated patients are presented in Table 3. Health status scores were lower for CIPII
treated patients as compared to both MDI and CSII users. In addition, CIPII treated patients
had a lower score on the perceived hypoglycaemia score, as compared to both MDI and CSII users.
Baseline characteristicstable 1
Data are presented as n (%), mean (SD) or median [IQR]. *p<0.05 as compared to CIPII, P-values are based on appropriate parametric and non-parametric tests. a Defined as the number of hypoglycaemic events < 4 (grade 1) during the last 14 days. b Defined as the number of hypoglycaemic events < 3.5 (grade 2) during the last 14 days. Abbreviations: BMI; body mass index, CIPII; continuous intraperitoneal infusion, SC; subcutaneous.
104 105
part 2 chapter 6
In addition, CIPII treated patients had worse scores for the DQOL satisfaction and impact
subscales and a higher treatment satisfaction score as compared to SC patients.
health status and general qolNo significant differences within both groups regarding change of health status and general
QoL were observed (Table 2). After adjustment for baseline differences, the SF-36 subscales
for social functioning (9.6, 95% CI 2.6, 16.6), role limitations due to physical functioning (23.8,
95% CI 10.0, 37.6), vitality (9.7, 95% CI 3.7, 15.6), bodily pain (15.2, 95% CI 7.7, 22.7) and general
health (7.3, 95% CI 2.1, 12.6) were significantly lower at the end of the study period among
patients treated with CIPII as compared to patients treated with SC insulin. In addition, both
the mental (6.9, 95% CI 2.4, 11.3) and physical (9.6, 95% CI 4.2, 15.0) component scores were
lower. After additional adjustment for baseline differences in microvascular complications
these differences remained present. After adjustment for baseline differences, the scores of the
WHO-5 questionnaire did not differ between the treatment groups. However, the percentage
of patients with a WHO-5 score indicative of a depression was significantly higher among CIPII
treated patients as compared to the SC treatment group: 37% vs. 28% at visit 1 and 47% vs.
24% at visit 2 (p<0.05 for both).
diabetes-related qol, diabetes-related distress and treatment satisfactionDuring the study period, no differences within both groups regarding diabetes-related QoL,
diabetes-related distress and treatment satisfaction were observed (Table 2). After adjustment
for baseline differences, CIPII treated patients reported the same diabetes-related QoL for
all 4 subscales of the DQOL questionnaire as compared to patients using SC insulin therapy.
Additionally, after adjustment for baseline differences, there were no differences in diabetes-
related distress between both treatment groups and subjects on CIPII perceived significantly
less hypoglycaemic events than subjects on SC insulin therapy: 0.7 (95% CI 0.1, 1.2).
MDI and CSII versus CIPIISubgroup analysis of patients using MDI (n=70) and CSII (n=74) as SC mode of insulin therapy
versus CIPII treated patients are presented in Table 3. Health status scores were lower for CIPII
treated patients as compared to both MDI and CSII users. In addition, CIPII treated patients
had a lower score on the perceived hypoglycaemia score, as compared to both MDI and CSII users.
Baseline characteristicstable 1
Data are presented as n (%), mean (SD) or median [IQR]. *p<0.05 as compared to CIPII, P-values are based on appropriate parametric and non-parametric tests. a Defined as the number of hypoglycaemic events < 4 (grade 1) during the last 14 days. b Defined as the number of hypoglycaemic events < 3.5 (grade 2) during the last 14 days. Abbreviations: BMI; body mass index, CIPII; continuous intraperitoneal infusion, SC; subcutaneous.
106 107
part 2 chapter 6
tabl
e 2Ou
tcom
es d
urin
g bas
elin
e and
last
visit
and
diffe
renc
es b
etw
een
the C
IPII
and
SC in
sulin
ther
apy g
roup
s.
Dat
a are
pre
sent
ed as
estim
ated
mea
n (S
D),
med
ian
[IQR]
or m
ean
chan
ge (9
5% C
I) w
ithin
and
betw
een
grou
ps. S
F-36
dat
a inc
ompl
ete f
or 18
(CIP
II n=
4, SC
n=1
4) p
atie
nts,
DQ
OL d
ata i
ncom
plet
e for
18
(CIP
II n=
4 an
d SC
n=1
4) p
atie
nts,
DTSQ
dat
a inc
ompl
ete f
or 25
(CIP
II n=
5, SC
n=5
) pat
ient
s and
PAID
dat
a inc
ompl
ete f
or d
ata 2
9 (CI
PII n
=8, S
C n=
21) p
atie
nts.
Abbr
evia
tions
: CIP
II, co
ntin
uous
intra
perit
onea
l in
sulin
infu
sion;
DQ
OL, d
iabe
tes q
ualit
y of l
ife; D
TSQ,
dia
bete
s tre
atm
ent s
atisf
actio
n qu
estio
nnai
re; P
AID,
pro
blem
area
s in
diab
etes
; MCS
, men
tal c
ompo
nent
scor
e; P
CS, p
hysic
al co
mpo
nent
scor
e; SC
, su
bcut
aneo
us; S
F-36
, 36-
item
shor
t-for
m h
ealth
surv
ey. †
p<0.
05 as
com
pare
d to
CIP
II at
bas
elin
e. *p
<0.
05.
tabl
e 3Ou
tcom
es d
urin
g bas
elin
e visi
t, cha
nges
with
in th
e MDI
and
CSII
grou
ps an
d di
ffere
nces
with
the C
IPII
grou
p.
Dat
a are
pre
sent
ed as
estim
ated
mea
n (S
D) a
nd m
ean
chan
ge (9
5% C
I) w
ithin
and
betw
een
grou
ps. S
F-36
dat
a inc
ompl
ete f
or 14
(MD
I n=6
, CSI
I n=8
) pat
ient
s, W
HO-
5 dat
a inc
ompl
ete f
or 14
(MD
I n=6
, CS
II n=
8) p
atie
nts,
DQ
OL d
ata i
ncom
plet
e for
14 (M
DI n
=7, C
SII n
=7) p
atie
nts,
DTSQ
dat
a inc
ompl
ete f
or 20
(MD
I n=1
0, C
SII n
=10)
pat
ient
s and
PAID
dat
a inc
ompl
ete f
or 31
(MD
I n=2
1, CS
II n=
8) p
atie
nts.
Abbr
evia
tions
: CIP
II, co
ntin
uous
intra
perit
onea
l ins
ulin
infu
sion;
DQ
OL,
diab
etes
qua
lity o
f life
; DTS
Q, d
iabe
tes t
reat
men
t sat
isfac
tion
ques
tionn
aire
; MCS
, men
tal c
ompo
nent
scor
e; PA
ID, p
robl
em ar
eas i
n di
abet
es ; P
CS, p
hysic
al co
mpo
nent
scor
e; SC
, sub
cuta
neou
s; SF
-36,
36-it
em sh
ort-f
orm
hea
lth su
rvey
; WH
O-5,
wor
ld h
ealth
org
aniz
atio
n-fiv
e wel
l-bei
ng in
dex.
*p <
0.05
.
106 107
part 2 chapter 6
tabl
e 2Ou
tcom
es d
urin
g bas
elin
e and
last
visit
and
diffe
renc
es b
etw
een
the C
IPII
and
SC in
sulin
ther
apy g
roup
s.
Dat
a are
pre
sent
ed as
estim
ated
mea
n (S
D),
med
ian
[IQR]
or m
ean
chan
ge (9
5% C
I) w
ithin
and
betw
een
grou
ps. S
F-36
dat
a inc
ompl
ete f
or 18
(CIP
II n=
4, SC
n=1
4) p
atie
nts,
DQ
OL d
ata i
ncom
plet
e for
18
(CIP
II n=
4 an
d SC
n=1
4) p
atie
nts,
DTSQ
dat
a inc
ompl
ete f
or 25
(CIP
II n=
5, SC
n=5
) pat
ient
s and
PAID
dat
a inc
ompl
ete f
or d
ata 2
9 (CI
PII n
=8, S
C n=
21) p
atie
nts.
Abbr
evia
tions
: CIP
II, co
ntin
uous
intra
perit
onea
l in
sulin
infu
sion;
DQ
OL, d
iabe
tes q
ualit
y of l
ife; D
TSQ,
dia
bete
s tre
atm
ent s
atisf
actio
n qu
estio
nnai
re; P
AID,
pro
blem
area
s in
diab
etes
; MCS
, men
tal c
ompo
nent
scor
e; P
CS, p
hysic
al co
mpo
nent
scor
e; SC
, su
bcut
aneo
us; S
F-36
, 36-
item
shor
t-for
m h
ealth
surv
ey. †
p<0.
05 as
com
pare
d to
CIP
II at
bas
elin
e. *p
<0.
05.
tabl
e 3Ou
tcom
es d
urin
g bas
elin
e visi
t, cha
nges
with
in th
e MDI
and
CSII
grou
ps an
d di
ffere
nces
with
the C
IPII
grou
p.
Dat
a are
pre
sent
ed as
estim
ated
mea
n (S
D) a
nd m
ean
chan
ge (9
5% C
I) w
ithin
and
betw
een
grou
ps. S
F-36
dat
a inc
ompl
ete f
or 14
(MD
I n=6
, CSI
I n=8
) pat
ient
s, W
HO-
5 dat
a inc
ompl
ete f
or 14
(MD
I n=6
, CS
II n=
8) p
atie
nts,
DQ
OL d
ata i
ncom
plet
e for
14 (M
DI n
=7, C
SII n
=7) p
atie
nts,
DTSQ
dat
a inc
ompl
ete f
or 20
(MD
I n=1
0, C
SII n
=10)
pat
ient
s and
PAID
dat
a inc
ompl
ete f
or 31
(MD
I n=2
1, CS
II n=
8) p
atie
nts.
Abbr
evia
tions
: CIP
II, co
ntin
uous
intra
perit
onea
l ins
ulin
infu
sion;
DQ
OL,
diab
etes
qua
lity o
f life
; DTS
Q, d
iabe
tes t
reat
men
t sat
isfac
tion
ques
tionn
aire
; MCS
, men
tal c
ompo
nent
scor
e; PA
ID, p
robl
em ar
eas i
n di
abet
es ; P
CS, p
hysic
al co
mpo
nent
scor
e; SC
, sub
cuta
neou
s; SF
-36,
36-it
em sh
ort-f
orm
hea
lth su
rvey
; WH
O-5,
wor
ld h
ealth
org
aniz
atio
n-fiv
e wel
l-bei
ng in
dex.
*p <
0.05
.
108 109
part 2 chapter 6
One might hypothesize that, since the presence of frequent hypoglycaemic episodes (often
combined with hypoglycaemia unawareness) is an indication for initiation of CIPII and IP
insulin administration results in more predictable glucose profiles and a restoration of the
hepatic response to hypoglycaemia, a reduction in perceived hypoglycaemia threat may be
an important determinant of (diabetes-related) QoL and treatment satisfaction among CIPII
treated patients 2–4. This is also reflected by the hyperglycaemic profiles and lower perceived
hypoglycaemia score even though there was no actual decrease in the number of self-reported
hypoglycaemic events, among CIPII treated subjects in the present study as compared to
patients treated with SC insulin 18. In addition to a lower frequency of hypoglycaemic episodes,
a reduction of the number of days spent in hospital during CIPII therapy, has been suggested to
have a positive influence of CIPII on diabetes-related QoL and treatment satisfaction 5,8,10.
This is the first large-scale study comparing different aspects of QoL among CIPII and
SC treated T1DM patients. Strengths include, amongst others, the use of both general
and diabetes-related questionnaires (including the PAID questionnaire). Nevertheless,
interpretations of the findings from our study are limited by various factors, including missing
data and lack of data capturing comorbidity, psychological (dys)function and patients’
perceptions toward hypoglycaemia. Furthermore, since CIPII is a last-resort treatment option
for T1DM at present, the group of CIPII treated patients is considered selected and more
complex as compared to SC treated patients and bias may well have occurred. As there is
no data available of QoL during SC therapy prior to CIPII therapy in the current study, no
conclusion can be drawn regarding the long-term changes in QoL from initiation of CIPII
to the present. Therefore, the results of our study should be interpreted with caution and
generalizability is limited. Nevertheless, the current design is the best available for the present
study objective given the real-life restrictions.
Conclusions
Among this complex, selected group of T1DM patients treated with long-term CIPII the
perceived health status, general- and (parts of the) diabetes-related QoL were lower, while
treatment satisfaction was higher as compared to patients treated with SC insulin therapy.
After adjustment for baseline differences, there were no differences in general and diabetes-
related QoL and treatment satisfaction, while the perceived health status remained lower with
CIPII as compared to SC insulin therapy. Taken together, these finding may imply that CIPII
positively influence (parts of the) diabetes related aspects of QoL and treatment satisfaction.
Discussion
The present study demonstrates that the perceived health status, general- and (parts of the)
diabetes-related QoL are lower, while treatment satisfaction is higher among T1DM patients
currently treated with CIPII as compared to patients treated with SC insulin therapy. After
adjustment for baseline differences, health status remained lower and, besides a lower
perceived hypoglycaemia score with CIPII, there were no differences in outcomes between
CIPII and SC insulin therapy concerning general and diabetes-related QoL and treatment
satisfaction.
We recently demonstrated that perceived health status is significantly lower among patients
that initiate CIPII therapy as compared to a reference group of subjects that continued SC
insulin therapy 19. In a previous cross-over study in our centre, in which a part of the present
study population participated, health status and general QoL improved significantly during 6
months of CIPII as compared to SC insulin therapy 9. During subsequent 6-years of follow-up,
the health status among these CIPII treated patients was stable 5. The present study adds to
these observations by demonstrating that the health status and general QoL among patients
treated with long-term CIPII is worse as compared to matched subjects treated with SC
insulin therapy. This latter finding was emphasized previously DeVries et al. demonstrating
low general QoL and a high number of patients with psychiatric symptoms, in particular
somatization, depression and insufficiency of thought or behaviour, among CIPII treated
patients as compared to a SC treated reference population 8.
In contrast to the poor health status and general QoL we found no differences in diabetes-
related worries, diabetes-related distress and even higher treatment satisfaction among
patients treated with CIPII as compared to patients using SC insulin therapy. This discrepancy
suggests that the poor health status and general QoL among these patients is not due to their
diabetes per se but that quite probably other factors also have an important influence. Possible
factors may include the poor social functioning, limited support or more (perceived) physical
limitations and pain. Additionally, the presence of the psychiatric symptoms, identified
previously by DeVries et al. and emphasized in the present study by the high number of CIPII
patients with a WHO-5 score indicative for depression, may explain this discrepancy. Although
it is unlikely that a mode of insulin administration could alleviate these factors, it seems that
long-term CIPII therapy stabilizes QoL but is unable to compensate for the full burden of poor
QoL.
108 109
part 2 chapter 6
One might hypothesize that, since the presence of frequent hypoglycaemic episodes (often
combined with hypoglycaemia unawareness) is an indication for initiation of CIPII and IP
insulin administration results in more predictable glucose profiles and a restoration of the
hepatic response to hypoglycaemia, a reduction in perceived hypoglycaemia threat may be
an important determinant of (diabetes-related) QoL and treatment satisfaction among CIPII
treated patients 2–4. This is also reflected by the hyperglycaemic profiles and lower perceived
hypoglycaemia score even though there was no actual decrease in the number of self-reported
hypoglycaemic events, among CIPII treated subjects in the present study as compared to
patients treated with SC insulin 18. In addition to a lower frequency of hypoglycaemic episodes,
a reduction of the number of days spent in hospital during CIPII therapy, has been suggested to
have a positive influence of CIPII on diabetes-related QoL and treatment satisfaction 5,8,10.
This is the first large-scale study comparing different aspects of QoL among CIPII and
SC treated T1DM patients. Strengths include, amongst others, the use of both general
and diabetes-related questionnaires (including the PAID questionnaire). Nevertheless,
interpretations of the findings from our study are limited by various factors, including missing
data and lack of data capturing comorbidity, psychological (dys)function and patients’
perceptions toward hypoglycaemia. Furthermore, since CIPII is a last-resort treatment option
for T1DM at present, the group of CIPII treated patients is considered selected and more
complex as compared to SC treated patients and bias may well have occurred. As there is
no data available of QoL during SC therapy prior to CIPII therapy in the current study, no
conclusion can be drawn regarding the long-term changes in QoL from initiation of CIPII
to the present. Therefore, the results of our study should be interpreted with caution and
generalizability is limited. Nevertheless, the current design is the best available for the present
study objective given the real-life restrictions.
Conclusions
Among this complex, selected group of T1DM patients treated with long-term CIPII the
perceived health status, general- and (parts of the) diabetes-related QoL were lower, while
treatment satisfaction was higher as compared to patients treated with SC insulin therapy.
After adjustment for baseline differences, there were no differences in general and diabetes-
related QoL and treatment satisfaction, while the perceived health status remained lower with
CIPII as compared to SC insulin therapy. Taken together, these finding may imply that CIPII
positively influence (parts of the) diabetes related aspects of QoL and treatment satisfaction.
Discussion
The present study demonstrates that the perceived health status, general- and (parts of the)
diabetes-related QoL are lower, while treatment satisfaction is higher among T1DM patients
currently treated with CIPII as compared to patients treated with SC insulin therapy. After
adjustment for baseline differences, health status remained lower and, besides a lower
perceived hypoglycaemia score with CIPII, there were no differences in outcomes between
CIPII and SC insulin therapy concerning general and diabetes-related QoL and treatment
satisfaction.
We recently demonstrated that perceived health status is significantly lower among patients
that initiate CIPII therapy as compared to a reference group of subjects that continued SC
insulin therapy 19. In a previous cross-over study in our centre, in which a part of the present
study population participated, health status and general QoL improved significantly during 6
months of CIPII as compared to SC insulin therapy 9. During subsequent 6-years of follow-up,
the health status among these CIPII treated patients was stable 5. The present study adds to
these observations by demonstrating that the health status and general QoL among patients
treated with long-term CIPII is worse as compared to matched subjects treated with SC
insulin therapy. This latter finding was emphasized previously DeVries et al. demonstrating
low general QoL and a high number of patients with psychiatric symptoms, in particular
somatization, depression and insufficiency of thought or behaviour, among CIPII treated
patients as compared to a SC treated reference population 8.
In contrast to the poor health status and general QoL we found no differences in diabetes-
related worries, diabetes-related distress and even higher treatment satisfaction among
patients treated with CIPII as compared to patients using SC insulin therapy. This discrepancy
suggests that the poor health status and general QoL among these patients is not due to their
diabetes per se but that quite probably other factors also have an important influence. Possible
factors may include the poor social functioning, limited support or more (perceived) physical
limitations and pain. Additionally, the presence of the psychiatric symptoms, identified
previously by DeVries et al. and emphasized in the present study by the high number of CIPII
patients with a WHO-5 score indicative for depression, may explain this discrepancy. Although
it is unlikely that a mode of insulin administration could alleviate these factors, it seems that
long-term CIPII therapy stabilizes QoL but is unable to compensate for the full burden of poor
QoL.
110 111
1 Renard E, Schaepelynck-Bélicar P, EVADIAC Group. Implantable insulin pumps. A position statement about their clinical use. Diabetes Metab 2007; 33: 158–66.2 Nathan DM, Dunn FL, Bruch J, et al. Postprandial insulin profiles with implantable pump therapy may explain decreased frequency of severe hypoglycemia, compared with intensive subcutaneous regimens, in insulin-dependent diabetes mellitus patients. Am J Med 1996; 100: 412–7.3 Wan CK, Giacca A, Matsuhisa M, et al. Increased responses of glucagon and glucose production to hypoglycemia with intraperitoneal versus subcutaneous insulin treatment. Metabolism 2000; 49: 984–9.4 Oskarsson PR, Lins PE, Backman L, Adamson UC. Continuous intraperitoneal insulin infusion partly restores the glucagon response to hypoglycaemia in type 1 diabetic patients. Diabetes Metab 2000; 26: 118–24.5 Van Dijk PR, Logtenberg SJ, Groenier KH, Gans RO, Kleefstra N, Bilo HJ. Continuous intraperitoneal insulin infusion in type 1 diabetes: a 6-year post-trial follow-up. BMC Endocr Disord 2014; 14: 30.6 Liebl A, Hoogma R, Renard E, et al. A reduction in severe hypoglycaemia in type 1 diabetes in a randomized crossover study of continuous intraperitoneal compared with subcutaneous insulin infusion. Diabetes Obes Metab 2009; 11: 1001–8.7 Logtenberg SJ, Kleefstra N, Houweling ST, Groenier KH, Gans RO, Bilo HJ. Health-related quality of life, treatment satisfaction, and costs associated with intraperitoneal versus subcutaneous insulin administration in type 1 diabetes: a randomized controlled trial. Diabetes Care 2010; 33: 1169–72.8 DeVries JH, Eskes SA, Snoek FJ, et al. Continuous intraperitoneal insulin infusion in patients with ‘brittle’ diabetes: favourable effects on glycaemic control and hospital stay. Diabet Med J Br Diabet Assoc 2002; 19: 496–501.9 Logtenberg SJJ, van Ballegooie E, Israêl-Bultman H, van Linde A, Bilo HJG. Glycaemic control, health status and treatment satisfaction with continuous intraperitoneal insulin infusion. Neth J Med 2007; 65: 65–70.10 Logtenberg SJ, Kleefstra N, Houweling ST, et al. Improved glycemic control with intraperitoneal versus subcutaneous insulin in type 1 diabetes: a randomized controlled trial. Diabetes Care 2009; 32: 1372–7.11 Ware JE Jr. SF-36 health survey update. Spine 2000; 25: 3130–9.12 World Health Organization, Regional Office for Europe Wellbeing measures in primary health care: the Depcare Project. Report on a WHO Meeting. 1998.13 Bech P, Olsen LR, Kjoller M, Rasmussen NK. Measuring well-being rather than the absence of distress symptoms: a com- parison of the SF-36 Mental Health subscale and the WHO-Five Well-Being Scale. Int J Methods Psychiatr Res 2003; 12: 85–91.14 Löwe B, Spitzer RL, Gräfe K, et al. Comparative validity of three screening questionnaires for DSM-IV depressive disorders and physicians’ diagnoses. J Affect Disord 2004; 78: 131–40.15 Reliability and validity of a diabetes quality-of-life measure for the diabetes control and complications trial (DCCT). The DCCT Research Group. Diabetes Care 1988; 11: 725–32.16 Jacobson AM, de Groot M, Samson JA. The effects of psychiatric disorders and symptoms on quality of life in patients with type I and type II diabetes mellitus. Qual Life Res Int J Qual Life Asp Treat Care Rehabil 1997; 6: 11–20.17 Bradley C : The diabetes quality of life measure. In Handbook of Psychology and Diabetes: a guide to psychological measurement in diabetes research and practice. Chur: Harwood Academic Publishers. 1994:65-8718 Van Dijk PR, Logtenberg SJJ, Groenier KH et al. Intraperitoneal insulin infusion is non-inferior to subcutaneous insulin infusion in the treatment of type 1 diabetes: a prospective matched-control study. Unpublished, see Chapter 519 Van Dijk PR, Logtenberg SJJ, Groenier KH, N et al. : Report of a 7 year case-control study of continuous intraperitoneal insulin infusion and subcutaneous insulin therapy among patients with poorly controlled type 1 diabetes mellitus: Favourable effects on hypoglycaemic episodes. Diabetes Res Clin Pract 2014.
part 2
references
110 111
1 Renard E, Schaepelynck-Bélicar P, EVADIAC Group. Implantable insulin pumps. A position statement about their clinical use. Diabetes Metab 2007; 33: 158–66.2 Nathan DM, Dunn FL, Bruch J, et al. Postprandial insulin profiles with implantable pump therapy may explain decreased frequency of severe hypoglycemia, compared with intensive subcutaneous regimens, in insulin-dependent diabetes mellitus patients. Am J Med 1996; 100: 412–7.3 Wan CK, Giacca A, Matsuhisa M, et al. Increased responses of glucagon and glucose production to hypoglycemia with intraperitoneal versus subcutaneous insulin treatment. Metabolism 2000; 49: 984–9.4 Oskarsson PR, Lins PE, Backman L, Adamson UC. Continuous intraperitoneal insulin infusion partly restores the glucagon response to hypoglycaemia in type 1 diabetic patients. Diabetes Metab 2000; 26: 118–24.5 Van Dijk PR, Logtenberg SJ, Groenier KH, Gans RO, Kleefstra N, Bilo HJ. Continuous intraperitoneal insulin infusion in type 1 diabetes: a 6-year post-trial follow-up. BMC Endocr Disord 2014; 14: 30.6 Liebl A, Hoogma R, Renard E, et al. A reduction in severe hypoglycaemia in type 1 diabetes in a randomized crossover study of continuous intraperitoneal compared with subcutaneous insulin infusion. Diabetes Obes Metab 2009; 11: 1001–8.7 Logtenberg SJ, Kleefstra N, Houweling ST, Groenier KH, Gans RO, Bilo HJ. Health-related quality of life, treatment satisfaction, and costs associated with intraperitoneal versus subcutaneous insulin administration in type 1 diabetes: a randomized controlled trial. Diabetes Care 2010; 33: 1169–72.8 DeVries JH, Eskes SA, Snoek FJ, et al. Continuous intraperitoneal insulin infusion in patients with ‘brittle’ diabetes: favourable effects on glycaemic control and hospital stay. Diabet Med J Br Diabet Assoc 2002; 19: 496–501.9 Logtenberg SJJ, van Ballegooie E, Israêl-Bultman H, van Linde A, Bilo HJG. Glycaemic control, health status and treatment satisfaction with continuous intraperitoneal insulin infusion. Neth J Med 2007; 65: 65–70.10 Logtenberg SJ, Kleefstra N, Houweling ST, et al. Improved glycemic control with intraperitoneal versus subcutaneous insulin in type 1 diabetes: a randomized controlled trial. Diabetes Care 2009; 32: 1372–7.11 Ware JE Jr. SF-36 health survey update. Spine 2000; 25: 3130–9.12 World Health Organization, Regional Office for Europe Wellbeing measures in primary health care: the Depcare Project. Report on a WHO Meeting. 1998.13 Bech P, Olsen LR, Kjoller M, Rasmussen NK. Measuring well-being rather than the absence of distress symptoms: a com- parison of the SF-36 Mental Health subscale and the WHO-Five Well-Being Scale. Int J Methods Psychiatr Res 2003; 12: 85–91.14 Löwe B, Spitzer RL, Gräfe K, et al. Comparative validity of three screening questionnaires for DSM-IV depressive disorders and physicians’ diagnoses. J Affect Disord 2004; 78: 131–40.15 Reliability and validity of a diabetes quality-of-life measure for the diabetes control and complications trial (DCCT). The DCCT Research Group. Diabetes Care 1988; 11: 725–32.16 Jacobson AM, de Groot M, Samson JA. The effects of psychiatric disorders and symptoms on quality of life in patients with type I and type II diabetes mellitus. Qual Life Res Int J Qual Life Asp Treat Care Rehabil 1997; 6: 11–20.17 Bradley C : The diabetes quality of life measure. In Handbook of Psychology and Diabetes: a guide to psychological measurement in diabetes research and practice. Chur: Harwood Academic Publishers. 1994:65-8718 Van Dijk PR, Logtenberg SJJ, Groenier KH et al. Intraperitoneal insulin infusion is non-inferior to subcutaneous insulin infusion in the treatment of type 1 diabetes: a prospective matched-control study. Unpublished, see Chapter 519 Van Dijk PR, Logtenberg SJJ, Groenier KH, N et al. : Report of a 7 year case-control study of continuous intraperitoneal insulin infusion and subcutaneous insulin therapy among patients with poorly controlled type 1 diabetes mellitus: Favourable effects on hypoglycaemic episodes. Diabetes Res Clin Pract 2014.
part 2
references
112 113
chapter 7 Abstract
introductionGlycaemic variability (GV) is, apart from HbA1c, a measure for glycaemic control. As
continuous intraperitoneal insulin infusion (CIPII) results in a more physiologic action of
insulin than subcutaneous (SC) insulin administration, we hypothesized that CIPII would
result in less GV than SC insulin therapy among T1DM patients.
patients and methodsData from continuous glucose measurements (CGM) performed during a prospective,
observational matched-control study were analysed. Measurements were performed at
baseline and after 26 weeks. The coefficient of variation (CV) was the primary measure of
GV. In addition, the standard deviation (SD) of the mean glucose, mean of daily differences
(MODD) and mean amplitude of glycaemic excursions (MAGE) were calculated. Analysis was
performed with ANCOVA, taking baseline differences into account.
resultsA total of 176 patients (36% male) with a mean age of 49 (standard deviation (SD) 13) years,
a median diabetes duration of 24 [interquartile range 17, 35] years and HbA1c of 63 (SD 10),
of which 37 used CIPII and 139 SC insulin therapy were analysed. CGM data were available
for 169 patients at baseline (CIPII n=35 and SC n=134) and for 164 patients at 26-weeks (CIPII
n= 35 and SC n=129). After adjustment for baseline differences, the CV was 4.9% (95% CI
1.0, 8.8) higher among SC treated patients as compared to CIPII treated patients. Subgroup
analysis demonstrated that this difference remained present when comparing SC treated
patients using multiple daily injections or continuous subcutaneous insulin infusion with
CIPII treated patients: 4.7% (95% CI 0.3, 9.2) and 5.0% (95% CI 0.8, 9.2) respectively. There
were no differences in other indices of GV between groups.
conclusionsDespite higher blood glucose concentrations, the GV is slightly lower with CIPII as compared
to SC insulin therapy in T1DM patients. Future studies are needed to study whether this
reduced GV results in prevention of hypoglycaemia and even possibly fewever microvascular
complications.
Continuous intraperi-toneal insulin infusion versus subcutaneous insulin therapy in the treatment of type 1 diabetes: positive effects on glycaemic variability
chapter 7part 2
112 113
chapter 7 Abstract
introductionGlycaemic variability (GV) is, apart from HbA1c, a measure for glycaemic control. As
continuous intraperitoneal insulin infusion (CIPII) results in a more physiologic action of
insulin than subcutaneous (SC) insulin administration, we hypothesized that CIPII would
result in less GV than SC insulin therapy among T1DM patients.
patients and methodsData from continuous glucose measurements (CGM) performed during a prospective,
observational matched-control study were analysed. Measurements were performed at
baseline and after 26 weeks. The coefficient of variation (CV) was the primary measure of
GV. In addition, the standard deviation (SD) of the mean glucose, mean of daily differences
(MODD) and mean amplitude of glycaemic excursions (MAGE) were calculated. Analysis was
performed with ANCOVA, taking baseline differences into account.
resultsA total of 176 patients (36% male) with a mean age of 49 (standard deviation (SD) 13) years,
a median diabetes duration of 24 [interquartile range 17, 35] years and HbA1c of 63 (SD 10),
of which 37 used CIPII and 139 SC insulin therapy were analysed. CGM data were available
for 169 patients at baseline (CIPII n=35 and SC n=134) and for 164 patients at 26-weeks (CIPII
n= 35 and SC n=129). After adjustment for baseline differences, the CV was 4.9% (95% CI
1.0, 8.8) higher among SC treated patients as compared to CIPII treated patients. Subgroup
analysis demonstrated that this difference remained present when comparing SC treated
patients using multiple daily injections or continuous subcutaneous insulin infusion with
CIPII treated patients: 4.7% (95% CI 0.3, 9.2) and 5.0% (95% CI 0.8, 9.2) respectively. There
were no differences in other indices of GV between groups.
conclusionsDespite higher blood glucose concentrations, the GV is slightly lower with CIPII as compared
to SC insulin therapy in T1DM patients. Future studies are needed to study whether this
reduced GV results in prevention of hypoglycaemia and even possibly fewever microvascular
complications.
Continuous intraperi-toneal insulin infusion versus subcutaneous insulin therapy in the treatment of type 1 diabetes: positive effects on glycaemic variability
chapter 7part 2
114 115
Introduction
Continuous intraperitoneal insulin infusion (CIPII) using an implantable pump is a last-
resort treatment option for selected patients with type 1 diabetes mellitus (T1DM) who
fail to achieve glycaemic control with intensive subcutaneous (SC) insulin therapy and
subsequently experience high HbA1c concentrations or blood glucose variability 1.
Intraperitoneal (IP) administered insulin is almost entirely absorbed in the portal system,
resulting in higher insulin concentrations in the portal vein catchment area, higher
hepatic uptake of insulin, lower peripheral plasma insulin concentrations and -thus- a
mode of insulin administration mimicking the normal physiology contrary to SC insulin
administration 2–7. Previous randomized studies have demonstrated favorable effects of
CIPII versus SC insulin therapy on HbA1c concentrations among T1DM patients 8–11. However,
the effects of CIPII on glycaemic variability (GV), another facet of glycaemic control and
suggested to help predict hypoglycaemia and diabetes related complications, are relatively
unknown 12,13.
The only 3 previous studies that assessed GV among CIPII treated T1DM subjects
demonstrated less GV, expressed as the standard deviation (SD) of the mean capillary
glucose from blood glucose self-measurement, during CIPII therapy as compared to SC
therapy 9–11. However, the mean capillary glucose was also lower during CIPII, the number
of participants in these studies was small (n=10 to 24) and most of these studies were
performed before the era of rapid acting insulin analogues and continuous glucose
measurement (CGM) systems.
In order to test the hypothesis that CIPII would result in less GV than SC insulin therapy in
T1DM patients, we studied the effects of CIPII on GV as compared to SC insulin therapy in a
large group of T1DM patients, all using rapid acting insulin analogues.
Patients and methods
study designThis investigator initiated study had a prospective, observational matched-control design.
Inclusion took place at the Isala (Zwolle, the Netherlands) and Diaconessenhuis hospital
(Meppel, the Netherlands). Primary aim of the original study was to compare the effects of
CIPII to SC insulin therapy, with respect to glycaemic control. As a secondary outcome, and
presented in this article, GV was assessed.
patient selectionCases were subjects on CIPII therapy using an implanted insulin pump (MIP 2007D,
Medtronic/Minimed, Northridge, CA, USA) for the past 4 years without interruptions of >30
days, in order to avoid effects related to initiating therapy. Inclusion criteria for cases were
identical to those of a prior study in our centre and have been described in detail previously 8. In brief, patients with T1DM, aged 18 to 70 years with a HbA1c ≥ 7.5% (58 mmol/mol) and/
or ≥ 5 incidents of hypoglycemia glucose (< 4.0 mmol/l) per week, were eligible.
The control group of the present study was age and gender matched to the cases and
consisted of T1DM patients, with SC insulin as mode of insulin administration (both multiple
daily injections (MDI) and continuous subcutaneous insulin infusion (CSII)) for the past 4
years without interruptions of >30 days and a HbA1c at time of matching ≥ 7.0% (53 mmol/
mol). The ratio of participants on the different therapies (CIPII:MDI:CSII) was 1:2:2. Exclusion
criteria for both cases and controls included impaired renal function, cardiac problems and
current use of oral corticosteroids (described in detail in Chapter 5).
study protocol There were four study visits. During the first visit, baseline characteristics were collected
using a standardized case record form and a blinded continuous glucose measurement
(CGM) device was inserted for a period of six days. During the second visit (five to seven days
later) the CGM device was removed and laboratory measurements were performed. During
the third visit, 26 weeks after visit 1, clinical parameters were collected and again a CGM
device was inserted for a period of six days. During the fourth visit, five to seven days after
the third visit, laboratory measurements were performed and the CGM device was removed.
During the study period all patients received usual care.
outcome measurementsThe 24-hours interstitial glucose profiles were recorded using a blinded CGM device (iPro2,
Medtronic, Northridge, CA, USA). The CGM device was inserted in the periumbilical area,
and in pump users contralateral to the (implanted) insulin pump. Patients injecting insulin
were asked not to inject insulin on the same side of the sensor insertion side. Patients were
instructed to perform a minimum of 4 blood glucose self-measurements daily during the
CGM period, using a blood glucose meter (Contour XT; Bayer) to calibrate the sensor.
chapter 7part 2
114 115
Introduction
Continuous intraperitoneal insulin infusion (CIPII) using an implantable pump is a last-
resort treatment option for selected patients with type 1 diabetes mellitus (T1DM) who
fail to achieve glycaemic control with intensive subcutaneous (SC) insulin therapy and
subsequently experience high HbA1c concentrations or blood glucose variability 1.
Intraperitoneal (IP) administered insulin is almost entirely absorbed in the portal system,
resulting in higher insulin concentrations in the portal vein catchment area, higher
hepatic uptake of insulin, lower peripheral plasma insulin concentrations and -thus- a
mode of insulin administration mimicking the normal physiology contrary to SC insulin
administration 2–7. Previous randomized studies have demonstrated favorable effects of
CIPII versus SC insulin therapy on HbA1c concentrations among T1DM patients 8–11. However,
the effects of CIPII on glycaemic variability (GV), another facet of glycaemic control and
suggested to help predict hypoglycaemia and diabetes related complications, are relatively
unknown 12,13.
The only 3 previous studies that assessed GV among CIPII treated T1DM subjects
demonstrated less GV, expressed as the standard deviation (SD) of the mean capillary
glucose from blood glucose self-measurement, during CIPII therapy as compared to SC
therapy 9–11. However, the mean capillary glucose was also lower during CIPII, the number
of participants in these studies was small (n=10 to 24) and most of these studies were
performed before the era of rapid acting insulin analogues and continuous glucose
measurement (CGM) systems.
In order to test the hypothesis that CIPII would result in less GV than SC insulin therapy in
T1DM patients, we studied the effects of CIPII on GV as compared to SC insulin therapy in a
large group of T1DM patients, all using rapid acting insulin analogues.
Patients and methods
study designThis investigator initiated study had a prospective, observational matched-control design.
Inclusion took place at the Isala (Zwolle, the Netherlands) and Diaconessenhuis hospital
(Meppel, the Netherlands). Primary aim of the original study was to compare the effects of
CIPII to SC insulin therapy, with respect to glycaemic control. As a secondary outcome, and
presented in this article, GV was assessed.
patient selectionCases were subjects on CIPII therapy using an implanted insulin pump (MIP 2007D,
Medtronic/Minimed, Northridge, CA, USA) for the past 4 years without interruptions of >30
days, in order to avoid effects related to initiating therapy. Inclusion criteria for cases were
identical to those of a prior study in our centre and have been described in detail previously 8. In brief, patients with T1DM, aged 18 to 70 years with a HbA1c ≥ 7.5% (58 mmol/mol) and/
or ≥ 5 incidents of hypoglycemia glucose (< 4.0 mmol/l) per week, were eligible.
The control group of the present study was age and gender matched to the cases and
consisted of T1DM patients, with SC insulin as mode of insulin administration (both multiple
daily injections (MDI) and continuous subcutaneous insulin infusion (CSII)) for the past 4
years without interruptions of >30 days and a HbA1c at time of matching ≥ 7.0% (53 mmol/
mol). The ratio of participants on the different therapies (CIPII:MDI:CSII) was 1:2:2. Exclusion
criteria for both cases and controls included impaired renal function, cardiac problems and
current use of oral corticosteroids (described in detail in Chapter 5).
study protocol There were four study visits. During the first visit, baseline characteristics were collected
using a standardized case record form and a blinded continuous glucose measurement
(CGM) device was inserted for a period of six days. During the second visit (five to seven days
later) the CGM device was removed and laboratory measurements were performed. During
the third visit, 26 weeks after visit 1, clinical parameters were collected and again a CGM
device was inserted for a period of six days. During the fourth visit, five to seven days after
the third visit, laboratory measurements were performed and the CGM device was removed.
During the study period all patients received usual care.
outcome measurementsThe 24-hours interstitial glucose profiles were recorded using a blinded CGM device (iPro2,
Medtronic, Northridge, CA, USA). The CGM device was inserted in the periumbilical area,
and in pump users contralateral to the (implanted) insulin pump. Patients injecting insulin
were asked not to inject insulin on the same side of the sensor insertion side. Patients were
instructed to perform a minimum of 4 blood glucose self-measurements daily during the
CGM period, using a blood glucose meter (Contour XT; Bayer) to calibrate the sensor.
chapter 7part 2
116 117
All procedures related to the CGM were performed by one, trained physician (PRVD).
To account for the higher mean glucose level expected in CIPII treated patients, as CIPII
therapy is used as a last-resort treatment and CIPII treated patients are more complex than
SC treated patients, the coefficient of variation (CV), which measures intra-day variation
of glucose patterns and is defined as the SD divided by the mean of blood glucose values,
was chosen as the primary outcome measure of GV 15–18. As secondary outcomes, additional
measures of GV were used. First, as measure of intra-day GV the mean amplitude of glucose
excursions (MAGE), defined as the mean of absolute differences between glycaemic
oscillation (peak and nadirs exceeding 1 SD), was used. As a measure of inter-day variation,
the mean of the daily differences (MODD), defined as the mean of absolute values of
differences between glucose values taken in two consecutive days was chosen 19. In order to
make comparisons with previous literature, the mean glucose with standard deviation (SD)
was used. In addition, comparisons between CIPII and patients using MDI and CSII were
made and data from self-measurements of blood glucose (SMBG) were analysed.
statistical analysisResults were expressed as mean (with SD) or median (with interquartile range [IQR]) for
normally distributed and non-normally distributed data, respectively. A significance level
of 5% (two sided) was used. Normality was examined with Q-Q plots. A regression model
based on covariate analysis (ANCOVA) was applied in order to take possible baseline
imbalance into account. In the model the fixed factors CIPII and SC insulin therapy were
used as determinants. The difference in scores was determined based on the b-coefficient
of the particular (CIPII or SC) group. Significance of the b-coefficient was investigated with
the Wald test based on a p<0.05. The quantity of the b-coefficient, with a 95% confidence
interval (CI), gives the difference between both treatment modalities over the study period
adjusted for baseline differences. Statistical analyses were performed using SPSS (IBM
SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp.). The study protocol was
registered prior to the start of the study at the appropriate local and international registers
(NCT01621308 and NL41037.075.12). The study protocol was approved by the local medical
ethics committee and all patients gave informed consent.
Results
patientsFrom December 2012 through August 2013, a total of 335 patients were screened and
received information about the study; 190 agreed to participate. After baseline laboratory
measurements, 6 patients were excluded because of C-peptide concentrations exceeding 0.2
nmol/l (n=4) or an eGFR<40 ml/min (n=2). Consequently, 184 patients were followed during
the 26-week study period. Seven patients refused to wear the CGM device and 1 patient
withdrew informed consent due to lack of interest after the first visit. Therefore, 176 patients
were analysed of which 37 used CIPII and 139 SC insulin infusion (65 MDI and 74 CSII) .
Main baseline characteristics of these patients are presented in Table 1. Patients treated with
CIPII were more often known with a microvascular complication, used more units of insulin
per day, had a higher HbA1c and a higher number of self-reported hypoglycaemic events.
CGM data were available for 169 (CIPII n=35 and SC n=134) and 164 (CIPII n= 35 and SC n=129)
patients at baseline and final measurement, respectively. The mean time patients wore the
CGM device was 5 (1) days.
primary outcome: coefficient of variationOver time, there was no significant change of the CV within groups (see Table 2). After
adjustment for baseline differences, the CV of CGM was 4.9% (95% CI 1.0, 8.8) higher among
patients treated with SC insulin therapy as compared to patients treated with CIPII. After
additional adjustment for differences in baseline HbA1c, number of hypoglycaemic episodes
and total daily insulin dose, the CV was 4.7% (95% CI 0.5, 8.8) higher among patients treated
with SC insulin therapy as compared to patients treated with CIPII.
secondary outcome: other indices of glycaemic variabilityAfter adjustment for baseline differences, the mean glucose during CGM was -0.9 mmol/l
(95% CI -1.6, -0.1) lower among patients using SC insulin therapy as compared to CIPII
treated patients (see Table 2). Although the MODD increased over time with 0.5 mmol/l
(95% CI 0.01, 1.0) among CIPII treated patients, there were no significant differences in the
SD, MAGE and MODD between the SC and CIPII treatment groups.
secondary outcome: subgroup analysis and data from SMBGSubgroup analysis demonstrate that patients using MDI and CSII had a lower mean glucose,
-0.9 mmol/l (95% CI -1.7, -0.1) and -0.9 mmol/l (95% CI -1.6, -0.1) respectively, and a higher
chapter 7part 2
116 117
All procedures related to the CGM were performed by one, trained physician (PRVD).
To account for the higher mean glucose level expected in CIPII treated patients, as CIPII
therapy is used as a last-resort treatment and CIPII treated patients are more complex than
SC treated patients, the coefficient of variation (CV), which measures intra-day variation
of glucose patterns and is defined as the SD divided by the mean of blood glucose values,
was chosen as the primary outcome measure of GV 15–18. As secondary outcomes, additional
measures of GV were used. First, as measure of intra-day GV the mean amplitude of glucose
excursions (MAGE), defined as the mean of absolute differences between glycaemic
oscillation (peak and nadirs exceeding 1 SD), was used. As a measure of inter-day variation,
the mean of the daily differences (MODD), defined as the mean of absolute values of
differences between glucose values taken in two consecutive days was chosen 19. In order to
make comparisons with previous literature, the mean glucose with standard deviation (SD)
was used. In addition, comparisons between CIPII and patients using MDI and CSII were
made and data from self-measurements of blood glucose (SMBG) were analysed.
statistical analysisResults were expressed as mean (with SD) or median (with interquartile range [IQR]) for
normally distributed and non-normally distributed data, respectively. A significance level
of 5% (two sided) was used. Normality was examined with Q-Q plots. A regression model
based on covariate analysis (ANCOVA) was applied in order to take possible baseline
imbalance into account. In the model the fixed factors CIPII and SC insulin therapy were
used as determinants. The difference in scores was determined based on the b-coefficient
of the particular (CIPII or SC) group. Significance of the b-coefficient was investigated with
the Wald test based on a p<0.05. The quantity of the b-coefficient, with a 95% confidence
interval (CI), gives the difference between both treatment modalities over the study period
adjusted for baseline differences. Statistical analyses were performed using SPSS (IBM
SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp.). The study protocol was
registered prior to the start of the study at the appropriate local and international registers
(NCT01621308 and NL41037.075.12). The study protocol was approved by the local medical
ethics committee and all patients gave informed consent.
Results
patientsFrom December 2012 through August 2013, a total of 335 patients were screened and
received information about the study; 190 agreed to participate. After baseline laboratory
measurements, 6 patients were excluded because of C-peptide concentrations exceeding 0.2
nmol/l (n=4) or an eGFR<40 ml/min (n=2). Consequently, 184 patients were followed during
the 26-week study period. Seven patients refused to wear the CGM device and 1 patient
withdrew informed consent due to lack of interest after the first visit. Therefore, 176 patients
were analysed of which 37 used CIPII and 139 SC insulin infusion (65 MDI and 74 CSII) .
Main baseline characteristics of these patients are presented in Table 1. Patients treated with
CIPII were more often known with a microvascular complication, used more units of insulin
per day, had a higher HbA1c and a higher number of self-reported hypoglycaemic events.
CGM data were available for 169 (CIPII n=35 and SC n=134) and 164 (CIPII n= 35 and SC n=129)
patients at baseline and final measurement, respectively. The mean time patients wore the
CGM device was 5 (1) days.
primary outcome: coefficient of variationOver time, there was no significant change of the CV within groups (see Table 2). After
adjustment for baseline differences, the CV of CGM was 4.9% (95% CI 1.0, 8.8) higher among
patients treated with SC insulin therapy as compared to patients treated with CIPII. After
additional adjustment for differences in baseline HbA1c, number of hypoglycaemic episodes
and total daily insulin dose, the CV was 4.7% (95% CI 0.5, 8.8) higher among patients treated
with SC insulin therapy as compared to patients treated with CIPII.
secondary outcome: other indices of glycaemic variabilityAfter adjustment for baseline differences, the mean glucose during CGM was -0.9 mmol/l
(95% CI -1.6, -0.1) lower among patients using SC insulin therapy as compared to CIPII
treated patients (see Table 2). Although the MODD increased over time with 0.5 mmol/l
(95% CI 0.01, 1.0) among CIPII treated patients, there were no significant differences in the
SD, MAGE and MODD between the SC and CIPII treatment groups.
secondary outcome: subgroup analysis and data from SMBGSubgroup analysis demonstrate that patients using MDI and CSII had a lower mean glucose,
-0.9 mmol/l (95% CI -1.7, -0.1) and -0.9 mmol/l (95% CI -1.6, -0.1) respectively, and a higher
chapter 7part 2
118 119
chapter 7part 2
Baseline characteristics.
Outcomes of glycaemic variability during baseline and last visit and changes between the CIPII and SC insulin therapy groups.
table 1
table 2
Data are presented as n (%), mean (SD) or median [IQR]. *p<0.05 as compared to CIPII, P-values are based on appropriate parametric and non-parametric tests. † Defined as the number of self-reported hypoglycaemic events < 4mmol/l (grade 1) during the last 14 days. ¥ Defined as the number of self-reported hypoglycaemic events< 3.5mmol/l (grade 2) during the last 14 days. Abbreviations: BMI; body mass index, CIPII; continuous intraperitoneal infusion, SC; subcutaneous.
Data are presented as estimated mean (SD), median [IQR] or mean change (95% CI) within and between groups. Abbreviations: CIPII, continuous intraperitoneal insulin infusion; CSII, continuous subcutaneous insulin infusion; CV, coefficient of variation; MDI, multiple daily injections; MAGE, mean amplitude of glucose excursions; MODD, mean of the daily differences, CGM, continuous glucose measurement. Mean glucose, SD, MAGE and MODD are all expressed in mmol/l. The CV is expressed in %. * p<0.05.
CV, 4.7% (95% CI 0.3, 9.2) and 5.0% (95% CI 0.8, 9.2) respectively, during CGM as compared
to CIPII treated patients (see Appendix 1).
Results of the SMBG demonstrate that, after adjustment for baseline differences, the CV of
the self-measured glucose was 5.6% (95% CI 1.2, 9.9) higher among patients using SC insulin
as compared to those using CIPII. Mean glucose was lower for patients using MDI, but not
for those using CSII (-0.8 mmol/l, 95% CI -1.6, -0.1), as compared to CIPII treated patients.
Adjusted for baseline differences, the CV of self-measured glucose concentrations was 6.5%
(95% CI 1.9, 11.2) higher among CSII treated patients as compared to subjects using CIPII.
Discussion
CIPII treated patients had a lower CV as compared to patients treated with SC insulin
therapy. Furthermore, despite a higher mean glucose concentration among CIPII treated
patients there were no differences in other indices of intra- and inter-day GV. Taken together,
the results of this study confirm our hypothesis that T1DM patients treated with CIPII have
less GV as compared to patients treated with SC insulin therapy. The magnitude of this
effect was approximately 5% as compared to both MDI and CSII treated patients, it was
found during both CGM- and SMBG and remained present after adjustment for baseline
differences in HbA1c, hypoglycaemic episodes and total daily insulin dose.
These findings suggest a positive influence of CIPII therapy on GV and may well be explained
by the pharmacokinetic and pharmacodynamic properties of IP administered insulin. After
IP administration, insulin takes approximately 15 minutes to reach its peak effect and allows
blood glucose values to return to baseline values more rapidly with reproducible and more
predictable insulin profiles as compared to SC insulin injections 5,20–22. In addition, IP insulin
improves the impaired glucagon secretion, also during exercise, and enhances hepatic
glucose production in response to hypoglycemia 23–27. Although the exact mechanisms
behind these latter two phenomena are unknown it has been hypothesized that lower
peripheral plasma insulin concentrations with CIPII may (partly) restore glucagon release
or that CIPII increases hepatic sensitivity to glucagon or hepatic glucose utilization during
hypoglycaemia 23,27.
The present study confirms the results of 3 previous studies reporting less GV among CIPII
treated patients. The most recent study by Catargi et al. demonstrated among 14 T1DM
118 119
chapter 7part 2
Baseline characteristics.
Outcomes of glycaemic variability during baseline and last visit and changes between the CIPII and SC insulin therapy groups.
table 1
table 2
Data are presented as n (%), mean (SD) or median [IQR]. *p<0.05 as compared to CIPII, P-values are based on appropriate parametric and non-parametric tests. † Defined as the number of self-reported hypoglycaemic events < 4mmol/l (grade 1) during the last 14 days. ¥ Defined as the number of self-reported hypoglycaemic events< 3.5mmol/l (grade 2) during the last 14 days. Abbreviations: BMI; body mass index, CIPII; continuous intraperitoneal infusion, SC; subcutaneous.
Data are presented as estimated mean (SD), median [IQR] or mean change (95% CI) within and between groups. Abbreviations: CIPII, continuous intraperitoneal insulin infusion; CSII, continuous subcutaneous insulin infusion; CV, coefficient of variation; MDI, multiple daily injections; MAGE, mean amplitude of glucose excursions; MODD, mean of the daily differences, CGM, continuous glucose measurement. Mean glucose, SD, MAGE and MODD are all expressed in mmol/l. The CV is expressed in %. * p<0.05.
CV, 4.7% (95% CI 0.3, 9.2) and 5.0% (95% CI 0.8, 9.2) respectively, during CGM as compared
to CIPII treated patients (see Appendix 1).
Results of the SMBG demonstrate that, after adjustment for baseline differences, the CV of
the self-measured glucose was 5.6% (95% CI 1.2, 9.9) higher among patients using SC insulin
as compared to those using CIPII. Mean glucose was lower for patients using MDI, but not
for those using CSII (-0.8 mmol/l, 95% CI -1.6, -0.1), as compared to CIPII treated patients.
Adjusted for baseline differences, the CV of self-measured glucose concentrations was 6.5%
(95% CI 1.9, 11.2) higher among CSII treated patients as compared to subjects using CIPII.
Discussion
CIPII treated patients had a lower CV as compared to patients treated with SC insulin
therapy. Furthermore, despite a higher mean glucose concentration among CIPII treated
patients there were no differences in other indices of intra- and inter-day GV. Taken together,
the results of this study confirm our hypothesis that T1DM patients treated with CIPII have
less GV as compared to patients treated with SC insulin therapy. The magnitude of this
effect was approximately 5% as compared to both MDI and CSII treated patients, it was
found during both CGM- and SMBG and remained present after adjustment for baseline
differences in HbA1c, hypoglycaemic episodes and total daily insulin dose.
These findings suggest a positive influence of CIPII therapy on GV and may well be explained
by the pharmacokinetic and pharmacodynamic properties of IP administered insulin. After
IP administration, insulin takes approximately 15 minutes to reach its peak effect and allows
blood glucose values to return to baseline values more rapidly with reproducible and more
predictable insulin profiles as compared to SC insulin injections 5,20–22. In addition, IP insulin
improves the impaired glucagon secretion, also during exercise, and enhances hepatic
glucose production in response to hypoglycemia 23–27. Although the exact mechanisms
behind these latter two phenomena are unknown it has been hypothesized that lower
peripheral plasma insulin concentrations with CIPII may (partly) restore glucagon release
or that CIPII increases hepatic sensitivity to glucagon or hepatic glucose utilization during
hypoglycaemia 23,27.
The present study confirms the results of 3 previous studies reporting less GV among CIPII
treated patients. The most recent study by Catargi et al. demonstrated among 14 T1DM
120 121
patients, who were treated sequentially with CSII (using short acting insulin lispro) and
CIPII, a significant decrease of the SD of all SMBG during a 45-day period: 3.8 versus
4.4 mmol/l 11. The results of the present study add by describing different measures of GV,
based on both (blinded) CGM and SMBG data, on two different occasions, in a large T1DM
population during usual care circumstances. As all subjects were on their current mode
of insulin administration for ≥ 4 years, this may suggest that the pharmacokinetic and
pharmacodynamic properties of IP administered insulin perpetuate over time. Although
hypothetically, this may also indicate that the course of the HbA1c among CIPII treated
patients, which has been reported to decrease shortly after initiation of CIPII but increases
during long-term use, is due to other factors (e.g. compliance) than physiologic adaption to
the effects of IP insulin 8–11,28–33.
At present, CIPII is a last-resort treatment option for selected patients and indications
include, amongst others, frequent episodes of severe hypoglycaemia (especially combined
with hypoglycaemia unawareness). Although long-term CIPII treatment does not seem to
offer further improvements of HbA1c and general quality of life as compared to short-term
results, treatment satisfaction remains high and patients report less hypoglycaemic events
as compared to previous SC insulin therapy. The reduced GV found in this study may well
account for this discrepancy 34.
It should be mentioned that debate exists in literature concerning the ‘optimal’ measure
of GV. There is no consensus at the moment. Therefore, based on available literature we
chose a limited set of indices and a primary outcome which adjusts for different levels of
mean glucose concentrations 35,36. In addition, post-hoc analysis demonstrated significant
correlations between CV, MAGE and the MODD during both measurements (see Appendix
2).
For the interpretation of the results of this study several limitations should be
acknowledged. First and foremost, since CIPII is a last-resort treatment option for T1DM,
the group of CIPII treated patients is considered selected and more complex as compared
to SC treated patients and bias may well have occurred. Second, as there is no data available
of GV during SC therapy prior to CIPII therapy in the current study, it can only be assumed
that the presence of less GV among the CIPII group is due to CIPII. Furthermore, it should be
acknowledged that the magnitude of the reduction (approximately 5%) is relatively small.
Since the clinical importance of GV with respect to diabetes related complications (including
quality of life) is unsure, the relevance of our findings with respect to clinical outcomes
chapter 7part 2
are unknown 12,13,37,38. In addition, we found no change in the number of self-reported
hypoglycaemic episodes between the both treatment groups in the present cohort (see
Chapter 5). Nevertheless, as current closed-loop systems using SC insulin therapy struggle
to reach postprandial normoglycaemia the favorable effects of IP insulin on GV may be of
importance for the question which route of insulin administration is the development for a
closed-loop system 40.
Conclusions
CIPII treated patients had a lower CV as compared to patients treated with SC insulin
therapy. Furthermore, despite a higher mean glucose concentration among CIPII treated
patients there were no differences in other indices of intra- and inter-day GV. These findings
suggest a positive influence of CIPII on GV as compared to SC insulin therapy. Future studies
are needed to study whether this reduced variability results in prevention of hypoglycaemia
and possibly fewer microvascular complications.
120 121
patients, who were treated sequentially with CSII (using short acting insulin lispro) and
CIPII, a significant decrease of the SD of all SMBG during a 45-day period: 3.8 versus
4.4 mmol/l 11. The results of the present study add by describing different measures of GV,
based on both (blinded) CGM and SMBG data, on two different occasions, in a large T1DM
population during usual care circumstances. As all subjects were on their current mode
of insulin administration for ≥ 4 years, this may suggest that the pharmacokinetic and
pharmacodynamic properties of IP administered insulin perpetuate over time. Although
hypothetically, this may also indicate that the course of the HbA1c among CIPII treated
patients, which has been reported to decrease shortly after initiation of CIPII but increases
during long-term use, is due to other factors (e.g. compliance) than physiologic adaption to
the effects of IP insulin 8–11,28–33.
At present, CIPII is a last-resort treatment option for selected patients and indications
include, amongst others, frequent episodes of severe hypoglycaemia (especially combined
with hypoglycaemia unawareness). Although long-term CIPII treatment does not seem to
offer further improvements of HbA1c and general quality of life as compared to short-term
results, treatment satisfaction remains high and patients report less hypoglycaemic events
as compared to previous SC insulin therapy. The reduced GV found in this study may well
account for this discrepancy 34.
It should be mentioned that debate exists in literature concerning the ‘optimal’ measure
of GV. There is no consensus at the moment. Therefore, based on available literature we
chose a limited set of indices and a primary outcome which adjusts for different levels of
mean glucose concentrations 35,36. In addition, post-hoc analysis demonstrated significant
correlations between CV, MAGE and the MODD during both measurements (see Appendix
2).
For the interpretation of the results of this study several limitations should be
acknowledged. First and foremost, since CIPII is a last-resort treatment option for T1DM,
the group of CIPII treated patients is considered selected and more complex as compared
to SC treated patients and bias may well have occurred. Second, as there is no data available
of GV during SC therapy prior to CIPII therapy in the current study, it can only be assumed
that the presence of less GV among the CIPII group is due to CIPII. Furthermore, it should be
acknowledged that the magnitude of the reduction (approximately 5%) is relatively small.
Since the clinical importance of GV with respect to diabetes related complications (including
quality of life) is unsure, the relevance of our findings with respect to clinical outcomes
chapter 7part 2
are unknown 12,13,37,38. In addition, we found no change in the number of self-reported
hypoglycaemic episodes between the both treatment groups in the present cohort (see
Chapter 5). Nevertheless, as current closed-loop systems using SC insulin therapy struggle
to reach postprandial normoglycaemia the favorable effects of IP insulin on GV may be of
importance for the question which route of insulin administration is the development for a
closed-loop system 40.
Conclusions
CIPII treated patients had a lower CV as compared to patients treated with SC insulin
therapy. Furthermore, despite a higher mean glucose concentration among CIPII treated
patients there were no differences in other indices of intra- and inter-day GV. These findings
suggest a positive influence of CIPII on GV as compared to SC insulin therapy. Future studies
are needed to study whether this reduced variability results in prevention of hypoglycaemia
and possibly fewer microvascular complications.
122 123
1 Renard E, Schaepelynck-Bélicar P, EVADIAC Group. Implantable insulin pumps. A position statement about their clinical use. Diabetes Metab 2007; 33: 158–66.2 Giacca A, Caumo A, Galimberti G, et al. Peritoneal and subcutaneous absorption of insulin in type I diabetic subjects. J Clin Endocrinol Metab 1993; 77: 738–42.3 Bratusch-Marrain PR, Waldhäusl WK, Gasić S, Hofer A. Hepatic disposal of biosynthetic human insulin and porcine C-peptide in humans. Metabolism 1984; 33: 151–7.4 Nathan DM, Dunn FL, Bruch J, et al. Postprandial insulin profiles with implantable pump therapy may explain decreased frequency of severe hypoglycemia, compared with intensive subcutaneous regimens, in insulin-dependent diabetes mellitus patients. Am J Med 1996; 100: 412–7.5 Schaepelynck Bélicar P, Vague P, Lassmann-Vague V. Reproducibility of plasma insulin kinetics during intraperitoneal insulin treatment by programmable pumps. Diabetes Metab 2003; 29: 344–8.6 Selam JL, Bergman RN, Raccah D, Jean-Didier N, Lozano J, Charles MA. Determination of portal insulin absorption from peritoneum via novel nonisotopic method. Diabetes 1990; 39: 1361–5.7 Schade DS, Eaton RP, Davis T, et al. The kinetics of peritoneal insulin absorption. Metabolism 1981; 30: 149–55.8 Logtenberg SJ, Kleefstra N, Houweling ST, et al. Improved glycemic control with intraperitoneal versus subcutaneous insulin in type 1 diabetes: a randomized controlled trial. Diabetes Care 2009; 32: 1372–7.9 Haardt MJ, Selam JL, Slama G, et al. A cost-benefit comparison of intensive diabetes management with implantable pumps versus multiple subcutaneous injections in patients with type I diabetes. Diabetes Care 1994; 17: 847–51.10 Selam JL, Raccah D, Jean-Didier N, Lozano JL, Waxman K, Charles MA. Randomized comparison of metabolic control achieved by intraperitoneal insulin infusion with implantable pumps versus intensive subcutaneous insulin therapy in type I diabetic patients. Diabetes Care 1992; 15: 53–8.11 Catargi B, Meyer L, Melki V, Renard E, Jeandidier N, EVADIAC Study Group. Comparison of blood glucose stability and HbA1C between implantable insulin pumps using U400 HOE 21PH insulin and external pumps using lispro in type 1 diabetic patients: a pilot study. Diabetes Metab 2002; 28: 133–7.12 Cox DJ, Kovatchev BP, Julian DM, et al. Frequency of severe hypoglycemia in insulin-dependent diabetes mellitus can be predicted from self-monitoring blood glucose data. J Clin Endocrinol Metab 1994; 79: 1659–62.13 Kilpatrick ES, Rigby AS, Goode K, Atkin SL. Relating mean blood glucose and glucose variability to the risk of multiple episodes of hypoglycaemia in type 1 diabetes. Diabetologia 2007; 50: 2553–61.14 Continuous intraperitoneal insulin infusion versus subcutaneous insulin therapy in the treatment of type 1 diabetes: a prospective, matched-control noninferiority study. .15 Snell-Bergeon JK, Roman R, Rodbard D, et al. Glycaemic variability is associated with coronary artery calcium in men with type 1 diabetes: the Coronary Artery Calcification in Type 1 Diabetes study. Diabet Med J Br Diabet Assoc 2010; 27: 1436–42.16 Rodbard D. Clinical interpretation of indices of quality of glycemic control and glycemic variability. Postgrad Med 2011; 123: 107–18.17 Rodbard D. Clinical interpretation of indices of quality of glycemic control and glycemic variability. Postgrad Med 2011; 123: 107–18.18 Borg R, Kuenen JC, Carstensen B, et al. Associations between features of glucose exposure and A1C: the A1C-Derived Average Glucose (ADAG) study. Diabetes 2010; 59: 1585–90.19 Molnar GD, Taylor WF, Ho MM. Day-to-day variation of continuously monitored glycaemia: a further measure of diabetic instability. Diabetologia 1972; 8: 342–8.20 Schade DS, Eaton RP, Spencer W, Goldman R, Corbett WT. The peritoneal absorption of insulin in diabetic man: a potential site for a mechanical insulin delivery system. Metabolism 1979; 28: 195–7.21 Nathan DM, Dunn FL, Bruch J, et al. Postprandial insulin profiles with implantable pump therapy may explain decreased frequency of severe hypoglycemia, compared with intensive subcutaneous regimens, in insulin-dependent diabetes mellitus patients. Am J Med 1996; 100: 412–7.22 Micossi P, Cristallo M, Librenti MC, et al. Free-insulin profiles after intraperitoneal, intramuscular, and subcutaneous
chapter 7part 2
references insulin administration. Diabetes Care 1986; 9: 575–8.23 Oskarsson PR, Lins PE, Backman L, Adamson UC. Continuous intraperitoneal insulin infusion partly restores the glucagon response to hypoglycaemia in type 1 diabetic patients. Diabetes Metab 2000; 26: 118–24.24 Wan CK, Giacca A, Matsuhisa M, et al. Increased responses of glucagon and glucose production to hypoglycemia with intraperitoneal versus subcutaneous insulin treatment. Metabolism 2000; 49: 984–9.25 Mason TM, Gupta N, Goh T, et al. Chronic intraperitoneal insulin delivery, as compared with subcutaneous delivery, improves hepatic glucose metabolism in streptozotocin diabetic rats. Metabolism 2000; 49: 1411–6.26 Oskarsson PR, Lins PE, Wallberg Henriksson H, Adamson UC. Metabolic and hormonal responses to exercise in type 1 diabetic patients during continuous subcutaneous, as compared to continuous intraperitoneal, insulin infusion. Diabetes Metab 1999; 25: 491–7.27 Selam JL, Medlej R, M’bemba J, et al. Symptoms, hormones, and glucose fluxes during a gradual hypoglycaemia induced by intraperitoneal vs venous insulin infusion in Type I diabetes. Diabet Med J Br Diabet Assoc 1995; 12: 1102–9.28 Logtenberg SJJ, van Ballegooie E, Israêl-Bultman H, van Linde A, Bilo HJG. Glycaemic control, health status and treat- ment satisfaction with continuous intraperitoneal insulin infusion. Neth J Med 2007; 65: 65–70.29 DeVries JH, Eskes SA, Snoek FJ, et al. Continuous intraperitoneal insulin infusion in patients with ‘brittle’ diabetes: favourable effects on glycaemic control and hospital stay. Diabet Med J Br Diabet Assoc 2002; 19: 496–501.30 Selam JL, Micossi P, Dunn FL, Nathan DM. Clinical trial of programmable implantable insulin pump for type I diabetes. Diabetes Care 1992; 15: 877–85.31 Schaepelynck P, Renard E, Jeandidier N, et al. A recent survey confirms the efficacy and the safety of implanted insulin pumps during long-term use in poorly controlled type 1 diabetes patients. Diabetes Technol Ther 2011; 13: 657–60.32 Gin H, Renard E, Melki V, et al. Combined improvements in implantable pump technology and insulin stability allow safe and effective long term intraperitoneal insulin delivery in type 1 diabetic patients: the EVADIAC experience. Diabetes Metab 2003; 29: 602–7.33 Hanaire-Broutin H, Broussolle C, Jeandidier N, et al. Feasibility of intraperitoneal insulin therapy with programmable implantable pumps in IDDM. A multicenter study. The EVADIAC Study Group. Evaluation dans le Diabète du Traitement par Implants Actifs. Diabetes Care 1995; 18: 388–92.34 Van Dijk PR, Logtenberg SJ, Groenier KH, Gans RO, Kleefstra N, Bilo HJ. Continuous intraperitoneal insulin infusion in type 1 diabetes: a 6-year post-trial follow-up. BMC Endocr Disord 2014; 14: 30.35 Rodbard D. The challenges of measuring glycemic variability. J Diabetes Sci Technol 2012; 6: 712–5.36 DeVries JH. Glucose variability: where it is important and how to measure it. Diabetes 2013; 62: 1405–8.37 Siegelaar SE, Holleman F, Hoekstra JBL, DeVries JH. Glucose variability; does it matter? Endocr Rev 2010; 31: 171–82.38 Kilpatrick ES. Arguments for and against the role of glucose variability in the development of diabetes complications. J Diabetes Sci Technol 2009; 3: 649–55.39 Van Dijk PR. Continuous intraperitoneal insulin infusion versus subcutaneous insulin therapy in the treatment of type 1 diabetes: a prospective, matched-control non-inferiority study. Submitted.40 Cobelli C, Renard E, Kovatchev B. Artificial pancreas: past, present, future. Diabetes 2011; 60: 2672–82.
122 123
1 Renard E, Schaepelynck-Bélicar P, EVADIAC Group. Implantable insulin pumps. A position statement about their clinical use. Diabetes Metab 2007; 33: 158–66.2 Giacca A, Caumo A, Galimberti G, et al. Peritoneal and subcutaneous absorption of insulin in type I diabetic subjects. J Clin Endocrinol Metab 1993; 77: 738–42.3 Bratusch-Marrain PR, Waldhäusl WK, Gasić S, Hofer A. Hepatic disposal of biosynthetic human insulin and porcine C-peptide in humans. Metabolism 1984; 33: 151–7.4 Nathan DM, Dunn FL, Bruch J, et al. Postprandial insulin profiles with implantable pump therapy may explain decreased frequency of severe hypoglycemia, compared with intensive subcutaneous regimens, in insulin-dependent diabetes mellitus patients. Am J Med 1996; 100: 412–7.5 Schaepelynck Bélicar P, Vague P, Lassmann-Vague V. Reproducibility of plasma insulin kinetics during intraperitoneal insulin treatment by programmable pumps. Diabetes Metab 2003; 29: 344–8.6 Selam JL, Bergman RN, Raccah D, Jean-Didier N, Lozano J, Charles MA. Determination of portal insulin absorption from peritoneum via novel nonisotopic method. Diabetes 1990; 39: 1361–5.7 Schade DS, Eaton RP, Davis T, et al. The kinetics of peritoneal insulin absorption. Metabolism 1981; 30: 149–55.8 Logtenberg SJ, Kleefstra N, Houweling ST, et al. Improved glycemic control with intraperitoneal versus subcutaneous insulin in type 1 diabetes: a randomized controlled trial. Diabetes Care 2009; 32: 1372–7.9 Haardt MJ, Selam JL, Slama G, et al. A cost-benefit comparison of intensive diabetes management with implantable pumps versus multiple subcutaneous injections in patients with type I diabetes. Diabetes Care 1994; 17: 847–51.10 Selam JL, Raccah D, Jean-Didier N, Lozano JL, Waxman K, Charles MA. Randomized comparison of metabolic control achieved by intraperitoneal insulin infusion with implantable pumps versus intensive subcutaneous insulin therapy in type I diabetic patients. Diabetes Care 1992; 15: 53–8.11 Catargi B, Meyer L, Melki V, Renard E, Jeandidier N, EVADIAC Study Group. Comparison of blood glucose stability and HbA1C between implantable insulin pumps using U400 HOE 21PH insulin and external pumps using lispro in type 1 diabetic patients: a pilot study. Diabetes Metab 2002; 28: 133–7.12 Cox DJ, Kovatchev BP, Julian DM, et al. Frequency of severe hypoglycemia in insulin-dependent diabetes mellitus can be predicted from self-monitoring blood glucose data. J Clin Endocrinol Metab 1994; 79: 1659–62.13 Kilpatrick ES, Rigby AS, Goode K, Atkin SL. Relating mean blood glucose and glucose variability to the risk of multiple episodes of hypoglycaemia in type 1 diabetes. Diabetologia 2007; 50: 2553–61.14 Continuous intraperitoneal insulin infusion versus subcutaneous insulin therapy in the treatment of type 1 diabetes: a prospective, matched-control noninferiority study. .15 Snell-Bergeon JK, Roman R, Rodbard D, et al. Glycaemic variability is associated with coronary artery calcium in men with type 1 diabetes: the Coronary Artery Calcification in Type 1 Diabetes study. Diabet Med J Br Diabet Assoc 2010; 27: 1436–42.16 Rodbard D. Clinical interpretation of indices of quality of glycemic control and glycemic variability. Postgrad Med 2011; 123: 107–18.17 Rodbard D. Clinical interpretation of indices of quality of glycemic control and glycemic variability. Postgrad Med 2011; 123: 107–18.18 Borg R, Kuenen JC, Carstensen B, et al. Associations between features of glucose exposure and A1C: the A1C-Derived Average Glucose (ADAG) study. Diabetes 2010; 59: 1585–90.19 Molnar GD, Taylor WF, Ho MM. Day-to-day variation of continuously monitored glycaemia: a further measure of diabetic instability. Diabetologia 1972; 8: 342–8.20 Schade DS, Eaton RP, Spencer W, Goldman R, Corbett WT. The peritoneal absorption of insulin in diabetic man: a potential site for a mechanical insulin delivery system. Metabolism 1979; 28: 195–7.21 Nathan DM, Dunn FL, Bruch J, et al. Postprandial insulin profiles with implantable pump therapy may explain decreased frequency of severe hypoglycemia, compared with intensive subcutaneous regimens, in insulin-dependent diabetes mellitus patients. Am J Med 1996; 100: 412–7.22 Micossi P, Cristallo M, Librenti MC, et al. Free-insulin profiles after intraperitoneal, intramuscular, and subcutaneous
chapter 7part 2
references insulin administration. Diabetes Care 1986; 9: 575–8.23 Oskarsson PR, Lins PE, Backman L, Adamson UC. Continuous intraperitoneal insulin infusion partly restores the glucagon response to hypoglycaemia in type 1 diabetic patients. Diabetes Metab 2000; 26: 118–24.24 Wan CK, Giacca A, Matsuhisa M, et al. Increased responses of glucagon and glucose production to hypoglycemia with intraperitoneal versus subcutaneous insulin treatment. Metabolism 2000; 49: 984–9.25 Mason TM, Gupta N, Goh T, et al. Chronic intraperitoneal insulin delivery, as compared with subcutaneous delivery, improves hepatic glucose metabolism in streptozotocin diabetic rats. Metabolism 2000; 49: 1411–6.26 Oskarsson PR, Lins PE, Wallberg Henriksson H, Adamson UC. Metabolic and hormonal responses to exercise in type 1 diabetic patients during continuous subcutaneous, as compared to continuous intraperitoneal, insulin infusion. Diabetes Metab 1999; 25: 491–7.27 Selam JL, Medlej R, M’bemba J, et al. Symptoms, hormones, and glucose fluxes during a gradual hypoglycaemia induced by intraperitoneal vs venous insulin infusion in Type I diabetes. Diabet Med J Br Diabet Assoc 1995; 12: 1102–9.28 Logtenberg SJJ, van Ballegooie E, Israêl-Bultman H, van Linde A, Bilo HJG. Glycaemic control, health status and treat- ment satisfaction with continuous intraperitoneal insulin infusion. Neth J Med 2007; 65: 65–70.29 DeVries JH, Eskes SA, Snoek FJ, et al. Continuous intraperitoneal insulin infusion in patients with ‘brittle’ diabetes: favourable effects on glycaemic control and hospital stay. Diabet Med J Br Diabet Assoc 2002; 19: 496–501.30 Selam JL, Micossi P, Dunn FL, Nathan DM. Clinical trial of programmable implantable insulin pump for type I diabetes. Diabetes Care 1992; 15: 877–85.31 Schaepelynck P, Renard E, Jeandidier N, et al. A recent survey confirms the efficacy and the safety of implanted insulin pumps during long-term use in poorly controlled type 1 diabetes patients. Diabetes Technol Ther 2011; 13: 657–60.32 Gin H, Renard E, Melki V, et al. Combined improvements in implantable pump technology and insulin stability allow safe and effective long term intraperitoneal insulin delivery in type 1 diabetic patients: the EVADIAC experience. Diabetes Metab 2003; 29: 602–7.33 Hanaire-Broutin H, Broussolle C, Jeandidier N, et al. Feasibility of intraperitoneal insulin therapy with programmable implantable pumps in IDDM. A multicenter study. The EVADIAC Study Group. Evaluation dans le Diabète du Traitement par Implants Actifs. Diabetes Care 1995; 18: 388–92.34 Van Dijk PR, Logtenberg SJ, Groenier KH, Gans RO, Kleefstra N, Bilo HJ. Continuous intraperitoneal insulin infusion in type 1 diabetes: a 6-year post-trial follow-up. BMC Endocr Disord 2014; 14: 30.35 Rodbard D. The challenges of measuring glycemic variability. J Diabetes Sci Technol 2012; 6: 712–5.36 DeVries JH. Glucose variability: where it is important and how to measure it. Diabetes 2013; 62: 1405–8.37 Siegelaar SE, Holleman F, Hoekstra JBL, DeVries JH. Glucose variability; does it matter? Endocr Rev 2010; 31: 171–82.38 Kilpatrick ES. Arguments for and against the role of glucose variability in the development of diabetes complications. J Diabetes Sci Technol 2009; 3: 649–55.39 Van Dijk PR. Continuous intraperitoneal insulin infusion versus subcutaneous insulin therapy in the treatment of type 1 diabetes: a prospective, matched-control non-inferiority study. Submitted.40 Cobelli C, Renard E, Kovatchev B. Artificial pancreas: past, present, future. Diabetes 2011; 60: 2672–82.
124 125
chapter 7part 2
appe
ndix
1In
dice
s of g
lyca
emic
varia
bilit
y for
pat
ient
s tre
ated
with
MDI
and
CSII.
Dat
a are
pre
sent
ed as
estim
ated
mea
n (S
D),
med
ian
[IQR]
or m
ean
chan
ge (9
5% C
I) w
ithin
and
betw
een
grou
ps. A
bbre
viat
ions
: CSI
I, con
tinuo
us su
bcut
aneo
us in
sulin
infu
sion;
CV,
coef
ficie
nt of
varia
tion;
M
DI, m
ultip
le d
aily
inje
ctio
ns; M
AGE,
mea
n am
plitu
de of
glu
cose
excu
rsio
ns; M
ODD,
mea
n of
the d
aily
diff
eren
ces,
CGM
, con
tinuo
us g
luco
se m
easu
rem
ent.
Mea
n gl
ucos
e, SD
, MAG
E an
d M
ODD
are a
ll ex
pres
sed
in m
mol
/l. T
he C
V is
expr
esse
d in
%. *
p<0
.05.
appe
ndix
2Po
st-h
oc an
alys
is of
the c
orre
latio
n co
effic
ient
(Pea
rson
) bet
wee
n di
ffere
nt m
easu
res o
f GV.
Abbr
evia
tions
: CV,
coef
ficie
nt of
varia
tion;
MAG
E, m
ean
ampl
itude
of g
luco
se ex
curs
ions
; MOD
D, m
ean
of th
e dai
ly d
iffer
ence
s; SD
, sta
ndar
d de
viat
ion.
SD, M
AGE
and
MOD
D ar
e all
expr
esse
d in
mm
ol/l.
The
CV
is ex
pres
sed
in %
. All
corre
latio
ns ar
e sig
nific
ant a
t p<0
.001
.
124 125
chapter 7part 2
appe
ndix
1In
dice
s of g
lyca
emic
varia
bilit
y for
pat
ient
s tre
ated
with
MDI
and
CSII.
Dat
a are
pre
sent
ed as
estim
ated
mea
n (S
D),
med
ian
[IQR]
or m
ean
chan
ge (9
5% C
I) w
ithin
and
betw
een
grou
ps. A
bbre
viat
ions
: CSI
I, con
tinuo
us su
bcut
aneo
us in
sulin
infu
sion;
CV,
coef
ficie
nt of
varia
tion;
M
DI, m
ultip
le d
aily
inje
ctio
ns; M
AGE,
mea
n am
plitu
de of
glu
cose
excu
rsio
ns; M
ODD,
mea
n of
the d
aily
diff
eren
ces,
CGM
, con
tinuo
us g
luco
se m
easu
rem
ent.
Mea
n gl
ucos
e, SD
, MAG
E an
d M
ODD
are a
ll ex
pres
sed
in m
mol
/l. T
he C
V is
expr
esse
d in
%. *
p<0
.05.
appe
ndix
2Po
st-h
oc an
alys
is of
the c
orre
latio
n co
effic
ient
(Pea
rson
) bet
wee
n di
ffere
nt m
easu
res o
f GV.
Abbr
evia
tions
: CV,
coef
ficie
nt of
varia
tion;
MAG
E, m
ean
ampl
itude
of g
luco
se ex
curs
ions
; MOD
D, m
ean
of th
e dai
ly d
iffer
ence
s; SD
, sta
ndar
d de
viat
ion.
SD, M
AGE
and
MOD
D ar
e all
expr
esse
d in
mm
ol/l.
The
CV
is ex
pres
sed
in %
. All
corre
latio
ns ar
e sig
nific
ant a
t p<0
.001
.
126 127
Effect of intraperitoneal insulin administration on IGF1 and
IGFBP1 in type 1 diabetes
After 6 years of intraperitoneal insulin administration IGF1
concentrations in T1DM patients are at low-normal level
Different effects of intraperitoneal and subcutaneous insulin
administration on the growth-hormone - insulin-like growth
factor-1 axis in type 1 diabetes
chapter 8
chapter 9
chapter 10
part iii
Effects of intraperitoneal insulin therapy - beyond glycaemia
126 127
Effect of intraperitoneal insulin administration on IGF1 and
IGFBP1 in type 1 diabetes
After 6 years of intraperitoneal insulin administration IGF1
concentrations in T1DM patients are at low-normal level
Different effects of intraperitoneal and subcutaneous insulin
administration on the growth-hormone - insulin-like growth
factor-1 axis in type 1 diabetes
chapter 8
chapter 9
chapter 10
part iii
Effects of intraperitoneal insulin therapy - beyond glycaemia
128 129
Van Dijk PR, Logtenberg SJJ, Groenier KH, Kleefstra N, Bilo
HJG, Arnqvist HJ.
Effect of i.p. insulin administration on IGF1 and IGFBP1 in
type 1 diabetes. Endocr Connect 2014; 3: 17–23.
chapter 8 Abstract
introductionIn type 1 diabetes mellitus (T1DM), low IGF1 concentrations and high levels of IGF binding
protein-1 (IGFBP1) have been reported. It has been suggested that these abnormalities
in the GH-IGF1 axis are due to low insulin levels in the portal vein. We hypothesized that
the intraperitoneal (IP) route of insulin administration increases IGF1 concentrations as
compared to subcutaneous (SC) insulin.
patients and methodsDetermination of IGF1 and IGFBP1 concentrations in samples derived from an open-label,
randomized cross-over trial comparing the effects of SC and IP insulin delivery on glycaemia.
T1DM patients were randomized to receive either 6 months continuous intraperitoneal
insulin infusion (CIPII) through an implantable pump (MIP 2007C, Medtronic) followed by
6 months SC insulin or vice versa with a washout phase in between.
resultsData from 16 patients, 6 males and 10 females with a median age of 42.4 [30.4, 49.4] years
and a diabetes duration of 21.7 [10.4, 30.5] years, who completed measurements during
both treatment phases was analysed. The change in IGF1 during CIPII was 10.4 μg/l (95%
confidence interval (CI) -0.94, 21.7 μg/l; p=0.06) and -2.2 μg/l (95% CI -13.5, 9.2 μg/l; p=0.69)
during SC insulin. Taking the effect of treatment order in account, the estimated change of
IGF1 was 12.6 μg/l (95% CI -3.1, 28.5 μg/l; p=0.11) with CIPII compared to SC insulin. IGFBP1
concentrations decreased with -100.7 μg/l (95% CI -143.0, -58.3 μg/l; p<0.01) with CIPII.
conclusionsDuring CIPII treatment parts of the growth hormone-IGF1 axis changed compared to SC
treatment. This supports the hypothesis that the IP route of insulin administration is of
importance in the IGF1 system.
published as
Effect of intraperitoneal insulin administration on IGF1 and IGFBP1 in type 1 diabetes
chapter 8part 3
128 129
Van Dijk PR, Logtenberg SJJ, Groenier KH, Kleefstra N, Bilo
HJG, Arnqvist HJ.
Effect of i.p. insulin administration on IGF1 and IGFBP1 in
type 1 diabetes. Endocr Connect 2014; 3: 17–23.
chapter 8 Abstract
introductionIn type 1 diabetes mellitus (T1DM), low IGF1 concentrations and high levels of IGF binding
protein-1 (IGFBP1) have been reported. It has been suggested that these abnormalities
in the GH-IGF1 axis are due to low insulin levels in the portal vein. We hypothesized that
the intraperitoneal (IP) route of insulin administration increases IGF1 concentrations as
compared to subcutaneous (SC) insulin.
patients and methodsDetermination of IGF1 and IGFBP1 concentrations in samples derived from an open-label,
randomized cross-over trial comparing the effects of SC and IP insulin delivery on glycaemia.
T1DM patients were randomized to receive either 6 months continuous intraperitoneal
insulin infusion (CIPII) through an implantable pump (MIP 2007C, Medtronic) followed by
6 months SC insulin or vice versa with a washout phase in between.
resultsData from 16 patients, 6 males and 10 females with a median age of 42.4 [30.4, 49.4] years
and a diabetes duration of 21.7 [10.4, 30.5] years, who completed measurements during
both treatment phases was analysed. The change in IGF1 during CIPII was 10.4 μg/l (95%
confidence interval (CI) -0.94, 21.7 μg/l; p=0.06) and -2.2 μg/l (95% CI -13.5, 9.2 μg/l; p=0.69)
during SC insulin. Taking the effect of treatment order in account, the estimated change of
IGF1 was 12.6 μg/l (95% CI -3.1, 28.5 μg/l; p=0.11) with CIPII compared to SC insulin. IGFBP1
concentrations decreased with -100.7 μg/l (95% CI -143.0, -58.3 μg/l; p<0.01) with CIPII.
conclusionsDuring CIPII treatment parts of the growth hormone-IGF1 axis changed compared to SC
treatment. This supports the hypothesis that the IP route of insulin administration is of
importance in the IGF1 system.
published as
Effect of intraperitoneal insulin administration on IGF1 and IGFBP1 in type 1 diabetes
chapter 8part 3
130 131
Introduction
Insulin and insulin like growth factor 1 (IGF1) are structurally and functionally closely related
peptides. IGF1, mainly synthesized in the liver after stimulation of the growth hormone (GH)
receptor, plays a central role in cell metabolism and growth regulation 1–3. In plasma, IGF1 is
bound to IGF-binding proteins (IGFBPs) of which IGFBP3 binds approximately 80% of the
total amount of IGF1 present in the circulation. It is only the free fraction of IGF1, comprising
less than 1% of the circulating IGF1, which is biologically active. IGFBP1 is produced in the
liver and regulated acutely (in an inverse direction) by insulin thereby allowing insulin to
regulate IGF1 bioactivity 4–7 .
Through an up-regulation of hepatic GH-receptor expression, insulin increases the hepatic
sensitivity of GH stimulation and subsequent increases IGF1 production 8. Furthermore,
insulin may increase IGF1 bioactivity by a down-regulation of IGFBP1 in the liver 5. In type
1 diabetes mellitus (T1DM), with insufficient insulinization of the liver due to lack of
endogenous insulin in the portal vein, there appears to be a dysfunction of the growth
hormone-IGF1 axis. This is characterized by low concentrations of total IGF1 and IGFBP3
and high concentrations of IGFBP1 and GH 9–14. Although these abnormalities have been
described in situation of poor glycaemic control, exogenous subcutaneous (SC) insulin only
attenuate these disturbances but do not completely reverse them 15–18.
With continuous intraperitoneal insulin infusion (CIPII) insulin is infused directly in the
intraperitoneal (IP) space and is almost entirely absorbed in the portal system, resulting in
higher portal insulin concentrations, higher hepatic uptake and lower peripheral plasma
insulin concentrations compared with SC insulin administration 19,20. This results in a more
physiologic mode of insulin administration compared to SC insulin administration and
could thus have a beneficial effect on the impaired GH-IGF1 axis 21. We tested the hypothesis
that IP administered insulin as compared to SC insulin results in an increase of IGF1
concentrations in samples derived from a randomized cross-over trial.
Patients and methods
study design and population The full study design has been published previously 22. In brief, the study from which the
samples were derived had an open-label randomized, crossover design and was conducted
at a single center (Isala, Zwolle, the Netherlands). The study consisted of 4 phases: the
qualification phase, the first treatment phase, the crossover phase, and the second
treatment phase. During a 3-month qualification phase, the patients’ prestudy insulin
therapy was used to attempt optimization of their glycemic control. Patients with T1DM
(aged 18–70 with fasting C-peptide concentrations <0.20 nmol/l, HbA1c ≥58 mmol/mol
and/or ≥5 incidents of hypoglycaemia (<4.0 mmol/l) per week and treated with multiple
daily injections (MDIs) or continuous subcutaneous insulin infusion (CSII) were randomly
allocated to continue their current SC mode of therapy or start with IP insulin administration
using an implantable pump. These 2 groups (start IP or continue SC) differed only in the
sequence of the mode of insulin administration. Randomisation was carried out using
sealed non-transparent envelopes, with adequate blinding of the content of the envelope.
Patients were assigned to the treatment order as defined by the code in the envelope (start
IP or continue SC). The randomization system used blocks of 4. In the original study, of the
50 patients that were screened for eligibility 25 entered the qualification phase. One patient
reached acceptable glycaemic control during the qualification phase, thus 24 patients were
randomly assigned and started the first treatment phase; 12 patients were assigned to
continue SC insulin and 12 patients to start with CIPII during the first phase of the trial. One
patient, with CIPII at start, withdrew consent during the trial. In the present analysis we only
included patients with complete IGF1 results in both treatment phases, therefore 7 patients
were excluded.
Insulin (U400 semi synthetic human insulin of porcine origin; Hoechst, Frankfurt, Germany,
nowadays Sanofi-Aventis) was administered with an implantable pump (MIP 2007C;
Medtronic/Minimed, Northridge, CA). The CIPII pump was implanted under general
anaesthesia at the start of the CIPII phase in all subjects. For subjects who received SC insulin
during the second treatment phase, the CIPII pump was filled with an inert fluid at the end
of the first treatment phase. SC insulin was delivered with either MDI or CSII, according to
what was used prior to the study.
Patients treated with MDIs continued to use their own insulin regime, i.e. rapid acting insulin
analogues before meals and a daily dose of long acting insulin. Between both treatment
phases of 6 months, a crossover phase of 4 weeks was instituted to minimize the carryover
effects of CIPII. During the crossover phase insulin was administered SC.
If the subject was using more than 40 IU of SC insulin per day prior to starting the CIPII
phase of the study, his or her starting dose was set at 90% of the prior SC dose. Subjects
chapter 8part 3
130 131
Introduction
Insulin and insulin like growth factor 1 (IGF1) are structurally and functionally closely related
peptides. IGF1, mainly synthesized in the liver after stimulation of the growth hormone (GH)
receptor, plays a central role in cell metabolism and growth regulation 1–3. In plasma, IGF1 is
bound to IGF-binding proteins (IGFBPs) of which IGFBP3 binds approximately 80% of the
total amount of IGF1 present in the circulation. It is only the free fraction of IGF1, comprising
less than 1% of the circulating IGF1, which is biologically active. IGFBP1 is produced in the
liver and regulated acutely (in an inverse direction) by insulin thereby allowing insulin to
regulate IGF1 bioactivity 4–7 .
Through an up-regulation of hepatic GH-receptor expression, insulin increases the hepatic
sensitivity of GH stimulation and subsequent increases IGF1 production 8. Furthermore,
insulin may increase IGF1 bioactivity by a down-regulation of IGFBP1 in the liver 5. In type
1 diabetes mellitus (T1DM), with insufficient insulinization of the liver due to lack of
endogenous insulin in the portal vein, there appears to be a dysfunction of the growth
hormone-IGF1 axis. This is characterized by low concentrations of total IGF1 and IGFBP3
and high concentrations of IGFBP1 and GH 9–14. Although these abnormalities have been
described in situation of poor glycaemic control, exogenous subcutaneous (SC) insulin only
attenuate these disturbances but do not completely reverse them 15–18.
With continuous intraperitoneal insulin infusion (CIPII) insulin is infused directly in the
intraperitoneal (IP) space and is almost entirely absorbed in the portal system, resulting in
higher portal insulin concentrations, higher hepatic uptake and lower peripheral plasma
insulin concentrations compared with SC insulin administration 19,20. This results in a more
physiologic mode of insulin administration compared to SC insulin administration and
could thus have a beneficial effect on the impaired GH-IGF1 axis 21. We tested the hypothesis
that IP administered insulin as compared to SC insulin results in an increase of IGF1
concentrations in samples derived from a randomized cross-over trial.
Patients and methods
study design and population The full study design has been published previously 22. In brief, the study from which the
samples were derived had an open-label randomized, crossover design and was conducted
at a single center (Isala, Zwolle, the Netherlands). The study consisted of 4 phases: the
qualification phase, the first treatment phase, the crossover phase, and the second
treatment phase. During a 3-month qualification phase, the patients’ prestudy insulin
therapy was used to attempt optimization of their glycemic control. Patients with T1DM
(aged 18–70 with fasting C-peptide concentrations <0.20 nmol/l, HbA1c ≥58 mmol/mol
and/or ≥5 incidents of hypoglycaemia (<4.0 mmol/l) per week and treated with multiple
daily injections (MDIs) or continuous subcutaneous insulin infusion (CSII) were randomly
allocated to continue their current SC mode of therapy or start with IP insulin administration
using an implantable pump. These 2 groups (start IP or continue SC) differed only in the
sequence of the mode of insulin administration. Randomisation was carried out using
sealed non-transparent envelopes, with adequate blinding of the content of the envelope.
Patients were assigned to the treatment order as defined by the code in the envelope (start
IP or continue SC). The randomization system used blocks of 4. In the original study, of the
50 patients that were screened for eligibility 25 entered the qualification phase. One patient
reached acceptable glycaemic control during the qualification phase, thus 24 patients were
randomly assigned and started the first treatment phase; 12 patients were assigned to
continue SC insulin and 12 patients to start with CIPII during the first phase of the trial. One
patient, with CIPII at start, withdrew consent during the trial. In the present analysis we only
included patients with complete IGF1 results in both treatment phases, therefore 7 patients
were excluded.
Insulin (U400 semi synthetic human insulin of porcine origin; Hoechst, Frankfurt, Germany,
nowadays Sanofi-Aventis) was administered with an implantable pump (MIP 2007C;
Medtronic/Minimed, Northridge, CA). The CIPII pump was implanted under general
anaesthesia at the start of the CIPII phase in all subjects. For subjects who received SC insulin
during the second treatment phase, the CIPII pump was filled with an inert fluid at the end
of the first treatment phase. SC insulin was delivered with either MDI or CSII, according to
what was used prior to the study.
Patients treated with MDIs continued to use their own insulin regime, i.e. rapid acting insulin
analogues before meals and a daily dose of long acting insulin. Between both treatment
phases of 6 months, a crossover phase of 4 weeks was instituted to minimize the carryover
effects of CIPII. During the crossover phase insulin was administered SC.
If the subject was using more than 40 IU of SC insulin per day prior to starting the CIPII
phase of the study, his or her starting dose was set at 90% of the prior SC dose. Subjects
chapter 8part 3
132 133
using less than 40 IU of SC insulin received a starting dose of 80% of the prior SC dose.
Initially the dose was equally divided between a basal rate (50%) and a bolus before meals.
During all study visits, the 7-point glucose readings were used to adjust the dose regimen if
necessary to achieve pre-prandial glucose levels between 4.0-7.0 mmol/l and post-prandial
levels between 4.0-9.0 mmol/l. Patients were instructed not to start a specific diet or weight
reduction program during the trial.
measurementsMeasurements of clinical and biochemical parameters were performed at baseline, the end
of the qualification phase, at the start, at the halfway point, and at the end of both treatment
phases. HbA1c levels were measured using a Primus Ultra2 using high-performance liquid
chromatography (reference value 20-42 mmol/mol). IGF1 and IGFBP1 levels, reported as μg/l,
were measured in 1.5 cc serum samples collected at random and nonfasting at the start and
end of each treatment phase and stored at -80°C until analysis in 2011, performed at the
department of clinical and experimental medicine of the Linköping University, Linköping,
Sweden. Total IGF1 was measured by a one-step ELISA after acid–ethanol extraction from its
binding protein using a commercial kit (Human IGF-I Quantikine ELISA Kit R&D Systems,
Minneapolis, MN, USA) 23. Interassay coefficients of variation were 10.9, 5.9, and 18.2%
for high (278 μg/l), medium (116 μg/l), and low (45 μg/l) controls respectively. IGFBP1 was
measured with ELISA (human IGFBP1 DuoSet, DY871, R&D Systems, Minneapolis, MN,
USA). The assay was performed according to the protocol provided by the manufacturer.
Microtiterplates, MaxiSorp (Nunc Roskilde Denmark), normal goat serum (Fisher Scientific)
and (tetrametylbenzidinedehydrochloride (Sigma Life Science) were used. The microtiter-
plates were coated overnight with capture antibody. Interassay coefficients of variation (CV)
was for high (1688 µg/l) and low (4 µg/l) controls 7.8% and 20.0% respectively.
outcomesThe primary outcome of this post-hoc analysis is the difference in IGF1 concentrations
between the two treatment phases. Secondary outcomes include changes in IGFBP1 during
both treatment phases, changes in IGF1 and IGFBP1 for patients with and without detectable
C-peptide and correlations of changes in HbA1c, total insulin dose, C-peptide and with IGF1
and IGFBP1.
statistical analysisResults were expressed as mean (with standard deviation (SD)) or median (with
interquartile range [IQR]) for normally distributed and non-normally distributed data,
respectively. To calculate the mean difference with a 95% confidence interval (CI) the Hills-
Armitage approach was used, which accounts for any period effect. Linear mixed models
(PROC MIXED, SAS 9.2) were used to test differences, taking treatment order into account.
The assumption of normal distribution of the residuals was examined using Q-Q plots. In
addition Q-Q plots were used to determine if the tested variable had a normal distribution
or not. Correlations were investigated using the Pearson product-moment correlation
coefficient or, when appropriate, the nonparametric Spearman’s rho. Comparisons between
outcomes during both treatment modalities were performed using t-test for paired
comparisons for IGF1 and Wilcoxon match-pair signed-rank tests for IGFBP1. Patients
with and without detectable C-peptide were compared with unpaired t-test. The IGFBP1
concentrations had a skewed distribution (right tail) and are presented as median and the
IQR. The differences of IGFBP1 were normal distributed. Besides the linear mixed models, all
analyses were performed using SPSS version 18.0, Inc, Chicago, Il, USA. A (two-sided) p-value
of less than 0.05 was considered statistically significant.
ethical considerationsThe study was performed in accordance with the Declaration of Helsinki. Informed consent
was obtained from all patients for the initial study. The protocol was approved by the
medical ethics committee of the Isala in Zwolle. For the present study additional informed
consent was obtained.
Results
patientsThe study sample consisted of 16 patients, 6 males and 10 females, with a median age of 42.4
[30.4, 49.4] years and a diabetes duration of 21.7 [10.4, 30.5] years. Three patients used MDI
and 13 CSII before the study, the qualification- and SC phase. The mean IGF1 concentrations at
the start of the SC and IP insulin phase did not differ: 83.7 (31.9) and 76.3 (24.5) μg/l, respectively.
IGF1 and IGFBP1The observed results of the IGF1 and IGFBP1 measurements during the different treatment
modalities are depicted in Table 1 and Figure 1. The observed IGF1 and IGFBP1 concentrations
were significant different between both treatment modalities at 3 and 6 months.
chapter 8part 3
132 133
using less than 40 IU of SC insulin received a starting dose of 80% of the prior SC dose.
Initially the dose was equally divided between a basal rate (50%) and a bolus before meals.
During all study visits, the 7-point glucose readings were used to adjust the dose regimen if
necessary to achieve pre-prandial glucose levels between 4.0-7.0 mmol/l and post-prandial
levels between 4.0-9.0 mmol/l. Patients were instructed not to start a specific diet or weight
reduction program during the trial.
measurementsMeasurements of clinical and biochemical parameters were performed at baseline, the end
of the qualification phase, at the start, at the halfway point, and at the end of both treatment
phases. HbA1c levels were measured using a Primus Ultra2 using high-performance liquid
chromatography (reference value 20-42 mmol/mol). IGF1 and IGFBP1 levels, reported as μg/l,
were measured in 1.5 cc serum samples collected at random and nonfasting at the start and
end of each treatment phase and stored at -80°C until analysis in 2011, performed at the
department of clinical and experimental medicine of the Linköping University, Linköping,
Sweden. Total IGF1 was measured by a one-step ELISA after acid–ethanol extraction from its
binding protein using a commercial kit (Human IGF-I Quantikine ELISA Kit R&D Systems,
Minneapolis, MN, USA) 23. Interassay coefficients of variation were 10.9, 5.9, and 18.2%
for high (278 μg/l), medium (116 μg/l), and low (45 μg/l) controls respectively. IGFBP1 was
measured with ELISA (human IGFBP1 DuoSet, DY871, R&D Systems, Minneapolis, MN,
USA). The assay was performed according to the protocol provided by the manufacturer.
Microtiterplates, MaxiSorp (Nunc Roskilde Denmark), normal goat serum (Fisher Scientific)
and (tetrametylbenzidinedehydrochloride (Sigma Life Science) were used. The microtiter-
plates were coated overnight with capture antibody. Interassay coefficients of variation (CV)
was for high (1688 µg/l) and low (4 µg/l) controls 7.8% and 20.0% respectively.
outcomesThe primary outcome of this post-hoc analysis is the difference in IGF1 concentrations
between the two treatment phases. Secondary outcomes include changes in IGFBP1 during
both treatment phases, changes in IGF1 and IGFBP1 for patients with and without detectable
C-peptide and correlations of changes in HbA1c, total insulin dose, C-peptide and with IGF1
and IGFBP1.
statistical analysisResults were expressed as mean (with standard deviation (SD)) or median (with
interquartile range [IQR]) for normally distributed and non-normally distributed data,
respectively. To calculate the mean difference with a 95% confidence interval (CI) the Hills-
Armitage approach was used, which accounts for any period effect. Linear mixed models
(PROC MIXED, SAS 9.2) were used to test differences, taking treatment order into account.
The assumption of normal distribution of the residuals was examined using Q-Q plots. In
addition Q-Q plots were used to determine if the tested variable had a normal distribution
or not. Correlations were investigated using the Pearson product-moment correlation
coefficient or, when appropriate, the nonparametric Spearman’s rho. Comparisons between
outcomes during both treatment modalities were performed using t-test for paired
comparisons for IGF1 and Wilcoxon match-pair signed-rank tests for IGFBP1. Patients
with and without detectable C-peptide were compared with unpaired t-test. The IGFBP1
concentrations had a skewed distribution (right tail) and are presented as median and the
IQR. The differences of IGFBP1 were normal distributed. Besides the linear mixed models, all
analyses were performed using SPSS version 18.0, Inc, Chicago, Il, USA. A (two-sided) p-value
of less than 0.05 was considered statistically significant.
ethical considerationsThe study was performed in accordance with the Declaration of Helsinki. Informed consent
was obtained from all patients for the initial study. The protocol was approved by the
medical ethics committee of the Isala in Zwolle. For the present study additional informed
consent was obtained.
Results
patientsThe study sample consisted of 16 patients, 6 males and 10 females, with a median age of 42.4
[30.4, 49.4] years and a diabetes duration of 21.7 [10.4, 30.5] years. Three patients used MDI
and 13 CSII before the study, the qualification- and SC phase. The mean IGF1 concentrations at
the start of the SC and IP insulin phase did not differ: 83.7 (31.9) and 76.3 (24.5) μg/l, respectively.
IGF1 and IGFBP1The observed results of the IGF1 and IGFBP1 measurements during the different treatment
modalities are depicted in Table 1 and Figure 1. The observed IGF1 and IGFBP1 concentrations
were significant different between both treatment modalities at 3 and 6 months.
chapter 8part 3
134 135
chapter 8part 3
Observed IGF1, IGFBP1 and HbA1c concentrations and estimated changes during SC- and IP insulin treatment.
Course of mean IGF1 (consecutive line) and median IGFBP1 (dashed line) concentrations during 6 months on SC (red line) or IP insulin (blue line).
table 1
figure 1
IGF1 and HbA1c are presented as mean (SD) and the IGFBP1 concentrations are presented as median [IQR]. N=16 for IGF1, IGFBP1 and HbA1c on all timepoints. *p<0.05 for CIPII versus SC at that moment in time. a 0 months: at end of 3-month qualification phase. b Estimated mean changes of IGF1, IGFBP1 (both in μg/l) and HbA1c (mmol/mol) per treatment modality (95% CI).
IGF1
and
IGFB
P1 co
ncen
tratio
ns (μ
g/l)
No significant carry-over effects between both treatment phases were present for IGF1
(p=0.33) and IGFBP1 (p=0.83). The estimated mean change in IGF1 concentrations
during CIPII was 10.4 μg/l (95% CI -0.94, 21.7) and -2.2 μg/l (95% CI -13.5, 9.2) during SC
insulin therapy. When taking the effect of treatment order in account, the estimated
difference between the IP phase and SC phase was 12.6 μg/l (95% CI -3.1, 28.5). The IGFBP1
concentrations decreased significantly during the IP phase, -100.7 μg/l (95% CI -143.0, -58.3),
but not during the SC phase, 9.4 μg/l (95% CI -33.0, 51.8). The estimated difference between
both phases was -110.4 μg/l (95% CI -170.0, -50.1).
Glycemic control HbA1c decreased with CIPII from 68 (16.5) mmol/mol to 60 (6.6) mmol/mol after 3 months
and remained stable at 6 months (61 (9.9) mmol/mol), see Table 1. During SC treatment
there was no change in HbA1c. No significant carry-over effects between both treatment
phases were present (p=0.05). HbA1c improved with -10.0 mmol/mol (95% CI -18.4, -1.6) with
CIPII compared to SC insulin treatment. During IP treatment, changes in HbA1c correlated
with changes in IGF1 (r=-0.5, p=0.04), but not with IGFBP1 (r=-0.3, p=0.33).
Total insulin dose, C-peptide and associations with IGF1 and IGFPBP1Mean daily insulin dose decreased with -2.0 IU/day (95% CI -13.7, 9.6) during IP treatment
as compared to SC insulin treatment. The Spearman’s correlation coefficient showed a
non-significant association between the mean difference in insulin dose and IGF1 during IP
treatment (r= -0.02, p=0.95). The change in IGFBP1 did not correlate with changes in total
insulin dose (r=0.19, p=0.48) during the IP treatment phase. Changes in IGF1 and IGFBP1
during CIPII did not show any significant correlation (r=-0.23, p=0.40).
There was no significant difference in the change in IGF1 during the IP phase between
patients with a undetectable (≤0.01 nmol/l, n=6) and detectable (>0.01 nmol/l, n=10)
C-peptide: 12.6 (22.2) ng/ml vs. 3.7 (22.1) ng/ml (p=0.45). For IGFBP1 these concentrations
were -49.5 [-222.9, -17.4] and -57.7 [-182.7, -12.3] μg/l, respectively. The association between
the level of C-peptide and the change in IGF1 during the IP or SC phase was also not
significant: r= -0.02 (p=0.94) and r=-0.16 (p=0.56).
134 135
chapter 8part 3
Observed IGF1, IGFBP1 and HbA1c concentrations and estimated changes during SC- and IP insulin treatment.
Course of mean IGF1 (consecutive line) and median IGFBP1 (dashed line) concentrations during 6 months on SC (red line) or IP insulin (blue line).
table 1
figure 1
IGF1 and HbA1c are presented as mean (SD) and the IGFBP1 concentrations are presented as median [IQR]. N=16 for IGF1, IGFBP1 and HbA1c on all timepoints. *p<0.05 for CIPII versus SC at that moment in time. a 0 months: at end of 3-month qualification phase. b Estimated mean changes of IGF1, IGFBP1 (both in μg/l) and HbA1c (mmol/mol) per treatment modality (95% CI).
IGF1
and
IGFB
P1 co
ncen
tratio
ns (μ
g/l)
No significant carry-over effects between both treatment phases were present for IGF1
(p=0.33) and IGFBP1 (p=0.83). The estimated mean change in IGF1 concentrations
during CIPII was 10.4 μg/l (95% CI -0.94, 21.7) and -2.2 μg/l (95% CI -13.5, 9.2) during SC
insulin therapy. When taking the effect of treatment order in account, the estimated
difference between the IP phase and SC phase was 12.6 μg/l (95% CI -3.1, 28.5). The IGFBP1
concentrations decreased significantly during the IP phase, -100.7 μg/l (95% CI -143.0, -58.3),
but not during the SC phase, 9.4 μg/l (95% CI -33.0, 51.8). The estimated difference between
both phases was -110.4 μg/l (95% CI -170.0, -50.1).
Glycemic control HbA1c decreased with CIPII from 68 (16.5) mmol/mol to 60 (6.6) mmol/mol after 3 months
and remained stable at 6 months (61 (9.9) mmol/mol), see Table 1. During SC treatment
there was no change in HbA1c. No significant carry-over effects between both treatment
phases were present (p=0.05). HbA1c improved with -10.0 mmol/mol (95% CI -18.4, -1.6) with
CIPII compared to SC insulin treatment. During IP treatment, changes in HbA1c correlated
with changes in IGF1 (r=-0.5, p=0.04), but not with IGFBP1 (r=-0.3, p=0.33).
Total insulin dose, C-peptide and associations with IGF1 and IGFPBP1Mean daily insulin dose decreased with -2.0 IU/day (95% CI -13.7, 9.6) during IP treatment
as compared to SC insulin treatment. The Spearman’s correlation coefficient showed a
non-significant association between the mean difference in insulin dose and IGF1 during IP
treatment (r= -0.02, p=0.95). The change in IGFBP1 did not correlate with changes in total
insulin dose (r=0.19, p=0.48) during the IP treatment phase. Changes in IGF1 and IGFBP1
during CIPII did not show any significant correlation (r=-0.23, p=0.40).
There was no significant difference in the change in IGF1 during the IP phase between
patients with a undetectable (≤0.01 nmol/l, n=6) and detectable (>0.01 nmol/l, n=10)
C-peptide: 12.6 (22.2) ng/ml vs. 3.7 (22.1) ng/ml (p=0.45). For IGFBP1 these concentrations
were -49.5 [-222.9, -17.4] and -57.7 [-182.7, -12.3] μg/l, respectively. The association between
the level of C-peptide and the change in IGF1 during the IP or SC phase was also not
significant: r= -0.02 (p=0.94) and r=-0.16 (p=0.56).
136 137
Discussion
Concentrations of IGFBP1 decreased significantly during CIPII compared to SC treatment.
IGF1 did not change significantly during IP treatment and compared to intensive SC insulin
treatment this was also not significant.
Since there is (almost) no insulin production in patients with T1DM it has been hypothesized
that low insulin levels in the portal vein causes decreased IGF1 concentrations through both
GH- receptor and IGFBP1 mediated mechanisms 5,8. In all three studies of the IGF system in
which subjects with T1DM were treated with IP insulin infusion a rise in IGF1 was observed.
Shishko et al. reported normalization of plasma IGF1 with intraportal infusion of insulin
in newly diagnosed patients with T1DM 24. Unfortunately that study lacks data regarding
the presence or absence of endogenous production of insulin. A longitudinal study by
Hanaire-Broutin et al. showed a steady rise in plasma IGF1 concentrations to a low-normal
level, one year after initiating CIPII despite a lack of improvement in HbA1c 18. In the current
study, IGF1 was significantly higher after 3 and 6 months with CIPII compared to SC and a
non-significant change of 10.4 μg/l was seen within the IP treatment period of 6 months.
Compared to SC insulin this change was not significant. These findings may be due to
sample size (n=16) and/or the duration of the present study. In the study of Hanaire-Broutin,
the IGF1 still tends to increase after 6 months. In severely uncontrolled diabetes IGF1 levels
are low but ordinary glycemic control probably has little effect on IGF1 levels as this study
suggests and Hedman et al. showed earlier 17,25.
At the start of the CIPII treatment several patients had very high IGFBP1 values. Due to these
outliers, the IGFBP1 levels at the start of the IP phase were high. Of interest, all 5 patients
with IGFBP1 concentrations >150 μg/l (range: 181.2 to 330.0) were in the ‘IP first’ crossover
group. It was remarkable that additional analysis showed a significantly longer median
duration between pump implantation and measurement of IGFBP1 for these 5 patients
compared to the other patients (0.5 vs. 0.0 years, p<0.001). Therefore we hypothesize that
the high IGFBP1 concentrations in these 5 individuals represent an acute effect in the start-
up phase of IP insulin. It has been reported that insulin withdrawal for 8 hours in T1DM
patients treated with CSII increased IGFBP1 levels 6-fold and it is conceivable that the high
IGFBP1 values could be due to a lag in insulin delivery 4. Nevertheless, post-hoc analysis of
patients with IGFBP1 concentrations <150 μg/l still showed that the change in IGFBP1during
IP treatment remained significant (-46.3 μg/l, 95% CI -80.2, -12.4) and, since a right skew
could influence the estimated difference between the treatment modalities, that the
chapter 8part 3
estimated difference between the treatment groups remained present -49.9 μg/l (95% CI
-97.9, -1.92). When paired comparisons of IGFBP1 levels were made during treatment at 3
and 6 months, IGFBP1 was lower with CIPII than with CSII. The lowering of IGFBP1 suggest
an increase in free IGF1 i.e. IGF1 bioactivity by CIPII 1. Since there was no increase in insulin
dose this is compatible with an enhanced insulin effect on the liver by CIPII 3. The observed
decrease of IGFBP1 concentrations in the current study are in line with previous reports
and, since IGFBP1 correlates to GH secretion and hepatic glucose production, may indicate
importance of the IP route of insulin administration 24,26,27.
For the interpretation of the results of this study, it must be acknowledged that the original
study was powered to detect differences in hypoglycemic events between IP and SC insulin,
and not in IGF1 or IGFBP1 concentrations. In contrast to the studies by Shishko and Hanaire-
Broutin, samples were taken at random and information about the antecedent insulin dose
is lacking 18,24. Finally, lack of a large reference population impairs comparison of the IGF1
concentrations found in the present study with those of healthy subjects.
Conclusions
Although the clinical significance of low IGF1 concentrations in patients with T1DM remains
unclear at the present, CIPII could have an additional benefit on top of glycemic control by
altering the dysregulated GH-IGF-system through increasing portal insulin concentration.
This is a hypothesis worth testing in future research.
136 137
Discussion
Concentrations of IGFBP1 decreased significantly during CIPII compared to SC treatment.
IGF1 did not change significantly during IP treatment and compared to intensive SC insulin
treatment this was also not significant.
Since there is (almost) no insulin production in patients with T1DM it has been hypothesized
that low insulin levels in the portal vein causes decreased IGF1 concentrations through both
GH- receptor and IGFBP1 mediated mechanisms 5,8. In all three studies of the IGF system in
which subjects with T1DM were treated with IP insulin infusion a rise in IGF1 was observed.
Shishko et al. reported normalization of plasma IGF1 with intraportal infusion of insulin
in newly diagnosed patients with T1DM 24. Unfortunately that study lacks data regarding
the presence or absence of endogenous production of insulin. A longitudinal study by
Hanaire-Broutin et al. showed a steady rise in plasma IGF1 concentrations to a low-normal
level, one year after initiating CIPII despite a lack of improvement in HbA1c 18. In the current
study, IGF1 was significantly higher after 3 and 6 months with CIPII compared to SC and a
non-significant change of 10.4 μg/l was seen within the IP treatment period of 6 months.
Compared to SC insulin this change was not significant. These findings may be due to
sample size (n=16) and/or the duration of the present study. In the study of Hanaire-Broutin,
the IGF1 still tends to increase after 6 months. In severely uncontrolled diabetes IGF1 levels
are low but ordinary glycemic control probably has little effect on IGF1 levels as this study
suggests and Hedman et al. showed earlier 17,25.
At the start of the CIPII treatment several patients had very high IGFBP1 values. Due to these
outliers, the IGFBP1 levels at the start of the IP phase were high. Of interest, all 5 patients
with IGFBP1 concentrations >150 μg/l (range: 181.2 to 330.0) were in the ‘IP first’ crossover
group. It was remarkable that additional analysis showed a significantly longer median
duration between pump implantation and measurement of IGFBP1 for these 5 patients
compared to the other patients (0.5 vs. 0.0 years, p<0.001). Therefore we hypothesize that
the high IGFBP1 concentrations in these 5 individuals represent an acute effect in the start-
up phase of IP insulin. It has been reported that insulin withdrawal for 8 hours in T1DM
patients treated with CSII increased IGFBP1 levels 6-fold and it is conceivable that the high
IGFBP1 values could be due to a lag in insulin delivery 4. Nevertheless, post-hoc analysis of
patients with IGFBP1 concentrations <150 μg/l still showed that the change in IGFBP1during
IP treatment remained significant (-46.3 μg/l, 95% CI -80.2, -12.4) and, since a right skew
could influence the estimated difference between the treatment modalities, that the
chapter 8part 3
estimated difference between the treatment groups remained present -49.9 μg/l (95% CI
-97.9, -1.92). When paired comparisons of IGFBP1 levels were made during treatment at 3
and 6 months, IGFBP1 was lower with CIPII than with CSII. The lowering of IGFBP1 suggest
an increase in free IGF1 i.e. IGF1 bioactivity by CIPII 1. Since there was no increase in insulin
dose this is compatible with an enhanced insulin effect on the liver by CIPII 3. The observed
decrease of IGFBP1 concentrations in the current study are in line with previous reports
and, since IGFBP1 correlates to GH secretion and hepatic glucose production, may indicate
importance of the IP route of insulin administration 24,26,27.
For the interpretation of the results of this study, it must be acknowledged that the original
study was powered to detect differences in hypoglycemic events between IP and SC insulin,
and not in IGF1 or IGFBP1 concentrations. In contrast to the studies by Shishko and Hanaire-
Broutin, samples were taken at random and information about the antecedent insulin dose
is lacking 18,24. Finally, lack of a large reference population impairs comparison of the IGF1
concentrations found in the present study with those of healthy subjects.
Conclusions
Although the clinical significance of low IGF1 concentrations in patients with T1DM remains
unclear at the present, CIPII could have an additional benefit on top of glycemic control by
altering the dysregulated GH-IGF-system through increasing portal insulin concentration.
This is a hypothesis worth testing in future research.
138 139
1 Frystyk J. Free insulin-like growth factors -- measurements and relationships to growth hormone secretion and glucose homeostasis. Growth Horm IGF Res Off J Growth Horm Res Soc Int IGF Res Soc 2004; 14: 337–75.2 LeRoith D, Yakar S. Mechanisms of disease: metabolic effects of growth hormone and insulin-like growth factor 1. Nat Clin Pract Endocrinol Metab 2007; 3: 302–10.3 Kim JJ, Accili D. Signalling through IGF-I and insulin receptors: where is the specificity? Growth Horm IGF Res Off J Growth Horm Res Soc Int IGF Res Soc 2002; 12: 84–90.4 Attia N, Caprio S, Jones TW, et al. Changes in free insulin-like growth factor-1 and leptin concentrations during acute metabolic decompensation in insulin withdrawn patients with type 1 diabetes. J Clin Endocrinol Metab 1999; 84: 2324–8.5 Brismar K, Fernqvist-Forbes E, Wahren J, Hall K. Effect of insulin on the hepatic production of insulin-like growth factor- binding protein-1 (IGFBP-1), IGFBP-3, and IGF-I in insulin-dependent diabetes. J Clin Endocrinol Metab 1994; 79: 872–8.6 Suikkari AM, Koivisto VA, Rutanen EM, Yki-Järvinen H, Karonen SL, Seppälä M. Insulin regulates the serum levels of low molecular weight insulin-like growth factor-binding protein. J Clin Endocrinol Metab 1988; 66: 266–72.7 Orlowski CC, Ooi GT, Brown DR, Yang YW, Tseng LY, Rechler MM. Insulin rapidly inhibits insulin-like growth factor- binding protein-1 gene expression in H4-II-E rat hepatoma cells. Mol Endocrinol Baltim Md 1991; 5: 1180–7.8 Leung KC, Doyle N, Ballesteros M, Waters MJ, Ho KK. Insulin regulation of human hepatic growth hormone receptors: divergent effects on biosynthesis and surface translocation. J Clin Endocrinol Metab 2000; 85: 4712–20.9 Hansen AP, Johansen K. Diurnal patterns of blood glucose, serum free fatty acids, insulin, glucagon and growth hormone in normals and juvenile diabetics. Diabetologia 1970; 6: 27–33.10 Merimee TJ, Gardner DF, Zapf J, Froesch ER. Effect of glycemic control on serum insulin-like growth factors in diabetes mellitus. Diabetes 1984; 33: 790–3.11 Amiel SA, Sherwin RS, Hintz RL, Gertner JM, Press CM, Tamborlane WV. Effect of diabetes and its control on insulin-like growth factors in the young subject with type I diabetes. Diabetes 1984; 33: 1175–9.12 Tan K, Baxter RC. Serum insulin-like growth factor I levels in adult diabetic patients: the effect of age. J Clin Endocrinol Metab 1986; 63: 651–5.13 Jehle PM, Jehle DR, Mohan S, Böhm BO. Serum levels of insulin-like growth factor system components and relationship to bone metabolism in Type 1 and Type 2 diabetes mellitus patients. J Endocrinol 1998; 159: 297–306.14 Bereket A, Lang CH, Wilson TA. Alterations in the growth hormone-insulin-like growth factor axis in insulin dependent diabetes mellitus. Horm Metab Res Horm Stoffwechselforschung Horm Métabolisme 1999; 31: 172–81.15 Ekman B, Nyström F, Arnqvist HJ. Circulating IGF-I concentrations are low and not correlated to glycaemic control in adults with type 1 diabetes. Eur J Endocrinol Eur Fed Endocr Soc 2000; 143: 505–10.16 Hedman CA, Orre-Pettersson AC, Lindström T, Arnqvist HJ. Treatment with insulin lispro changes the insulin profile but does not affect the plasma concentrations of IGF-I and IGFBP-1 in type 1 diabetes. Clin Endocrinol (Oxf) 2001; 55: 107–12.17 Hedman CA, Frystyk J, Lindström T, et al. Residual beta-cell function more than glycemic control determines abnormal- ities of the insulin-like growth factor system in type 1 diabetes. J Clin Endocrinol Metab 2004; 89: 6305–9.18 Hanaire-Broutin H, Sallerin-Caute B, Poncet MF, et al. Insulin therapy and GH-IGF-I axis disorders in diabetes: impact of glycaemic control and hepatic insulinization. Diabetes Metab 1996; 22: 245–50.19 Nathan DM, Dunn FL, Bruch J, et al. Postprandial insulin profiles with implantable pump therapy may explain decreased frequency of severe hypoglycemia, compared with intensive subcutaneous regimens, in insulin-dependent diabetes mellitus patients. Am J Med 1996; 100: 412–7.20 Selam JL, Bergman RN, Raccah D, Jean-Didier N, Lozano J, Charles MA. Determination of portal insulin absorption from peritoneum via novel nonisotopic method. Diabetes 1990; 39: 1361–5.21 Schade DS, Eaton RP, Davis T, et al. The kinetics of peritoneal insulin absorption. Metabolism 1981; 30: 149–55.22 Logtenberg SJ, Kleefstra N, Houweling ST, et al. Improved glycemic control with intraperitoneal versus subcutaneous insulin in type 1 diabetes: a randomized controlled trial. Diabetes Care 2009; 32: 1372–7.23 Andreassen M, Nielsen K, Raymond I, Kristensen LØ, Faber J. Characteristics and reference ranges of Insulin-Like Growth Factor-I measured with a commercially available immunoassay in 724 healthy adult Caucasians.
chapter 8part 3
references
Scand J Clin Lab Invest 2009; 69: 880–5.24 Shishko PI, Dreval AV, Abugova IA, Zajarny IU, Goncharov VC. Insulin-like growth factors and binding proteins in patients with recent-onset type 1 (insulin-dependent) diabetes mellitus: influence of diabetes control and intraportal insulin infusion. Diabetes Res Clin Pract 1994; 25: 1–12.25 Rieu M, Binoux M. Serum levels of insulin-like growth factor (IGF) and IGF binding protein in insulin-dependent diabetics during an episode of severe metabolic decompensation and the recovery phase. J Clin Endocrinol Metab 1985; 60: 781–5.26 Hilding A, Brismar K, Degerblad M, Thorén M, Hall K. Altered relation between circulating levels of insulin-like growth factor-binding protein-1 and insulin in growth hormone-deficient patients and insulin-dependent diabetic patients compared to that in healthy subjects. J Clin Endocrinol Metab 1995; 80: 2646–52.27 Brismar K, Lewitt MS. The IGF and IGFBP system in insulin resistance and diabetes mellitus. The Humana Press Inc. IGF and nutrition in health and disease, editor Houston S, Holly J, Feldman E, chapter 14, page 251-270, 2004
138 139
1 Frystyk J. Free insulin-like growth factors -- measurements and relationships to growth hormone secretion and glucose homeostasis. Growth Horm IGF Res Off J Growth Horm Res Soc Int IGF Res Soc 2004; 14: 337–75.2 LeRoith D, Yakar S. Mechanisms of disease: metabolic effects of growth hormone and insulin-like growth factor 1. Nat Clin Pract Endocrinol Metab 2007; 3: 302–10.3 Kim JJ, Accili D. Signalling through IGF-I and insulin receptors: where is the specificity? Growth Horm IGF Res Off J Growth Horm Res Soc Int IGF Res Soc 2002; 12: 84–90.4 Attia N, Caprio S, Jones TW, et al. Changes in free insulin-like growth factor-1 and leptin concentrations during acute metabolic decompensation in insulin withdrawn patients with type 1 diabetes. J Clin Endocrinol Metab 1999; 84: 2324–8.5 Brismar K, Fernqvist-Forbes E, Wahren J, Hall K. Effect of insulin on the hepatic production of insulin-like growth factor- binding protein-1 (IGFBP-1), IGFBP-3, and IGF-I in insulin-dependent diabetes. J Clin Endocrinol Metab 1994; 79: 872–8.6 Suikkari AM, Koivisto VA, Rutanen EM, Yki-Järvinen H, Karonen SL, Seppälä M. Insulin regulates the serum levels of low molecular weight insulin-like growth factor-binding protein. J Clin Endocrinol Metab 1988; 66: 266–72.7 Orlowski CC, Ooi GT, Brown DR, Yang YW, Tseng LY, Rechler MM. Insulin rapidly inhibits insulin-like growth factor- binding protein-1 gene expression in H4-II-E rat hepatoma cells. Mol Endocrinol Baltim Md 1991; 5: 1180–7.8 Leung KC, Doyle N, Ballesteros M, Waters MJ, Ho KK. Insulin regulation of human hepatic growth hormone receptors: divergent effects on biosynthesis and surface translocation. J Clin Endocrinol Metab 2000; 85: 4712–20.9 Hansen AP, Johansen K. Diurnal patterns of blood glucose, serum free fatty acids, insulin, glucagon and growth hormone in normals and juvenile diabetics. Diabetologia 1970; 6: 27–33.10 Merimee TJ, Gardner DF, Zapf J, Froesch ER. Effect of glycemic control on serum insulin-like growth factors in diabetes mellitus. Diabetes 1984; 33: 790–3.11 Amiel SA, Sherwin RS, Hintz RL, Gertner JM, Press CM, Tamborlane WV. Effect of diabetes and its control on insulin-like growth factors in the young subject with type I diabetes. Diabetes 1984; 33: 1175–9.12 Tan K, Baxter RC. Serum insulin-like growth factor I levels in adult diabetic patients: the effect of age. J Clin Endocrinol Metab 1986; 63: 651–5.13 Jehle PM, Jehle DR, Mohan S, Böhm BO. Serum levels of insulin-like growth factor system components and relationship to bone metabolism in Type 1 and Type 2 diabetes mellitus patients. J Endocrinol 1998; 159: 297–306.14 Bereket A, Lang CH, Wilson TA. Alterations in the growth hormone-insulin-like growth factor axis in insulin dependent diabetes mellitus. Horm Metab Res Horm Stoffwechselforschung Horm Métabolisme 1999; 31: 172–81.15 Ekman B, Nyström F, Arnqvist HJ. Circulating IGF-I concentrations are low and not correlated to glycaemic control in adults with type 1 diabetes. Eur J Endocrinol Eur Fed Endocr Soc 2000; 143: 505–10.16 Hedman CA, Orre-Pettersson AC, Lindström T, Arnqvist HJ. Treatment with insulin lispro changes the insulin profile but does not affect the plasma concentrations of IGF-I and IGFBP-1 in type 1 diabetes. Clin Endocrinol (Oxf) 2001; 55: 107–12.17 Hedman CA, Frystyk J, Lindström T, et al. Residual beta-cell function more than glycemic control determines abnormal- ities of the insulin-like growth factor system in type 1 diabetes. J Clin Endocrinol Metab 2004; 89: 6305–9.18 Hanaire-Broutin H, Sallerin-Caute B, Poncet MF, et al. Insulin therapy and GH-IGF-I axis disorders in diabetes: impact of glycaemic control and hepatic insulinization. Diabetes Metab 1996; 22: 245–50.19 Nathan DM, Dunn FL, Bruch J, et al. Postprandial insulin profiles with implantable pump therapy may explain decreased frequency of severe hypoglycemia, compared with intensive subcutaneous regimens, in insulin-dependent diabetes mellitus patients. Am J Med 1996; 100: 412–7.20 Selam JL, Bergman RN, Raccah D, Jean-Didier N, Lozano J, Charles MA. Determination of portal insulin absorption from peritoneum via novel nonisotopic method. Diabetes 1990; 39: 1361–5.21 Schade DS, Eaton RP, Davis T, et al. The kinetics of peritoneal insulin absorption. Metabolism 1981; 30: 149–55.22 Logtenberg SJ, Kleefstra N, Houweling ST, et al. Improved glycemic control with intraperitoneal versus subcutaneous insulin in type 1 diabetes: a randomized controlled trial. Diabetes Care 2009; 32: 1372–7.23 Andreassen M, Nielsen K, Raymond I, Kristensen LØ, Faber J. Characteristics and reference ranges of Insulin-Like Growth Factor-I measured with a commercially available immunoassay in 724 healthy adult Caucasians.
chapter 8part 3
references
Scand J Clin Lab Invest 2009; 69: 880–5.24 Shishko PI, Dreval AV, Abugova IA, Zajarny IU, Goncharov VC. Insulin-like growth factors and binding proteins in patients with recent-onset type 1 (insulin-dependent) diabetes mellitus: influence of diabetes control and intraportal insulin infusion. Diabetes Res Clin Pract 1994; 25: 1–12.25 Rieu M, Binoux M. Serum levels of insulin-like growth factor (IGF) and IGF binding protein in insulin-dependent diabetics during an episode of severe metabolic decompensation and the recovery phase. J Clin Endocrinol Metab 1985; 60: 781–5.26 Hilding A, Brismar K, Degerblad M, Thorén M, Hall K. Altered relation between circulating levels of insulin-like growth factor-binding protein-1 and insulin in growth hormone-deficient patients and insulin-dependent diabetic patients compared to that in healthy subjects. J Clin Endocrinol Metab 1995; 80: 2646–52.27 Brismar K, Lewitt MS. The IGF and IGFBP system in insulin resistance and diabetes mellitus. The Humana Press Inc. IGF and nutrition in health and disease, editor Houston S, Holly J, Feldman E, chapter 14, page 251-270, 2004
140 141
chapter 9 Abstract
backgroundLow concentrations of insulin-like growth factor-1 (IGF1) have been reported in type 1 diabetes
mellitus (T1DM). This has been suggested to be due to low insulin concentrations in the portal
vein. Aim was to describe the long-term course of IGF1 concentrations among T1DM subjects
treated with continuous intraperitoneal (IP) insulin infusion (CIPII).
methodsNineteen patients that participated in a randomized cross-over trial comparing CIPII and
subcutaneous (SC) insulin therapy in 2006 were followed until 2012. IGF1 measurements
were performed at the start of the 2006 study, after the 6 month SC- and CIPII treatment
phase in 2006 and during CIPII therapy in 2012. Linear mixed models were used to calculate
estimated values and to test differences between the moments in time.
resultsIn 2012, IGF1 concentrations (123.1 μg/l; 95% confidence interval (CI) 111.1, 135.0) were
significantly higher than at the start of the 2006 study (62.0 μg/l; 95% CI 44.7, 79.3), the end of
the SC (69.4 μg/l; 95% CI 55.8, 82.9) and CIPII (81.5 μg/l; 95% CI 68.7, 94.3) treatment phase with
a mean difference of: -61.1 μg/l (95% CI -82.1, -40.0), -53.7 μg/l (95% CI -71.3, -36.0) and -41.5 μg/l
(95% CI -58.6, -24.4), respectively. As compared to a non-DM reference population the Z-score
for IGF1 in 2012 was -0.7 (95% CI -1.3, -0.2) and this score was significantly higher than the
Z-scores measured in 2006.
conclusionsAfter 6 years of treatment with CIPII, IGF1 concentrations among T1DM patients increased to
a level that is higher than during prior SC insulin treatment and is in the lower normal range
compared to a non-DM reference population. The results of this study suggest that long-
term IP insulin administration influences the IGF system in T1DM.
After 6 years of intra- peritoneal insulin administration IGF1 concentrations in T1DM patients are at low- normal level
chapter 9part 3
140 141
chapter 9 Abstract
backgroundLow concentrations of insulin-like growth factor-1 (IGF1) have been reported in type 1 diabetes
mellitus (T1DM). This has been suggested to be due to low insulin concentrations in the portal
vein. Aim was to describe the long-term course of IGF1 concentrations among T1DM subjects
treated with continuous intraperitoneal (IP) insulin infusion (CIPII).
methodsNineteen patients that participated in a randomized cross-over trial comparing CIPII and
subcutaneous (SC) insulin therapy in 2006 were followed until 2012. IGF1 measurements
were performed at the start of the 2006 study, after the 6 month SC- and CIPII treatment
phase in 2006 and during CIPII therapy in 2012. Linear mixed models were used to calculate
estimated values and to test differences between the moments in time.
resultsIn 2012, IGF1 concentrations (123.1 μg/l; 95% confidence interval (CI) 111.1, 135.0) were
significantly higher than at the start of the 2006 study (62.0 μg/l; 95% CI 44.7, 79.3), the end of
the SC (69.4 μg/l; 95% CI 55.8, 82.9) and CIPII (81.5 μg/l; 95% CI 68.7, 94.3) treatment phase with
a mean difference of: -61.1 μg/l (95% CI -82.1, -40.0), -53.7 μg/l (95% CI -71.3, -36.0) and -41.5 μg/l
(95% CI -58.6, -24.4), respectively. As compared to a non-DM reference population the Z-score
for IGF1 in 2012 was -0.7 (95% CI -1.3, -0.2) and this score was significantly higher than the
Z-scores measured in 2006.
conclusionsAfter 6 years of treatment with CIPII, IGF1 concentrations among T1DM patients increased to
a level that is higher than during prior SC insulin treatment and is in the lower normal range
compared to a non-DM reference population. The results of this study suggest that long-
term IP insulin administration influences the IGF system in T1DM.
After 6 years of intra- peritoneal insulin administration IGF1 concentrations in T1DM patients are at low- normal level
chapter 9part 3
142 143
Introduction
Insulin-like growth factor-1 (IGF1) is synthesized in the liver after stimulation of the growth
hormone (GH)-receptor and plays a central role in cell metabolism and growth regulation 1. Insulin seems to increase the sensitivity of the liver to GH stimulation, probably by up
regulating GH receptor expression, and thereby augments IGF1 production 2. Insulin may
also increase IGF1 bioactivity indirectly by down regulating the hepatic production of the IGF
binding protein (IGFBP)-1 3,4.
In type 1 diabetes mellitus (T1DM), a decrease in IGF1 concentrations has been described
together with low concentrations of IGFBP3 and high concentrations of IGFBP1 and GH 5–7.
It has been suggested that these abnormalities in the IGF-system are due to poor glycaemic
control, however, there is increasing evidence for a role of insufficient insulinization of the
liver secondary to low insulin concentrations in the portal vein 8–13.
With continuous intraperitoneal insulin infusion (CIPII), insulin is directly infused in the
intraperitoneal (IP) space where it is absorbed via the peritoneum into the catchment area
of the portal vein, resulting in higher insulin concentrations in the portal vein, higher hepatic
uptake of insulin and lower peripheral plasma insulin concentrations as compared to SC
insulin administration 14,15. Although some previous studies among CIPII treated T1DM
patients demonstrated increases in IGF1 concentrations, the long-term effects of CIPII
therapy on IGF1 concentrations are unknown.
Patients and methods
study design and populationIn order to describe long-term course of the IGF1 during CIPII therapy, also in comparison
with previous SC insulin therapy, we compared data from IGF1 measurements in 2012/2013
with data derived from an open-label, randomized cross-over trial in 2006. Aims, design,
population, procedures and outcomes of these studies, including analysis of IGF1
concentrations during the previous cross-over study, have been reported previously 16–19.
In brief, 23 T1DM patients (fasting C-peptide concentrations <0.20 nmol/l) in intermediate
or poor glycaemic control, defined as HbA1c ≥58 mmol/mol and/or ≥5 incidents of
hypoglycaemia (<4.0 mmol/l) per week, who were aged 18-70 years and treated with
SC insulin, initiated CIPII therapy in 2006. After the cross-over study all patients chose
to continue CIPII. Follow-up measurements for the present analysis were performed in
December 2012 until March 2013 (referred to as ‘2012 measurements’). Between 2006 and
2012, all patients received standard care at the outpatient clinic of the Isala (Zwolle, The
Netherlands) 20.
Insulin (U-400 HOE 21PH, semi synthetic human insulin of porcine origin, trade name:
Insuplant® Hoechst, Frankfurt, Germany, nowadays Sanofi-Aventis) was administered
with the implantable pump (MIP 2007D, Medtronic/Minimed, Northridge, CA, USA).
Insulin pump, implantation, insulin dosage and -refill procedures have been described 17,21.
Since there were no batches left of the U400 semi synthetic human insulin, a new human
recombinant insulin (400 IU/ml; human insulin of E. Coli origin, trade name: Insuman
Implantable®, Frankfurt, Germany, Sanofi-Aventis) was used from 2010 onwards.
measurements HbA1c was measured with a Primus Ultra2 system using high-performance liquid
chromatography (reference value 20-42 mmol/mol). IGF1 in the 2006 samples was
measured by a one-step ELISA after acid-ethanol extraction from its binding protein using
a commercial kit (Human IGF-I Quantikine ELISA Kit R&D Systems, Minneapolis, MN,
USA) 22. Interassay coefficients of variation (CV) were 10.9%, 5.9%, and 18.2% for high (278
μg/l), medium (116 μg/l), and low (45 μg/l) controls respectively. In the 2012/2013 samples
IGF1 was measured by a solid-phase, enzyme-labeled chemiluminescent immunometric
assay (IMMULITE® 2000 immunoassay system, Siemens Healthcare Diagnostics, Mölndal,
Sweden). Interassay CV were 5.7% and 6.6% at IGF1 levels of 105 and 330 µg/l, respectively.
statistical analysis Results were expressed as mean (with standard deviation (SD)) or median (with
interquartile range [IQR]) for normally distributed and non-normally distributed data,
respectively. Linear mixed models with Bonferroni correction were used to calculate and to
test differences in time. Correlations were investigated using the nonparametric Spearman’s
rho. In order to compare the IGF1 concentrations with age-specific normative range values
of a non-DM reference population, Z-scores were calculated 22,23. Statistical analysis were
performed with SPSS software (IBM SPSS Statistics for Windows, Version 20.0. Armonk,
NY: IBM Corp.). Studies were performed in accordance with the Declaration of Helsinki and
approved by the medical ethics committee of Isala (Zwolle, the Netherlands).
chapter 9part 3
142 143
Introduction
Insulin-like growth factor-1 (IGF1) is synthesized in the liver after stimulation of the growth
hormone (GH)-receptor and plays a central role in cell metabolism and growth regulation 1. Insulin seems to increase the sensitivity of the liver to GH stimulation, probably by up
regulating GH receptor expression, and thereby augments IGF1 production 2. Insulin may
also increase IGF1 bioactivity indirectly by down regulating the hepatic production of the IGF
binding protein (IGFBP)-1 3,4.
In type 1 diabetes mellitus (T1DM), a decrease in IGF1 concentrations has been described
together with low concentrations of IGFBP3 and high concentrations of IGFBP1 and GH 5–7.
It has been suggested that these abnormalities in the IGF-system are due to poor glycaemic
control, however, there is increasing evidence for a role of insufficient insulinization of the
liver secondary to low insulin concentrations in the portal vein 8–13.
With continuous intraperitoneal insulin infusion (CIPII), insulin is directly infused in the
intraperitoneal (IP) space where it is absorbed via the peritoneum into the catchment area
of the portal vein, resulting in higher insulin concentrations in the portal vein, higher hepatic
uptake of insulin and lower peripheral plasma insulin concentrations as compared to SC
insulin administration 14,15. Although some previous studies among CIPII treated T1DM
patients demonstrated increases in IGF1 concentrations, the long-term effects of CIPII
therapy on IGF1 concentrations are unknown.
Patients and methods
study design and populationIn order to describe long-term course of the IGF1 during CIPII therapy, also in comparison
with previous SC insulin therapy, we compared data from IGF1 measurements in 2012/2013
with data derived from an open-label, randomized cross-over trial in 2006. Aims, design,
population, procedures and outcomes of these studies, including analysis of IGF1
concentrations during the previous cross-over study, have been reported previously 16–19.
In brief, 23 T1DM patients (fasting C-peptide concentrations <0.20 nmol/l) in intermediate
or poor glycaemic control, defined as HbA1c ≥58 mmol/mol and/or ≥5 incidents of
hypoglycaemia (<4.0 mmol/l) per week, who were aged 18-70 years and treated with
SC insulin, initiated CIPII therapy in 2006. After the cross-over study all patients chose
to continue CIPII. Follow-up measurements for the present analysis were performed in
December 2012 until March 2013 (referred to as ‘2012 measurements’). Between 2006 and
2012, all patients received standard care at the outpatient clinic of the Isala (Zwolle, The
Netherlands) 20.
Insulin (U-400 HOE 21PH, semi synthetic human insulin of porcine origin, trade name:
Insuplant® Hoechst, Frankfurt, Germany, nowadays Sanofi-Aventis) was administered
with the implantable pump (MIP 2007D, Medtronic/Minimed, Northridge, CA, USA).
Insulin pump, implantation, insulin dosage and -refill procedures have been described 17,21.
Since there were no batches left of the U400 semi synthetic human insulin, a new human
recombinant insulin (400 IU/ml; human insulin of E. Coli origin, trade name: Insuman
Implantable®, Frankfurt, Germany, Sanofi-Aventis) was used from 2010 onwards.
measurements HbA1c was measured with a Primus Ultra2 system using high-performance liquid
chromatography (reference value 20-42 mmol/mol). IGF1 in the 2006 samples was
measured by a one-step ELISA after acid-ethanol extraction from its binding protein using
a commercial kit (Human IGF-I Quantikine ELISA Kit R&D Systems, Minneapolis, MN,
USA) 22. Interassay coefficients of variation (CV) were 10.9%, 5.9%, and 18.2% for high (278
μg/l), medium (116 μg/l), and low (45 μg/l) controls respectively. In the 2012/2013 samples
IGF1 was measured by a solid-phase, enzyme-labeled chemiluminescent immunometric
assay (IMMULITE® 2000 immunoassay system, Siemens Healthcare Diagnostics, Mölndal,
Sweden). Interassay CV were 5.7% and 6.6% at IGF1 levels of 105 and 330 µg/l, respectively.
statistical analysis Results were expressed as mean (with standard deviation (SD)) or median (with
interquartile range [IQR]) for normally distributed and non-normally distributed data,
respectively. Linear mixed models with Bonferroni correction were used to calculate and to
test differences in time. Correlations were investigated using the nonparametric Spearman’s
rho. In order to compare the IGF1 concentrations with age-specific normative range values
of a non-DM reference population, Z-scores were calculated 22,23. Statistical analysis were
performed with SPSS software (IBM SPSS Statistics for Windows, Version 20.0. Armonk,
NY: IBM Corp.). Studies were performed in accordance with the Declaration of Helsinki and
approved by the medical ethics committee of Isala (Zwolle, the Netherlands).
chapter 9part 3
144 145
Results
patientsOf 23 patients who participated in the previous cross-over study, 22 were still treated
with CIPII in 2012. Two patients were excluded from the current analysis: 1 due to chronic
glucocorticosteroid use for myasthenia gravis and 1 due to participation in an in vitro
fertilization program. One patient refused participation. Therefore, 19 patients (53% male)
are included in the present analysis, with a mean age of 45 (10) years and a diabetes duration
of 23 [16, 33] years at the start of the 2006 study. Baseline HbA1c was 69 (12) mmol/mol and
the total insulin dose was 50 [35, 70] IU/day, of which 28 [22, 31] U/day were given in a basal
and 16 [10, 25] IU/day in a bolus manner: these parameters did not change over time.
IGF1The observed outcomes for IGF1 are presented in Figure 1. IGF1 concentrations measured in
2012 were 123.1 μg/l (95% CI 111.1, 135.0), with a subsequent Z-score of -0.7 (95% CI -1.3, -0.2)
in comparison to a non-DM reference population. As presented in Table 1, both the IGF1
concentrations and the Z-scores measured in 2012 were higher than during measurements at
the start, end of the SC- and the end of the CIPII treatment phase of the 2006 cross-over study.
There were no significant correlations between the mean difference of measurements at the
end of the IP phase of the 2006 study and 2012 follow-up measurements for IGF1 and HbA1c
(r=-0.18, p=0.47) and daily insulin dose (r= 0.25, p=0.33).
Discussion
With long-term use of IP insulin administration, IGF1 levels approach concentrations as
measured in a non-DM reference population. In addition, IGF1 concentrations seem to be
significantly higher on long-term CIPII treatment as compared to previous intensive SC
insulin therapy. Taken together, the results of this study support the hypothesis that IP
insulin administration influences the IGF system in T1DM.
Few studies have investigated the effects of IP insulin on IGF1 concentrations in T1DM.
Although a previous post-hoc analysis of IGF1 concentrations derived from samples from
the cross-over period did not demonstrated differences in IGF1 between the CIPII and SC
treatment phase in the short-term, most studies did find increases of IGF1 during IP insulin
administration 17. Shishko et al. demonstrated that IP insulin infusion, but not SC insulin
therapy, among newly diagnosed T1DM patients normalized IGF1 concentrations 11. It should
be noted that remaining endogenous insulin production, which has reported to be of more
importance than glycaemic control in normalizing the IGF system, may have been present
among these subjects 5. Hanaire-Broutin et al. demonstrated that after one year of CIPII
therapy IGF1 concentrations were higher among 18 C-peptide negative T1DM patients, also
when compared to prior intensive SC therapy 10. Further evidence was provided recently
by Hedman et al. by finding, in addition to higher IGF1 concentrations, increased IGF1
bioactivity during CIPII as compared to CSII in T1DM patients 12.
chapter 9part 3
Estimated outcomes and differences between the different points in time.table 1
Data are presented as mean (95% CI) IGF1 in μg/l. Abbreviations: CIPII, continuous intraperitoneal insulin infusion; IGF1, insulin-like growth factor-1; SC, subcutaneous. * p<0.05.
Observed outcomes of IGF1 at different points in time.figure 1
The line represents IGF1 concentrations at different points in time with 95% CI (vertical). Abbreviations: CIPII, continuous intraperitoneal insulin infusion; IGF1, insulin-like growth factor-1; SC, subcutaneous.
144 145
Results
patientsOf 23 patients who participated in the previous cross-over study, 22 were still treated
with CIPII in 2012. Two patients were excluded from the current analysis: 1 due to chronic
glucocorticosteroid use for myasthenia gravis and 1 due to participation in an in vitro
fertilization program. One patient refused participation. Therefore, 19 patients (53% male)
are included in the present analysis, with a mean age of 45 (10) years and a diabetes duration
of 23 [16, 33] years at the start of the 2006 study. Baseline HbA1c was 69 (12) mmol/mol and
the total insulin dose was 50 [35, 70] IU/day, of which 28 [22, 31] U/day were given in a basal
and 16 [10, 25] IU/day in a bolus manner: these parameters did not change over time.
IGF1The observed outcomes for IGF1 are presented in Figure 1. IGF1 concentrations measured in
2012 were 123.1 μg/l (95% CI 111.1, 135.0), with a subsequent Z-score of -0.7 (95% CI -1.3, -0.2)
in comparison to a non-DM reference population. As presented in Table 1, both the IGF1
concentrations and the Z-scores measured in 2012 were higher than during measurements at
the start, end of the SC- and the end of the CIPII treatment phase of the 2006 cross-over study.
There were no significant correlations between the mean difference of measurements at the
end of the IP phase of the 2006 study and 2012 follow-up measurements for IGF1 and HbA1c
(r=-0.18, p=0.47) and daily insulin dose (r= 0.25, p=0.33).
Discussion
With long-term use of IP insulin administration, IGF1 levels approach concentrations as
measured in a non-DM reference population. In addition, IGF1 concentrations seem to be
significantly higher on long-term CIPII treatment as compared to previous intensive SC
insulin therapy. Taken together, the results of this study support the hypothesis that IP
insulin administration influences the IGF system in T1DM.
Few studies have investigated the effects of IP insulin on IGF1 concentrations in T1DM.
Although a previous post-hoc analysis of IGF1 concentrations derived from samples from
the cross-over period did not demonstrated differences in IGF1 between the CIPII and SC
treatment phase in the short-term, most studies did find increases of IGF1 during IP insulin
administration 17. Shishko et al. demonstrated that IP insulin infusion, but not SC insulin
therapy, among newly diagnosed T1DM patients normalized IGF1 concentrations 11. It should
be noted that remaining endogenous insulin production, which has reported to be of more
importance than glycaemic control in normalizing the IGF system, may have been present
among these subjects 5. Hanaire-Broutin et al. demonstrated that after one year of CIPII
therapy IGF1 concentrations were higher among 18 C-peptide negative T1DM patients, also
when compared to prior intensive SC therapy 10. Further evidence was provided recently
by Hedman et al. by finding, in addition to higher IGF1 concentrations, increased IGF1
bioactivity during CIPII as compared to CSII in T1DM patients 12.
chapter 9part 3
Estimated outcomes and differences between the different points in time.table 1
Data are presented as mean (95% CI) IGF1 in μg/l. Abbreviations: CIPII, continuous intraperitoneal insulin infusion; IGF1, insulin-like growth factor-1; SC, subcutaneous. * p<0.05.
Observed outcomes of IGF1 at different points in time.figure 1
The line represents IGF1 concentrations at different points in time with 95% CI (vertical). Abbreviations: CIPII, continuous intraperitoneal insulin infusion; IGF1, insulin-like growth factor-1; SC, subcutaneous.
146 147
For the interpretation of this study, some limitations should be taken into account including
the small sample size, lack of a SC reference population and a change in insulin formulation
during the study period. Importantly, the results should be interpreted with caution since
IGF1 levels obtained by different assays may differ 24. In normal reference populations lower
IGF1 values were obtained by the IGF1 method from R&D used in our previous report than
with the Immulite method used in the present follow-up 22,23,25. Finally, although IGF1 has
been suggested to be involved in improvement of insulin resistance and development of
long-term complications, the clinical relevance of our findings are unclear at present 26,27.
Conclusion
After 6 years of treatment with CIPII among T1DM patients, IGF1 concentrations increased
to a level that seems to be higher than during prior SC insulin treatment and is in the lower
normal range compared to subjects without DM.
1 Kim JJ, Accili D. Signalling through IGF-I and insulin receptors: where is the specificity? Growth Horm IGF Res Off J Growth Horm Res Soc Int IGF Res Soc 2002; 12: 84–90.2 Leung KC, Doyle N, Ballesteros M, Waters MJ, Ho KK. Insulin regulation of human hepatic growth hormone receptors: divergent effects on biosynthesis and surface translocation. J Clin Endocrinol Metab 2000; 85: 4712–20.3 Brismar K, Fernqvist-Forbes E, Wahren J, Hall K. Effect of insulin on the hepatic production of insulin-like growth factor- binding protein-1 (IGFBP-1), IGFBP-3, and IGF-I in insulin-dependent diabetes. J Clin Endocrinol Metab 1994; 79: 872–8.4 Frystyk J. Free insulin-like growth factors -- measurements and relationships to growth hormone secretion and glucose homeostasis. Growth Horm IGF Res Off J Growth Horm Res Soc Int IGF Res Soc 2004; 14: 337–75.5 Hedman CA, Frystyk J, Lindström T, et al. Residual beta-cell function more than glycemic control determines abnormal- ities of the insulin-like growth factor system in type 1 diabetes. J Clin Endocrinol Metab 2004; 89: 6305–9.6 Frystyk J, Bek T, Flyvbjerg A, Skjaerbaek C, Ørskov H. The relationship between the circulating IGF system and the presence of retinopathy in Type 1 diabetic patients. Diabet Med J Br Diabet Assoc 2003; 20: 269–76.7 Bereket A, Lang CH, Wilson TA. Alterations in the growth hormone-insulin-like growth factor axis in insulin dependent diabetes mellitus. Horm Metab Res Horm Stoffwechselforschung Horm Métabolisme 1999; 31: 172–81.8 Amiel SA, Sherwin RS, Hintz RL, Gertner JM, Press CM, Tamborlane WV. Effect of diabetes and its control on insulin- like growth factors in the young subject with type I diabetes. Diabetes 1984; 33: 1175–9.9 Ekman B, Nyström F, Arnqvist HJ. Circulating IGF-I concentrations are low and not correlated to glycaemic control in adults with type 1 diabetes. Eur J Endocrinol Eur Fed Endocr Soc 2000; 143: 505–10.10 Hanaire-Broutin H, Sallerin-Caute B, Poncet MF, et al. Effect of intraperitoneal insulin delivery on growth hormone binding protein, insulin-like growth factor (IGF)-I, and IGF-binding protein-3 in IDDM. Diabetologia 1996; 39: 1498–504.11 Shishko PI, Dreval AV, Abugova IA, Zajarny IU, Goncharov VC. Insulin-like growth factors and binding proteins in patients with recent-onset type 1 (insulin-dependent) diabetes mellitus: influence of diabetes control and intraportal insulin infusion. Diabetes Res Clin Pract 1994; 25: 1–12.12 Hedman CA, Frystyk J, Lindström T, Oskarsson P, Arnqvist HJ. Intraperitoneal insulin delivery to patients with type 1 diabetes results in higher serum IGF-I bioactivity than continuous subcutaneous insulin infusion. Clin Endocrinol (Oxf) 2013. doi:10.1111/cen.12296.13 Van Dijk PR, Logtenberg SJJ, Groenier KH, Kleefstra N, Bilo H, Arnqvist H. Effect of intraperitoneal insulin administration on IGF1 and IGFBP1 in type 1 diabetes. Endocr Connect 2013. doi:10.1530/EC-13-0089.14 Nathan DM, Dunn FL, Bruch J, et al. Postprandial insulin profiles with implantable pump therapy may explain decreased frequency of severe hypoglycemia, compared with intensive subcutaneous regimens, in insulin-dependent diabetes mellitus patients. Am J Med 1996; 100: 412–7.15 Selam JL, Bergman RN, Raccah D, Jean-Didier N, Lozano J, Charles MA. Determination of portal insulin absorption from peritoneum via novel nonisotopic method. Diabetes 1990; 39: 1361–5.16 Logtenberg SJ, Kleefstra N, Houweling ST, et al. Improved glycemic control with intraperitoneal versus subcutaneous insulin in type 1 diabetes: a randomized controlled trial. Diabetes Care 2009; 32: 1372–7.17 Van Dijk PR, Logtenberg SJJ, Groenier KH, Kleefstra N, Bilo H, Arnqvist H. Effect of intraperitoneal insulin administration on IGF1 and IGFBP1 in type 1 diabetes. Endocr Connect 2013. doi:10.1530/EC-13-0089.18 Van Dijk PR, Logtenberg SJ, Groenier KH, Gans RO, Kleefstra N, Bilo HJ. Continuous intraperitoneal insulin infusion in type 1 diabetes: a 6-year post-trial follow-up. BMC Endocr Disord 2014; 14: 30.19 Van Dijk PR, Logtenberg SJJ, Chisalita SI et al. Different effects of intraperitoneal and subcutaneous insulin administration on the growth-hormone - insulin-like growth factor-1 axis in type 1 diabetes. Unpublished, see Chapter 1020 Van Dijk PR, Logtenberg SJ, Groenier KH, Gans RO, Kleefstra N, Bilo HJ. Continuous intraperitoneal insulin infusion in type 1 diabetes: a 6-year post-trial follow-up. BMC Endocr Disord 2014; 14: 30.21 Haveman JW, Logtenberg SJJ, Kleefstra N, Groenier KH, Bilo HJG, Blomme AM. Surgical aspects and complications of continuous intraperitoneal insulin infusion with an implantable pump. Langenbecks Arch Surg Dtsch Ges Für Chir 2010; 395: 65–71.
chapter 9part 3
references
146 147
For the interpretation of this study, some limitations should be taken into account including
the small sample size, lack of a SC reference population and a change in insulin formulation
during the study period. Importantly, the results should be interpreted with caution since
IGF1 levels obtained by different assays may differ 24. In normal reference populations lower
IGF1 values were obtained by the IGF1 method from R&D used in our previous report than
with the Immulite method used in the present follow-up 22,23,25. Finally, although IGF1 has
been suggested to be involved in improvement of insulin resistance and development of
long-term complications, the clinical relevance of our findings are unclear at present 26,27.
Conclusion
After 6 years of treatment with CIPII among T1DM patients, IGF1 concentrations increased
to a level that seems to be higher than during prior SC insulin treatment and is in the lower
normal range compared to subjects without DM.
1 Kim JJ, Accili D. Signalling through IGF-I and insulin receptors: where is the specificity? Growth Horm IGF Res Off J Growth Horm Res Soc Int IGF Res Soc 2002; 12: 84–90.2 Leung KC, Doyle N, Ballesteros M, Waters MJ, Ho KK. Insulin regulation of human hepatic growth hormone receptors: divergent effects on biosynthesis and surface translocation. J Clin Endocrinol Metab 2000; 85: 4712–20.3 Brismar K, Fernqvist-Forbes E, Wahren J, Hall K. Effect of insulin on the hepatic production of insulin-like growth factor- binding protein-1 (IGFBP-1), IGFBP-3, and IGF-I in insulin-dependent diabetes. J Clin Endocrinol Metab 1994; 79: 872–8.4 Frystyk J. Free insulin-like growth factors -- measurements and relationships to growth hormone secretion and glucose homeostasis. Growth Horm IGF Res Off J Growth Horm Res Soc Int IGF Res Soc 2004; 14: 337–75.5 Hedman CA, Frystyk J, Lindström T, et al. Residual beta-cell function more than glycemic control determines abnormal- ities of the insulin-like growth factor system in type 1 diabetes. J Clin Endocrinol Metab 2004; 89: 6305–9.6 Frystyk J, Bek T, Flyvbjerg A, Skjaerbaek C, Ørskov H. The relationship between the circulating IGF system and the presence of retinopathy in Type 1 diabetic patients. Diabet Med J Br Diabet Assoc 2003; 20: 269–76.7 Bereket A, Lang CH, Wilson TA. Alterations in the growth hormone-insulin-like growth factor axis in insulin dependent diabetes mellitus. Horm Metab Res Horm Stoffwechselforschung Horm Métabolisme 1999; 31: 172–81.8 Amiel SA, Sherwin RS, Hintz RL, Gertner JM, Press CM, Tamborlane WV. Effect of diabetes and its control on insulin- like growth factors in the young subject with type I diabetes. Diabetes 1984; 33: 1175–9.9 Ekman B, Nyström F, Arnqvist HJ. Circulating IGF-I concentrations are low and not correlated to glycaemic control in adults with type 1 diabetes. Eur J Endocrinol Eur Fed Endocr Soc 2000; 143: 505–10.10 Hanaire-Broutin H, Sallerin-Caute B, Poncet MF, et al. Effect of intraperitoneal insulin delivery on growth hormone binding protein, insulin-like growth factor (IGF)-I, and IGF-binding protein-3 in IDDM. Diabetologia 1996; 39: 1498–504.11 Shishko PI, Dreval AV, Abugova IA, Zajarny IU, Goncharov VC. Insulin-like growth factors and binding proteins in patients with recent-onset type 1 (insulin-dependent) diabetes mellitus: influence of diabetes control and intraportal insulin infusion. Diabetes Res Clin Pract 1994; 25: 1–12.12 Hedman CA, Frystyk J, Lindström T, Oskarsson P, Arnqvist HJ. Intraperitoneal insulin delivery to patients with type 1 diabetes results in higher serum IGF-I bioactivity than continuous subcutaneous insulin infusion. Clin Endocrinol (Oxf) 2013. doi:10.1111/cen.12296.13 Van Dijk PR, Logtenberg SJJ, Groenier KH, Kleefstra N, Bilo H, Arnqvist H. Effect of intraperitoneal insulin administration on IGF1 and IGFBP1 in type 1 diabetes. Endocr Connect 2013. doi:10.1530/EC-13-0089.14 Nathan DM, Dunn FL, Bruch J, et al. Postprandial insulin profiles with implantable pump therapy may explain decreased frequency of severe hypoglycemia, compared with intensive subcutaneous regimens, in insulin-dependent diabetes mellitus patients. Am J Med 1996; 100: 412–7.15 Selam JL, Bergman RN, Raccah D, Jean-Didier N, Lozano J, Charles MA. Determination of portal insulin absorption from peritoneum via novel nonisotopic method. Diabetes 1990; 39: 1361–5.16 Logtenberg SJ, Kleefstra N, Houweling ST, et al. Improved glycemic control with intraperitoneal versus subcutaneous insulin in type 1 diabetes: a randomized controlled trial. Diabetes Care 2009; 32: 1372–7.17 Van Dijk PR, Logtenberg SJJ, Groenier KH, Kleefstra N, Bilo H, Arnqvist H. Effect of intraperitoneal insulin administration on IGF1 and IGFBP1 in type 1 diabetes. Endocr Connect 2013. doi:10.1530/EC-13-0089.18 Van Dijk PR, Logtenberg SJ, Groenier KH, Gans RO, Kleefstra N, Bilo HJ. Continuous intraperitoneal insulin infusion in type 1 diabetes: a 6-year post-trial follow-up. BMC Endocr Disord 2014; 14: 30.19 Van Dijk PR, Logtenberg SJJ, Chisalita SI et al. Different effects of intraperitoneal and subcutaneous insulin administration on the growth-hormone - insulin-like growth factor-1 axis in type 1 diabetes. Unpublished, see Chapter 1020 Van Dijk PR, Logtenberg SJ, Groenier KH, Gans RO, Kleefstra N, Bilo HJ. Continuous intraperitoneal insulin infusion in type 1 diabetes: a 6-year post-trial follow-up. BMC Endocr Disord 2014; 14: 30.21 Haveman JW, Logtenberg SJJ, Kleefstra N, Groenier KH, Bilo HJG, Blomme AM. Surgical aspects and complications of continuous intraperitoneal insulin infusion with an implantable pump. Langenbecks Arch Surg Dtsch Ges Für Chir 2010; 395: 65–71.
chapter 9part 3
references
148 149
22 Andreassen M, Nielsen K, Raymond I, Kristensen LØ, Faber J. Characteristics and reference ranges of Insulin-Like Growth Factor-I measured with a commercially available immunoassay in 724 healthy adult Caucasians. Scand J Clin Lab Invest 2009; 69: 880–5.23 Elmlinger MW, Kühnel W, Weber MM, Ranke MB. Reference ranges for two automated chemiluminescent assays for serum insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3). Clin Chem Lab Med CCLM FESCC 2004; 42: 654–64.24 Pokrajac A, Wark G, Ellis AR, Wear J, Wieringa GE, Trainer PJ. Variation in GH and IGF-I assays limits the applicability of international consensus criteria to local practice. Clin Endocrinol (Oxf) 2007; 67: 65–70.25 Van Dijk PR, Logtenberg SJJ, Groenier KH, Kleefstra N, Bilo HJG, Arnqvist HJ. Effect of i.p. insulin administration on IGF1 and IGFBP1 in type 1 diabetes. Endocr Connect 2014; 3: 17–23.26 Clemmons DR. Modifying IGF1 activity: an approach to treat endocrine disorders, atherosclerosis and cancer. Nat Rev Drug Discov 2007; 6: 821–33.27 Janssen JA, Jacobs ML, Derkx FH, Weber RF, van der Lely AJ, Lamberts SW. Free and total insulin-like growth factor I (IGF-I), IGF-binding protein-1 (IGFBP-1), and IGFBP-3 and their relationships to the presence of diabetic retinopathy and glomerular hyperfiltration in insulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1997; 82: 2809–15.
part 3
148 149
22 Andreassen M, Nielsen K, Raymond I, Kristensen LØ, Faber J. Characteristics and reference ranges of Insulin-Like Growth Factor-I measured with a commercially available immunoassay in 724 healthy adult Caucasians. Scand J Clin Lab Invest 2009; 69: 880–5.23 Elmlinger MW, Kühnel W, Weber MM, Ranke MB. Reference ranges for two automated chemiluminescent assays for serum insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3). Clin Chem Lab Med CCLM FESCC 2004; 42: 654–64.24 Pokrajac A, Wark G, Ellis AR, Wear J, Wieringa GE, Trainer PJ. Variation in GH and IGF-I assays limits the applicability of international consensus criteria to local practice. Clin Endocrinol (Oxf) 2007; 67: 65–70.25 Van Dijk PR, Logtenberg SJJ, Groenier KH, Kleefstra N, Bilo HJG, Arnqvist HJ. Effect of i.p. insulin administration on IGF1 and IGFBP1 in type 1 diabetes. Endocr Connect 2014; 3: 17–23.26 Clemmons DR. Modifying IGF1 activity: an approach to treat endocrine disorders, atherosclerosis and cancer. Nat Rev Drug Discov 2007; 6: 821–33.27 Janssen JA, Jacobs ML, Derkx FH, Weber RF, van der Lely AJ, Lamberts SW. Free and total insulin-like growth factor I (IGF-I), IGF-binding protein-1 (IGFBP-1), and IGFBP-3 and their relationships to the presence of diabetic retinopathy and glomerular hyperfiltration in insulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1997; 82: 2809–15.
part 3
150 151
chapter 10 Abstract
introductionIn patients with type 1 diabetes mellitus (T1DM), low levels of insulin-like growth factor -1
(IGF1) and high levels of growth hormone (GH) and IGF binding protein-1 (IGFBP1) are present,
probably due to low insulin levels in the portal vein. We hypothesized that the GH-IGF1 axis
is affected by the route of insulin administration and that continuous intraperitoneal insulin
infusion (CIPII) has a more pronounced effect than subcutaneous (SC) insulin therapy.
patients and methodsThis is a prospective, observational matched-control study. IGF1, IGFBP1 and GH were measured
at baseline and after 26 weeks in T1DM patients treated with CIPII and SC insulin therapy.
resultsA total of 183 patients, 39 using CIPII and 144 SC insulin therapy, with a mean age of 50
(standard deviation (SD) 12) years, diabetes duration of 26 (SD 13) years and HbA1c of 64
(SD 11) mmol/mol were analysed. IGF1 concentration were higher among CIPII treated
patients as compared to patients treated with SC insulin therapy: 123.7 μg/l (95% CI 110.8,
138.1) versus 108.1 μg/l (95% CI 101.7, 114.9), p=0.035. IGFBP1 and GH concentrations were
significantly lower among CIPII treated patients as compared to subjects treated with SC
insulin therapy: 50.9 μg/l (95% CI 37.9, 68.2) versus 102.6 μg/l (95% CI 87.8, 119.8) (p<0.001)
for IGFBP1 and 0.68 μg/l (95% CI 0.44, 1.06) versus 1.21 μg/l (95% CI 0.95, 1.54) (p=0.027)
for GH, respectively. During the study period there were no changes in IGF1 and GH
concentrations within both groups. Only IGFBP1 decreased more during CIPII as compared
to SC insulin therapy.
conclusionCIPII treated T1DM patients have higher IGF1 concentrations as compared to patients
treated with SC insulin therapy. Furthermore, IGFBP1 and GH concentrations are lower
among CIPII treated patients. These findings suggest that CIPII has beneficial effects as
compared to SC insulin on the altered GH-IGF1 axis in T1DM.
Different effects of intraperitoneal and subcutaneous insulin administration on the growth-hormone- insulin-like growth factor-1 axis in type 1 diabetes
chapter 10part 3
150 151
chapter 10 Abstract
introductionIn patients with type 1 diabetes mellitus (T1DM), low levels of insulin-like growth factor -1
(IGF1) and high levels of growth hormone (GH) and IGF binding protein-1 (IGFBP1) are present,
probably due to low insulin levels in the portal vein. We hypothesized that the GH-IGF1 axis
is affected by the route of insulin administration and that continuous intraperitoneal insulin
infusion (CIPII) has a more pronounced effect than subcutaneous (SC) insulin therapy.
patients and methodsThis is a prospective, observational matched-control study. IGF1, IGFBP1 and GH were measured
at baseline and after 26 weeks in T1DM patients treated with CIPII and SC insulin therapy.
resultsA total of 183 patients, 39 using CIPII and 144 SC insulin therapy, with a mean age of 50
(standard deviation (SD) 12) years, diabetes duration of 26 (SD 13) years and HbA1c of 64
(SD 11) mmol/mol were analysed. IGF1 concentration were higher among CIPII treated
patients as compared to patients treated with SC insulin therapy: 123.7 μg/l (95% CI 110.8,
138.1) versus 108.1 μg/l (95% CI 101.7, 114.9), p=0.035. IGFBP1 and GH concentrations were
significantly lower among CIPII treated patients as compared to subjects treated with SC
insulin therapy: 50.9 μg/l (95% CI 37.9, 68.2) versus 102.6 μg/l (95% CI 87.8, 119.8) (p<0.001)
for IGFBP1 and 0.68 μg/l (95% CI 0.44, 1.06) versus 1.21 μg/l (95% CI 0.95, 1.54) (p=0.027)
for GH, respectively. During the study period there were no changes in IGF1 and GH
concentrations within both groups. Only IGFBP1 decreased more during CIPII as compared
to SC insulin therapy.
conclusionCIPII treated T1DM patients have higher IGF1 concentrations as compared to patients
treated with SC insulin therapy. Furthermore, IGFBP1 and GH concentrations are lower
among CIPII treated patients. These findings suggest that CIPII has beneficial effects as
compared to SC insulin on the altered GH-IGF1 axis in T1DM.
Different effects of intraperitoneal and subcutaneous insulin administration on the growth-hormone- insulin-like growth factor-1 axis in type 1 diabetes
chapter 10part 3
152 153
Introduction
Insulin and insulin-like growth factor 1 (IGF1) are structurally and functionally closely related
peptides. IGF1, mainly synthesized in the liver after stimulation of the growth hormone (GH)
receptor, plays a central role in cell metabolism and growth regulation 1–3. In plasma, IGF1 is
bound to IGF-binding proteins (IGFBPs) of which IGFBP3 binds approximately 80% of the
total amount of IGF1 present in the circulation. It is only the free fraction of IGF1, comprising
less than 1% of the circulating IGF1, which is biologically active. IGFBP1 is produced in the
liver and regulated acutely (in the opposite direction) by insulin thereby allowing insulin to
regulate IGF1 bioactivity 4–7.
Evidence suggests that through an up-regulation of hepatic GH-receptor expression,
insulin increases the hepatic sensitivity of GH stimulation and subsequent increases IGF1
production 8. Furthermore, insulin down-regulates IGFBP1 synthesis in the liver which
may increases IGF1 bioactivity 5. In patients with type 1 diabetes mellitus (T1DM), it is
hypothesized that insulinopenia in the portal system leads to insufficient insulinization of
the liver and subsequent alterations of the GH-IGF1 axis. These alterations are characterized
by low concentrations of total IGF1 and IGFBP3 and high concentrations of IGFBP1 and GH
(Figure 1) 9–16.
Although these abnormalities have been described in situation of poor glycaemic control,
intensified exogenous subcutaneous (SC) insulin therapy only attenuates these disturbances
but does not correct them 15–18. With continuous intraperitoneal insulin infusion (CIPII),
insulin is infused directly in the intraperitoneal (IP) space, resulting in higher concentrations
in the portal vein catchment area, higher hepatic extraction of insulin and lower peripheral
plasma insulin concentrations compared with SC insulin administration 19,20.
Some of the previous studies towards the effects of IP insulin administration on the IGF1-
GH axis in T1DM patients showed an increase of IGF1, and a decrease of GH and IGFBP1 as
compared to SC insulin therapy 21–23, while other studies found no changes in IGF1 24. Most of
these studies had a short duration (ranging from days to 1 year) and the number of patients
was limited (ranging from 10 to 36) 21–24.
We hypothesized that the GH-IGF1 axis is affected by the route of insulin administration
and that IP administration of insulin has a different effect compared to SC insulin therapy.
Therefore we investigated the effects of CIPII, as compared to SC insulin therapy, on the
GH-IGF1 axis in T1DM patients.
Patients and methods
study design This investigator initiated study had a prospective, observational matched-control design.
Inclusion took place at Isala (Zwolle, the Netherlands) and Diaconessenhuis hospital
(Meppel, the Netherlands). Primary aim was to compare the effects of long-term CIPII to SC
insulin therapy, with respect to glycaemic control. As secondary outcome, and presented in
this chapter, measures of the GH-IGF1 axis were assessed.
patient selectionCases were subjects on CIPII therapy using an implanted insulin pump (MIP 2007D,
Medtronic/Minimed, Northridge, CA, USA) for the past 4 years without interruptions of >30
days, in order to avoid effects related to initiating therapy. Inclusion criteria for cases were
identical to those of a prior study in our centre and have been described in detail previously 25.
chapter 10part 3
Alterations in GH-IGF1 axis in T1DM.figure 1
The (+) and (-) indicate positive and negative associations, respectively. The (<arriba>) and (<abajo>) indicate increases and decreases of concentrations as found in previous studies 9–16. Abbreviations: GH, growth hormone; IGF1, insulin-like growth factor-1, IGFBP1/-3, insulin-like growth factor binding protein -1/-3.
152 153
Introduction
Insulin and insulin-like growth factor 1 (IGF1) are structurally and functionally closely related
peptides. IGF1, mainly synthesized in the liver after stimulation of the growth hormone (GH)
receptor, plays a central role in cell metabolism and growth regulation 1–3. In plasma, IGF1 is
bound to IGF-binding proteins (IGFBPs) of which IGFBP3 binds approximately 80% of the
total amount of IGF1 present in the circulation. It is only the free fraction of IGF1, comprising
less than 1% of the circulating IGF1, which is biologically active. IGFBP1 is produced in the
liver and regulated acutely (in the opposite direction) by insulin thereby allowing insulin to
regulate IGF1 bioactivity 4–7.
Evidence suggests that through an up-regulation of hepatic GH-receptor expression,
insulin increases the hepatic sensitivity of GH stimulation and subsequent increases IGF1
production 8. Furthermore, insulin down-regulates IGFBP1 synthesis in the liver which
may increases IGF1 bioactivity 5. In patients with type 1 diabetes mellitus (T1DM), it is
hypothesized that insulinopenia in the portal system leads to insufficient insulinization of
the liver and subsequent alterations of the GH-IGF1 axis. These alterations are characterized
by low concentrations of total IGF1 and IGFBP3 and high concentrations of IGFBP1 and GH
(Figure 1) 9–16.
Although these abnormalities have been described in situation of poor glycaemic control,
intensified exogenous subcutaneous (SC) insulin therapy only attenuates these disturbances
but does not correct them 15–18. With continuous intraperitoneal insulin infusion (CIPII),
insulin is infused directly in the intraperitoneal (IP) space, resulting in higher concentrations
in the portal vein catchment area, higher hepatic extraction of insulin and lower peripheral
plasma insulin concentrations compared with SC insulin administration 19,20.
Some of the previous studies towards the effects of IP insulin administration on the IGF1-
GH axis in T1DM patients showed an increase of IGF1, and a decrease of GH and IGFBP1 as
compared to SC insulin therapy 21–23, while other studies found no changes in IGF1 24. Most of
these studies had a short duration (ranging from days to 1 year) and the number of patients
was limited (ranging from 10 to 36) 21–24.
We hypothesized that the GH-IGF1 axis is affected by the route of insulin administration
and that IP administration of insulin has a different effect compared to SC insulin therapy.
Therefore we investigated the effects of CIPII, as compared to SC insulin therapy, on the
GH-IGF1 axis in T1DM patients.
Patients and methods
study design This investigator initiated study had a prospective, observational matched-control design.
Inclusion took place at Isala (Zwolle, the Netherlands) and Diaconessenhuis hospital
(Meppel, the Netherlands). Primary aim was to compare the effects of long-term CIPII to SC
insulin therapy, with respect to glycaemic control. As secondary outcome, and presented in
this chapter, measures of the GH-IGF1 axis were assessed.
patient selectionCases were subjects on CIPII therapy using an implanted insulin pump (MIP 2007D,
Medtronic/Minimed, Northridge, CA, USA) for the past 4 years without interruptions of >30
days, in order to avoid effects related to initiating therapy. Inclusion criteria for cases were
identical to those of a prior study in our centre and have been described in detail previously 25.
chapter 10part 3
Alterations in GH-IGF1 axis in T1DM.figure 1
The (+) and (-) indicate positive and negative associations, respectively. The (<arriba>) and (<abajo>) indicate increases and decreases of concentrations as found in previous studies 9–16. Abbreviations: GH, growth hormone; IGF1, insulin-like growth factor-1, IGFBP1/-3, insulin-like growth factor binding protein -1/-3.
154 155
In brief, patients with T1DM, aged 18 to 70 years who fulfilled abovementioned criteria for
CIPII and had a HbA1c ≥ 58 mmol/mol and/or ≥ 5 incidents of hypoglycaemia glucose (< 4.0
mmol/l) per week, were eligible.
The SC control group of the present study was age and gender matched to the cases. The SC
control group consisted of T1DM patients, with SC insulin as mode of insulin administration
(both multiple daily injections (MDI) and continuous subcutaneous insulin infusion (CSII)),
for the past 4 years without interruptions of >30 days and a HbA1c at time of matching
≥ 53 mmol/mol. Exclusion criteria, similar to the previous cross-over study, were identical for
both cases and controls included impaired renal function, cardiac problems and current use
or oral corticosteroids 25. The ratio of participants on the different therapies (CIPII:MDI:CSII)
was 1:2:2.
study protocol There were four study visits. During the first visit, baseline characteristics were collected
using a standardized case record form. During the second visit (5-7 days later) laboratory
measurements were performed. During the third visit, 26 weeks after visit 1, clinical
parameters were collected. During the fourth visit, 5-7 days after the third visit, laboratory
measurements were performed. Patients were instructed to visit the laboratory in a fasting
state.
Throughout the study period, insulin (human insulin of E. Coli origin, 400 IU/ml, trade
name: Insuman Implantable®, Sanofi-Aventis) was administered with an implantable pump
for CIPII users and patients using CSII or MDI continued their own insulin regime consisting
of fast-acting insulin analogues and for MDI patients also long-acting insulin analogues or
NPH-insulin. All patients received standard care. The implanted insulin pump and related
procedures have been described in more detail previously 24,26.
measurementsDemographic and clinical parameters included: age, gender, weight, length, blood pressure,
smoking and alcohol habits, co-morbidities, medication use, year of diagnosis of diabetes,
presence of microvascular (nephropathy, neuropathy and/or retinopathy) and macrovascular
complications (angina pectoris, myocardial infarction, coronary artery bypass grafting,
percutaneous transluminal coronary angioplasty, stroke, transient ischaemic attack,
peripheral artery disease) and previous days insulin therapy (kind of insulin, dosage and, |
if applicable, the number of daily injections). Blood pressure was measured using a blood
pressure monitor (M6 comfort; OMRON Healthcare) using the highest mean of
4 measurements (2 on each arm). Laboratory measurements included, creatinine, c-peptide,
total cholesterol, aspartate aminotransferase (AST), alanine aminotransferase (ALT),
y-glutamyl transpeptidase (gamma-GT), alkaline phosphatase and urine albumin/creatinine
ratio and HbA1c. HbA1c was measured with a Primus Ultra2 system using high-
performance liquid chromatography (reference value 20-42 mmol/mol). Serum samples for
specific measurements were stored at -80°C until analysis, performed at the Department
of Clinical and Experimental Medicine, Linköping University. Serum IGF1 was measured
by a solid-phase, enzyme-labeled chemiluminescent immunometric assay (IMMULITE®
2000 immunoassay system, Siemens Healthcare Diagnostics, Mölndal, Sweden).
Interassay coefficients of variation (CV) were 5.7% and 6.6% at IGF1 levels of 105 and
330 µg/l, respectively. Total plasma IGFBP1 was measured by a one-step enzyme-linked
immunosorbent assay (ELISA) (R&D Systems, Minneapolis, MN, USA). Interassay CV was
for high (2051 µg/l) and low (4 µg/l) controls 8.9% and 20.0% respectively. GH was analysed
with a solid-phase, two-site chemiluminescent immunometric assay, (IMMULITE® 2000
immunoassay system, Siemens Healthcare Diagnostics, Mölndal, Sweden).
outcome measuresThe primary outcome measure was the difference in IGF1 concentrations over the study
period between CIPII and SC treated subjects. Secondary outcomes included differences in
GH and IGFBP1 concentrations between CIPII and SC treated subjects, differences within
groups during the study period, and differences between the different SC treatment
modalities (e.g. MDI and CSII) and CIPII.
statistical analysisResults were expressed as mean (with standard deviation (SD)) or median (with interquartile
range [IQR]) for normally distributed and non-normally distributed data, respectively.
A significance level of 5% (two sided) was used. Normality was examined with Q-Q plots.
IGF1, IGFBP1 and GH concentrations were log transformed for the analysis and results were
back transformed to geometric means. In addition concentrations of IGF1 were compared
with the age-specific normative range values using Z-scores 27. Differences between CIPII
and SC groups averaged over the study period and in time were estimated using the general
linear model. Multivariate regression analysis was performed with the mean score over
the study period of either IGF1, IGFBP1 or GH as dependent variables and age, gender, BMI,
mode of insulin therapy, total insulin dose and HbA1c as covariates.
Statistical analyses were performed using SPSS (IBM SPSS Statistics for Windows, Version
20.0. Armonk, NY: IBM Corp.). The study protocol was registered prior to the start of
chapter 10part 3
154 155
In brief, patients with T1DM, aged 18 to 70 years who fulfilled abovementioned criteria for
CIPII and had a HbA1c ≥ 58 mmol/mol and/or ≥ 5 incidents of hypoglycaemia glucose (< 4.0
mmol/l) per week, were eligible.
The SC control group of the present study was age and gender matched to the cases. The SC
control group consisted of T1DM patients, with SC insulin as mode of insulin administration
(both multiple daily injections (MDI) and continuous subcutaneous insulin infusion (CSII)),
for the past 4 years without interruptions of >30 days and a HbA1c at time of matching
≥ 53 mmol/mol. Exclusion criteria, similar to the previous cross-over study, were identical for
both cases and controls included impaired renal function, cardiac problems and current use
or oral corticosteroids 25. The ratio of participants on the different therapies (CIPII:MDI:CSII)
was 1:2:2.
study protocol There were four study visits. During the first visit, baseline characteristics were collected
using a standardized case record form. During the second visit (5-7 days later) laboratory
measurements were performed. During the third visit, 26 weeks after visit 1, clinical
parameters were collected. During the fourth visit, 5-7 days after the third visit, laboratory
measurements were performed. Patients were instructed to visit the laboratory in a fasting
state.
Throughout the study period, insulin (human insulin of E. Coli origin, 400 IU/ml, trade
name: Insuman Implantable®, Sanofi-Aventis) was administered with an implantable pump
for CIPII users and patients using CSII or MDI continued their own insulin regime consisting
of fast-acting insulin analogues and for MDI patients also long-acting insulin analogues or
NPH-insulin. All patients received standard care. The implanted insulin pump and related
procedures have been described in more detail previously 24,26.
measurementsDemographic and clinical parameters included: age, gender, weight, length, blood pressure,
smoking and alcohol habits, co-morbidities, medication use, year of diagnosis of diabetes,
presence of microvascular (nephropathy, neuropathy and/or retinopathy) and macrovascular
complications (angina pectoris, myocardial infarction, coronary artery bypass grafting,
percutaneous transluminal coronary angioplasty, stroke, transient ischaemic attack,
peripheral artery disease) and previous days insulin therapy (kind of insulin, dosage and, |
if applicable, the number of daily injections). Blood pressure was measured using a blood
pressure monitor (M6 comfort; OMRON Healthcare) using the highest mean of
4 measurements (2 on each arm). Laboratory measurements included, creatinine, c-peptide,
total cholesterol, aspartate aminotransferase (AST), alanine aminotransferase (ALT),
y-glutamyl transpeptidase (gamma-GT), alkaline phosphatase and urine albumin/creatinine
ratio and HbA1c. HbA1c was measured with a Primus Ultra2 system using high-
performance liquid chromatography (reference value 20-42 mmol/mol). Serum samples for
specific measurements were stored at -80°C until analysis, performed at the Department
of Clinical and Experimental Medicine, Linköping University. Serum IGF1 was measured
by a solid-phase, enzyme-labeled chemiluminescent immunometric assay (IMMULITE®
2000 immunoassay system, Siemens Healthcare Diagnostics, Mölndal, Sweden).
Interassay coefficients of variation (CV) were 5.7% and 6.6% at IGF1 levels of 105 and
330 µg/l, respectively. Total plasma IGFBP1 was measured by a one-step enzyme-linked
immunosorbent assay (ELISA) (R&D Systems, Minneapolis, MN, USA). Interassay CV was
for high (2051 µg/l) and low (4 µg/l) controls 8.9% and 20.0% respectively. GH was analysed
with a solid-phase, two-site chemiluminescent immunometric assay, (IMMULITE® 2000
immunoassay system, Siemens Healthcare Diagnostics, Mölndal, Sweden).
outcome measuresThe primary outcome measure was the difference in IGF1 concentrations over the study
period between CIPII and SC treated subjects. Secondary outcomes included differences in
GH and IGFBP1 concentrations between CIPII and SC treated subjects, differences within
groups during the study period, and differences between the different SC treatment
modalities (e.g. MDI and CSII) and CIPII.
statistical analysisResults were expressed as mean (with standard deviation (SD)) or median (with interquartile
range [IQR]) for normally distributed and non-normally distributed data, respectively.
A significance level of 5% (two sided) was used. Normality was examined with Q-Q plots.
IGF1, IGFBP1 and GH concentrations were log transformed for the analysis and results were
back transformed to geometric means. In addition concentrations of IGF1 were compared
with the age-specific normative range values using Z-scores 27. Differences between CIPII
and SC groups averaged over the study period and in time were estimated using the general
linear model. Multivariate regression analysis was performed with the mean score over
the study period of either IGF1, IGFBP1 or GH as dependent variables and age, gender, BMI,
mode of insulin therapy, total insulin dose and HbA1c as covariates.
Statistical analyses were performed using SPSS (IBM SPSS Statistics for Windows, Version
20.0. Armonk, NY: IBM Corp.). The study protocol was registered prior to the start of
chapter 10part 3
156 157
the study (NCT01621308 and NL41037.075.12) and approved by the local medical ethics
committee. All patients gave informed consent.
Results
patientsFrom December 2012 through August 2013, a total of 335 patients were screened and
received information about the study; 190 agreed to participate. After baseline laboratory
measurements, 6 patients were excluded because of C-peptide concentrations exceeding
0.2 nmol/l (n=4) and an eGFR<40 ml/min (n=2). Consequently, 184 patients were followed
during the 26-week study period. After the first visit one patient withdrew informant
consent due to lack of interest. Therefore, 183 patients were analysed.
Baseline characteristics are presented in Table 1. All patients treated with SC insulin used a
regimen consisting on short-acting analogues with, for MDI treated patients, additionally a
long-acting insulin analogue (85.7%) or NPH-insulin (14.3%). Compared to patients using SC
insulin therapy, CIPII patients used more units of insulin per day and had neuropathy more
often.
primary outcome - IGF1Estimated geometric mean IGF1 concentration over the whole study period was higher
among CIPII treated patients as compared to patients treated with SC insulin therapy: 123.7
μg/l (95% CI 110.8, 138.1) versus 108.1 μg/l (95% CI 101.7, 114.9), p=0.035. In addition, the
Z-scores for IGF1 over the whole study period were significantly higher among CIPII treated
patients as compared to patients treated with SC insulin therapy: -1.3 (95% CI -1.5, -1.1) versus
-0.7 (95% CI -1.1, -0.4), p=0.02. During the study period, there were no differences in IGF1
concentrations within both groups (Table 2). There was no difference in the change of IGF1
concentrations over time between both groups (p=0.70)
chapter 10part 3
Baseline characteristics.table 1
Data are presented as n (%), mean (SD) or median [IQR]. *p<0.05 as compared to CIPII. † p<0.05 for MDI versus CSII. P-values are based on appropriate parametric and non-parametric tests. Retinopathy, neuropathy and nephropathy categories do not add up. Abbreviations: ALT; alanine aminotransferase, AST; aspartate aminotransferase, BMI; body mass index, CSII; continuous intraperitoneal insulin infusion, CIPII; continuous intraperitoneal infusion, Gamma-GT; Gamma-glutamyl transpeptidase, MDI; multiple daily injections, SC; subcutaneous. a based on n=32 (CIPII), n=125 (SC), n=56 (MDI), and n=69 (CSII).
Estimated outcomes at baseline and end for all, CIPII and SC treated T1DM patients. table 2
Data are presented as estimated concentrations (95% CI). Concentrations are in μg/l. # p<0.05 compared to baseline. *p<0.05 SC compared with CIPII.
secondary outcome - IGFBP1 and GHConcentrations of IGFBP1 and GH were significantly lower among CIPII treated patients as
compared to subjects treated with SC insulin therapy: 50.9 μg/l (95% CI 37.9, 68.2) versus
102.6 μg/l (95% CI 87.8, 119.8) (p<0.001) for IGFBP1 and 0.68 μg/l (95% CI 0.44, 1.06)
versus 1.21 μg/l (95% CI 0.95, 1.54) (p=0.027) for GH, respectively. Over time, there were no
significant differences in GH within the groups, while for IGFBP1 there was a significant
difference between baseline and end of the study in the CIPII group (p=0.003) (Table 2).
156 157
the study (NCT01621308 and NL41037.075.12) and approved by the local medical ethics
committee. All patients gave informed consent.
Results
patientsFrom December 2012 through August 2013, a total of 335 patients were screened and
received information about the study; 190 agreed to participate. After baseline laboratory
measurements, 6 patients were excluded because of C-peptide concentrations exceeding
0.2 nmol/l (n=4) and an eGFR<40 ml/min (n=2). Consequently, 184 patients were followed
during the 26-week study period. After the first visit one patient withdrew informant
consent due to lack of interest. Therefore, 183 patients were analysed.
Baseline characteristics are presented in Table 1. All patients treated with SC insulin used a
regimen consisting on short-acting analogues with, for MDI treated patients, additionally a
long-acting insulin analogue (85.7%) or NPH-insulin (14.3%). Compared to patients using SC
insulin therapy, CIPII patients used more units of insulin per day and had neuropathy more
often.
primary outcome - IGF1Estimated geometric mean IGF1 concentration over the whole study period was higher
among CIPII treated patients as compared to patients treated with SC insulin therapy: 123.7
μg/l (95% CI 110.8, 138.1) versus 108.1 μg/l (95% CI 101.7, 114.9), p=0.035. In addition, the
Z-scores for IGF1 over the whole study period were significantly higher among CIPII treated
patients as compared to patients treated with SC insulin therapy: -1.3 (95% CI -1.5, -1.1) versus
-0.7 (95% CI -1.1, -0.4), p=0.02. During the study period, there were no differences in IGF1
concentrations within both groups (Table 2). There was no difference in the change of IGF1
concentrations over time between both groups (p=0.70)
chapter 10part 3
Baseline characteristics.table 1
Data are presented as n (%), mean (SD) or median [IQR]. *p<0.05 as compared to CIPII. † p<0.05 for MDI versus CSII. P-values are based on appropriate parametric and non-parametric tests. Retinopathy, neuropathy and nephropathy categories do not add up. Abbreviations: ALT; alanine aminotransferase, AST; aspartate aminotransferase, BMI; body mass index, CSII; continuous intraperitoneal insulin infusion, CIPII; continuous intraperitoneal infusion, Gamma-GT; Gamma-glutamyl transpeptidase, MDI; multiple daily injections, SC; subcutaneous. a based on n=32 (CIPII), n=125 (SC), n=56 (MDI), and n=69 (CSII).
Estimated outcomes at baseline and end for all, CIPII and SC treated T1DM patients. table 2
Data are presented as estimated concentrations (95% CI). Concentrations are in μg/l. # p<0.05 compared to baseline. *p<0.05 SC compared with CIPII.
secondary outcome - IGFBP1 and GHConcentrations of IGFBP1 and GH were significantly lower among CIPII treated patients as
compared to subjects treated with SC insulin therapy: 50.9 μg/l (95% CI 37.9, 68.2) versus
102.6 μg/l (95% CI 87.8, 119.8) (p<0.001) for IGFBP1 and 0.68 μg/l (95% CI 0.44, 1.06)
versus 1.21 μg/l (95% CI 0.95, 1.54) (p=0.027) for GH, respectively. Over time, there were no
significant differences in GH within the groups, while for IGFBP1 there was a significant
difference between baseline and end of the study in the CIPII group (p=0.003) (Table 2).
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chapter 10part 3
Outcomes of multivariate regression analysis for IGF1, IGFBP1 and GH.table 4
Data are presented as B (SE) (95% CI). R2=0.30 for the model with IGF1, R2=0.16 for the model with IGFBP1 and R2=0.15 for the model with GH as dependent variable.*p<0.05.Estimated outcomes for MDI and CSII treated T1DM patients. table 3
Data are presented as estimated concentrations (95% CI) at baseline, end and over the whole study period. Concentrations are in μg/l. *p<0.05 compared with CIPII.
secondary outcome - MDI and CSII versus CIPIINo statistically significant differences were present between and within MDI and CSII
treated patients in IGF1, IGFBP1 and GH concentrations (Table 3). Mean IGF1 concentrations
among MDI and CSII treated patients were non-significantly lower in CIPII treated subjects.
IGFBP1 concentrations among MDI (p<0.001) and CSII (p=0.004) treated patients were
higher as compared to CIPII treated patients. GH concentrations were significantly higher
for CSII (p=0.039) treated subjects but not for MDI treated patients (p=0.39) as compared to
CIPII treated patients.
secondary outcome - multivariate regression analysisIn multivariate regression analysis with mean IGF1 score over the whole study period as
dependent variable, age, BMI and total daily insulin dose were significant while gender,
mode of insulin therapy and HbA1c were not (Table 4). In the same model with mean IGFBP1
score as dependent variable, age, gender,and mode of insulin therapy were significant.
When using the mean GH score as dependent variable, gender and mode of insulin therapy
were significant.
For hypothesis generation ultivariate regression analysis with IGF1, IGFBP1 or GH as
dependent variable and HbA1c and total insulin dose as covariates was repeated within
both the CIPII and SC group separately. Among SC treated patients, the total daily insulin
dose was significant associated with IGF1, IGFBP1 and GH (B= 0.47 (standard error (SE) 0.17,
95% CI 0.13, 0.81 and adjusted r2= 0.05) for IGF1; B=-1.06 (SE -0.25, 95% CI -1.84, -0.28 and
adjusted r2=0.06) for IGFBP1; B=-0.03 (SE 0.01, 95% CI -0.05, -0.001 and r2=0.16) for GH) but
not among CIPII treated subjects. HbA1c was not significant in any of the models.
Discussion
Main finding of the present study is that CIPII treated T1DM patients have higher
concentrations of IGF1 as compared to patients treated with SC insulin therapy. Furthermore,
IGFBP1 and GH concentrations are significantly lower among patients treated with CIPII.
Over the study period, IGF1 and GH concentrations were stable within groups: only IGFBP1
decreased more with CIPII as compared to SC insulin therapy. Taken together, these findings
show a role of IP insulin in the GH-IGF1 axis.
Decreased hepatic insulinization due to insulinopenia in the portal vein has been suggested
to cause alterations in the GH-IGF1 axis among T1DM patients. Although the low IGF1 levels
are ascribed to insulinopenia, insulin has no direct effect on IGF1 synthesis but there is strong
evidence that insulin is, indirectly, essential for GH-stimulation of hepatic IGF1 production.
In experimental diabetes GH-binding to the liver is reduced and can be increased by insulin
treatment indicating that GH-receptor number is regulated by insulin 28.
Data from human hepatocytes are lacking but in a human hepatoma cell line insulin has been
reported to augment GH-receptor expression and affect surface translocation 8. The higher
IGF1 concentrations in combination with lower GH concentrations among CIPII treated
patients as compared to SC treated patients found in this study, support the hypothesis that
increased hepatic insulinization due to IP insulin administration results in increased hepatic
GH sensitivity and, subsequently, higher IGF1 levels. Accordingly, as GH secretion is under
negative feedback by concentrations of IGF1, the lower GH concentrations among CIPII
treated patients is probably the result of a near-normalization of IGF1 concentrations.
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chapter 10part 3
Outcomes of multivariate regression analysis for IGF1, IGFBP1 and GH.table 4
Data are presented as B (SE) (95% CI). R2=0.30 for the model with IGF1, R2=0.16 for the model with IGFBP1 and R2=0.15 for the model with GH as dependent variable.*p<0.05.Estimated outcomes for MDI and CSII treated T1DM patients. table 3
Data are presented as estimated concentrations (95% CI) at baseline, end and over the whole study period. Concentrations are in μg/l. *p<0.05 compared with CIPII.
secondary outcome - MDI and CSII versus CIPIINo statistically significant differences were present between and within MDI and CSII
treated patients in IGF1, IGFBP1 and GH concentrations (Table 3). Mean IGF1 concentrations
among MDI and CSII treated patients were non-significantly lower in CIPII treated subjects.
IGFBP1 concentrations among MDI (p<0.001) and CSII (p=0.004) treated patients were
higher as compared to CIPII treated patients. GH concentrations were significantly higher
for CSII (p=0.039) treated subjects but not for MDI treated patients (p=0.39) as compared to
CIPII treated patients.
secondary outcome - multivariate regression analysisIn multivariate regression analysis with mean IGF1 score over the whole study period as
dependent variable, age, BMI and total daily insulin dose were significant while gender,
mode of insulin therapy and HbA1c were not (Table 4). In the same model with mean IGFBP1
score as dependent variable, age, gender,and mode of insulin therapy were significant.
When using the mean GH score as dependent variable, gender and mode of insulin therapy
were significant.
For hypothesis generation ultivariate regression analysis with IGF1, IGFBP1 or GH as
dependent variable and HbA1c and total insulin dose as covariates was repeated within
both the CIPII and SC group separately. Among SC treated patients, the total daily insulin
dose was significant associated with IGF1, IGFBP1 and GH (B= 0.47 (standard error (SE) 0.17,
95% CI 0.13, 0.81 and adjusted r2= 0.05) for IGF1; B=-1.06 (SE -0.25, 95% CI -1.84, -0.28 and
adjusted r2=0.06) for IGFBP1; B=-0.03 (SE 0.01, 95% CI -0.05, -0.001 and r2=0.16) for GH) but
not among CIPII treated subjects. HbA1c was not significant in any of the models.
Discussion
Main finding of the present study is that CIPII treated T1DM patients have higher
concentrations of IGF1 as compared to patients treated with SC insulin therapy. Furthermore,
IGFBP1 and GH concentrations are significantly lower among patients treated with CIPII.
Over the study period, IGF1 and GH concentrations were stable within groups: only IGFBP1
decreased more with CIPII as compared to SC insulin therapy. Taken together, these findings
show a role of IP insulin in the GH-IGF1 axis.
Decreased hepatic insulinization due to insulinopenia in the portal vein has been suggested
to cause alterations in the GH-IGF1 axis among T1DM patients. Although the low IGF1 levels
are ascribed to insulinopenia, insulin has no direct effect on IGF1 synthesis but there is strong
evidence that insulin is, indirectly, essential for GH-stimulation of hepatic IGF1 production.
In experimental diabetes GH-binding to the liver is reduced and can be increased by insulin
treatment indicating that GH-receptor number is regulated by insulin 28.
Data from human hepatocytes are lacking but in a human hepatoma cell line insulin has been
reported to augment GH-receptor expression and affect surface translocation 8. The higher
IGF1 concentrations in combination with lower GH concentrations among CIPII treated
patients as compared to SC treated patients found in this study, support the hypothesis that
increased hepatic insulinization due to IP insulin administration results in increased hepatic
GH sensitivity and, subsequently, higher IGF1 levels. Accordingly, as GH secretion is under
negative feedback by concentrations of IGF1, the lower GH concentrations among CIPII
treated patients is probably the result of a near-normalization of IGF1 concentrations.
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chapter 10part 3
Insulin also affects IGF1 concentrations by altering the concentrations of its binding proteins.
The lower IGFBP1 concentrations among CIPII treated patients, as compared to patients
treated with SC insulin, found in the present study are in line with previous reports 21,23 .
Except in pregnancy, IGFBP1 is exclusively produced in the liver. In contrast to IGF1, IGFBP1 is
directly regulated by insulin at the transcriptional level. As IGFBP1 is regulated in an inverse
manner by insulin levels in the portal vein, IP insulin may causes higher IGF1-bioactivity/free
IGF1 in addition to the change in total IGF1 enhancing the effect of IGF1 and the feedback on
GH-secretion 21,23,24.
In addition to portal insulinopenia, metabolic control has also been suggested to impact the
GH-IGF1 system. In the present study however, HbA1c had no significant association with
IGF1 concentrations in multivariate analysis. On the other hand, the total daily insulin dose
(positive) and BMI (negative) did have an significant association with IGF1 concentrations.
Although no data on plasma insulin concentrations is available in the present study, this
may suggest that the effects of insulin on IGF1 are dependent on the rate of absorption and
degradation of insulin to create a subsequent more physiologic systemic to portal insulin
gradient, and not via ordinary glycaemic control 15,16. Accordingly, although all patients in
the present study used insulin analogues, diversity in within and between the effects of MDI
and CSII on the GH-IGF1 axis could be a result of differences in the rate of absorption and
degradation of insulin precipitations.
To our knowledge, the present study is the largest investigating the effects of CIPII relative
to SC insulin therapy among T1DM on the GH-IGF1 axis. Nevertheless, the lack of differences
in IGF1 in subgroup analysis of MDI and CSII versus CIPII could be due to small numbers.
Furthermore, the results of this unique study need confirmation. Other strengths of the
present study include the use of patients who have been using their current mode of
therapy for several year, thus creating a stable situation, patients used insulin analogues
and measurements made on two points in time. At present, the clinical consequences of
our findings remain to be determined. Nevertheless, based on the insulin antagonizing
actions of GH and the insulin sensitizing actions of IGF1, increased insulin sensitivity among
CIPII patients could be hypothesized and may also contribute to prevention of late-term
complications 29–32.
Conclusion
Among T1DM patients treated with CIPII, concentrations of IGF1 are higher and closer to
normal as compared to patients treated with SC insulin therapy. Additionally, IGFBP1 and
GH concentrations were lower among CIPII treated patients as compared to SC treated
patients. These findings suggest that CIPII is more beneficial than SC insulin in correcting
the altered GH-IGF1 axis in T1DM.
160 161
chapter 10part 3
Insulin also affects IGF1 concentrations by altering the concentrations of its binding proteins.
The lower IGFBP1 concentrations among CIPII treated patients, as compared to patients
treated with SC insulin, found in the present study are in line with previous reports 21,23 .
Except in pregnancy, IGFBP1 is exclusively produced in the liver. In contrast to IGF1, IGFBP1 is
directly regulated by insulin at the transcriptional level. As IGFBP1 is regulated in an inverse
manner by insulin levels in the portal vein, IP insulin may causes higher IGF1-bioactivity/free
IGF1 in addition to the change in total IGF1 enhancing the effect of IGF1 and the feedback on
GH-secretion 21,23,24.
In addition to portal insulinopenia, metabolic control has also been suggested to impact the
GH-IGF1 system. In the present study however, HbA1c had no significant association with
IGF1 concentrations in multivariate analysis. On the other hand, the total daily insulin dose
(positive) and BMI (negative) did have an significant association with IGF1 concentrations.
Although no data on plasma insulin concentrations is available in the present study, this
may suggest that the effects of insulin on IGF1 are dependent on the rate of absorption and
degradation of insulin to create a subsequent more physiologic systemic to portal insulin
gradient, and not via ordinary glycaemic control 15,16. Accordingly, although all patients in
the present study used insulin analogues, diversity in within and between the effects of MDI
and CSII on the GH-IGF1 axis could be a result of differences in the rate of absorption and
degradation of insulin precipitations.
To our knowledge, the present study is the largest investigating the effects of CIPII relative
to SC insulin therapy among T1DM on the GH-IGF1 axis. Nevertheless, the lack of differences
in IGF1 in subgroup analysis of MDI and CSII versus CIPII could be due to small numbers.
Furthermore, the results of this unique study need confirmation. Other strengths of the
present study include the use of patients who have been using their current mode of
therapy for several year, thus creating a stable situation, patients used insulin analogues
and measurements made on two points in time. At present, the clinical consequences of
our findings remain to be determined. Nevertheless, based on the insulin antagonizing
actions of GH and the insulin sensitizing actions of IGF1, increased insulin sensitivity among
CIPII patients could be hypothesized and may also contribute to prevention of late-term
complications 29–32.
Conclusion
Among T1DM patients treated with CIPII, concentrations of IGF1 are higher and closer to
normal as compared to patients treated with SC insulin therapy. Additionally, IGFBP1 and
GH concentrations were lower among CIPII treated patients as compared to SC treated
patients. These findings suggest that CIPII is more beneficial than SC insulin in correcting
the altered GH-IGF1 axis in T1DM.
162 163
1 Frystyk J. Free insulin-like growth factors -- measurements and relationships to growth hormone secretion and glucose homeostasis. Growth Horm IGF Res Off J Growth Horm Res Soc Int IGF Res Soc 2004; 14: 337–75.2 LeRoith D, Yakar S. Mechanisms of disease: metabolic effects of growth hormone and insulin-like growth factor 1. Nat Clin Pract Endocrinol Metab 2007; 3: 302–10.3 Kim JJ, Accili D. Signalling through IGF-I and insulin receptors: where is the specificity? Growth Horm IGF Res Off J Growth Horm Res Soc Int IGF Res Soc 2002; 12: 84–90.4 Attia N, Caprio S, Jones TW, et al. Changes in free insulin-like growth factor-1 and leptin concentrations during acute metabolic decompensation in insulin withdrawn patients with type 1 diabetes. J Clin Endocrinol Metab 1999; 84: 2324–8.5 Brismar K, Fernqvist-Forbes E, Wahren J, Hall K. Effect of insulin on the hepatic production of insulin-like growth factor- binding protein-1 (IGFBP-1), IGFBP-3, and IGF-I in insulin-dependent diabetes. J Clin Endocrinol Metab 1994; 79: 872–8.6 Suikkari AM, Koivisto VA, Rutanen EM, Yki-Järvinen H, Karonen SL, Seppälä M. Insulin regulates the serum levels of low molecular weight insulin-like growth factor-binding protein. J Clin Endocrinol Metab 1988; 66: 266–72.7 Orlowski CC, Ooi GT, Brown DR, Yang YW, Tseng LY, Rechler MM. Insulin rapidly inhibits insulin-like growth factor- binding protein-1 gene expression in H4-II-E rat hepatoma cells. Mol Endocrinol Baltim Md 1991; 5: 1180–7.8 Leung KC, Doyle N, Ballesteros M, Waters MJ, Ho KK. Insulin regulation of human hepatic growth hormone receptors: divergent effects on biosynthesis and surface translocation. J Clin Endocrinol Metab 2000; 85: 4712–20.9 Hansen AP, Johansen K. Diurnal patterns of blood glucose, serum free fatty acids, insulin, glucagon and growth hormone in normals and juvenile diabetics. Diabetologia 1970; 6: 27–33.10 Merimee TJ, Gardner DF, Zapf J, Froesch ER. Effect of glycemic control on serum insulin-like growth factors in diabetes mellitus. Diabetes 1984; 33: 790–3.11 Amiel SA, Sherwin RS, Hintz RL, Gertner JM, Press CM, Tamborlane WV. Effect of diabetes and its control on insulin-like growth factors in the young subject with type I diabetes. Diabetes 1984; 33: 1175–9.12 Tan K, Baxter RC. Serum insulin-like growth factor I levels in adult diabetic patients: the effect of age. J Clin Endocrinol Metab 1986; 63: 651–5.13 Jehle PM, Jehle DR, Mohan S, Böhm BO. Serum levels of insulin-like growth factor system components and relationship to bone metabolism in Type 1 and Type 2 diabetes mellitus patients. J Endocrinol 1998; 159: 297–306.14 Bereket A, Lang CH, Wilson TA. Alterations in the growth hormone-insulin-like growth factor axis in insulin dependent diabetes mellitus. Horm Metab Res Horm Stoffwechselforschung Horm Métabolisme 1999; 31: 172–81.15 Hedman CA, Frystyk J, Lindström T, et al. Residual beta-cell function more than glycemic control determines abnormal- ities of the insulin-like growth factor system in type 1 diabetes. J Clin Endocrinol Metab 2004; 89: 6305–9.16 Ekman B, Nyström F, Arnqvist HJ. Circulating IGF-I concentrations are low and not correlated to glycaemic control in adults with type 1 diabetes. Eur J Endocrinol Eur Fed Endocr Soc 2000; 143: 505–10.17 Hedman CA, Orre-Pettersson AC, Lindström T, Arnqvist HJ. Treatment with insulin lispro changes the insulin profile but does not affect the plasma concentrations of IGF-I and IGFBP-1 in type 1 diabetes. Clin Endocrinol (Oxf) 2001; 55: 107–12.18 Hanaire-Broutin H, Sallerin-Caute B, Poncet MF, et al. Insulin therapy and GH-IGF-I axis disorders in diabetes: impact of glycaemic control and hepatic insulinization. Diabetes Metab 1996; 22: 245–50.19 Nathan DM, Dunn FL, Bruch J, et al. Postprandial insulin profiles with implantable pump therapy may explain decreased frequency of severe hypoglycemia, compared with intensive subcutaneous regimens, in insulin-dependent diabetes mellitus patients. Am J Med 1996; 100: 412–7.20 Selam JL, Bergman RN, Raccah D, Jean-Didier N, Lozano J, Charles MA. Determination of portal insulin absorption from peritoneum via novel nonisotopic method. Diabetes 1990; 39: 1361–5.21 Hedman CA, Frystyk J, Lindström T, Oskarsson P, Arnqvist HJ. Intraperitoneal insulin delivery to patients with type 1 diabetes results in higher serum IGF-I bioactivity than continuous subcutaneous insulin infusion. Clin Endocrinol (Oxf) 2013. doi:10.1111/cen.12296.22 Hanaire-Broutin H, Sallerin-Caute B, Poncet MF, et al. Effect of intraperitoneal insulin delivery on growth hormone binding protein, insulin-like growth factor (IGF)-I, and IGF-binding protein-3 in IDDM. Diabetologia 1996; 39: 1498–504.
23 Shishko PI, Dreval AV, Abugova IA, Zajarny IU, Goncharov VC. Insulin-like growth factors and binding proteins in patients with recent-onset type 1 (insulin-dependent) diabetes mellitus: influence of diabetes control and intraportal insulin infusion. Diabetes Res Clin Pract 1994; 25: 1–12.24 Van Dijk PR, Logtenberg SJJ, Groenier KH, Kleefstra N, Bilo H, Arnqvist H. Effect of intraperitoneal insulin administration on IGF1 and IGFBP1 in type 1 diabetes. Endocr Connect 2013. doi:10.1530/EC-13-0089.25 Logtenberg SJ, Kleefstra N, Houweling ST, et al. Improved glycemic control with intraperitoneal versus subcutaneous insulin in type 1 diabetes: a randomized controlled trial. Diabetes Care 2009; 32: 1372–7.26 Haveman JW, Logtenberg SJJ, Kleefstra N, Groenier KH, Bilo HJG, Blomme AM. Surgical aspects and complications of continuous intraperitoneal insulin infusion with an implantable pump. Langenbecks Arch Surg Dtsch Ges Für Chir 2010; 395: 65–71.27 Elmlinger MW, Kühnel W, Weber MM, Ranke MB. Reference ranges for two automated chemiluminescent assays for serum insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3). Clin Chem Lab Med CCLM FESCC 2004; 42: 654–64.28 Baxter RC, Bryson JM, Turtle JR. The effect of fasting on liver receptors for prolactin and growth hormone. Metabolism 1981; 30: 1086–90.29 Clemmons DR. Modifying IGF1 activity: an approach to treat endocrine disorders, atherosclerosis and cancer. Nat Rev Drug Discov 2007; 6: 821–33. 30 Janssen JA, Jacobs ML, Derkx FH, Weber RF, van der Lely AJ, Lamberts SW. Free and total insulin-like growth factor I (IGF-I), IGF-binding protein-1 (IGFBP-1), and IGFBP-3 and their relationships to the presence of diabetic retinopathy and glomerular hyperfiltration in insulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1997; 82: 2809–15.31 Frystyk J. The growth hormone hypothesis - 2005 revision. Horm Metab Res Horm Stoffwechselforschung Horm Métabolisme 2005; 37 Suppl 1: 44–8.32 Cingel-Ristić V, Flyvbjerg A, Drop SLS. The physiological and pathophysiological roles of the GH/IGF-axis in the kidney: lessons from experimental rodent models. Growth Horm IGF Res Off J Growth Horm Res Soc Int IGF Res Soc 2004; 14: 418–30.
chapter 10part 3
references
162 163
1 Frystyk J. Free insulin-like growth factors -- measurements and relationships to growth hormone secretion and glucose homeostasis. Growth Horm IGF Res Off J Growth Horm Res Soc Int IGF Res Soc 2004; 14: 337–75.2 LeRoith D, Yakar S. Mechanisms of disease: metabolic effects of growth hormone and insulin-like growth factor 1. Nat Clin Pract Endocrinol Metab 2007; 3: 302–10.3 Kim JJ, Accili D. Signalling through IGF-I and insulin receptors: where is the specificity? Growth Horm IGF Res Off J Growth Horm Res Soc Int IGF Res Soc 2002; 12: 84–90.4 Attia N, Caprio S, Jones TW, et al. Changes in free insulin-like growth factor-1 and leptin concentrations during acute metabolic decompensation in insulin withdrawn patients with type 1 diabetes. J Clin Endocrinol Metab 1999; 84: 2324–8.5 Brismar K, Fernqvist-Forbes E, Wahren J, Hall K. Effect of insulin on the hepatic production of insulin-like growth factor- binding protein-1 (IGFBP-1), IGFBP-3, and IGF-I in insulin-dependent diabetes. J Clin Endocrinol Metab 1994; 79: 872–8.6 Suikkari AM, Koivisto VA, Rutanen EM, Yki-Järvinen H, Karonen SL, Seppälä M. Insulin regulates the serum levels of low molecular weight insulin-like growth factor-binding protein. J Clin Endocrinol Metab 1988; 66: 266–72.7 Orlowski CC, Ooi GT, Brown DR, Yang YW, Tseng LY, Rechler MM. Insulin rapidly inhibits insulin-like growth factor- binding protein-1 gene expression in H4-II-E rat hepatoma cells. Mol Endocrinol Baltim Md 1991; 5: 1180–7.8 Leung KC, Doyle N, Ballesteros M, Waters MJ, Ho KK. Insulin regulation of human hepatic growth hormone receptors: divergent effects on biosynthesis and surface translocation. J Clin Endocrinol Metab 2000; 85: 4712–20.9 Hansen AP, Johansen K. Diurnal patterns of blood glucose, serum free fatty acids, insulin, glucagon and growth hormone in normals and juvenile diabetics. Diabetologia 1970; 6: 27–33.10 Merimee TJ, Gardner DF, Zapf J, Froesch ER. Effect of glycemic control on serum insulin-like growth factors in diabetes mellitus. Diabetes 1984; 33: 790–3.11 Amiel SA, Sherwin RS, Hintz RL, Gertner JM, Press CM, Tamborlane WV. Effect of diabetes and its control on insulin-like growth factors in the young subject with type I diabetes. Diabetes 1984; 33: 1175–9.12 Tan K, Baxter RC. Serum insulin-like growth factor I levels in adult diabetic patients: the effect of age. J Clin Endocrinol Metab 1986; 63: 651–5.13 Jehle PM, Jehle DR, Mohan S, Böhm BO. Serum levels of insulin-like growth factor system components and relationship to bone metabolism in Type 1 and Type 2 diabetes mellitus patients. J Endocrinol 1998; 159: 297–306.14 Bereket A, Lang CH, Wilson TA. Alterations in the growth hormone-insulin-like growth factor axis in insulin dependent diabetes mellitus. Horm Metab Res Horm Stoffwechselforschung Horm Métabolisme 1999; 31: 172–81.15 Hedman CA, Frystyk J, Lindström T, et al. Residual beta-cell function more than glycemic control determines abnormal- ities of the insulin-like growth factor system in type 1 diabetes. J Clin Endocrinol Metab 2004; 89: 6305–9.16 Ekman B, Nyström F, Arnqvist HJ. Circulating IGF-I concentrations are low and not correlated to glycaemic control in adults with type 1 diabetes. Eur J Endocrinol Eur Fed Endocr Soc 2000; 143: 505–10.17 Hedman CA, Orre-Pettersson AC, Lindström T, Arnqvist HJ. Treatment with insulin lispro changes the insulin profile but does not affect the plasma concentrations of IGF-I and IGFBP-1 in type 1 diabetes. Clin Endocrinol (Oxf) 2001; 55: 107–12.18 Hanaire-Broutin H, Sallerin-Caute B, Poncet MF, et al. Insulin therapy and GH-IGF-I axis disorders in diabetes: impact of glycaemic control and hepatic insulinization. Diabetes Metab 1996; 22: 245–50.19 Nathan DM, Dunn FL, Bruch J, et al. Postprandial insulin profiles with implantable pump therapy may explain decreased frequency of severe hypoglycemia, compared with intensive subcutaneous regimens, in insulin-dependent diabetes mellitus patients. Am J Med 1996; 100: 412–7.20 Selam JL, Bergman RN, Raccah D, Jean-Didier N, Lozano J, Charles MA. Determination of portal insulin absorption from peritoneum via novel nonisotopic method. Diabetes 1990; 39: 1361–5.21 Hedman CA, Frystyk J, Lindström T, Oskarsson P, Arnqvist HJ. Intraperitoneal insulin delivery to patients with type 1 diabetes results in higher serum IGF-I bioactivity than continuous subcutaneous insulin infusion. Clin Endocrinol (Oxf) 2013. doi:10.1111/cen.12296.22 Hanaire-Broutin H, Sallerin-Caute B, Poncet MF, et al. Effect of intraperitoneal insulin delivery on growth hormone binding protein, insulin-like growth factor (IGF)-I, and IGF-binding protein-3 in IDDM. Diabetologia 1996; 39: 1498–504.
23 Shishko PI, Dreval AV, Abugova IA, Zajarny IU, Goncharov VC. Insulin-like growth factors and binding proteins in patients with recent-onset type 1 (insulin-dependent) diabetes mellitus: influence of diabetes control and intraportal insulin infusion. Diabetes Res Clin Pract 1994; 25: 1–12.24 Van Dijk PR, Logtenberg SJJ, Groenier KH, Kleefstra N, Bilo H, Arnqvist H. Effect of intraperitoneal insulin administration on IGF1 and IGFBP1 in type 1 diabetes. Endocr Connect 2013. doi:10.1530/EC-13-0089.25 Logtenberg SJ, Kleefstra N, Houweling ST, et al. Improved glycemic control with intraperitoneal versus subcutaneous insulin in type 1 diabetes: a randomized controlled trial. Diabetes Care 2009; 32: 1372–7.26 Haveman JW, Logtenberg SJJ, Kleefstra N, Groenier KH, Bilo HJG, Blomme AM. Surgical aspects and complications of continuous intraperitoneal insulin infusion with an implantable pump. Langenbecks Arch Surg Dtsch Ges Für Chir 2010; 395: 65–71.27 Elmlinger MW, Kühnel W, Weber MM, Ranke MB. Reference ranges for two automated chemiluminescent assays for serum insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3). Clin Chem Lab Med CCLM FESCC 2004; 42: 654–64.28 Baxter RC, Bryson JM, Turtle JR. The effect of fasting on liver receptors for prolactin and growth hormone. Metabolism 1981; 30: 1086–90.29 Clemmons DR. Modifying IGF1 activity: an approach to treat endocrine disorders, atherosclerosis and cancer. Nat Rev Drug Discov 2007; 6: 821–33. 30 Janssen JA, Jacobs ML, Derkx FH, Weber RF, van der Lely AJ, Lamberts SW. Free and total insulin-like growth factor I (IGF-I), IGF-binding protein-1 (IGFBP-1), and IGFBP-3 and their relationships to the presence of diabetic retinopathy and glomerular hyperfiltration in insulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1997; 82: 2809–15.31 Frystyk J. The growth hormone hypothesis - 2005 revision. Horm Metab Res Horm Stoffwechselforschung Horm Métabolisme 2005; 37 Suppl 1: 44–8.32 Cingel-Ristić V, Flyvbjerg A, Drop SLS. The physiological and pathophysiological roles of the GH/IGF-axis in the kidney: lessons from experimental rodent models. Growth Horm IGF Res Off J Growth Horm Res Soc Int IGF Res Soc 2004; 14: 418–30.
chapter 10part 3
references
164 165
Van Dijk PR, Logtenberg SJJ, Gans ROB, Bilo HJG, Kleefstra N.
Intraperitoneal insulin infusion: treatment option for type
1 diabetes resulting in beneficial endocrine effects beyond
glycaemia. Clin Endocrinol (Oxf) 2014; 81: 488-97.
chapter 11 This thesis aims to provide an update and extension about the knowledge of continuous
intraperitoneal insulin infusion (CIPII) therapy in type 1 diabetes mellitus (T1DM) by
investigating several important and relative new aspects of this treatment modality. The first
part of this thesis describes the complications of CIPII therapy using an implanted pump.
In the second part, the effects of long-term CIPII therapy on glycaemia, quality of life and
treatment satisfaction, also in comparison with subcutaneous (SC) insulin administration,
were studied. Furthermore, as the effect of insulin administration via the intraperitoneal (IP)
route reaches beyond glycaemia, the influence of CIPII on the growth hormone
(GH) - insulin-like growth factor -1 (IGF1) axis was studied in the third part of this thesis.
In this chapter the most important findings will be highlighted. Furthermore, after
discussing study limitations, the implications of the results and future perspectives on both
the use of CIPII in clinical practice and in research will be discussed.
1. Main findings
1.1 part i - complications of cipii therapy using an implantable pumpAs demonstrated in Chapter 2, CIPII therapy with an implantable pump is associated with
complications at a rate of one complication per four patient years. In the studied group of
56 patients, almost two-thirds of patients experience at least one complication during the
period 2000-2011. Occlusion of the catheter attached to the pump (8.1 per 100 patient years),
dysfunction of the pump (4.2 per 100 patient years) and pain at the pump site (3.9 per 100
patient years) are the most frequently observed complications. Complications resulted in
50 re-operations and 69 hospital re-admissions. Among the patients in which re-operation
was necessary, the period between implantation of the pump and the first re-operation was
4.5 years (95% confidence interval (CI) 4.1, 4.8 years) and stayed stable over the last decade.
A total number of 5 patients stopped CIPII therapy due to infections (n=2), pain (n=1),
inadequate glycaemic control (n=1) or at own choice (n=1). One episode of peritonitis and no
pump-related mortality has been reported.
1.2 part ii - effects of intraperitoneal insulin therapy - glycaemia, quality of life and treatment satisfaction.The baseline situation concerning glycaemic control, prior to initiating CIPII, is
demonstrated in Chapter 3. Overall, patients are poorly controlled, with a median HbA1c of
70 mmol/mol (8.6%), spending only 47% of time in euglycaemia and experiencing a median
of 4 episodes of grade 1 (blood glucose reading <4.0 mmol/l) and 3 episodes of grade 2
parts of this chapter were published as
Discussion and perspectives
chapter 11discussions & perspectives
164 165
Van Dijk PR, Logtenberg SJJ, Gans ROB, Bilo HJG, Kleefstra N.
Intraperitoneal insulin infusion: treatment option for type
1 diabetes resulting in beneficial endocrine effects beyond
glycaemia. Clin Endocrinol (Oxf) 2014; 81: 488-97.
chapter 11 This thesis aims to provide an update and extension about the knowledge of continuous
intraperitoneal insulin infusion (CIPII) therapy in type 1 diabetes mellitus (T1DM) by
investigating several important and relative new aspects of this treatment modality. The first
part of this thesis describes the complications of CIPII therapy using an implanted pump.
In the second part, the effects of long-term CIPII therapy on glycaemia, quality of life and
treatment satisfaction, also in comparison with subcutaneous (SC) insulin administration,
were studied. Furthermore, as the effect of insulin administration via the intraperitoneal (IP)
route reaches beyond glycaemia, the influence of CIPII on the growth hormone
(GH) - insulin-like growth factor -1 (IGF1) axis was studied in the third part of this thesis.
In this chapter the most important findings will be highlighted. Furthermore, after
discussing study limitations, the implications of the results and future perspectives on both
the use of CIPII in clinical practice and in research will be discussed.
1. Main findings
1.1 part i - complications of cipii therapy using an implantable pumpAs demonstrated in Chapter 2, CIPII therapy with an implantable pump is associated with
complications at a rate of one complication per four patient years. In the studied group of
56 patients, almost two-thirds of patients experience at least one complication during the
period 2000-2011. Occlusion of the catheter attached to the pump (8.1 per 100 patient years),
dysfunction of the pump (4.2 per 100 patient years) and pain at the pump site (3.9 per 100
patient years) are the most frequently observed complications. Complications resulted in
50 re-operations and 69 hospital re-admissions. Among the patients in which re-operation
was necessary, the period between implantation of the pump and the first re-operation was
4.5 years (95% confidence interval (CI) 4.1, 4.8 years) and stayed stable over the last decade.
A total number of 5 patients stopped CIPII therapy due to infections (n=2), pain (n=1),
inadequate glycaemic control (n=1) or at own choice (n=1). One episode of peritonitis and no
pump-related mortality has been reported.
1.2 part ii - effects of intraperitoneal insulin therapy - glycaemia, quality of life and treatment satisfaction.The baseline situation concerning glycaemic control, prior to initiating CIPII, is
demonstrated in Chapter 3. Overall, patients are poorly controlled, with a median HbA1c of
70 mmol/mol (8.6%), spending only 47% of time in euglycaemia and experiencing a median
of 4 episodes of grade 1 (blood glucose reading <4.0 mmol/l) and 3 episodes of grade 2
parts of this chapter were published as
Discussion and perspectives
chapter 11discussions & perspectives
166 167
(blood glucose reading <3.5 mmol/l) hypoglycaemic episodes per week.
Additionally, in Chapter 3 it is shown that after 6 years of CIPII therapy, patients have a
more hyperglycaemic profile and the initial HbA1c improvement reached after 6 months
of CIPII disappears. Nevertheless, HbA1c concentrations are still comparable to that of
prior intensive SC insulin therapy under trial circumstances while the number of grade 2
hypoglycaemic episodes was significantly lower during CIPII.
As compared to a population of T1DM patients in poor glycaemic control treated with SC
insulin therapy, the number of hypoglycaemic episodes is substantially lower with CIPII
therapy over a 7-year period despite the fact that HbA1c levels do not show differences
(Chapter 4). Nevertheless, as presented in Chapter 5, T1DM patients using CIPII spend more
time in hyperglycaemia and less in euglycaemia than matched subjects using SC insulin
therapy, but CIPII therapy appeared to be non-inferior to SC insulin therapy with respect to
HbA1c. Additionally, in Chapter 7 it is demonstrated that, despite higher mean blood glucose
concentrations, CIPII therapy seem to have a modest positive effect on glycaemic variability
as compared to SC insulin therapy.
The results of Chapters 3 and 4 demonstrate that prior to initiating CIPII, health status,
general quality of life and treatment satisfaction are poor, also in comparison to a reference
group of SC treated patients in poor glycaemic control: most scores are only two-third of the
optimal scores. After 6-years of follow-up the treatment satisfaction remains higher than
before despite health status and general quality of life remaining poor. The longitudinal
comparisons between T1DM patients treated with CIPII and SC insulin therapy made in
Chapter 4 show that the course of general quality of life does not seem to differ between
both treatment groups. In the 26-week study period, described in Chapter 6, the difference
in health status and general quality of life between CIPII and SC treated patients remained
present while treatment satisfaction was higher among CIPII treated patients. After
adjustment for baseline differences, health status was worse but there were no differences
regarding general and diabetes-related quality of life and treatment satisfaction between
both treatments .
1.3 part iii - effects of intraperitoneal insulin therapy - beyond glycaemiaIn Chapter 8, 9 and 10 the effects of CIPII on the GH-IGF1 axis, as compared to SC insulin
therapy are investigated. In Chapter 8, CIPII during a period of 6 months resulted in lower
levels of IGF binding protein (IGFBP)-1, the production of which is acutely down regulated
by the presence of insulin in the portal vein and suggested to regulate IGF1 bioactivity, as
compared to SC insulin therapy 1. Nevertheless, no significant differences in IGF1 between
CIPII and SC treatment were observed. In Chapter 9 the course of IGF1 concentrations over
a period of 6 years are described in a CIPII treated population. Results demonstrate an
ongoing improvement of IGF1 during the studied period. In addition, although the use of
different IGF1 assays should be taken into account, concentrations of IGF1 were higher than
during previous intensive SC insulin therapy among these patients. Finally, in order to gain a
more comprehensive view, more parameters of the GH-IGF1 axis were investigated in a larger
population of T1DM patients during a 26-week observational study (Chapter 10). During this
period, concentrations of IGF1 among CIPII treated T1DM patients were stable, at a level that
is near-normal as compared to a non-DM reference population and significantly higher as
compared to patients treated with SC insulin therapy. In addition, concentrations of IGFBP1
and GH were lower among CIPII treated patients as compared to patients treated with SC
insulin therapy. Only IGFBP1 concentrations continued to decrease during the 26-week study
period with CIPII as compared to SC insulin therapy.
2. Study limitations
At present, CIPII using an implantable pump is a last-resort treatment option for selected
patients with T1DM who do not tolerate or do not sufficiently respond to SC insulin therapy
and therefore fail to reach adequate and stable glycaemic control. It is also considered
only as a last-resort because of restricted pump availability in recent years, a rather high
complication rate and the associated costs.
Consequently, patients using CIPII are a small, heterogeneous and at the same time very
selective and complex group of patients who are beyond the stage of intensified SC insulin
therapy. Amongst others, this is reflected by the observation that T1DM patients in poor
glycaemic control (defined as HbA1c≥ 58 mmol/mol (7.5%) and/or ≥ 5 incidents of hypo-
glycaemia per week) who initiate CIPII therapy have more often microvascular
complications, experience more hypoglycaemic episodes and have a lower quality of life
as compared to patients with the same HbA1c level that remained on SC insulin therapy
(Chapter 4). These considerations have important consequences for the internal- and
external validity of the studies in this thesis.
chapter 11discussions & perspectives
166 167
(blood glucose reading <3.5 mmol/l) hypoglycaemic episodes per week.
Additionally, in Chapter 3 it is shown that after 6 years of CIPII therapy, patients have a
more hyperglycaemic profile and the initial HbA1c improvement reached after 6 months
of CIPII disappears. Nevertheless, HbA1c concentrations are still comparable to that of
prior intensive SC insulin therapy under trial circumstances while the number of grade 2
hypoglycaemic episodes was significantly lower during CIPII.
As compared to a population of T1DM patients in poor glycaemic control treated with SC
insulin therapy, the number of hypoglycaemic episodes is substantially lower with CIPII
therapy over a 7-year period despite the fact that HbA1c levels do not show differences
(Chapter 4). Nevertheless, as presented in Chapter 5, T1DM patients using CIPII spend more
time in hyperglycaemia and less in euglycaemia than matched subjects using SC insulin
therapy, but CIPII therapy appeared to be non-inferior to SC insulin therapy with respect to
HbA1c. Additionally, in Chapter 7 it is demonstrated that, despite higher mean blood glucose
concentrations, CIPII therapy seem to have a modest positive effect on glycaemic variability
as compared to SC insulin therapy.
The results of Chapters 3 and 4 demonstrate that prior to initiating CIPII, health status,
general quality of life and treatment satisfaction are poor, also in comparison to a reference
group of SC treated patients in poor glycaemic control: most scores are only two-third of the
optimal scores. After 6-years of follow-up the treatment satisfaction remains higher than
before despite health status and general quality of life remaining poor. The longitudinal
comparisons between T1DM patients treated with CIPII and SC insulin therapy made in
Chapter 4 show that the course of general quality of life does not seem to differ between
both treatment groups. In the 26-week study period, described in Chapter 6, the difference
in health status and general quality of life between CIPII and SC treated patients remained
present while treatment satisfaction was higher among CIPII treated patients. After
adjustment for baseline differences, health status was worse but there were no differences
regarding general and diabetes-related quality of life and treatment satisfaction between
both treatments .
1.3 part iii - effects of intraperitoneal insulin therapy - beyond glycaemiaIn Chapter 8, 9 and 10 the effects of CIPII on the GH-IGF1 axis, as compared to SC insulin
therapy are investigated. In Chapter 8, CIPII during a period of 6 months resulted in lower
levels of IGF binding protein (IGFBP)-1, the production of which is acutely down regulated
by the presence of insulin in the portal vein and suggested to regulate IGF1 bioactivity, as
compared to SC insulin therapy 1. Nevertheless, no significant differences in IGF1 between
CIPII and SC treatment were observed. In Chapter 9 the course of IGF1 concentrations over
a period of 6 years are described in a CIPII treated population. Results demonstrate an
ongoing improvement of IGF1 during the studied period. In addition, although the use of
different IGF1 assays should be taken into account, concentrations of IGF1 were higher than
during previous intensive SC insulin therapy among these patients. Finally, in order to gain a
more comprehensive view, more parameters of the GH-IGF1 axis were investigated in a larger
population of T1DM patients during a 26-week observational study (Chapter 10). During this
period, concentrations of IGF1 among CIPII treated T1DM patients were stable, at a level that
is near-normal as compared to a non-DM reference population and significantly higher as
compared to patients treated with SC insulin therapy. In addition, concentrations of IGFBP1
and GH were lower among CIPII treated patients as compared to patients treated with SC
insulin therapy. Only IGFBP1 concentrations continued to decrease during the 26-week study
period with CIPII as compared to SC insulin therapy.
2. Study limitations
At present, CIPII using an implantable pump is a last-resort treatment option for selected
patients with T1DM who do not tolerate or do not sufficiently respond to SC insulin therapy
and therefore fail to reach adequate and stable glycaemic control. It is also considered
only as a last-resort because of restricted pump availability in recent years, a rather high
complication rate and the associated costs.
Consequently, patients using CIPII are a small, heterogeneous and at the same time very
selective and complex group of patients who are beyond the stage of intensified SC insulin
therapy. Amongst others, this is reflected by the observation that T1DM patients in poor
glycaemic control (defined as HbA1c≥ 58 mmol/mol (7.5%) and/or ≥ 5 incidents of hypo-
glycaemia per week) who initiate CIPII therapy have more often microvascular
complications, experience more hypoglycaemic episodes and have a lower quality of life
as compared to patients with the same HbA1c level that remained on SC insulin therapy
(Chapter 4). These considerations have important consequences for the internal- and
external validity of the studies in this thesis.
chapter 11discussions & perspectives
168 169
2.1. internal validity First, the studies in this thesis are limited by the small number of patients. In Chapters 3,
4 and 8 the small number of CIPII treated patients, at most n=21, and patients that were
eligible to function as controls could well have led to relatively wide confidence intervals
and not enough power to detect differences. It could be hypothesized that, in particular, the
quality of life questionnaires, used in Chapters 3 and 4, and IGF1 concentrations, described in
Chapter 8, which both seemed to increase in the CIPII group during the study period could
become significant if there were more (CIPII treated) patients available.
Second, due to both the selected and heterogeneous nature of patients treated with CIPII,
relevant differences in (baseline) characteristics were present as compared to subjects
treated with SC insulin therapy. These differences may well have influenced the results. In
Chapter 4, for example, subjects initiating CIPII experienced more episodes of hypoglycaemia
at baseline, as compared to the reference group of SC treated subjects and thus a more
pronounced effect of CIPII on the number of hypoglycaemic episodes could be expected.
Nevertheless, in Chapter 4, differences in HbA1c and indices of quality of life between the
CIPII and SC treatment groups were adjusted for the number of hypoglycaemic episodes
at baseline and the change in hypoglycaemic episodes between groups was adjusted for
HbA1c. Furthermore, subgroup analysis were performed to make separate comparisons
within groups of patients with a high HbA1c and those with frequent hypoglycaemic
episodes at baseline. Although the decrease of HbA1c within the CIPII treated group was no
longer present in subgroup analysis, the decrease in hypoglycaemic episodes with CIPII was.
In order to overcome aforementioned limitations, i.e. small numbers, selected and
heterogeneous nature of CIPII treated patients, related to the last-resort use of CIPII
therapy and subsequent difficulties in comparing CIPII with SC treated patients, ideally,
a randomized controlled trial with sufficient follow-up would be performed to reveal
the effects of long-term CIPII and SC therapy. However, due to the limited number of
implantable pumps, costs and the consideration that it would be undesirable and unethical
to interrupt the IP insulin administration in patients who are currently treated with CIPII, a
randomized controlled trial is impossible at present.
Given these considerations, a prospective matched-control study was seen as most
suited to compare the long-term effects of CIPII with SC insulin therapy among T1DM in
poor glycaemic control (Chapters 5, 6, 7 and 10). Furthermore, since patients treated with
CIPII, the last-resort treatment option, are considered to be in general far more complex
than patients using SC insulin therapy regarding glycaemic control, a hypothesis of non-
inferiority regarding the primary outcome, HbA1c, was chosen. While fully acknowledging
the drawbacks of a non-inferiority assessment, the rationale for the use of this method is
based on the consideration that finding non-inferiority of CIPII as compared to SC insulin
would be an outcome that would support the use of CIPII in this selected population, given
the complexity of the diabetes of patients selected for CIPII and the last-resort character of
CIPII relative to SC insulin therapy and, importantly, the presence of advantages of CIPII with
respect to e.g. hypoglycaemic episodes, quality of life and hospital admissions as reported
in Chapters 3, 4 and during previous studies 2–7. This is in accordance with consolidated
standards of reporting trials (CONSORT) point of view regarding the rationale and use of
non-inferiority in studies 8. Furthermore, the non-invasive and observational nature of
study and the clear predefined study-protocol, including a non-inferiority margin based on
previous literature and the use of both an intention-to-treat and per-protocol analysis, also
support the use of the current study design 8,9.
The group of currently treated CIPII patients is heterogeneous, consisting of both patients
with a high frequency of hypoglycaemic episodes with (relatively) low HbA1c concentrations
and patients without hypoglycaemic episodes but high HbA1c concentrations 10. In order
to gain more resemblance (i.e. prevent baseline imbalance) between CIPII treated patients
and controls on SC insulin therapy regarding hypoglycaemic episodes, a lower HbA1c
inclusion criterion was chosen for patients using SC insulin therapy. Additionally, patients
were matched on age and gender, had to use their current mode of therapy for more than 4
years in order to reflect a stable situation, measurements were made on 2 points in time and
outcomes were adjusted for baseline imbalance using analysis of covariance.
2.2. external validity It should be stressed that the population under investigation in this thesis is highly selected.
Taken together with the aforementioned limitations regarding the internal validity of the
results, the external validity of the studies, in particular those concerning glycaemic control
and those making comparisons between CIPII and SC insulin therapy, is limited.
chapter 11discussions & perspectives
168 169
2.1. internal validity First, the studies in this thesis are limited by the small number of patients. In Chapters 3,
4 and 8 the small number of CIPII treated patients, at most n=21, and patients that were
eligible to function as controls could well have led to relatively wide confidence intervals
and not enough power to detect differences. It could be hypothesized that, in particular, the
quality of life questionnaires, used in Chapters 3 and 4, and IGF1 concentrations, described in
Chapter 8, which both seemed to increase in the CIPII group during the study period could
become significant if there were more (CIPII treated) patients available.
Second, due to both the selected and heterogeneous nature of patients treated with CIPII,
relevant differences in (baseline) characteristics were present as compared to subjects
treated with SC insulin therapy. These differences may well have influenced the results. In
Chapter 4, for example, subjects initiating CIPII experienced more episodes of hypoglycaemia
at baseline, as compared to the reference group of SC treated subjects and thus a more
pronounced effect of CIPII on the number of hypoglycaemic episodes could be expected.
Nevertheless, in Chapter 4, differences in HbA1c and indices of quality of life between the
CIPII and SC treatment groups were adjusted for the number of hypoglycaemic episodes
at baseline and the change in hypoglycaemic episodes between groups was adjusted for
HbA1c. Furthermore, subgroup analysis were performed to make separate comparisons
within groups of patients with a high HbA1c and those with frequent hypoglycaemic
episodes at baseline. Although the decrease of HbA1c within the CIPII treated group was no
longer present in subgroup analysis, the decrease in hypoglycaemic episodes with CIPII was.
In order to overcome aforementioned limitations, i.e. small numbers, selected and
heterogeneous nature of CIPII treated patients, related to the last-resort use of CIPII
therapy and subsequent difficulties in comparing CIPII with SC treated patients, ideally,
a randomized controlled trial with sufficient follow-up would be performed to reveal
the effects of long-term CIPII and SC therapy. However, due to the limited number of
implantable pumps, costs and the consideration that it would be undesirable and unethical
to interrupt the IP insulin administration in patients who are currently treated with CIPII, a
randomized controlled trial is impossible at present.
Given these considerations, a prospective matched-control study was seen as most
suited to compare the long-term effects of CIPII with SC insulin therapy among T1DM in
poor glycaemic control (Chapters 5, 6, 7 and 10). Furthermore, since patients treated with
CIPII, the last-resort treatment option, are considered to be in general far more complex
than patients using SC insulin therapy regarding glycaemic control, a hypothesis of non-
inferiority regarding the primary outcome, HbA1c, was chosen. While fully acknowledging
the drawbacks of a non-inferiority assessment, the rationale for the use of this method is
based on the consideration that finding non-inferiority of CIPII as compared to SC insulin
would be an outcome that would support the use of CIPII in this selected population, given
the complexity of the diabetes of patients selected for CIPII and the last-resort character of
CIPII relative to SC insulin therapy and, importantly, the presence of advantages of CIPII with
respect to e.g. hypoglycaemic episodes, quality of life and hospital admissions as reported
in Chapters 3, 4 and during previous studies 2–7. This is in accordance with consolidated
standards of reporting trials (CONSORT) point of view regarding the rationale and use of
non-inferiority in studies 8. Furthermore, the non-invasive and observational nature of
study and the clear predefined study-protocol, including a non-inferiority margin based on
previous literature and the use of both an intention-to-treat and per-protocol analysis, also
support the use of the current study design 8,9.
The group of currently treated CIPII patients is heterogeneous, consisting of both patients
with a high frequency of hypoglycaemic episodes with (relatively) low HbA1c concentrations
and patients without hypoglycaemic episodes but high HbA1c concentrations 10. In order
to gain more resemblance (i.e. prevent baseline imbalance) between CIPII treated patients
and controls on SC insulin therapy regarding hypoglycaemic episodes, a lower HbA1c
inclusion criterion was chosen for patients using SC insulin therapy. Additionally, patients
were matched on age and gender, had to use their current mode of therapy for more than 4
years in order to reflect a stable situation, measurements were made on 2 points in time and
outcomes were adjusted for baseline imbalance using analysis of covariance.
2.2. external validity It should be stressed that the population under investigation in this thesis is highly selected.
Taken together with the aforementioned limitations regarding the internal validity of the
results, the external validity of the studies, in particular those concerning glycaemic control
and those making comparisons between CIPII and SC insulin therapy, is limited.
chapter 11discussions & perspectives
170 171
3. Implications of the results
In this paragraph, the implications of this thesis, taking the current situation of CIPII in
clinical practice into account, will be discussed.
3.1 part i - complications of cipii therapy using an implantable pumpAs demonstrated in Chapter 2, most of the complications of CIPII with an implanted pump
are due to the device and not the IP insulin. Subsequently, the question can be raised
whether there is a way to avoid the disadvantages of the current implantable pump and
catheter, while retaining the benefits associated with the IP mode of insulin delivery. One
such way could be insulin delivery by means of an externally placed pump which delivers
insulin IP.
Such a method is currently available: the so-called Diaport system which consists of a metal
body with a catheter that is placed transcutaneously in the peritoneal space. A catheter
is attached to the metal body inserted in the abdominal wall and delivers insulin from an
externally placed pump into the Diaport system and eventually the IP space. A randomized
cross-over study among 60 T1DM patients by Liebl et al. demonstrated effectiveness of
this system with respect to reducing the number of severe hypoglycaemic episodes as
compared to patients using continuous subcutaneous insulin infusion (CSII). Nevertheless,
complications of this method, in particular the high number of infections of the port (47
per 100 patient years) related to the use of a catheter, and the limited long-term results
are drawbacks hampering a more widespread use of this system. Thus, it seems that an
implanted pump is, at the moment, the best available option for delivering IP insulin.
Another way to keep the advantages of IP insulin delivery without the disadvantages of the
current implanted implanted device would be to update the currently used insulin pump
or develop a new model. Bearing the most frequent complications mentioned in Chapter
2 in mind several adjustments could be suggested. In paragraph 4 of this chapter these
suggestions will be discussed in more detail.
As CIPII treatment is continued with the currently used implantable pump, measures should
be taken to reduce the number of complications. In coincidence with the introduction of a
new insulin formulation for IP infusion in the year 2011 (400 IU/ml; human insulin of E. Coli
origin, trade name: Insuman Implantable®, Sanofi-Aventis), a shorter interval to perform
a refill of insulin (previously: at least every 3 months, now: at least every 6 weeks) and a
rinse procedures (previously: every 9 months, now: every 6 months) had to be acquainted
according to European Medicines Agency’s regulation 11. Additionally, a lower threshold for
insulin underdelivery necessitating a rinse procedure (the ratio between programmed and
actually infused insulin volume upon programmed insulin, previously: 20%, now: 12%) was
set. In theory, this should results in a decrease in the number of catheter obstructions due to
insulin aggregate 4. On the other hand, these measures will translate into higher costs, more
procedure related risks and may decrease treatment satisfaction. Altogether, it should be
concluded that ongoing monitoring of CIPII related complications is of utmost importance.
3.2 part ii - effects of intraperitoneal insulin therapy - glycaemia, quality of life and treatment satisfactionThe most pronounced effect of long-term CIPII therapy is the reduction of hypoglycaemic
episodes (Chapters 3 and 4). This finding can in part be explained by the pharmacokinetic
and pharmacodynamic properties of insulin administration in the IP space. In Chapter 7
of this thesis it is demonstrated that there is indeed less blood glucose variability during
continuous glucose measurements among CIPII treated patients as compared to subjects
treated with SC insulin. The high treatment satisfaction on the subscale “perceived
hypoglycaemia”, found in Chapter 6 among CIPII treated patients emphasizes the relevance
of reduced blood glucose variability. In addition, a reduction in hypoglycaemic episodes may
reduce the risk of a range hypoglycaemia associated clinical adverse events and mortality 12. Nevertheless, as the clinical importance of glycaemic variability with respect to diabetes
related complications (including quality of life) is unsure, the relevance of this specific
finding with respect to clinical outcomes is unknown 13–16. Taken together, these findings
emphasize that high blood glucose variability is positively influenced by CIPII therapy and
should be one of the more prominent selection criterion for CIPII therapy.
In T1DM patients using CIPII, health status is poor and worse as compared to patients using
SC insulin. The discrepancy between the poor general quality of life and health status and
the relatively normal and stable measures of diabetes specific quality of life among CIPIII
treated patients, found in Chapter 6, suggests that the poor health status among these
patients is not due to their diabetes per se but that probably other factors have an important
influence. In the present thesis, possible factors such as poor social functioning, limited peer
support or more (perceived) physical limitations and pain have been suggested.
Additionally, the presence of physical comorbidity and psychiatric symptoms, in particular
depression, could be hypothesized as a determinant of the poor health status 17.
chapter 11discussions & perspectives
170 171
3. Implications of the results
In this paragraph, the implications of this thesis, taking the current situation of CIPII in
clinical practice into account, will be discussed.
3.1 part i - complications of cipii therapy using an implantable pumpAs demonstrated in Chapter 2, most of the complications of CIPII with an implanted pump
are due to the device and not the IP insulin. Subsequently, the question can be raised
whether there is a way to avoid the disadvantages of the current implantable pump and
catheter, while retaining the benefits associated with the IP mode of insulin delivery. One
such way could be insulin delivery by means of an externally placed pump which delivers
insulin IP.
Such a method is currently available: the so-called Diaport system which consists of a metal
body with a catheter that is placed transcutaneously in the peritoneal space. A catheter
is attached to the metal body inserted in the abdominal wall and delivers insulin from an
externally placed pump into the Diaport system and eventually the IP space. A randomized
cross-over study among 60 T1DM patients by Liebl et al. demonstrated effectiveness of
this system with respect to reducing the number of severe hypoglycaemic episodes as
compared to patients using continuous subcutaneous insulin infusion (CSII). Nevertheless,
complications of this method, in particular the high number of infections of the port (47
per 100 patient years) related to the use of a catheter, and the limited long-term results
are drawbacks hampering a more widespread use of this system. Thus, it seems that an
implanted pump is, at the moment, the best available option for delivering IP insulin.
Another way to keep the advantages of IP insulin delivery without the disadvantages of the
current implanted implanted device would be to update the currently used insulin pump
or develop a new model. Bearing the most frequent complications mentioned in Chapter
2 in mind several adjustments could be suggested. In paragraph 4 of this chapter these
suggestions will be discussed in more detail.
As CIPII treatment is continued with the currently used implantable pump, measures should
be taken to reduce the number of complications. In coincidence with the introduction of a
new insulin formulation for IP infusion in the year 2011 (400 IU/ml; human insulin of E. Coli
origin, trade name: Insuman Implantable®, Sanofi-Aventis), a shorter interval to perform
a refill of insulin (previously: at least every 3 months, now: at least every 6 weeks) and a
rinse procedures (previously: every 9 months, now: every 6 months) had to be acquainted
according to European Medicines Agency’s regulation 11. Additionally, a lower threshold for
insulin underdelivery necessitating a rinse procedure (the ratio between programmed and
actually infused insulin volume upon programmed insulin, previously: 20%, now: 12%) was
set. In theory, this should results in a decrease in the number of catheter obstructions due to
insulin aggregate 4. On the other hand, these measures will translate into higher costs, more
procedure related risks and may decrease treatment satisfaction. Altogether, it should be
concluded that ongoing monitoring of CIPII related complications is of utmost importance.
3.2 part ii - effects of intraperitoneal insulin therapy - glycaemia, quality of life and treatment satisfactionThe most pronounced effect of long-term CIPII therapy is the reduction of hypoglycaemic
episodes (Chapters 3 and 4). This finding can in part be explained by the pharmacokinetic
and pharmacodynamic properties of insulin administration in the IP space. In Chapter 7
of this thesis it is demonstrated that there is indeed less blood glucose variability during
continuous glucose measurements among CIPII treated patients as compared to subjects
treated with SC insulin. The high treatment satisfaction on the subscale “perceived
hypoglycaemia”, found in Chapter 6 among CIPII treated patients emphasizes the relevance
of reduced blood glucose variability. In addition, a reduction in hypoglycaemic episodes may
reduce the risk of a range hypoglycaemia associated clinical adverse events and mortality 12. Nevertheless, as the clinical importance of glycaemic variability with respect to diabetes
related complications (including quality of life) is unsure, the relevance of this specific
finding with respect to clinical outcomes is unknown 13–16. Taken together, these findings
emphasize that high blood glucose variability is positively influenced by CIPII therapy and
should be one of the more prominent selection criterion for CIPII therapy.
In T1DM patients using CIPII, health status is poor and worse as compared to patients using
SC insulin. The discrepancy between the poor general quality of life and health status and
the relatively normal and stable measures of diabetes specific quality of life among CIPIII
treated patients, found in Chapter 6, suggests that the poor health status among these
patients is not due to their diabetes per se but that probably other factors have an important
influence. In the present thesis, possible factors such as poor social functioning, limited peer
support or more (perceived) physical limitations and pain have been suggested.
Additionally, the presence of physical comorbidity and psychiatric symptoms, in particular
depression, could be hypothesized as a determinant of the poor health status 17.
chapter 11discussions & perspectives
172 173
Nevertheless, although these suggested factors may not be directly related to diabetes at
the present, an indirect relation with diabetes such as problems with social functioning at
present due to unemployment after frequent hypoglycaemic episodes or previous frequent
hospitalization during childhood, may still be present. As quality of life is an important
outcome in the management of T1DM and influences glycaemic control, the need for
ongoing psychological support for a substantial portion of CIPII treated patients is evident 18,19. Additionally, a psychological assessment prior to starting CIPII therapy could not only be
advocated to screen for amongst others depression and fear for hypoglycaemia, but also to
identify psychosocial or psychological barriers to reach adequate glycaemic control.
3.3 part iii - effects of intraperitoneal insulin therapy - beyond glycaemiaAmong T1DM patients it has been suggested previously, that low concentrations of insulin
in the portal vein catchment area would lead to insufficient hepatic insulinization and
subsequent low IGF1 and IGFBP3 concentrations and high concentrations of IGFBP1 and GH 20–25. Since CIPII results in higher levels of insulin in the portal vein catchment area, it was
hypothesized in the present thesis that the GH-IGF1 axis is affected by the route of insulin
administration and that CIPII has a more pronounced effect than SC insulin therapy 26–30.
The findings of Chapters 8, 9 and 10 indicate that CIPII is more beneficial than SC insulin
in correcting the altered GH-IGF1 axis in T1DM. IGF1 concentrations even increased to a
near-normal level as compared to non-DM subjects. The higher IGF1 concentrations in
combination with lower GH concentrations among CIPII treated patients as compared
to SC treated patients, found in Chapter 10, provide clinical support for hypothesis that
increased hepatic insulinization due to IP insulin administration results in increased hepatic
GH sensitivity and, subsequently, higher IGF1 levels. Accordingly, as GH secretion is under
negative feedback by concentrations of IGF1, the lower GH concentrations among CIPII
treated patients could well be the results of a near-normalization of IGF1 concentrations.
Moreover, as IGFBP1 is regulated directly by insulin levels in the portal vein, the finding of
lower IGFBP1 levels with CIPII are compatible with an enhanced hepatic effect of insulin and,
furthermore, IP insulin may cause higher IGF1-bioactivity in addition to the change in total
IGF1 enhancing the effect of IGF1 and the feed-back on GH-secretion 31–33.
Since GH has insulin antagonizing and IGF1 insulin sensitizing effects, some restoration
of the GH-IGF1 axis could beneficially influence the whole body insulin resistance and the
subsequent development of T1DM related complications 34,35. Additionally, altered IGF1
concentrations have been suggested to be involved in carcinogenesis in T1DM patients 36.
It should be noticed however, that the clinical relevance of these findings is not clear at the
moment. Nevertheless, the observations made in the present thesis may provide insight in
the effects of insulin and it’s route of administration on the GH-IGF1 axis.
3.4 current use of cipii At present, the use of CIPII is largely restricted to Europe, especially Belgium, France, Sweden
and the Netherlands. In the Netherlands there are two centers (Isala, Zwolle and Medical
Centre Haaglanden, The Hague) that provide this treatment option: only 70 T1DM patients,
on a total approximately 85.000 T1DM patients, are currently treated with CIPII. In 2007, the
Dutch Internist Associated acknowledged the following indications for starting and using
CIPII 37:
• Subcutaneousinsulinresistance
• ‘Brittle’diabetes
• Hypoglycaemiaunawareness
• Delayedinsulinabsorption
• Allergies
• Lipohypertrophyorlipoatrophy
• Veryleansubjects
• Needlephobia
• Severeskinscarringorchronicdermatologicproblems.
Alternative current last-resort treatments with overlapping patient criteria include
pancreas- and beta-cell transplantation. Although both treatments are emerging and yield
the promise of curing diabetes, the risk-benefit ratio is unfavorable at present for most
patients. Also, there is limited availability. The need for a surgical procedure in case of a
pancreas transplantation with possible severe peri- and post transplantation complications,
the need for donor tissue, possible rejection and the use of prolonged systemic
immunosuppression are factors which have to be taken into account when weighing in the
possible effects like insulin independence and diminishing the chance of occurrence or
deterioration of diabetes related complications 38–40. It should also be mentioned that both
procedures are still in development, costs are high (approximately an average of 77,745
euro for the procedure and the subsequent year) and the amount of evidence and clinical
experience is scarce but growing 40,41. Although direct comparisons are lacking, it can well be
advocated that CIPII using an implantable pump is more viable as a last-resort alternative
for T1DM patients than pancreas- and beta-cell transplantation.
chapter 11discussions & perspectives
172 173
Nevertheless, although these suggested factors may not be directly related to diabetes at
the present, an indirect relation with diabetes such as problems with social functioning at
present due to unemployment after frequent hypoglycaemic episodes or previous frequent
hospitalization during childhood, may still be present. As quality of life is an important
outcome in the management of T1DM and influences glycaemic control, the need for
ongoing psychological support for a substantial portion of CIPII treated patients is evident 18,19. Additionally, a psychological assessment prior to starting CIPII therapy could not only be
advocated to screen for amongst others depression and fear for hypoglycaemia, but also to
identify psychosocial or psychological barriers to reach adequate glycaemic control.
3.3 part iii - effects of intraperitoneal insulin therapy - beyond glycaemiaAmong T1DM patients it has been suggested previously, that low concentrations of insulin
in the portal vein catchment area would lead to insufficient hepatic insulinization and
subsequent low IGF1 and IGFBP3 concentrations and high concentrations of IGFBP1 and GH 20–25. Since CIPII results in higher levels of insulin in the portal vein catchment area, it was
hypothesized in the present thesis that the GH-IGF1 axis is affected by the route of insulin
administration and that CIPII has a more pronounced effect than SC insulin therapy 26–30.
The findings of Chapters 8, 9 and 10 indicate that CIPII is more beneficial than SC insulin
in correcting the altered GH-IGF1 axis in T1DM. IGF1 concentrations even increased to a
near-normal level as compared to non-DM subjects. The higher IGF1 concentrations in
combination with lower GH concentrations among CIPII treated patients as compared
to SC treated patients, found in Chapter 10, provide clinical support for hypothesis that
increased hepatic insulinization due to IP insulin administration results in increased hepatic
GH sensitivity and, subsequently, higher IGF1 levels. Accordingly, as GH secretion is under
negative feedback by concentrations of IGF1, the lower GH concentrations among CIPII
treated patients could well be the results of a near-normalization of IGF1 concentrations.
Moreover, as IGFBP1 is regulated directly by insulin levels in the portal vein, the finding of
lower IGFBP1 levels with CIPII are compatible with an enhanced hepatic effect of insulin and,
furthermore, IP insulin may cause higher IGF1-bioactivity in addition to the change in total
IGF1 enhancing the effect of IGF1 and the feed-back on GH-secretion 31–33.
Since GH has insulin antagonizing and IGF1 insulin sensitizing effects, some restoration
of the GH-IGF1 axis could beneficially influence the whole body insulin resistance and the
subsequent development of T1DM related complications 34,35. Additionally, altered IGF1
concentrations have been suggested to be involved in carcinogenesis in T1DM patients 36.
It should be noticed however, that the clinical relevance of these findings is not clear at the
moment. Nevertheless, the observations made in the present thesis may provide insight in
the effects of insulin and it’s route of administration on the GH-IGF1 axis.
3.4 current use of cipii At present, the use of CIPII is largely restricted to Europe, especially Belgium, France, Sweden
and the Netherlands. In the Netherlands there are two centers (Isala, Zwolle and Medical
Centre Haaglanden, The Hague) that provide this treatment option: only 70 T1DM patients,
on a total approximately 85.000 T1DM patients, are currently treated with CIPII. In 2007, the
Dutch Internist Associated acknowledged the following indications for starting and using
CIPII 37:
• Subcutaneousinsulinresistance
• ‘Brittle’diabetes
• Hypoglycaemiaunawareness
• Delayedinsulinabsorption
• Allergies
• Lipohypertrophyorlipoatrophy
• Veryleansubjects
• Needlephobia
• Severeskinscarringorchronicdermatologicproblems.
Alternative current last-resort treatments with overlapping patient criteria include
pancreas- and beta-cell transplantation. Although both treatments are emerging and yield
the promise of curing diabetes, the risk-benefit ratio is unfavorable at present for most
patients. Also, there is limited availability. The need for a surgical procedure in case of a
pancreas transplantation with possible severe peri- and post transplantation complications,
the need for donor tissue, possible rejection and the use of prolonged systemic
immunosuppression are factors which have to be taken into account when weighing in the
possible effects like insulin independence and diminishing the chance of occurrence or
deterioration of diabetes related complications 38–40. It should also be mentioned that both
procedures are still in development, costs are high (approximately an average of 77,745
euro for the procedure and the subsequent year) and the amount of evidence and clinical
experience is scarce but growing 40,41. Although direct comparisons are lacking, it can well be
advocated that CIPII using an implantable pump is more viable as a last-resort alternative
for T1DM patients than pancreas- and beta-cell transplantation.
chapter 11discussions & perspectives
174 175
The (+) and (-) indicate positive and negative associations, respectively. The (<arriba>) and (<abajo>) indicate increases and decreases of concentrations as found in previous studies 9–16. Abbreviations: GH, growth hormone; IGF1, insulin-like growth factor-1, IGFBP1/-3, insulin-like growth factor binding protein -1/-3.
It should be concluded that, based on the complications and effects on glycaemic control
as described in the present thesis, lack of other literature, current costs and available
alternatives, there are insufficient arguments to extent the indications or the use of CIPII to
a wider range of patients. Nevertheless, future developments, in particular those regarding
incorporation of IP insulin administration in a closed-loop system, and more research
towards the effects of IP insulin beyond glycaemic control may change this point of view (see
paragraph 4.4).
4. Future research, developments and use of CIPII
CIPII provides unique in vivo research opportunities to study the effects of IP insulin
administration, relative to SC insulin therapy, on glycaemia and beyond. In this paragraph
several lines of possible research are discussed. Finally, a point of view on possible
developments on the implanted pump and future use of CIPII therapy is given.
4.1 research beyond glycaemiaAs known, insulin does not only have effects on glucose control but influences a wide range
of endocrine and metabolic processes. Because IP insulin is to a large extent absorbed in the
portal vein catchment area, the insulin concentration in the portal vein and the peripheral
plasma insulin concentration are much more physiological compared to SC administered
insulin 26–29. In this thesis the effects of CIPII on the GH-IGF1 axis were investigated.
Additionally, IP insulin could also alter, and even improve, several other metabolic
parameters (see Figure 1).
Higher insulin concentrations in the portal vein inhibit the production of the hepatic
glycoprotein sex hormone-binding globulin (SHBG), irrespective of glycaemic control 42.
In the presence of higher SHBG- and normal testosterone concentrations, lower
concentrations of free testosterone are present among T1DM men using SC insulin therapy 43. Lassmann-Vague et al. tested the hypothesis that IP insulin lowers SHBG concentrations
among T1DM patients who switched from SC insulin therapy to CIPII. Indeed, during IP
insulin infusion there was a significant decrease of SHBG concentrations 44. Therefore,
a switch to treatment with IP insulin could offer an advantage. Further testing of this
hypothesis needs to be performed and the clinical significance, e.g. on the reproductive
function, of this finding remains to be investigated.
Insulin influences the lipoprotein metabolism by activation of lipoprotein lipase (LPL)
and hepatic lipase and by inhibition of the hepatic very low density lipoprotein (VLDL)
production 45. Among individual with T1DM and poor glycaemic control there is an increased
plasma concentration of triglycerides (TG) as a result of an increased VLDL production and
an increased circulation of free fatty acids secondary to insulin deficiency. Furthermore,
low density lipoprotein (LDL) may be increased, with, formation of small, dense oxydated
particles 45. In well-regulated T1DM patients both TG and LDL levels are (virtually) normal
due to VLDL down regulation secondary to insulin use 46. The lower peripheral plasma
insulin concentrations due to IP insulin are associated with a normalization of the activity
of the enzymes cholesteryl-ester-transferase and LPL in comparison with SC insulin therapy 30,47,48. Furthermore, there is an increase in hepatic lipase activity 49. The hypothesis that IP
insulin administration leads to further beneficial modification of lipids and lipoproteins
has been tested in a few studies. In one report, there was an increase in TG, whereas TG
were unchanged in 3 other studies 47,49–51. Total cholesterol and apolipoprotein B were also
unchanged, while high density lipoprotein (HDL) cholesterol decreased or remained the
same 47,49–51. It should be mentioned, however, that in all these studies the number of patients
was small (n<14), the degree of glycaemic control was variable and the duration of IP
chapter 11discussions & perspectives
Alterations in GH-IGF1 axis in T1DMfigure 1
174 175
The (+) and (-) indicate positive and negative associations, respectively. The (<arriba>) and (<abajo>) indicate increases and decreases of concentrations as found in previous studies 9–16. Abbreviations: GH, growth hormone; IGF1, insulin-like growth factor-1, IGFBP1/-3, insulin-like growth factor binding protein -1/-3.
It should be concluded that, based on the complications and effects on glycaemic control
as described in the present thesis, lack of other literature, current costs and available
alternatives, there are insufficient arguments to extent the indications or the use of CIPII to
a wider range of patients. Nevertheless, future developments, in particular those regarding
incorporation of IP insulin administration in a closed-loop system, and more research
towards the effects of IP insulin beyond glycaemic control may change this point of view (see
paragraph 4.4).
4. Future research, developments and use of CIPII
CIPII provides unique in vivo research opportunities to study the effects of IP insulin
administration, relative to SC insulin therapy, on glycaemia and beyond. In this paragraph
several lines of possible research are discussed. Finally, a point of view on possible
developments on the implanted pump and future use of CIPII therapy is given.
4.1 research beyond glycaemiaAs known, insulin does not only have effects on glucose control but influences a wide range
of endocrine and metabolic processes. Because IP insulin is to a large extent absorbed in the
portal vein catchment area, the insulin concentration in the portal vein and the peripheral
plasma insulin concentration are much more physiological compared to SC administered
insulin 26–29. In this thesis the effects of CIPII on the GH-IGF1 axis were investigated.
Additionally, IP insulin could also alter, and even improve, several other metabolic
parameters (see Figure 1).
Higher insulin concentrations in the portal vein inhibit the production of the hepatic
glycoprotein sex hormone-binding globulin (SHBG), irrespective of glycaemic control 42.
In the presence of higher SHBG- and normal testosterone concentrations, lower
concentrations of free testosterone are present among T1DM men using SC insulin therapy 43. Lassmann-Vague et al. tested the hypothesis that IP insulin lowers SHBG concentrations
among T1DM patients who switched from SC insulin therapy to CIPII. Indeed, during IP
insulin infusion there was a significant decrease of SHBG concentrations 44. Therefore,
a switch to treatment with IP insulin could offer an advantage. Further testing of this
hypothesis needs to be performed and the clinical significance, e.g. on the reproductive
function, of this finding remains to be investigated.
Insulin influences the lipoprotein metabolism by activation of lipoprotein lipase (LPL)
and hepatic lipase and by inhibition of the hepatic very low density lipoprotein (VLDL)
production 45. Among individual with T1DM and poor glycaemic control there is an increased
plasma concentration of triglycerides (TG) as a result of an increased VLDL production and
an increased circulation of free fatty acids secondary to insulin deficiency. Furthermore,
low density lipoprotein (LDL) may be increased, with, formation of small, dense oxydated
particles 45. In well-regulated T1DM patients both TG and LDL levels are (virtually) normal
due to VLDL down regulation secondary to insulin use 46. The lower peripheral plasma
insulin concentrations due to IP insulin are associated with a normalization of the activity
of the enzymes cholesteryl-ester-transferase and LPL in comparison with SC insulin therapy 30,47,48. Furthermore, there is an increase in hepatic lipase activity 49. The hypothesis that IP
insulin administration leads to further beneficial modification of lipids and lipoproteins
has been tested in a few studies. In one report, there was an increase in TG, whereas TG
were unchanged in 3 other studies 47,49–51. Total cholesterol and apolipoprotein B were also
unchanged, while high density lipoprotein (HDL) cholesterol decreased or remained the
same 47,49–51. It should be mentioned, however, that in all these studies the number of patients
was small (n<14), the degree of glycaemic control was variable and the duration of IP
chapter 11discussions & perspectives
Alterations in GH-IGF1 axis in T1DMfigure 1
176 177
treatment was limited (ranging from a few days to 9 months). Although it has been reported
that high concentrations of IP administered insulin can reverse focal hepatic steatosis in
T1DM patients, the clinical relevance of the effects of IP insulin on lipid metabolism is as yet
unclear 52.
Adiponectin, an adipocyte-released peptide hormone, is regarded as a marker for insulin
sensitivity with anti-inflammatory and -atherosclerotic properties. In T1DM, adiponectin
concentrations are increased and these raised concentrations are positively associated with
insulin resistance 53. In 2 recent studies, increased adiponectin concentrations were found
to be related to the presence of microvascular complications and an increased all cause
and cardiovascular mortality in patients with T1DM 54,55. Adiponectin concentrations are
positively associated with LPL activity and inversely associated with plasma hepatic lipase
activity 56,57. Thus, one could hypothesize that CIPII lowers adiponectin concentrations as
compared to SC insulin administration. However, the only study testing this hypothesis
found no differences among 7 T1DM patients with almost 2 years of IP insulin therapy in
adiponectin concentrations as compared to the situation during SC insulin use 50.
Considering metabolic consequences, it was shown by Freyse et al. that IP insulin
administration in an insulin-dependent dog model increased energy expenditure as
compared with systemic insulin administration 58. In addition, synthesis of hepatic
production of proteins such as albumin, fibrinogen as well as tissue proteins resembled
more closely the non-diabetic situation during pre-portal insulin administration 58.
In a small study by Colette et al. differences in vitamin D metabolism were present between
patients using SC insulin and CIPII therapy 59. Although there were no differences in
1,25-dihydroxyvitamin D (calcitriol) concentrations, CIPII treated T1DM patients had higher
concentrations of plasma 25-hydroxyvitamin D (calcidiol), also after correction for glycaemic
control, and 24,25-dihydroxyvitamin D (inactive metabolite) as compared to SC insulin users.
These findings may indicate that higher concentrations of insulin as present with use of IP
insulin stimulate the activity of the hepatic enzyme 25-hydroxylase, which in turn promotes
the turnover of cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2) to calcidiol.
4.2 research regarding glycaemic controlIt should be acknowledged that the amount and level of evidence strongly supporting the
use of CIPII therapy as a method to substantially improve metabolic control is rather low.
Further evidence concerning the effectiveness of CIPII in comparison to other emerging
(last-resort) treatment options is necessary in order to get a better understanding regarding
indications and most eligible patients. In particular a trial comparing the effects of CIPII with
sensor augmented CSII insulin therapy, currently the most frequently used kind of SC insulin
therapy prior to CIPII therapy, could give further insight in the kind of and magnitude of
differences between both treatment modes.
If the outcomes of such as study would point out to positive effects of CIPII, further study
should be performed towards the actual cost-effectiveness and the number of patients who
would be eligible for CIPII therapy, given the specific category of patients that would profit
most from CIPII therapy, as these two points are largely unknown at the present or, at best,
estimated using expert based opinion. Of course, patient preferences should be taken into
account.
The effect of CIPII on hypoglycaemia incidence should also be focus of additional
investigations. Previous research suggested that IP insulin improves the previously impaired
glucagon secretion, also during exercise, and enhances hepatic glucose production in
response to hypoglycaemia 29,60–63. Investigating details regarding the possible underlying
mechanism hypothesized to be due to restoration of the glucagon release or hepatic glucose
utilization during hypoglycaemia, should be encouraged 60. The finding of less glycaemic
variability in Chapter 7, suggest perpetuating of this mechanism during long-term therapy,
and may be of importance in the current patient population with frequent hypoglycaemia
(unawareness). Additionally, this finding may be relevant for developing a closed-loop
system (see paragraph 4.4).
4.3 further development of the implantable insulin pumpAs demonstrated in Chapter 2, most complications of CIPII with an implanted pump are
due to the device and not the IP insulin. Another way to keep the advantages of IP insulin
delivery without the disadvantages of an implanted device would be to update the present
insulin pump or develop a new model. Bearing the most frequent complications in mind
several adjustments could be suggested. First, the electronics should be updated to
modern’s day technologic standards. Such a development could contribute to a decrease in
the number of pump dysfunctions, add to minimization of the size of the implanted pump
and may offer means for communication with other devices, i.e. smartphones. This latter
could also make the present patient-pump communicator redundant and would aid to the
incorporation of the implanted insulin pump in a closed-loop system. Second, the size or
shape of the present discus-shaped pump with a diameter of approximately 8 cm diameter
chapter 11discussions & perspectives
176 177
treatment was limited (ranging from a few days to 9 months). Although it has been reported
that high concentrations of IP administered insulin can reverse focal hepatic steatosis in
T1DM patients, the clinical relevance of the effects of IP insulin on lipid metabolism is as yet
unclear 52.
Adiponectin, an adipocyte-released peptide hormone, is regarded as a marker for insulin
sensitivity with anti-inflammatory and -atherosclerotic properties. In T1DM, adiponectin
concentrations are increased and these raised concentrations are positively associated with
insulin resistance 53. In 2 recent studies, increased adiponectin concentrations were found
to be related to the presence of microvascular complications and an increased all cause
and cardiovascular mortality in patients with T1DM 54,55. Adiponectin concentrations are
positively associated with LPL activity and inversely associated with plasma hepatic lipase
activity 56,57. Thus, one could hypothesize that CIPII lowers adiponectin concentrations as
compared to SC insulin administration. However, the only study testing this hypothesis
found no differences among 7 T1DM patients with almost 2 years of IP insulin therapy in
adiponectin concentrations as compared to the situation during SC insulin use 50.
Considering metabolic consequences, it was shown by Freyse et al. that IP insulin
administration in an insulin-dependent dog model increased energy expenditure as
compared with systemic insulin administration 58. In addition, synthesis of hepatic
production of proteins such as albumin, fibrinogen as well as tissue proteins resembled
more closely the non-diabetic situation during pre-portal insulin administration 58.
In a small study by Colette et al. differences in vitamin D metabolism were present between
patients using SC insulin and CIPII therapy 59. Although there were no differences in
1,25-dihydroxyvitamin D (calcitriol) concentrations, CIPII treated T1DM patients had higher
concentrations of plasma 25-hydroxyvitamin D (calcidiol), also after correction for glycaemic
control, and 24,25-dihydroxyvitamin D (inactive metabolite) as compared to SC insulin users.
These findings may indicate that higher concentrations of insulin as present with use of IP
insulin stimulate the activity of the hepatic enzyme 25-hydroxylase, which in turn promotes
the turnover of cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2) to calcidiol.
4.2 research regarding glycaemic controlIt should be acknowledged that the amount and level of evidence strongly supporting the
use of CIPII therapy as a method to substantially improve metabolic control is rather low.
Further evidence concerning the effectiveness of CIPII in comparison to other emerging
(last-resort) treatment options is necessary in order to get a better understanding regarding
indications and most eligible patients. In particular a trial comparing the effects of CIPII with
sensor augmented CSII insulin therapy, currently the most frequently used kind of SC insulin
therapy prior to CIPII therapy, could give further insight in the kind of and magnitude of
differences between both treatment modes.
If the outcomes of such as study would point out to positive effects of CIPII, further study
should be performed towards the actual cost-effectiveness and the number of patients who
would be eligible for CIPII therapy, given the specific category of patients that would profit
most from CIPII therapy, as these two points are largely unknown at the present or, at best,
estimated using expert based opinion. Of course, patient preferences should be taken into
account.
The effect of CIPII on hypoglycaemia incidence should also be focus of additional
investigations. Previous research suggested that IP insulin improves the previously impaired
glucagon secretion, also during exercise, and enhances hepatic glucose production in
response to hypoglycaemia 29,60–63. Investigating details regarding the possible underlying
mechanism hypothesized to be due to restoration of the glucagon release or hepatic glucose
utilization during hypoglycaemia, should be encouraged 60. The finding of less glycaemic
variability in Chapter 7, suggest perpetuating of this mechanism during long-term therapy,
and may be of importance in the current patient population with frequent hypoglycaemia
(unawareness). Additionally, this finding may be relevant for developing a closed-loop
system (see paragraph 4.4).
4.3 further development of the implantable insulin pumpAs demonstrated in Chapter 2, most complications of CIPII with an implanted pump are
due to the device and not the IP insulin. Another way to keep the advantages of IP insulin
delivery without the disadvantages of an implanted device would be to update the present
insulin pump or develop a new model. Bearing the most frequent complications in mind
several adjustments could be suggested. First, the electronics should be updated to
modern’s day technologic standards. Such a development could contribute to a decrease in
the number of pump dysfunctions, add to minimization of the size of the implanted pump
and may offer means for communication with other devices, i.e. smartphones. This latter
could also make the present patient-pump communicator redundant and would aid to the
incorporation of the implanted insulin pump in a closed-loop system. Second, the size or
shape of the present discus-shaped pump with a diameter of approximately 8 cm diameter
chapter 11discussions & perspectives
178 179
and a thickness of 1.8 cm should be reduced. A smaller, more convex-shaped pump could
diminish the complaints of pain and cutaneous erosions. In addition, alteration in the size
and shape of the pump could offer an improved esthetics.
4.4 future use of cipii therapyFuture use of CIPII will partly depend on further development regarding the pump. Whether
proposed research and developments will take place depends on several factors.
First, as there is only one manufacturer of the implantable pump at present, improvements
by renewal and updates is not stimulated very much. Developing a new (implantable)
device for IP insulin administration is challenging, in particular for interested new parties,
due to the considerable amount of knowledge, time and, very important, resources needed.
These matters are closely related to the amount of patients which would be eligible for such
a (re)new(ed) model for CIPII. At present, CIPII with in implantable pump is a treatment
option for a niche of T1DM patients. Second, it should be emphasized that the current
evidence supporting a more extensive use of for CIPII treatment is virtually absent. Third,
as alternative treatment options for T1DM, i.e. islet transplantation and the closed-loop
system, are developing in fast pace, the urgency for further development of the current
implantable pump system could be questioned.
Further development of IP insulin infusion will also be dependent of the possibility of
incorporating IP insulin administration in a closed-loop system. Over the last decade
considerable advances have been made in the development of closed-loop systems. Aiming
towards optimal blood glucose regulation in various situations without patient involvement,
the present research on closed-loop systems combines continuous glucose sensing, mono-
(insulin) or bihormonal (insulin and glucagon) SC delivery devices and control algorithms
with automated data transfer, real-time control action and automated command of the
insulin delivery device 64. After showing safety and efficacy of closed-loop systems in
controlled (overnight) clinical settings, the field of research has progressed to study the
ability for the closed-loop systems to function in ambulant, non-clinical environments 65,66. Nevertheless, as SC insulin is absorbed slower than ingested glucose, current closed-
loop systems using SC insulin are unable to reach postprandial normoglycaemia, and the
delayed insulin action may sometimes result in hypoglycaemia in the hours following a
meal 64,67–69. Theoretically, with fast insulin action to peak and fast return to baseline, the
near physiological portal:systemic insulin ratio and the reproducibility of insulin absorption
the IP route of insulin delivery could be able to overcome these challenges posed by the
SC administration 70. Furthermore, one could hypothesize that the use of IP insulin would
diminish the need for glucagon, as a counter regulatory hormone in the closed-loop system.
A recent feasibility study among 8 T1DM patients in which a 2-day closed-loop CIPII driven
by a SC glucose sensor via a proportional-integral-derivative algorithm found almost 40% of
the time spent with blood glucose levels between 4.4 and 6.6 mmol/l (as compared to 28%
during self-monitoring data). This was mostly due to better glycaemic regulation during the
non-postprandial period 71. As speculated upon by the authors, this problem may be resolved
by further developments of the control algorithm, used in combination with CIPII, with
handling of (pre)meal insulin requirements. Another solution may include faster glucose
sensing by using an IP or intravenous (instead of a SC) placed glucose sensor, in combination
with IP insulin delivery 72.
In addition to these positive effects on glycaemic regulation, the historical drawbacks of
CIPII such as complications, limited experience and data on long-term efficacy have, to a
certain extent, been overcome in the recent years. Nevertheless, there is still a need for more
research focusing on the effects of CIPII, as compared to intensive SC insulin therapy, with
specific attention for glycaemic control, glucose variability and aforementioned endocrine
and metabolic effects beyond glycaemic control. If such large-scale, (randomized) studies
among T1DM patients in intermediate to good glycaemic control would yield relevant
positive results and patient preferences would still be in favor of CIPII, costs would be
lowered and availability would be sufficient, a shift in focus from SC to IP insulin as the
preferred route of insulin administration in the closed-loop system may ultimately be
advocated on sufficiently validated ground.
In the meantime, CIPII using an implantable pump remains a feasible last-resort treatment
option in selected patients who fail to reach adequate glycaemic control with intensive SC
insulin therapy and experience high blood glucose variability.
chapter 11discussions & perspectives
178 179
and a thickness of 1.8 cm should be reduced. A smaller, more convex-shaped pump could
diminish the complaints of pain and cutaneous erosions. In addition, alteration in the size
and shape of the pump could offer an improved esthetics.
4.4 future use of cipii therapyFuture use of CIPII will partly depend on further development regarding the pump. Whether
proposed research and developments will take place depends on several factors.
First, as there is only one manufacturer of the implantable pump at present, improvements
by renewal and updates is not stimulated very much. Developing a new (implantable)
device for IP insulin administration is challenging, in particular for interested new parties,
due to the considerable amount of knowledge, time and, very important, resources needed.
These matters are closely related to the amount of patients which would be eligible for such
a (re)new(ed) model for CIPII. At present, CIPII with in implantable pump is a treatment
option for a niche of T1DM patients. Second, it should be emphasized that the current
evidence supporting a more extensive use of for CIPII treatment is virtually absent. Third,
as alternative treatment options for T1DM, i.e. islet transplantation and the closed-loop
system, are developing in fast pace, the urgency for further development of the current
implantable pump system could be questioned.
Further development of IP insulin infusion will also be dependent of the possibility of
incorporating IP insulin administration in a closed-loop system. Over the last decade
considerable advances have been made in the development of closed-loop systems. Aiming
towards optimal blood glucose regulation in various situations without patient involvement,
the present research on closed-loop systems combines continuous glucose sensing, mono-
(insulin) or bihormonal (insulin and glucagon) SC delivery devices and control algorithms
with automated data transfer, real-time control action and automated command of the
insulin delivery device 64. After showing safety and efficacy of closed-loop systems in
controlled (overnight) clinical settings, the field of research has progressed to study the
ability for the closed-loop systems to function in ambulant, non-clinical environments 65,66. Nevertheless, as SC insulin is absorbed slower than ingested glucose, current closed-
loop systems using SC insulin are unable to reach postprandial normoglycaemia, and the
delayed insulin action may sometimes result in hypoglycaemia in the hours following a
meal 64,67–69. Theoretically, with fast insulin action to peak and fast return to baseline, the
near physiological portal:systemic insulin ratio and the reproducibility of insulin absorption
the IP route of insulin delivery could be able to overcome these challenges posed by the
SC administration 70. Furthermore, one could hypothesize that the use of IP insulin would
diminish the need for glucagon, as a counter regulatory hormone in the closed-loop system.
A recent feasibility study among 8 T1DM patients in which a 2-day closed-loop CIPII driven
by a SC glucose sensor via a proportional-integral-derivative algorithm found almost 40% of
the time spent with blood glucose levels between 4.4 and 6.6 mmol/l (as compared to 28%
during self-monitoring data). This was mostly due to better glycaemic regulation during the
non-postprandial period 71. As speculated upon by the authors, this problem may be resolved
by further developments of the control algorithm, used in combination with CIPII, with
handling of (pre)meal insulin requirements. Another solution may include faster glucose
sensing by using an IP or intravenous (instead of a SC) placed glucose sensor, in combination
with IP insulin delivery 72.
In addition to these positive effects on glycaemic regulation, the historical drawbacks of
CIPII such as complications, limited experience and data on long-term efficacy have, to a
certain extent, been overcome in the recent years. Nevertheless, there is still a need for more
research focusing on the effects of CIPII, as compared to intensive SC insulin therapy, with
specific attention for glycaemic control, glucose variability and aforementioned endocrine
and metabolic effects beyond glycaemic control. If such large-scale, (randomized) studies
among T1DM patients in intermediate to good glycaemic control would yield relevant
positive results and patient preferences would still be in favor of CIPII, costs would be
lowered and availability would be sufficient, a shift in focus from SC to IP insulin as the
preferred route of insulin administration in the closed-loop system may ultimately be
advocated on sufficiently validated ground.
In the meantime, CIPII using an implantable pump remains a feasible last-resort treatment
option in selected patients who fail to reach adequate glycaemic control with intensive SC
insulin therapy and experience high blood glucose variability.
chapter 11discussions & perspectives
180 181
1 Brismar K, Fernqvist-Forbes E, Wahren J, Hall K. Effect of insulin on the hepatic production of insulin-like growth factor- binding protein-1 (IGFBP-1), IGFBP-3, and IGF-I in insulin-dependent diabetes. J Clin Endocrinol Metab 1994; 79: 872–8.2 Logtenberg SJ, Kleefstra N, Houweling ST, Groenier KH, Gans RO, Bilo HJ. Health-related quality of life, treatment satisfaction, and costs associated with intraperitoneal versus subcutaneous insulin administration in type 1 diabetes: a randomized controlled trial. Diabetes Care 2010; 33: 1169–72.3 Haardt MJ, Selam JL, Slama G, et al. A cost-benefit comparison of intensive diabetes management with implantable pumps versus multiple subcutaneous injections in patients with type I diabetes. Diabetes Care 1994; 17: 847–51.4 Gin H, Renard E, Melki V, et al. Combined improvements in implantable pump technology and insulin stability allow safe and effective long term intraperitoneal insulin delivery in type 1 diabetic patients: the EVADIAC experience. Diabetes Metab 2003; 29: 602–7.5 Schaepelynck P, Renard E, Jeandidier N, et al. A recent survey confirms the efficacy and the safety of implanted insulin pumps during long-term use in poorly controlled type 1 diabetes patients. Diabetes Technol Ther 2011; 13: 657–60.6 Logtenberg SJJ, van Ballegooie E, Israêl-Bultman H, van Linde A, Bilo HJG. Glycaemic control, health status and treat- ment satisfaction with continuous intraperitoneal insulin infusion. Neth J Med 2007; 65: 65–70.7 Van Hateren KJJ, Kleefstra N, Bilo HJ. Preregistration of study design and non-inferiority margin. Lancet 2013; 381: 115.8 Piaggio G, Elbourne DR, Pocock SJ, Evans SJW, Altman DG, CONSORT Group. Reporting of noninferiority and equivalence randomized trials: extension of the CONSORT 2010 statement. JAMA J Am Med Assoc 2012; 308: 2594–604.9 Soonawala D, Dekkers OM. [’Non-inferiority’ trials. Tips for the critical reader. Research methodology 3. Ned Tijdschr Geneeskd 2012; 156: A4665.10 Logtenberg SJ, Kleefstra N, Houweling ST, et al. Improved glycemic control with intraperitoneal versus subcutaneous insulin in type 1 diabetes: a randomized controlled trial. Diabetes Care 2009; 32: 1372–7.11 European Medicinces Agency. Assessment report: Insuman. London 2013.12 Cryer PE. The barrier of hypoglycemia in diabetes. Diabetes 2008; 57: 3169–76.13 Siegelaar SE, Holleman F, Hoekstra JBL, DeVries JH. Glucose variability; does it matter? Endocr Rev 2010; 31: 171–82.14 Kilpatrick ES. Arguments for and against the role of glucose variability in the development of diabetes complications. J Diabetes Sci Technol 2009; 3: 649–55.15 Kilpatrick ES, Rigby AS, Goode K, Atkin SL. Relating mean blood glucose and glucose variability to the risk of multiple episodes of hypoglycaemia in type 1 diabetes. Diabetologia 2007; 50: 2553–61.16 Cox DJ, Kovatchev BP, Julian DM, et al. Frequency of severe hypoglycemia in insulin-dependent diabetes mellitus can be predicted from self-monitoring blood glucose data. J Clin Endocrinol Metab 1994; 79: 1659–62.17 DeVries JH, Eskes SA, Snoek FJ, et al. Continuous intraperitoneal insulin infusion in patients with ‘brittle’ diabetes: favourable effects on glycaemic control and hospital stay. Diabet Med J Br Diabet Assoc 2002; 19: 496–501.18 Grant P, Dworakowska D, DeZoysa N, Barnes D. The impact of anxiety and depression on patients within a large type 1 diabetes insulin pump population. An observational study. Diabetes Metab 2013; 39: 439–44.19 Jacobson AM, Braffett BH, Cleary PA, Gubitosi-Klug RA, Larkin ME, DCCT/EDIC Research Group. The long-term effects of type 1 diabetes treatment and complications on health-related quality of life: a 23-year follow-up of the Diabetes Control and Complications/Epidemiology of Diabetes Interventions and Complications cohort. Diabetes Care 2013; 36: 3131–8.20 Hansen AP, Johansen K. Diurnal patterns of blood glucose, serum free fatty acids, insulin, glucagon and growth hormone in normals and juvenile diabetics. Diabetologia 1970; 6: 27–33.21 Merimee TJ, Gardner DF, Zapf J, Froesch ER. Effect of glycemic control on serum insulin-like growth factors in diabetes mellitus. Diabetes 1984; 33: 790–3.22 Amiel SA, Sherwin RS, Hintz RL, Gertner JM, Press CM, Tamborlane WV. Effect of diabetes and its control on insulin-like growth factors in the young subject with type I diabetes. Diabetes 1984; 33: 1175–9.23 Tan K, Baxter RC. Serum insulin-like growth factor I levels in adult diabetic patients: the effect of age. J Clin Endocrinol Metab 1986; 63: 651–5.24 Jehle PM, Jehle DR, Mohan S, Böhm BO. Serum levels of insulin-like growth factor system components and relation-
ship to bone metabolism in Type 1 and Type 2 diabetes mellitus patients. J Endocrinol 1998; 159: 297–306.25 Bereket A, Lang CH, Wilson TA. Alterations in the growth hormone-insulin-like growth factor axis in insulin dependent diabetes mellitus. Horm Metab Res Horm Stoffwechselforschung Horm Métabolisme 1999; 31: 172–81.26 Nathan DM, Dunn FL, Bruch J, et al. Postprandial insulin profiles with implantable pump therapy may explain decreased frequency of severe hypoglycemia, compared with intensive subcutaneous regimens, in insulin-dependent diabetes mellitus patients. Am J Med 1996; 100: 412–7.27 Selam JL, Bergman RN, Raccah D, Jean-Didier N, Lozano J, Charles MA. Determination of portal insulin absorption from peritoneum via novel nonisotopic method. Diabetes 1990; 39: 1361–5.28 Giacca A, Caumo A, Galimberti G, et al. Peritoneal and subcutaneous absorption of insulin in type I diabetic subjects. J Clin Endocrinol Metab 1993; 77: 738–42.29 Oskarsson PR, Lins PE, Backman L, Adamson UC. Continuous intraperitoneal insulin infusion partly restores the glucagon response to hypoglycaemia in type 1 diabetic patients. Diabetes Metab 2000; 26: 118–24.30 Bratusch-Marrain PR, Waldhäusl WK, Gasić S, Hofer A. Hepatic disposal of biosynthetic human insulin and porcine C-peptide in humans. Metabolism 1984; 33: 151–7.31 Van Dijk PR, Logtenberg SJJ, Groenier KH, Kleefstra N, Bilo H, Arnqvist H. Effect of intraperitoneal insulin administration on IGF1 and IGFBP1 in type 1 diabetes. Endocr Connect 2013. doi:10.1530/EC-13-0089.32 Hedman CA, Frystyk J, Lindström T, Oskarsson P, Arnqvist HJ. Intraperitoneal insulin delivery to patients with type 1 diabetes results in higher serum IGF-I bioactivity than continuous subcutaneous insulin infusion. Clin Endocrinol (Oxf) 2013. doi:10.1111/cen.12296.33 Shishko PI, Dreval AV, Abugova IA, Zajarny IU, Goncharov VC. Insulin-like growth factors and binding proteins in patients with recent-onset type 1 (insulin-dependent) diabetes mellitus: influence of diabetes control and intraportal insulin infusion. Diabetes Res Clin Pract 1994; 25: 1–12.34 Janssen JA, Jacobs ML, Derkx FH, Weber RF, van der Lely AJ, Lamberts SW. Free and total insulin-like growth factor I (IGF-I), IGF-binding protein-1 (IGFBP-1), and IGFBP-3 and their relationships to the presence of diabetic retinopathy and glomerular hyperfiltration in insulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1997; 82: 2809–15.35 Clemmons DR. Modifying IGF1 activity: an approach to treat endocrine disorders, atherosclerosis and cancer. Nat Rev Drug Discov 2007; 6: 821–33.36 Pandey A, Forte V, Abdallah M, et al. Diabetes mellitus and the risk of cancer. Minerva Endocrinol 2011; 36: 187–209.37 Nederlandse Internisten Vereniging: Statement concerning indications for continuous intraperitoneal insulin infusion, 2007. 38 Ryan EA, Paty BW, Senior PA, et al. Five-Year Follow-Up After Clinical Islet Transplantation. Diabetes 2005; 54: 2060–9.39 Kort H d., Koning EJ d., Rabelink TJ, Bruijn JA, Bajema IM. Islet transplantation in type 1 diabetes. BMJ 2011; 342: d217–d217.40 Khan MH, Harlan DM. Counterpoint: clinical islet transplantation: not ready for prime time. Diabetes Care 2009; 32: 1570–4.41 Guignard AP, Oberholzer J, Benhamou P-Y, et al. Cost analysis of human islet transplantation for the treatment of type 1 diabetes in the Swiss-French Consortium GRAGIL. Diabetes Care 2004; 27: 895–900.42 Yki-Järvinen H, Mäkimattila S, Utriainen T, Rutanen EM. Portal insulin concentrations rather than insulin sensitivity regulate serum sex hormone-binding globulin and insulin-like growth factor binding protein 1 in vivo. J Clin Endocrinol Metab 1995; 80: 3227–32.43 Van Dam EWCM, Dekker JM, Lentjes EGWM, et al. Steroids in adult men with type 1 diabetes: a tendency to hypo- gonadism. Diabetes Care 2003; 26: 1812–8.44 Lassmann-Vague V, Raccah D, Pugeat M, Bautrant D, Belicar P, Vague P. SHBG (sex hormone binding globulin) levels in insulin dependent diabetic patients according to the route of insulin administration. Horm Metab Res Horm Stoffwechselforschung Horm Métabolisme 1994; 26: 436–7.45 Vergès B. Lipid disorders in type 1 diabetes. Diabetes Metab 2009; 35: 353–60.46 Dullaart RP. Plasma lipoprotein abnormalities in type 1 (insulin-dependent) diabetes mellitus. Neth J Med 1995; 46: 44–54.47 Bagdade JD, Dunn FL, Eckel RH, Ritter MC. Intraperitoneal insulin therapy corrects abnormalities in cholesteryl ester transfer and lipoprotein lipase activities in insulin-dependent diabetes mellitus. Arterioscler Thromb J Vasc Biol Am
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1 Brismar K, Fernqvist-Forbes E, Wahren J, Hall K. Effect of insulin on the hepatic production of insulin-like growth factor- binding protein-1 (IGFBP-1), IGFBP-3, and IGF-I in insulin-dependent diabetes. J Clin Endocrinol Metab 1994; 79: 872–8.2 Logtenberg SJ, Kleefstra N, Houweling ST, Groenier KH, Gans RO, Bilo HJ. Health-related quality of life, treatment satisfaction, and costs associated with intraperitoneal versus subcutaneous insulin administration in type 1 diabetes: a randomized controlled trial. Diabetes Care 2010; 33: 1169–72.3 Haardt MJ, Selam JL, Slama G, et al. A cost-benefit comparison of intensive diabetes management with implantable pumps versus multiple subcutaneous injections in patients with type I diabetes. Diabetes Care 1994; 17: 847–51.4 Gin H, Renard E, Melki V, et al. Combined improvements in implantable pump technology and insulin stability allow safe and effective long term intraperitoneal insulin delivery in type 1 diabetic patients: the EVADIAC experience. Diabetes Metab 2003; 29: 602–7.5 Schaepelynck P, Renard E, Jeandidier N, et al. A recent survey confirms the efficacy and the safety of implanted insulin pumps during long-term use in poorly controlled type 1 diabetes patients. Diabetes Technol Ther 2011; 13: 657–60.6 Logtenberg SJJ, van Ballegooie E, Israêl-Bultman H, van Linde A, Bilo HJG. Glycaemic control, health status and treat- ment satisfaction with continuous intraperitoneal insulin infusion. Neth J Med 2007; 65: 65–70.7 Van Hateren KJJ, Kleefstra N, Bilo HJ. Preregistration of study design and non-inferiority margin. Lancet 2013; 381: 115.8 Piaggio G, Elbourne DR, Pocock SJ, Evans SJW, Altman DG, CONSORT Group. Reporting of noninferiority and equivalence randomized trials: extension of the CONSORT 2010 statement. JAMA J Am Med Assoc 2012; 308: 2594–604.9 Soonawala D, Dekkers OM. [’Non-inferiority’ trials. Tips for the critical reader. Research methodology 3. Ned Tijdschr Geneeskd 2012; 156: A4665.10 Logtenberg SJ, Kleefstra N, Houweling ST, et al. Improved glycemic control with intraperitoneal versus subcutaneous insulin in type 1 diabetes: a randomized controlled trial. Diabetes Care 2009; 32: 1372–7.11 European Medicinces Agency. Assessment report: Insuman. London 2013.12 Cryer PE. The barrier of hypoglycemia in diabetes. Diabetes 2008; 57: 3169–76.13 Siegelaar SE, Holleman F, Hoekstra JBL, DeVries JH. Glucose variability; does it matter? Endocr Rev 2010; 31: 171–82.14 Kilpatrick ES. Arguments for and against the role of glucose variability in the development of diabetes complications. J Diabetes Sci Technol 2009; 3: 649–55.15 Kilpatrick ES, Rigby AS, Goode K, Atkin SL. Relating mean blood glucose and glucose variability to the risk of multiple episodes of hypoglycaemia in type 1 diabetes. Diabetologia 2007; 50: 2553–61.16 Cox DJ, Kovatchev BP, Julian DM, et al. Frequency of severe hypoglycemia in insulin-dependent diabetes mellitus can be predicted from self-monitoring blood glucose data. J Clin Endocrinol Metab 1994; 79: 1659–62.17 DeVries JH, Eskes SA, Snoek FJ, et al. Continuous intraperitoneal insulin infusion in patients with ‘brittle’ diabetes: favourable effects on glycaemic control and hospital stay. Diabet Med J Br Diabet Assoc 2002; 19: 496–501.18 Grant P, Dworakowska D, DeZoysa N, Barnes D. The impact of anxiety and depression on patients within a large type 1 diabetes insulin pump population. An observational study. Diabetes Metab 2013; 39: 439–44.19 Jacobson AM, Braffett BH, Cleary PA, Gubitosi-Klug RA, Larkin ME, DCCT/EDIC Research Group. The long-term effects of type 1 diabetes treatment and complications on health-related quality of life: a 23-year follow-up of the Diabetes Control and Complications/Epidemiology of Diabetes Interventions and Complications cohort. Diabetes Care 2013; 36: 3131–8.20 Hansen AP, Johansen K. Diurnal patterns of blood glucose, serum free fatty acids, insulin, glucagon and growth hormone in normals and juvenile diabetics. Diabetologia 1970; 6: 27–33.21 Merimee TJ, Gardner DF, Zapf J, Froesch ER. Effect of glycemic control on serum insulin-like growth factors in diabetes mellitus. Diabetes 1984; 33: 790–3.22 Amiel SA, Sherwin RS, Hintz RL, Gertner JM, Press CM, Tamborlane WV. Effect of diabetes and its control on insulin-like growth factors in the young subject with type I diabetes. Diabetes 1984; 33: 1175–9.23 Tan K, Baxter RC. Serum insulin-like growth factor I levels in adult diabetic patients: the effect of age. J Clin Endocrinol Metab 1986; 63: 651–5.24 Jehle PM, Jehle DR, Mohan S, Böhm BO. Serum levels of insulin-like growth factor system components and relation-
ship to bone metabolism in Type 1 and Type 2 diabetes mellitus patients. J Endocrinol 1998; 159: 297–306.25 Bereket A, Lang CH, Wilson TA. Alterations in the growth hormone-insulin-like growth factor axis in insulin dependent diabetes mellitus. Horm Metab Res Horm Stoffwechselforschung Horm Métabolisme 1999; 31: 172–81.26 Nathan DM, Dunn FL, Bruch J, et al. Postprandial insulin profiles with implantable pump therapy may explain decreased frequency of severe hypoglycemia, compared with intensive subcutaneous regimens, in insulin-dependent diabetes mellitus patients. Am J Med 1996; 100: 412–7.27 Selam JL, Bergman RN, Raccah D, Jean-Didier N, Lozano J, Charles MA. Determination of portal insulin absorption from peritoneum via novel nonisotopic method. Diabetes 1990; 39: 1361–5.28 Giacca A, Caumo A, Galimberti G, et al. Peritoneal and subcutaneous absorption of insulin in type I diabetic subjects. J Clin Endocrinol Metab 1993; 77: 738–42.29 Oskarsson PR, Lins PE, Backman L, Adamson UC. Continuous intraperitoneal insulin infusion partly restores the glucagon response to hypoglycaemia in type 1 diabetic patients. Diabetes Metab 2000; 26: 118–24.30 Bratusch-Marrain PR, Waldhäusl WK, Gasić S, Hofer A. Hepatic disposal of biosynthetic human insulin and porcine C-peptide in humans. Metabolism 1984; 33: 151–7.31 Van Dijk PR, Logtenberg SJJ, Groenier KH, Kleefstra N, Bilo H, Arnqvist H. Effect of intraperitoneal insulin administration on IGF1 and IGFBP1 in type 1 diabetes. Endocr Connect 2013. doi:10.1530/EC-13-0089.32 Hedman CA, Frystyk J, Lindström T, Oskarsson P, Arnqvist HJ. Intraperitoneal insulin delivery to patients with type 1 diabetes results in higher serum IGF-I bioactivity than continuous subcutaneous insulin infusion. Clin Endocrinol (Oxf) 2013. doi:10.1111/cen.12296.33 Shishko PI, Dreval AV, Abugova IA, Zajarny IU, Goncharov VC. Insulin-like growth factors and binding proteins in patients with recent-onset type 1 (insulin-dependent) diabetes mellitus: influence of diabetes control and intraportal insulin infusion. Diabetes Res Clin Pract 1994; 25: 1–12.34 Janssen JA, Jacobs ML, Derkx FH, Weber RF, van der Lely AJ, Lamberts SW. Free and total insulin-like growth factor I (IGF-I), IGF-binding protein-1 (IGFBP-1), and IGFBP-3 and their relationships to the presence of diabetic retinopathy and glomerular hyperfiltration in insulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1997; 82: 2809–15.35 Clemmons DR. Modifying IGF1 activity: an approach to treat endocrine disorders, atherosclerosis and cancer. Nat Rev Drug Discov 2007; 6: 821–33.36 Pandey A, Forte V, Abdallah M, et al. Diabetes mellitus and the risk of cancer. Minerva Endocrinol 2011; 36: 187–209.37 Nederlandse Internisten Vereniging: Statement concerning indications for continuous intraperitoneal insulin infusion, 2007. 38 Ryan EA, Paty BW, Senior PA, et al. Five-Year Follow-Up After Clinical Islet Transplantation. Diabetes 2005; 54: 2060–9.39 Kort H d., Koning EJ d., Rabelink TJ, Bruijn JA, Bajema IM. Islet transplantation in type 1 diabetes. BMJ 2011; 342: d217–d217.40 Khan MH, Harlan DM. Counterpoint: clinical islet transplantation: not ready for prime time. Diabetes Care 2009; 32: 1570–4.41 Guignard AP, Oberholzer J, Benhamou P-Y, et al. Cost analysis of human islet transplantation for the treatment of type 1 diabetes in the Swiss-French Consortium GRAGIL. Diabetes Care 2004; 27: 895–900.42 Yki-Järvinen H, Mäkimattila S, Utriainen T, Rutanen EM. Portal insulin concentrations rather than insulin sensitivity regulate serum sex hormone-binding globulin and insulin-like growth factor binding protein 1 in vivo. J Clin Endocrinol Metab 1995; 80: 3227–32.43 Van Dam EWCM, Dekker JM, Lentjes EGWM, et al. Steroids in adult men with type 1 diabetes: a tendency to hypo- gonadism. Diabetes Care 2003; 26: 1812–8.44 Lassmann-Vague V, Raccah D, Pugeat M, Bautrant D, Belicar P, Vague P. SHBG (sex hormone binding globulin) levels in insulin dependent diabetic patients according to the route of insulin administration. Horm Metab Res Horm Stoffwechselforschung Horm Métabolisme 1994; 26: 436–7.45 Vergès B. Lipid disorders in type 1 diabetes. Diabetes Metab 2009; 35: 353–60.46 Dullaart RP. Plasma lipoprotein abnormalities in type 1 (insulin-dependent) diabetes mellitus. Neth J Med 1995; 46: 44–54.47 Bagdade JD, Dunn FL, Eckel RH, Ritter MC. Intraperitoneal insulin therapy corrects abnormalities in cholesteryl ester transfer and lipoprotein lipase activities in insulin-dependent diabetes mellitus. Arterioscler Thromb J Vasc Biol Am
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Heart Assoc 1994; 14: 1933–9.48 Taskinen MR. Lipoprotein lipase in diabetes. Diabetes Metab Rev 1987; 3: 551–70.49 Ruotolo G, Parlavecchia M, Taskinen MR, et al. Normalization of lipoprotein composition by intraperitoneal insulin in IDDM. Role of increased hepatic lipase activity. Diabetes Care 1994; 17: 6–12.50 Selam JL, Kashyap M, Alberti KG, et al. Comparison of intraperitoneal and subcutaneous insulin administration on lipids, apolipoproteins, fuel metabolites, and hormones in type I diabetes mellitus. Metabolism 1989; 38: 908–12.51 Duvillard L, Florentin E, Baillot-Rudoni S, et al. Comparison of apolipoprotein B100 metabolism between continuous subcutaneous and intraperitoneal insulin therapy in type 1 diabetes. J Clin Endocrinol Metab 2005; 90: 5761–4.52 Meyer L, Jeantroux J, Riveline JP, et al. Reversible focal hepatic steatosis in type 1 diabetic patients treated with intra- peritoneal insulin implantable pump therapy. Diabetes Care 2008; 31: e49.53 Pereira RI, Snell-Bergeon JK, Erickson C, et al. Adiponectin dysregulation and insulin resistance in type 1 diabetes. J Clin Endocrinol Metab 2012; 97: E642–647.54 Forsblom C, Thomas MC, Moran J, et al. Serum adiponectin concentration is a positive predictor of all-cause and cardio- vascular mortality in type 1 diabetes. J Intern Med 2011; 270: 346–55.55 Hadjadj S, Aubert R, Fumeron F, et al. Increased plasma adiponectin concentrations are associated with microangio- pathy in type 1 diabetic subjects. Diabetologia 2005; 48: 1088–92.56 Schneider JG, von Eynatten M, Schiekofer S, Nawroth PP, Dugi KA. Low plasma adiponectin levels are associated with increased hepatic lipase activity in vivo. Diabetes Care 2005; 28: 2181–6.57 Von Eynatten M, Schneider JG, Humpert PM, et al. Decreased plasma lipoprotein lipase in hypoadiponectinemia: an association independent of systemic inflammation and insulin resistance. Diabetes Care 2004; 27: 2925–9.58 Freyse E-J, Fischer U, Knospe S, Ford GC, Nair KS. Differences in protein and energy metabolism following portal versus systemic administration of insulin in diabetic dogs. Diabetologia 2006; 49: 543–51.59 Colette C, Pares-Herbute N, Monnier L, Selam JL, Thomas N, Mirouze J. Effect of different insulin administration modalities on vitamin D metabolism of insulin-dependent diabetic patients. Horm Metab Res Horm Stoffwechselforschung Horm Métabolisme 1989; 21: 37–41.60 Wan CK, Giacca A, Matsuhisa M, et al. Increased responses of glucagon and glucose production to hypoglycemia with intraperitoneal versus subcutaneous insulin treatment. Metabolism 2000; 49: 984–9.61 Mason TM, Gupta N, Goh T, et al. Chronic intraperitoneal insulin delivery, as compared with subcutaneous delivery, improves hepatic glucose metabolism in streptozotocin diabetic rats. Metabolism 2000; 49: 1411–6.62 Oskarsson PR, Lins PE, Wallberg Henriksson H, Adamson UC. Metabolic and hormonal responses to exercise in type 1 diabetic patients during continuous subcutaneous, as compared to continuous intraperitoneal, insulin infusion. Diabetes Metab 1999; 25: 491–7.63 Selam JL, Medlej R, M’bemba J, et al. Symptoms, hormones, and glucose fluxes during a gradual hypoglycaemia induced by intraperitoneal vs venous insulin infusion in Type I diabetes. Diabet Med J Br Diabet Assoc 1995; 12: 1102–9.64 Kovatchev BP. Diabetes technology: markers, monitoring, assessment, and control of blood glucose fluctuations in diabetes. Scientifica 2012; 2012: 283821.65 Kovatchev BP, Renard E, Cobelli C, et al. Feasibility of outpatient fully integrated closed-loop control: first studies of wearable artificial pancreas. Diabetes Care 2013; 36: 1851–8.66 Russell SJ, El-Khatib FH, Sinha M, et al. Outpatient glycemic control with a bionic pancreas in type 1 diabetes. N Engl J Med 2014; 371: 313–25.67 Steil GM, Panteleon AE, Rebrin K. Closed-loop insulin delivery-the path to physiological glucose control. Adv Drug Deliv Rev 2004; 56: 125–44.68 Cobelli C, Renard E, Kovatchev B. Artificial pancreas: past, present, future. Diabetes 2011; 60: 2672–82.69 Elleri D, Dunger DB, Hovorka R. Closed-loop insulin delivery for treatment of type 1 diabetes. BMC Med 2011; 9: 120.70 Renard E. Insulin delivery route for the artificial pancreas: subcutaneous, intraperitoneal, or intravenous? Pros and cons. J Diabetes Sci Technol 2008; 2: 735–8.71 Renard E, Place J, Cantwell M, Chevassus H, Palerm CC. Closed-loop insulin delivery using a subcutaneous glucose sensor and intraperitoneal insulin delivery: feasibility study testing a new model for the artificial pancreas. Diabetes Care 2010; 33: 121–7.
72 Burnett DR, Huyett LM, Zisser HC, Doyle FJ 3rd, Mensh BD. Glucose Sensing in the Peritoneal Space Offers Faster Kinetics than Sensing in the Subcutaneous Space. Diabetes 2014. doi:10.2337/db13-1649.
discussions & perspectives chapter 11
182 183
Heart Assoc 1994; 14: 1933–9.48 Taskinen MR. Lipoprotein lipase in diabetes. Diabetes Metab Rev 1987; 3: 551–70.49 Ruotolo G, Parlavecchia M, Taskinen MR, et al. Normalization of lipoprotein composition by intraperitoneal insulin in IDDM. Role of increased hepatic lipase activity. Diabetes Care 1994; 17: 6–12.50 Selam JL, Kashyap M, Alberti KG, et al. Comparison of intraperitoneal and subcutaneous insulin administration on lipids, apolipoproteins, fuel metabolites, and hormones in type I diabetes mellitus. Metabolism 1989; 38: 908–12.51 Duvillard L, Florentin E, Baillot-Rudoni S, et al. Comparison of apolipoprotein B100 metabolism between continuous subcutaneous and intraperitoneal insulin therapy in type 1 diabetes. J Clin Endocrinol Metab 2005; 90: 5761–4.52 Meyer L, Jeantroux J, Riveline JP, et al. Reversible focal hepatic steatosis in type 1 diabetic patients treated with intra- peritoneal insulin implantable pump therapy. Diabetes Care 2008; 31: e49.53 Pereira RI, Snell-Bergeon JK, Erickson C, et al. Adiponectin dysregulation and insulin resistance in type 1 diabetes. J Clin Endocrinol Metab 2012; 97: E642–647.54 Forsblom C, Thomas MC, Moran J, et al. Serum adiponectin concentration is a positive predictor of all-cause and cardio- vascular mortality in type 1 diabetes. J Intern Med 2011; 270: 346–55.55 Hadjadj S, Aubert R, Fumeron F, et al. Increased plasma adiponectin concentrations are associated with microangio- pathy in type 1 diabetic subjects. Diabetologia 2005; 48: 1088–92.56 Schneider JG, von Eynatten M, Schiekofer S, Nawroth PP, Dugi KA. Low plasma adiponectin levels are associated with increased hepatic lipase activity in vivo. Diabetes Care 2005; 28: 2181–6.57 Von Eynatten M, Schneider JG, Humpert PM, et al. Decreased plasma lipoprotein lipase in hypoadiponectinemia: an association independent of systemic inflammation and insulin resistance. Diabetes Care 2004; 27: 2925–9.58 Freyse E-J, Fischer U, Knospe S, Ford GC, Nair KS. Differences in protein and energy metabolism following portal versus systemic administration of insulin in diabetic dogs. Diabetologia 2006; 49: 543–51.59 Colette C, Pares-Herbute N, Monnier L, Selam JL, Thomas N, Mirouze J. Effect of different insulin administration modalities on vitamin D metabolism of insulin-dependent diabetic patients. Horm Metab Res Horm Stoffwechselforschung Horm Métabolisme 1989; 21: 37–41.60 Wan CK, Giacca A, Matsuhisa M, et al. Increased responses of glucagon and glucose production to hypoglycemia with intraperitoneal versus subcutaneous insulin treatment. Metabolism 2000; 49: 984–9.61 Mason TM, Gupta N, Goh T, et al. Chronic intraperitoneal insulin delivery, as compared with subcutaneous delivery, improves hepatic glucose metabolism in streptozotocin diabetic rats. Metabolism 2000; 49: 1411–6.62 Oskarsson PR, Lins PE, Wallberg Henriksson H, Adamson UC. Metabolic and hormonal responses to exercise in type 1 diabetic patients during continuous subcutaneous, as compared to continuous intraperitoneal, insulin infusion. Diabetes Metab 1999; 25: 491–7.63 Selam JL, Medlej R, M’bemba J, et al. Symptoms, hormones, and glucose fluxes during a gradual hypoglycaemia induced by intraperitoneal vs venous insulin infusion in Type I diabetes. Diabet Med J Br Diabet Assoc 1995; 12: 1102–9.64 Kovatchev BP. Diabetes technology: markers, monitoring, assessment, and control of blood glucose fluctuations in diabetes. Scientifica 2012; 2012: 283821.65 Kovatchev BP, Renard E, Cobelli C, et al. Feasibility of outpatient fully integrated closed-loop control: first studies of wearable artificial pancreas. Diabetes Care 2013; 36: 1851–8.66 Russell SJ, El-Khatib FH, Sinha M, et al. Outpatient glycemic control with a bionic pancreas in type 1 diabetes. N Engl J Med 2014; 371: 313–25.67 Steil GM, Panteleon AE, Rebrin K. Closed-loop insulin delivery-the path to physiological glucose control. Adv Drug Deliv Rev 2004; 56: 125–44.68 Cobelli C, Renard E, Kovatchev B. Artificial pancreas: past, present, future. Diabetes 2011; 60: 2672–82.69 Elleri D, Dunger DB, Hovorka R. Closed-loop insulin delivery for treatment of type 1 diabetes. BMC Med 2011; 9: 120.70 Renard E. Insulin delivery route for the artificial pancreas: subcutaneous, intraperitoneal, or intravenous? Pros and cons. J Diabetes Sci Technol 2008; 2: 735–8.71 Renard E, Place J, Cantwell M, Chevassus H, Palerm CC. Closed-loop insulin delivery using a subcutaneous glucose sensor and intraperitoneal insulin delivery: feasibility study testing a new model for the artificial pancreas. Diabetes Care 2010; 33: 121–7.
72 Burnett DR, Huyett LM, Zisser HC, Doyle FJ 3rd, Mensh BD. Glucose Sensing in the Peritoneal Space Offers Faster Kinetics than Sensing in the Subcutaneous Space. Diabetes 2014. doi:10.2337/db13-1649.
discussions & perspectives chapter 11
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chapter 12 De behandeling van type 1 diabetes mellitus (T1DM) bestaat uit het toedienen van het
hormoon insuline met als doel de glucoseconcentraties in het bloed binnen acceptabele
grenzen te houden. Onderhuidse toediening van insuline, zogenaamde subcutane (SC)
insulinetoediening, middels multipele dagelijkse injecties (MDI) en continue subcutane
insuline-infusie (CSII) met behulp van een uitwendig geplaatste pomp zijn de meest
frequent gebruikte toedieningsvormen.
Er is echter een groep patiënten met T1DM waarbij met SC insulinetoediening geen
acceptabele glucoseregulatie kan worden bereikt. Deze mensen hebben klachten van
verhoogde of instabiele bloedglucoseconcentraties, die dermate ernstig zijn dat dit
resulteert in een verhoogde kans op aan diabetes gerelateerde complicaties, het frequent
optreden van (symptomatische) hypoglykemieën, langdurige ziekenhuisopnames en
een sterk verminderde kwaliteit van leven. Een behandelingsoptie voor deze patiënten is
toediening van insuline in de buikholte, zogenaamde intraperitoneale insulinetoediening,
middels een inwendig geplaatste insulinepomp.
De inwendige insulinepomp wordt geïmplanteerd in het onderhuids vet van de buikwand,
bovenop de spieren. Vanuit de insulinepomp loopt een slangetje (katheter) door de buik-
wand heen de buikholte in. De pomp wordt door de patiënt bediend met een afstands-
bediening. Op dit moment worden er wereldwijd ruim 300 mensen behandeld met deze
unieke manier van insulinetoediening, voluit; continue intraperitoneale insuline-infusie
(CIPII). In Nederland is deze therapie in 1983 geïntroduceerd door dr. Evert van Ballegooie en
worden er momenteel ongeveer 70 mensen met CIPII behandeld, voornamelijk in de Isala in
Zwolle. Insuline die intraperitoneaal wordt afgegeven wordt direct via het poortadersysteem
opgenomen en richting de lever getransporteerd waar het werkzaam is, zoals dat bij
gezonde personen ook het geval is als de insuline door de alvleesklier wordt afgegeven.
Bij SC toediening zal de insuline eerst in de bloedbaan worden opgenomen, zich daar
verspreiden en daarna pas (voor een deel) de lever passeren.
Teneinde de bestaande kennis te vergroten omtrent CIPII middels een inwendig geplaatste
pomp in de behandeling van T1DM, werden voor dit proefschrift verschillende aspecten
van CIPII onderzocht. In het eerste deel van dit proefschrift zijn de complicaties van CIPII
beschreven. In deel twee worden de effecten van CIPII op de glucoseregulatie in het bloed,
kwaliteit van leven en behandelingstevredenheid op de langere termijn, ook in vergelijking
met SC insulinetoediening, onderzocht. Insuline is een pleitroop hormoon, dat wil zeggen
dat het méér dan één effect in het lichaam heeft. Daarom worden in deel drie van dit
Summary in Dutch
chapter 12summary in dutch
184 185
chapter 12 De behandeling van type 1 diabetes mellitus (T1DM) bestaat uit het toedienen van het
hormoon insuline met als doel de glucoseconcentraties in het bloed binnen acceptabele
grenzen te houden. Onderhuidse toediening van insuline, zogenaamde subcutane (SC)
insulinetoediening, middels multipele dagelijkse injecties (MDI) en continue subcutane
insuline-infusie (CSII) met behulp van een uitwendig geplaatste pomp zijn de meest
frequent gebruikte toedieningsvormen.
Er is echter een groep patiënten met T1DM waarbij met SC insulinetoediening geen
acceptabele glucoseregulatie kan worden bereikt. Deze mensen hebben klachten van
verhoogde of instabiele bloedglucoseconcentraties, die dermate ernstig zijn dat dit
resulteert in een verhoogde kans op aan diabetes gerelateerde complicaties, het frequent
optreden van (symptomatische) hypoglykemieën, langdurige ziekenhuisopnames en
een sterk verminderde kwaliteit van leven. Een behandelingsoptie voor deze patiënten is
toediening van insuline in de buikholte, zogenaamde intraperitoneale insulinetoediening,
middels een inwendig geplaatste insulinepomp.
De inwendige insulinepomp wordt geïmplanteerd in het onderhuids vet van de buikwand,
bovenop de spieren. Vanuit de insulinepomp loopt een slangetje (katheter) door de buik-
wand heen de buikholte in. De pomp wordt door de patiënt bediend met een afstands-
bediening. Op dit moment worden er wereldwijd ruim 300 mensen behandeld met deze
unieke manier van insulinetoediening, voluit; continue intraperitoneale insuline-infusie
(CIPII). In Nederland is deze therapie in 1983 geïntroduceerd door dr. Evert van Ballegooie en
worden er momenteel ongeveer 70 mensen met CIPII behandeld, voornamelijk in de Isala in
Zwolle. Insuline die intraperitoneaal wordt afgegeven wordt direct via het poortadersysteem
opgenomen en richting de lever getransporteerd waar het werkzaam is, zoals dat bij
gezonde personen ook het geval is als de insuline door de alvleesklier wordt afgegeven.
Bij SC toediening zal de insuline eerst in de bloedbaan worden opgenomen, zich daar
verspreiden en daarna pas (voor een deel) de lever passeren.
Teneinde de bestaande kennis te vergroten omtrent CIPII middels een inwendig geplaatste
pomp in de behandeling van T1DM, werden voor dit proefschrift verschillende aspecten
van CIPII onderzocht. In het eerste deel van dit proefschrift zijn de complicaties van CIPII
beschreven. In deel twee worden de effecten van CIPII op de glucoseregulatie in het bloed,
kwaliteit van leven en behandelingstevredenheid op de langere termijn, ook in vergelijking
met SC insulinetoediening, onderzocht. Insuline is een pleitroop hormoon, dat wil zeggen
dat het méér dan één effect in het lichaam heeft. Daarom worden in deel drie van dit
Summary in Dutch
chapter 12summary in dutch
186 187
proefschrift de effecten van CIPII op de groeihormoon (GH) - insuline-achtige groeifactor-1
(Engels: Insulin-like growth factor-1, IGF1) as onderzocht, als model voor de effecten van
intraperitoneale insulinetoediening in engere zin.
deel i. complicaties van cipii middels een inwendig geplaatste pompIn Hoofdstuk 2 worden de complicaties van CIPII middels een inwendige pomp gedurende
de periode 2000-2012 bestudeerd. In de onderzochte groep van 56 T1DM-patiënten trad
één complicatie per 4 patiëntjaren op. Blokkade van de katheter (8.1 per 100 patiëntjaren),
dysfunctie van de pomp (4.2 per 100 patiëntjaren) en pijn ter plekke van de pomp (3.9 per
100 patiëntjaren) waren de meest frequent voorkomende complicaties. Eén episode van
peritonitis is gerapporteerd. Er trad geen mortaliteit op. Ten gevolge van complicaties
waren 50 re-operaties en 69 klinische opnames nodig. Gedurende de onderzochte periode
bleef de periode tussen implantatie van de pomp en de eerste re-operatie stabiel: 4.5 jaar
(95% betrouwbaarheidsinterval (BI) 4.1, 4.8). In totaal staakten 5 patiënten CIPII therapie.
Redenen hiervoor waren infecties (n=2), pijn (n=1), het niet bereiken van acceptabele
glucoseregulatie (n=1) en eigen verzoek (n=1).
deel ii. effecten van cipii - glucoseregulatie, kwaliteit van leven en behandelings-tevredenheidIn Hoofdstuk 3 is de mate van glucosecontrole voorafgaande aan het starten van CIPII
beschreven. Patiënten hadden een mediane HbA1c concentratie van 70 mmol/mol (8.6%),
brachten tijdens geblindeerde continue glucosesensormetingen slechts 47% van de tijd
door in euglykemie (bloedglucose tussen 4.0 en 10.0 mmol/l) en ervoeren 4 episodes van
een graad 1 (bloedglucose <4.0 mmol/l) en 3 episodes van een graad 2 (bloedglucose
<3.5 mmol/l) hypoglykemie per week. In Hoofdstuk 3 is tevens de mate van glucoseregulatie
6 jaar na het starten van CIPII beschreven en uitgezet tegen de resultaten tijdens de
aan de CIPII voorafgaande SC insulinetherapie. Het bleek dat patiënten meer tijd in
hyperglykemie (bloedglucose >10.0 mmol/l) doorbrachten tijdens geblindeerde continue
glucosesensormetingen en dat de aanvankelijke HbA1c daling, die gedurende de eerste
6 maanden na het starten van CIPII optrad, verdween. Desalniettemin zijn deze HbA1c
concentraties vergelijkbaar met de concentraties die bij deze patiënten met eerdere SC
insulinetherapie werden bereikt, terwijl het aantal episodes van een graad 2 hypoglykemie
lager ligt met CIPII.
De resultaten van Hoofdstuk 4, waarin een retrospectieve case-control studie is beschreven,
laten eveneens zien dat patiënten die met CIPII startten (n=21) in vergelijking met matig
gereguleerde T1DM-patiënten die hun SC behandelingsmodaliteit continueerden (n=74),
na een periode van 7 jaar minder hypoglykemische episodes ervoeren terwijl het HbA1c niet
verschilde tussen beide groepen.
Teneinde de glykemische situatie van een grotere groep T1DM-patiënten (n=39) die
gedurende meerdere jaren met CIPII werd behandeld op prospectieve wijze te vergelijken
met een in leeftijd en geslacht overeenkomstige populatie van met SC insuline behandelde
patiënten (n=144), is een prospectieve, observationele matched-control studie uitgevoerd,
beschreven in Hoofdstuk 5. Alhoewel de groep CIPII-behandelde patiënten meer tijd in
hyper-, en minder in euglykemie doorbracht dan de groep SC-behandelde patiënten, leidde
dit tot een niet-inferieur verschil in HbA1c concentratie van 3.0 mmol/mol (95% BI -5.0,
-1.0) (-0.27%, 95% BI -0.46, -0.09). Gezien de huidige plaats van CIPII in het therapeutische
spectrum als laatste redmiddel, met dientengevolge selectie van een complexe en uiterst
moeizaam te behandelden populatie, valt te concluderen dat de bevinding van een niet-
inferieur verschil in HbA1c het gebruik van CIPII bij geselecteerde patiënten ondersteunt.
In Hoofdstuk 7 worden, op basis van zowel bloedglucose-zelfmetingen als geblindeerde
continue glucosesensormetingen (verricht tijdens de studie beschreven in hoofdstuk 5),
de effecten van CIPII en SC insulinetoediening op de variabiliteit in glucosewaarden
beschreven. Met CIPII treedt er, ondanks hogere gemiddelde bloedglucosewaarden in
vergelijking met SC insuline behandelde patiënten, zowel binnen als tussen verschillende
dagen minder variabiliteit in glucosewaarden op.
Aangaande kwaliteit van leven blijkt uit de studies zoals beschreven in de Hoofdstukken 3 en
4 dat voorafgaande aan de start van CIPII moet worden geconstateerd dat de ervaren
gezondheidstoestand, algemene gezondheidgerelateerde kwaliteit van leven en
behandelingstevredenheid laag zijn, ook in vergelijking met een referentiegroep patiënten
die met SC insuline worden behandeld: de meeste scores bedragen slechts tweederde van
de maximale score.
Separate analyses, verricht in Hoofdstuk 3, binnen een groep personen die gedurende 6 jaar
met CIPII is behandeld, laten zien dat, in vergelijking met voorafgaande SC insulinetherapie,
de behandelingstevredenheid is toegenomen, terwijl de gezondheidstoestand en algemene
gezondheidgerelateerde kwaliteit van leven persisterend laag blijven.
De retrospectieve vergelijking tussen met CIPII en SC insulinetherapie behandelde T1DM-
patiënten, beschreven in Hoofdstuk 4, laat geen verschil zien in het beloop van de algemene
gezondheidgerelateerde kwaliteit van leven tussen beide groepen gedurende een periode
van 7 jaar. Uit de prospectieve, observationele case-control studie beschreven in Hoofdstuk 6
volgt, dat in de onderzochte T1DM-populatie de verschillen in ervaren gezondheidstoestand
en algemene gezondheidgerelateerde kwaliteit van leven tussen met CIPII en SC
chapter 12summary in dutch
186 187
proefschrift de effecten van CIPII op de groeihormoon (GH) - insuline-achtige groeifactor-1
(Engels: Insulin-like growth factor-1, IGF1) as onderzocht, als model voor de effecten van
intraperitoneale insulinetoediening in engere zin.
deel i. complicaties van cipii middels een inwendig geplaatste pompIn Hoofdstuk 2 worden de complicaties van CIPII middels een inwendige pomp gedurende
de periode 2000-2012 bestudeerd. In de onderzochte groep van 56 T1DM-patiënten trad
één complicatie per 4 patiëntjaren op. Blokkade van de katheter (8.1 per 100 patiëntjaren),
dysfunctie van de pomp (4.2 per 100 patiëntjaren) en pijn ter plekke van de pomp (3.9 per
100 patiëntjaren) waren de meest frequent voorkomende complicaties. Eén episode van
peritonitis is gerapporteerd. Er trad geen mortaliteit op. Ten gevolge van complicaties
waren 50 re-operaties en 69 klinische opnames nodig. Gedurende de onderzochte periode
bleef de periode tussen implantatie van de pomp en de eerste re-operatie stabiel: 4.5 jaar
(95% betrouwbaarheidsinterval (BI) 4.1, 4.8). In totaal staakten 5 patiënten CIPII therapie.
Redenen hiervoor waren infecties (n=2), pijn (n=1), het niet bereiken van acceptabele
glucoseregulatie (n=1) en eigen verzoek (n=1).
deel ii. effecten van cipii - glucoseregulatie, kwaliteit van leven en behandelings-tevredenheidIn Hoofdstuk 3 is de mate van glucosecontrole voorafgaande aan het starten van CIPII
beschreven. Patiënten hadden een mediane HbA1c concentratie van 70 mmol/mol (8.6%),
brachten tijdens geblindeerde continue glucosesensormetingen slechts 47% van de tijd
door in euglykemie (bloedglucose tussen 4.0 en 10.0 mmol/l) en ervoeren 4 episodes van
een graad 1 (bloedglucose <4.0 mmol/l) en 3 episodes van een graad 2 (bloedglucose
<3.5 mmol/l) hypoglykemie per week. In Hoofdstuk 3 is tevens de mate van glucoseregulatie
6 jaar na het starten van CIPII beschreven en uitgezet tegen de resultaten tijdens de
aan de CIPII voorafgaande SC insulinetherapie. Het bleek dat patiënten meer tijd in
hyperglykemie (bloedglucose >10.0 mmol/l) doorbrachten tijdens geblindeerde continue
glucosesensormetingen en dat de aanvankelijke HbA1c daling, die gedurende de eerste
6 maanden na het starten van CIPII optrad, verdween. Desalniettemin zijn deze HbA1c
concentraties vergelijkbaar met de concentraties die bij deze patiënten met eerdere SC
insulinetherapie werden bereikt, terwijl het aantal episodes van een graad 2 hypoglykemie
lager ligt met CIPII.
De resultaten van Hoofdstuk 4, waarin een retrospectieve case-control studie is beschreven,
laten eveneens zien dat patiënten die met CIPII startten (n=21) in vergelijking met matig
gereguleerde T1DM-patiënten die hun SC behandelingsmodaliteit continueerden (n=74),
na een periode van 7 jaar minder hypoglykemische episodes ervoeren terwijl het HbA1c niet
verschilde tussen beide groepen.
Teneinde de glykemische situatie van een grotere groep T1DM-patiënten (n=39) die
gedurende meerdere jaren met CIPII werd behandeld op prospectieve wijze te vergelijken
met een in leeftijd en geslacht overeenkomstige populatie van met SC insuline behandelde
patiënten (n=144), is een prospectieve, observationele matched-control studie uitgevoerd,
beschreven in Hoofdstuk 5. Alhoewel de groep CIPII-behandelde patiënten meer tijd in
hyper-, en minder in euglykemie doorbracht dan de groep SC-behandelde patiënten, leidde
dit tot een niet-inferieur verschil in HbA1c concentratie van 3.0 mmol/mol (95% BI -5.0,
-1.0) (-0.27%, 95% BI -0.46, -0.09). Gezien de huidige plaats van CIPII in het therapeutische
spectrum als laatste redmiddel, met dientengevolge selectie van een complexe en uiterst
moeizaam te behandelden populatie, valt te concluderen dat de bevinding van een niet-
inferieur verschil in HbA1c het gebruik van CIPII bij geselecteerde patiënten ondersteunt.
In Hoofdstuk 7 worden, op basis van zowel bloedglucose-zelfmetingen als geblindeerde
continue glucosesensormetingen (verricht tijdens de studie beschreven in hoofdstuk 5),
de effecten van CIPII en SC insulinetoediening op de variabiliteit in glucosewaarden
beschreven. Met CIPII treedt er, ondanks hogere gemiddelde bloedglucosewaarden in
vergelijking met SC insuline behandelde patiënten, zowel binnen als tussen verschillende
dagen minder variabiliteit in glucosewaarden op.
Aangaande kwaliteit van leven blijkt uit de studies zoals beschreven in de Hoofdstukken 3 en
4 dat voorafgaande aan de start van CIPII moet worden geconstateerd dat de ervaren
gezondheidstoestand, algemene gezondheidgerelateerde kwaliteit van leven en
behandelingstevredenheid laag zijn, ook in vergelijking met een referentiegroep patiënten
die met SC insuline worden behandeld: de meeste scores bedragen slechts tweederde van
de maximale score.
Separate analyses, verricht in Hoofdstuk 3, binnen een groep personen die gedurende 6 jaar
met CIPII is behandeld, laten zien dat, in vergelijking met voorafgaande SC insulinetherapie,
de behandelingstevredenheid is toegenomen, terwijl de gezondheidstoestand en algemene
gezondheidgerelateerde kwaliteit van leven persisterend laag blijven.
De retrospectieve vergelijking tussen met CIPII en SC insulinetherapie behandelde T1DM-
patiënten, beschreven in Hoofdstuk 4, laat geen verschil zien in het beloop van de algemene
gezondheidgerelateerde kwaliteit van leven tussen beide groepen gedurende een periode
van 7 jaar. Uit de prospectieve, observationele case-control studie beschreven in Hoofdstuk 6
volgt, dat in de onderzochte T1DM-populatie de verschillen in ervaren gezondheidstoestand
en algemene gezondheidgerelateerde kwaliteit van leven tussen met CIPII en SC
chapter 12summary in dutch
188 189
insulinetherapie behandelde patiënten blijven bestaan, terwijl er nagenoeg geen verschillen
zijn in de diabetesgerelateerde kwaliteit van leven en behandelingstevredenheid.
deel iii. effecten van cipii - glucoseregulatie overstijgendIn de Hoofdstukken 8, 9 en 10 is het effect van CIPII op de GH-IGF1 as bij T1DM-patiënten
onderzocht. In Hoofdstuk 8, een post-hoc analyse van een cross-over studie waarbij CIPII
en SC insulinetoediening met elkaar zijn vergeleken, bleek dat in vergelijking met SC
insulinetherapie, CIPII gedurende 6 maanden bij 16 T1DM-patiënten resulteerde in lagere
concentraties van het IGF bindende eiwit-1. De synthese van dit eiwit, dat de bioactiviteit van
IGF1 reguleert, wordt verminderd door de aanwezigheid van insuline in de poortader.
Er waren echter geen significante verschillen in IGF1 detecteerbaar.
In Hoofdstuk 9 wordt het beloop van IGF1 concentraties bij met CIPII-behandelde T1DM-
patiënten beschreven, ook in vergelijking met voorafgaande SC insulinetherapie. Gedurende
de studieperiode van 6 jaar was er een stijging van het IGF1 en, alhoewel er verschillende
analysemethodes zijn gebruikt, lagen de concentraties gemeten aan het einde van de
studieperiode significant hoger dan kort na het starten van CIPII en tijdens de aan de CIPII
voorafgaande SC insulinetherapie.
Teneinde een meer omvattend beeld te verkrijgen zijn in Hoofdstuk 10 aanvullende indices
van de GH-IGF1 as, afgenomen op twee tijdstippen (t=0 en t=26 weken), in een omvangrijke
T1DM-populatie (n=183) onderzocht. Gedurende de studieperiode bleken IGF1 concentraties
bij CIPII behandelde patiënten (n=39) op een stabiel en in vergelijking met SC behandelde
T1DM-patiënten significant hoger niveau te liggen: 123.7 μg/l (95% BI 110.8, 138.1) versus
108.1 μg/l (95% BI 101.7, 114.9). In vergelijking met de SC insuline behandelingsgroep lagen
deze waarden voor patiënten behandeld met CIPII dichter, in een laag-normaal gebied,
bij de normaalwaarden zoals die bekend zijn bij mensen zonder diabetes mellitus. Tevens
bleken concentraties van het IGFBP1, die gedurende de studieperiode doorstegen binnen de
CIPII groep, en GH lager te zijn in de CIPII behandelde groep patiënten in vergelijking met
de SC groep.
Conclusies
Samenvattend beschrijft dit proefschrift belangrijke aspecten van CIPII bij patiënten met
T1DM. Alhoewel beperkingen in de interne en externe validiteit van de verrichte studies
nopen tot voorzichtige en weloverwogen conclusies, kan gesteld worden dat langdurige
behandeling met CIPII een veilige en effectieve therapie is voor geselecteerde patiënten met
T1DM. Het voornaamste effect van langdurige behandeling met CIPII is een reductie in de
frequentie van hypoglykemische episoden, terwijl het HbA1c acceptabel blijft. Tevens is er
sprake van een hoge behandelingstevredenheid ondanks een persisterend slecht ervaren
gezondheidstoestand en algemene gezondheidgerelateerde kwaliteit van leven. Ten slotte
kan gesteld worden dat, door de gevonden verbetering van de GH-IGF1 as gedurende
langdurige therapie met CIPII, dit proefschrift aantoont dat de positieve effecten van CIPII
bij geselecteerde patiënten met T1DM verder reiken dan alleen glucoseregulatie.
chapter 12summary in dutch
188 189
insulinetherapie behandelde patiënten blijven bestaan, terwijl er nagenoeg geen verschillen
zijn in de diabetesgerelateerde kwaliteit van leven en behandelingstevredenheid.
deel iii. effecten van cipii - glucoseregulatie overstijgendIn de Hoofdstukken 8, 9 en 10 is het effect van CIPII op de GH-IGF1 as bij T1DM-patiënten
onderzocht. In Hoofdstuk 8, een post-hoc analyse van een cross-over studie waarbij CIPII
en SC insulinetoediening met elkaar zijn vergeleken, bleek dat in vergelijking met SC
insulinetherapie, CIPII gedurende 6 maanden bij 16 T1DM-patiënten resulteerde in lagere
concentraties van het IGF bindende eiwit-1. De synthese van dit eiwit, dat de bioactiviteit van
IGF1 reguleert, wordt verminderd door de aanwezigheid van insuline in de poortader.
Er waren echter geen significante verschillen in IGF1 detecteerbaar.
In Hoofdstuk 9 wordt het beloop van IGF1 concentraties bij met CIPII-behandelde T1DM-
patiënten beschreven, ook in vergelijking met voorafgaande SC insulinetherapie. Gedurende
de studieperiode van 6 jaar was er een stijging van het IGF1 en, alhoewel er verschillende
analysemethodes zijn gebruikt, lagen de concentraties gemeten aan het einde van de
studieperiode significant hoger dan kort na het starten van CIPII en tijdens de aan de CIPII
voorafgaande SC insulinetherapie.
Teneinde een meer omvattend beeld te verkrijgen zijn in Hoofdstuk 10 aanvullende indices
van de GH-IGF1 as, afgenomen op twee tijdstippen (t=0 en t=26 weken), in een omvangrijke
T1DM-populatie (n=183) onderzocht. Gedurende de studieperiode bleken IGF1 concentraties
bij CIPII behandelde patiënten (n=39) op een stabiel en in vergelijking met SC behandelde
T1DM-patiënten significant hoger niveau te liggen: 123.7 μg/l (95% BI 110.8, 138.1) versus
108.1 μg/l (95% BI 101.7, 114.9). In vergelijking met de SC insuline behandelingsgroep lagen
deze waarden voor patiënten behandeld met CIPII dichter, in een laag-normaal gebied,
bij de normaalwaarden zoals die bekend zijn bij mensen zonder diabetes mellitus. Tevens
bleken concentraties van het IGFBP1, die gedurende de studieperiode doorstegen binnen de
CIPII groep, en GH lager te zijn in de CIPII behandelde groep patiënten in vergelijking met
de SC groep.
Conclusies
Samenvattend beschrijft dit proefschrift belangrijke aspecten van CIPII bij patiënten met
T1DM. Alhoewel beperkingen in de interne en externe validiteit van de verrichte studies
nopen tot voorzichtige en weloverwogen conclusies, kan gesteld worden dat langdurige
behandeling met CIPII een veilige en effectieve therapie is voor geselecteerde patiënten met
T1DM. Het voornaamste effect van langdurige behandeling met CIPII is een reductie in de
frequentie van hypoglykemische episoden, terwijl het HbA1c acceptabel blijft. Tevens is er
sprake van een hoge behandelingstevredenheid ondanks een persisterend slecht ervaren
gezondheidstoestand en algemene gezondheidgerelateerde kwaliteit van leven. Ten slotte
kan gesteld worden dat, door de gevonden verbetering van de GH-IGF1 as gedurende
langdurige therapie met CIPII, dit proefschrift aantoont dat de positieve effecten van CIPII
bij geselecteerde patiënten met T1DM verder reiken dan alleen glucoseregulatie.
chapter 12summary in dutch
190 191
acknowledgements
“If I have seen further it has been by standing on the shoulders of giants.” sir isaac newton ( 1643-1727 )
Deze woorden van sir Isaac Newton zijn de beste samenvatting van mijn gevoel van dank-
baarheid aan iedereen die heeft bijgedragen aan dit proefschrift. Door op hun schouders
te mogen staan is dit proefschrift geworden tot wat het nu is: een dissertatie waar ik trots
op ben. Op deze plaats wil ik graag een aantal mensen in het bijzonder bedanken voor hun
bijdrage.
Allereerst gaat mijn dank uit naar alle personen met type 1 diabetes mellitus die hun mede-
werking hebben verleend aan de onderzoeken die beschreven staan in dit proefschrift.
Ik ben hen niet alleen dankbaar voor participatie aan de onderzoeken maar vooral ook voor
het inzicht dat ze mij hiermee hebben willen geven in de wijze waarop ze met hun diabetes
omgaan. Hier heb ik ontzaglijk veel respect voor.
Hooggeleerde prof. dr. Bilo, beste Henk. Voor het allereerste begin van dit proefschrift
moeten we misschien wel 12 jaar terug in de tijd, toen je mij als scholier met een stapel dikke
anatomieboeken, een stoomcursus zoeken van medische literatuur en veel enthousiasme
hielp met mijn scriptie voor de middelbare school. Niet veel later heb je mij, als eerstejaars
geneeskundestudent op de kruk naast je, kennis laten maken met de diabetologie.
De afgelopen periode heb ik ontzettend veel van je mogen leren als promotor. Alhoewel
de manier waarop onze paden zich de afgelopen jaren hebben gekruist bijzonder is, is er in
essentie nooit iets veranderd: je bent een bron van enthousiasme, kennis, inspiratie, steun
en vertrouwen. Ik ben je hier ongelooflijk dankbaar voor.
Hooggeleerde prof. dr. Gans, beste Rijk. Ik ben bevoorrecht met jou als promotor. Voor je
kritische maar vooral ook hartelijke en inspirerende wijze van begeleiden ben ik je veel dank
verschuldigd. Bovenal wil ik je bedanken voor het vertrouwen dat je me hebt gegeven: de
afgelopen jaren als promotor en daarvoor al door mij vroeg aan te nemen voor de opleiding
190 191
acknowledgements
“If I have seen further it has been by standing on the shoulders of giants.” sir isaac newton ( 1643-1727 )
Deze woorden van sir Isaac Newton zijn de beste samenvatting van mijn gevoel van dank-
baarheid aan iedereen die heeft bijgedragen aan dit proefschrift. Door op hun schouders
te mogen staan is dit proefschrift geworden tot wat het nu is: een dissertatie waar ik trots
op ben. Op deze plaats wil ik graag een aantal mensen in het bijzonder bedanken voor hun
bijdrage.
Allereerst gaat mijn dank uit naar alle personen met type 1 diabetes mellitus die hun mede-
werking hebben verleend aan de onderzoeken die beschreven staan in dit proefschrift.
Ik ben hen niet alleen dankbaar voor participatie aan de onderzoeken maar vooral ook voor
het inzicht dat ze mij hiermee hebben willen geven in de wijze waarop ze met hun diabetes
omgaan. Hier heb ik ontzaglijk veel respect voor.
Hooggeleerde prof. dr. Bilo, beste Henk. Voor het allereerste begin van dit proefschrift
moeten we misschien wel 12 jaar terug in de tijd, toen je mij als scholier met een stapel dikke
anatomieboeken, een stoomcursus zoeken van medische literatuur en veel enthousiasme
hielp met mijn scriptie voor de middelbare school. Niet veel later heb je mij, als eerstejaars
geneeskundestudent op de kruk naast je, kennis laten maken met de diabetologie.
De afgelopen periode heb ik ontzettend veel van je mogen leren als promotor. Alhoewel
de manier waarop onze paden zich de afgelopen jaren hebben gekruist bijzonder is, is er in
essentie nooit iets veranderd: je bent een bron van enthousiasme, kennis, inspiratie, steun
en vertrouwen. Ik ben je hier ongelooflijk dankbaar voor.
Hooggeleerde prof. dr. Gans, beste Rijk. Ik ben bevoorrecht met jou als promotor. Voor je
kritische maar vooral ook hartelijke en inspirerende wijze van begeleiden ben ik je veel dank
verschuldigd. Bovenal wil ik je bedanken voor het vertrouwen dat je me hebt gegeven: de
afgelopen jaren als promotor en daarvoor al door mij vroeg aan te nemen voor de opleiding
192 193
interne geneeskunde. Zo veel vertrouwen is weergaloos: het heeft een belangrijk stempel
gedrukt op de wijze waarop ik de afgelopen jaren heb kunnen functioneren.
Weledelzeergeleerde dr. Kleefstra, beste Nanno. Ik ben bijzonder blij, vereerd zelfs, dat jij
mijn copromotor bent. Dag in, dag uit heb je de afgelopen jaren voor me klaargestaan,
ondanks alle tegenwind die je zelf hebt gehad. Je stimuleert, bent kritisch, standvastig tot
het tegendeel bewezen is en gaat alleen voor goud. Je hebt mij laten zien dat het verrichten
van onderzoek topsport is. Hierdoor is de naam ‘Kleefstra N’ bij een publicatie tot een kwaliteits-
keurmerk verworden.
Weledelzeergeleerde dr. Logtenberg, beste Susan. Wat heb ik een ontzettend geluk gehad
dat jij mij bent voorgegaan in het onderzoek naar intraperitoneale insuline toediening en
dat je mijn copromotor bent! Je snelle, heldere en kordate manier van werken heb ik als
bijzonder prettig ervaren. Ik hoop dat we onze samenwerking en deze onderzoekslijn nog
lang kunnen voortzetten.
Weledelzeergeleerde dr. Groenier, beste Klaas. Ik ben je veel dank verontschuldigd voor
je hulp in de statistische analyses van de studies in dit proefschrift. Ingewikkelde materie
inzichtelijk en interessant maken maar tegelijkertijd ook nuanceren, zoals jij dat kunt, is
voorbehouden aan een zeer select gezelschap: wat dat aangaat ben je de Bob Ross van de
statistiek.
Alle mede-auteurs van de hoofdstukken in dit proefschrift wil ik bedanken voor hun kritische
commentaren en, vooral, de prettige samenwerking.
Prof. dr. Wolffenbuttel, prof. dr. de Koning en prof. dr. Arnqvist wil ik bedanken voor hun bereid-
willigheid om zitting te nemen in de leescommissie en het goedkeuren van dit proefschrift.
Tijdens mijn studie in Nijmegen heb ik mijn eerste echte stappen in de wetenschap mogen
zetten onder de vleugels van dr. Martine Ploeg, prof. dr. Bart Kiemeney en prof. dr. Fred Witjes
op de afdeling urologie en, later, dr. Jan van den Brand, dr. Julia Hofstra en prof dr. Jack Wetzels
op de afdeling nefrologie. Zonder jullie steun en geduld was ik nooit tot mijn eerste publicatie
en congrespresentatie gekomen. De basis van wetenschappelijk onderzoek ligt in de kliniek.
Daarom wil ik prof. dr. Jaques Lenders, dr. Mirian Janssen, dr. Wim Willemsen en dr. Paul
Groeneveld bedanken voor de wijze waarop ze mij tot arts hebben gevormd: hiervan heb ik
als promovendus iedere dag geprofiteerd.
Vanuit Nijmegen ben ik in dé Zwolse onderzoeksgroep terecht gekomen. Een groep van
ambitieuze, talentvolle en hardwerkende onderzoekers uit verschillende medische disciplines.
Het is geen toeval dat we met deze groep veel en hoog scoren met klinisch relevant
diabetesonderzoek. Angelien, Alaa, Bas, Gijs, Hans, Leonie, Ilse, Iefke, Helen, Esther, Yvonne,
Steven, Hanneke en Hanneke: bedankt dat ik deel van jullie team mag uitmaken en nu mag
aansluiten in de rij van promovendi. De lat ligt hoog!
In dezelfde adem wil ik hier Anneke, Corry en Greetje bedanken voor hun hulp bij alle
randzaken van het onderzoek en, niet in de laatste plaats, omdat zij eerdergenoemde onder-
zoeksgroep in bedwang weten te houden.
Een van de meest aantrekkelijke ‘verplichtingen’ van een Zwols promotietraject is het begeleiden
van onbevangen en getalenteerde studenten. Dinante, Larissa, Steven en Margarita:
bedankt dat ik jullie heb mogen begeleiden.
Alle studies in dit proefschrift zijn verricht binnen het Isala ziekenhuis in Zwolle. Hiermee
toont de Isala wederom aan dat een perifeer (top)klinisch ziekenhuis vruchtbare grond is
voor wetenschappelijk onderzoek. Ik besef dat dit niet vanzelfsprekend is en naast de hoop
uit te spreken dat deze positie bestendigt, ben ik alle betrokkenen hier dankbaar voor.
De Zwolse internisten wil ik bedanken voor de samenwerking en de mogelijkheid om binnen
de afdeling interne geneeskunde onderzoek te mogen verrichten.
De medewerkers van het klinisch chemisch laboratorium van de Isala, met name Marieke
van der Saag, Marc Slingschroder en Jack van Dijk, wil ik bedanken voor hun rol in het opzetten
en uitvoeren van de studies in dit proefschrift.
De diabetesverpleegkundigen en physician assistant van het diabetes centrum zijn van
onschatbare waarde geweest voor dit proefschrift. Anita, Anne-Marijke, Dineke, Folkje, Gonny,
Hélöise, Hilma, Lianne, Mariska, Esther, Huib, Folkje, Gerrie: bedankt voor de hartelijke
samenwerking de afgelopen jaren en voor alle extra stappen die jullie hebben willen zetten.
Zonder een secretariaat is een afdeling, maar zeker ook een promovendus, hulpeloos. Aline,
Carolien, Henriëtte, Joke, Ineke, Miranda en Martine: bedankt voor alles.
Voor de onderdelen van dit proefschrift die in het Diaconessen ziekenhuis in Meppel zijn
verricht gaat mijn dank uit naar de afdeling interne geneeskunde, dr. Hans Feenstra, Gina en
Elise in het bijzonder.
acknowledgements acknowledgements
192 193
interne geneeskunde. Zo veel vertrouwen is weergaloos: het heeft een belangrijk stempel
gedrukt op de wijze waarop ik de afgelopen jaren heb kunnen functioneren.
Weledelzeergeleerde dr. Kleefstra, beste Nanno. Ik ben bijzonder blij, vereerd zelfs, dat jij
mijn copromotor bent. Dag in, dag uit heb je de afgelopen jaren voor me klaargestaan,
ondanks alle tegenwind die je zelf hebt gehad. Je stimuleert, bent kritisch, standvastig tot
het tegendeel bewezen is en gaat alleen voor goud. Je hebt mij laten zien dat het verrichten
van onderzoek topsport is. Hierdoor is de naam ‘Kleefstra N’ bij een publicatie tot een kwaliteits-
keurmerk verworden.
Weledelzeergeleerde dr. Logtenberg, beste Susan. Wat heb ik een ontzettend geluk gehad
dat jij mij bent voorgegaan in het onderzoek naar intraperitoneale insuline toediening en
dat je mijn copromotor bent! Je snelle, heldere en kordate manier van werken heb ik als
bijzonder prettig ervaren. Ik hoop dat we onze samenwerking en deze onderzoekslijn nog
lang kunnen voortzetten.
Weledelzeergeleerde dr. Groenier, beste Klaas. Ik ben je veel dank verontschuldigd voor
je hulp in de statistische analyses van de studies in dit proefschrift. Ingewikkelde materie
inzichtelijk en interessant maken maar tegelijkertijd ook nuanceren, zoals jij dat kunt, is
voorbehouden aan een zeer select gezelschap: wat dat aangaat ben je de Bob Ross van de
statistiek.
Alle mede-auteurs van de hoofdstukken in dit proefschrift wil ik bedanken voor hun kritische
commentaren en, vooral, de prettige samenwerking.
Prof. dr. Wolffenbuttel, prof. dr. de Koning en prof. dr. Arnqvist wil ik bedanken voor hun bereid-
willigheid om zitting te nemen in de leescommissie en het goedkeuren van dit proefschrift.
Tijdens mijn studie in Nijmegen heb ik mijn eerste echte stappen in de wetenschap mogen
zetten onder de vleugels van dr. Martine Ploeg, prof. dr. Bart Kiemeney en prof. dr. Fred Witjes
op de afdeling urologie en, later, dr. Jan van den Brand, dr. Julia Hofstra en prof dr. Jack Wetzels
op de afdeling nefrologie. Zonder jullie steun en geduld was ik nooit tot mijn eerste publicatie
en congrespresentatie gekomen. De basis van wetenschappelijk onderzoek ligt in de kliniek.
Daarom wil ik prof. dr. Jaques Lenders, dr. Mirian Janssen, dr. Wim Willemsen en dr. Paul
Groeneveld bedanken voor de wijze waarop ze mij tot arts hebben gevormd: hiervan heb ik
als promovendus iedere dag geprofiteerd.
Vanuit Nijmegen ben ik in dé Zwolse onderzoeksgroep terecht gekomen. Een groep van
ambitieuze, talentvolle en hardwerkende onderzoekers uit verschillende medische disciplines.
Het is geen toeval dat we met deze groep veel en hoog scoren met klinisch relevant
diabetesonderzoek. Angelien, Alaa, Bas, Gijs, Hans, Leonie, Ilse, Iefke, Helen, Esther, Yvonne,
Steven, Hanneke en Hanneke: bedankt dat ik deel van jullie team mag uitmaken en nu mag
aansluiten in de rij van promovendi. De lat ligt hoog!
In dezelfde adem wil ik hier Anneke, Corry en Greetje bedanken voor hun hulp bij alle
randzaken van het onderzoek en, niet in de laatste plaats, omdat zij eerdergenoemde onder-
zoeksgroep in bedwang weten te houden.
Een van de meest aantrekkelijke ‘verplichtingen’ van een Zwols promotietraject is het begeleiden
van onbevangen en getalenteerde studenten. Dinante, Larissa, Steven en Margarita:
bedankt dat ik jullie heb mogen begeleiden.
Alle studies in dit proefschrift zijn verricht binnen het Isala ziekenhuis in Zwolle. Hiermee
toont de Isala wederom aan dat een perifeer (top)klinisch ziekenhuis vruchtbare grond is
voor wetenschappelijk onderzoek. Ik besef dat dit niet vanzelfsprekend is en naast de hoop
uit te spreken dat deze positie bestendigt, ben ik alle betrokkenen hier dankbaar voor.
De Zwolse internisten wil ik bedanken voor de samenwerking en de mogelijkheid om binnen
de afdeling interne geneeskunde onderzoek te mogen verrichten.
De medewerkers van het klinisch chemisch laboratorium van de Isala, met name Marieke
van der Saag, Marc Slingschroder en Jack van Dijk, wil ik bedanken voor hun rol in het opzetten
en uitvoeren van de studies in dit proefschrift.
De diabetesverpleegkundigen en physician assistant van het diabetes centrum zijn van
onschatbare waarde geweest voor dit proefschrift. Anita, Anne-Marijke, Dineke, Folkje, Gonny,
Hélöise, Hilma, Lianne, Mariska, Esther, Huib, Folkje, Gerrie: bedankt voor de hartelijke
samenwerking de afgelopen jaren en voor alle extra stappen die jullie hebben willen zetten.
Zonder een secretariaat is een afdeling, maar zeker ook een promovendus, hulpeloos. Aline,
Carolien, Henriëtte, Joke, Ineke, Miranda en Martine: bedankt voor alles.
Voor de onderdelen van dit proefschrift die in het Diaconessen ziekenhuis in Meppel zijn
verricht gaat mijn dank uit naar de afdeling interne geneeskunde, dr. Hans Feenstra, Gina en
Elise in het bijzonder.
acknowledgements acknowledgements
194 195
Familie en vrienden, bedankt voor al jullie steun en niet aflatende interesse in mijn werk,
hoe abstract het ‘doen van onderzoek’ soms ook heeft geklonken.
Vader, moeder, Esther, Mirjam en Emma. Zonder jullie liefde en steun had ik hier niet gestaan.
Lieve Marije, niets is mooier dan samen met jou er op uit te trekken. Van het besef dat er nog
zoveel op ons wacht kan ik alleen maar heel gelukkig worden. Kom je mee?
acknowledgements
194 195
Familie en vrienden, bedankt voor al jullie steun en niet aflatende interesse in mijn werk,
hoe abstract het ‘doen van onderzoek’ soms ook heeft geklonken.
Vader, moeder, Esther, Mirjam en Emma. Zonder jullie liefde en steun had ik hier niet gestaan.
Lieve Marije, niets is mooier dan samen met jou er op uit te trekken. Van het besef dat er nog
zoveel op ons wacht kan ik alleen maar heel gelukkig worden. Kom je mee?
acknowledgements
196 197
articlesVan Dijk PR, Kramer A, Logtenberg SJJ, Hoitsma AJ, Kleefstra N, Jager KJ, Bilo HJG.
Incidence of renal replacement therapy for diabetic nephropathy in The Netherlands: Dutch
diabetes estimates (DUDE)-3. BMJ Open (accepted for publication).
Hendriks SH, van Dijk PR, Groenier KH, Houpt P, Bilo HJG, Kleefstra N. Type 2 diabetes seems
not to be a risk factor for the carpal tunnel syndrome: a case control study. BMC Musculoskelet
Disord. 2014; 15: 346.
Van Dijk PR, Logtenberg SJJ, Gans ROB, Bilo HJG, Kleefstra N. Intraperitoneal insulin infusion:
treatment option for type 1 diabetes resulting in beneficial endocrine effects beyond glycaemia.
Clin Endocrinol (Oxf) 2014; 81: 488-97.
Van Dijk PR, Logtenberg SJJ, Groenier KH, Gans ROB, Bilo HJG, Kleefstra N. Report of a 7 year
case-control study of continuous intraperitoneal insulin infusion and subcutaneous insulin
therapy among patients with poorly controlled type 1 diabetes mellitus: Favourable effects
on hypoglycaemic episodes. Diabetes Res Clin Pract. 2014 [Epub ahead of print].
Van Dijk PR, Logtenberg SJJ, Groenier KH, Kleefstra N, Bilo H, Arnqvist H. Effect of intra-
peritoneal insulin administration on IGF1 and IGFBP1 in type 1 diabetes. Endocr Connect
2014 ;3: 17-23.
Landman GWD, de Bock GH, van Hateren KJJ, van Dijk PR, Groenier KH, Gans ROB, Houweling ST,
Bilo HJG, Kleefstra N. Safety and efficacy of gliclazide as treatment for type 2 diabetes:
a systematic review and meta-analysis of randomized trials. PloS One 2014; 9: e82880.
Van Dijk PR, Logtenberg SJ, Groenier KH, Keers JC, Bilo HJG, Kleefstra N. Fifteen-year follow-up
of quality of life in type 1 diabetes mellitus. World J Diabetes 2014; 5: 569-76.
Landman GWD, van Dijk PR, Drion I, van Hateren KJJ, Struck J, Groenier KH, Gans RO, Bilo HJ,
Bakker SJ, Kleefstra N. Mid-Regional fragment of pro-Adrenomedullin, new-onset Albuminuria,
Cardiovascular and all-cause Mortality in Patients with Type 2 Diabetes (ZODIAC-30).
Diabetes Care 2014; 37: 839-45.
curriculum vitae publications
Peter Ruben van Dijk was born in Zwolle, The Netherlands on October 7th, 1986.
After finishing VWO at Carolus Clusius College in Zwolle, he started medical school at the
Radboud University Nijmegen in 2005. During his study, he participated in scientific research
towards muscle invasive bladder cancer at the department of Urology and idiopatic
membranous nephropathy at the department of Nephrology. After finishing medical school,
Peter started his PhD at the Isala Diabetes Centre in Zwolle studying continuous intra-
peritoneal insulin infusion in type 1 diabetes mellitus (promoters prof. dr. H.J.G. Bilo and
prof. dr. R.O.B. Gans). After the defence of his thesis he will start his clinical training in internal
medicine at the Isala (dr. P.H.P. Groeneveld) and the University Medical Centre Groningen
(prof. dr. R.O.B. Gans).
curriculum vitae publications
196 197
articlesVan Dijk PR, Kramer A, Logtenberg SJJ, Hoitsma AJ, Kleefstra N, Jager KJ, Bilo HJG.
Incidence of renal replacement therapy for diabetic nephropathy in The Netherlands: Dutch
diabetes estimates (DUDE)-3. BMJ Open (accepted for publication).
Hendriks SH, van Dijk PR, Groenier KH, Houpt P, Bilo HJG, Kleefstra N. Type 2 diabetes seems
not to be a risk factor for the carpal tunnel syndrome: a case control study. BMC Musculoskelet
Disord. 2014; 15: 346.
Van Dijk PR, Logtenberg SJJ, Gans ROB, Bilo HJG, Kleefstra N. Intraperitoneal insulin infusion:
treatment option for type 1 diabetes resulting in beneficial endocrine effects beyond glycaemia.
Clin Endocrinol (Oxf) 2014; 81: 488-97.
Van Dijk PR, Logtenberg SJJ, Groenier KH, Gans ROB, Bilo HJG, Kleefstra N. Report of a 7 year
case-control study of continuous intraperitoneal insulin infusion and subcutaneous insulin
therapy among patients with poorly controlled type 1 diabetes mellitus: Favourable effects
on hypoglycaemic episodes. Diabetes Res Clin Pract. 2014 [Epub ahead of print].
Van Dijk PR, Logtenberg SJJ, Groenier KH, Kleefstra N, Bilo H, Arnqvist H. Effect of intra-
peritoneal insulin administration on IGF1 and IGFBP1 in type 1 diabetes. Endocr Connect
2014 ;3: 17-23.
Landman GWD, de Bock GH, van Hateren KJJ, van Dijk PR, Groenier KH, Gans ROB, Houweling ST,
Bilo HJG, Kleefstra N. Safety and efficacy of gliclazide as treatment for type 2 diabetes:
a systematic review and meta-analysis of randomized trials. PloS One 2014; 9: e82880.
Van Dijk PR, Logtenberg SJ, Groenier KH, Keers JC, Bilo HJG, Kleefstra N. Fifteen-year follow-up
of quality of life in type 1 diabetes mellitus. World J Diabetes 2014; 5: 569-76.
Landman GWD, van Dijk PR, Drion I, van Hateren KJJ, Struck J, Groenier KH, Gans RO, Bilo HJ,
Bakker SJ, Kleefstra N. Mid-Regional fragment of pro-Adrenomedullin, new-onset Albuminuria,
Cardiovascular and all-cause Mortality in Patients with Type 2 Diabetes (ZODIAC-30).
Diabetes Care 2014; 37: 839-45.
curriculum vitae publications
Peter Ruben van Dijk was born in Zwolle, The Netherlands on October 7th, 1986.
After finishing VWO at Carolus Clusius College in Zwolle, he started medical school at the
Radboud University Nijmegen in 2005. During his study, he participated in scientific research
towards muscle invasive bladder cancer at the department of Urology and idiopatic
membranous nephropathy at the department of Nephrology. After finishing medical school,
Peter started his PhD at the Isala Diabetes Centre in Zwolle studying continuous intra-
peritoneal insulin infusion in type 1 diabetes mellitus (promoters prof. dr. H.J.G. Bilo and
prof. dr. R.O.B. Gans). After the defence of his thesis he will start his clinical training in internal
medicine at the Isala (dr. P.H.P. Groeneveld) and the University Medical Centre Groningen
(prof. dr. R.O.B. Gans).
curriculum vitae publications
198 199
Landman GWD, van Hateren KJJ, van Dijk PR, Logtenberg SJJ, Houweling ST, Groenier KH,
Bilo HJG, Kleefstra N. Efficacy of Device-Guided Breathing for Hypertension in Blinded,
Randomized, Active-Controlled Trials: A Meta-analysis of Individual Patient Data.
JAMA Intern Med 2014; 174: 1815-21.
Van Dijk PR, Logtenberg SJJ, Groenier KH, Gans ROB, Kleefstra N, Bilo HJG. Continuous
intraperitoneal insulin infusion in type 1 diabetes: a 6-year post-trial follow-up. BMC Endocr
Disord 2014; 14: 30.
Van den Brand JAJG, van Dijk PR, Hofstra JM, Wetzels JFM. Cancer risk after cyclophos-
phamide treatment in idiopathic membranous nephropathy. Clin J Am Soc Nephrol 2014;
9(6): 1066-73.
Van den Brand JAJG, van Dijk PR, Hofstra JM, Wetzels JFM. Long-term outcomes in idiopathic
membranous nephropathy using a restrictive treatment strategy. J Am Soc Nephrol 2014;
25: 150-8.
Van Dijk PR, Landman GWD, van Hateren KJJ, Logtenberg SJJ, Bilo HJG, Kleefstra N. Call for
a re-evaluation of the American Heart Association’s standpoint concerning device-guided
slow breathing using the RESPeRATE device. Hypertension 2013; 62: e17.
Logtenberg SJJ, Van Dijk PR, Kleefstra N, Bilo HJG. Continuous intraperitoneal insulin infusion;
the Dutch experience - 2013 update. Infusystems Int 2013; 8: 33-8.
De Groot-Kamphuis DM, van Dijk PR, Groenier KH, Houweling ST, Bilo HJG, Kleefstra N.
Vitamin B12 deficiency and the lack of its consequences in type 2 diabetes patients using
metformin. Neth J Med 2013; 71: 386-90.
Van Dijk PR, Ham JC, Bloembergen P, Groeneveld PHP. Capnocytophaga canimorsus
bacteriëmie: niet alleen door een bijtwond. Tijdschrift voor infectieziekten 2013; 1: 22-6.
Van Dijk PR, Franken AA, Groeneveld PHP. Verhoogde bezinking uit de tropen. Tijdschrift
voor infectieziekten 2012; 7: 104.
Van Dijk PR, Landman GWD, Bilo HJG. Role of metformin in diabetes treatment - is
metformin falling from grace? Ned Tijdschr Geneeskd 2012; 156: A5297.
Van Dijk PR, Van Beukering M, Goessens B, Pal T. Veneuze trombo-embolieën en vliegreizen:
betekenis voor de bedrijfsarts. Tijdschrift voor bedrijfs- en verzekeringsgeneeskunde 2011;
8: 357-60.
Van Dijk PR, Ploeg M, Aben KKH, Weijerman PC, Karthaus HFM, van Berkel JTH, Viddeleer
AC, Geboers A, van Boven E, Witjes JA, Kiemeney LA. Downstaging of TURBT-Based Muscle-
Invasive Bladder Cancer by Radical Cystectomy Predicts Better Survival. ISRN Urol 2011; 2011:
458930.
books Van Dijk PR, Hendriks SH, Houweling ST, Bilo HJG, Kleefstra N, Verhoeven S. Problemen bij
diabetes - 40 casus uit de dagelijkse praktijk. Langerhans school of diabetes. 2014.
publicationspublications
198 199
Landman GWD, van Hateren KJJ, van Dijk PR, Logtenberg SJJ, Houweling ST, Groenier KH,
Bilo HJG, Kleefstra N. Efficacy of Device-Guided Breathing for Hypertension in Blinded,
Randomized, Active-Controlled Trials: A Meta-analysis of Individual Patient Data.
JAMA Intern Med 2014; 174: 1815-21.
Van Dijk PR, Logtenberg SJJ, Groenier KH, Gans ROB, Kleefstra N, Bilo HJG. Continuous
intraperitoneal insulin infusion in type 1 diabetes: a 6-year post-trial follow-up. BMC Endocr
Disord 2014; 14: 30.
Van den Brand JAJG, van Dijk PR, Hofstra JM, Wetzels JFM. Cancer risk after cyclophos-
phamide treatment in idiopathic membranous nephropathy. Clin J Am Soc Nephrol 2014;
9(6): 1066-73.
Van den Brand JAJG, van Dijk PR, Hofstra JM, Wetzels JFM. Long-term outcomes in idiopathic
membranous nephropathy using a restrictive treatment strategy. J Am Soc Nephrol 2014;
25: 150-8.
Van Dijk PR, Landman GWD, van Hateren KJJ, Logtenberg SJJ, Bilo HJG, Kleefstra N. Call for
a re-evaluation of the American Heart Association’s standpoint concerning device-guided
slow breathing using the RESPeRATE device. Hypertension 2013; 62: e17.
Logtenberg SJJ, Van Dijk PR, Kleefstra N, Bilo HJG. Continuous intraperitoneal insulin infusion;
the Dutch experience - 2013 update. Infusystems Int 2013; 8: 33-8.
De Groot-Kamphuis DM, van Dijk PR, Groenier KH, Houweling ST, Bilo HJG, Kleefstra N.
Vitamin B12 deficiency and the lack of its consequences in type 2 diabetes patients using
metformin. Neth J Med 2013; 71: 386-90.
Van Dijk PR, Ham JC, Bloembergen P, Groeneveld PHP. Capnocytophaga canimorsus
bacteriëmie: niet alleen door een bijtwond. Tijdschrift voor infectieziekten 2013; 1: 22-6.
Van Dijk PR, Franken AA, Groeneveld PHP. Verhoogde bezinking uit de tropen. Tijdschrift
voor infectieziekten 2012; 7: 104.
Van Dijk PR, Landman GWD, Bilo HJG. Role of metformin in diabetes treatment - is
metformin falling from grace? Ned Tijdschr Geneeskd 2012; 156: A5297.
Van Dijk PR, Van Beukering M, Goessens B, Pal T. Veneuze trombo-embolieën en vliegreizen:
betekenis voor de bedrijfsarts. Tijdschrift voor bedrijfs- en verzekeringsgeneeskunde 2011;
8: 357-60.
Van Dijk PR, Ploeg M, Aben KKH, Weijerman PC, Karthaus HFM, van Berkel JTH, Viddeleer
AC, Geboers A, van Boven E, Witjes JA, Kiemeney LA. Downstaging of TURBT-Based Muscle-
Invasive Bladder Cancer by Radical Cystectomy Predicts Better Survival. ISRN Urol 2011; 2011:
458930.
books Van Dijk PR, Hendriks SH, Houweling ST, Bilo HJG, Kleefstra N, Verhoeven S. Problemen bij
diabetes - 40 casus uit de dagelijkse praktijk. Langerhans school of diabetes. 2014.
publicationspublications
200 201
This thesis is published within the Diabetes Centre of the Isala in Zwolle. Previous dissertations
at the Diabetes Centre:
Drion I. (2014) Renal function estimation: the implications for clinical practice. Promotores:
prof. dr. H.J.G. Bilo, prof. dr. J.F.M. Wetzels Copromotor: dr. N. Kleefstra.
Joosten J.M.H. (2014) Defining risk factors associated with renal and cognitive dysfunction.
Promotores: prof. dr. H.J.G. Bilo, prof. dr. J.P.J. Slaets. Copromotores: dr. R.T. Gansevoort, dr.
G.J. Izaks.
Hortensius J. (2013) Self-monitoring of blood glucose in insulin-treated patients with
diabetes. Promotores: prof. dr. H.J.G. Bilo, prof. dr. R.O.B. Gans. Copromotores: dr. J.J. van der
Bijl, dr. N. Kleefstra.
Alkhalaf A. (2013) Novel approaches in Diabetic Nephropathy. Promotores: prof. dr. G.J.
Navis, prof. dr. H.J.G. Bilo. Copromotores: dr. S.J.L. Bakker, dr. N. Kleefstra.
Hateren K.J.J. (2013) Diabetes care in old age. Promotores: prof. dr. H.J.G. Bilo, prof. dr. K. van
der Meer. Copromotores: dr. N. Kleefstra, dr. S.T. Houweling.
Gerrits E.G. (2013) Cardiovascular risk and its determinants in high risk patients. Promotores:
prof. dr. H.J.G. Bilo, prof. dr. R.O.B. Gans. Copromotores: dr. A.J. Smit, dr. H.L. Lutgers.
Landman G.W.D. (2012) Mortality predictors in patients with type 2 diabetes. Promotores:
prof. dr. H.J.G. Bilo, prof. dr. R.O.B. Gans. Copromotores: dr. N. Kleefstra, dr K.H. Groenier.
Lenters-Westra W.B. (2011) Hemoglobin A1c: Standardisation, analytical performance and
interpretation. Promotores: prof. dr. H.J.G. Bilo, prof. dr. R.O.B. Gans. Copromotores: dr. R.J.
Slingerland.
Kleefstra N. (2010) Self-care interventions in type 2 diabetes. Promotores: prof. dr. H.J.G. Bilo,
prof. dr. R.O.B. Gans. Copromotores: dr. S.T. Houweling, dr. K.H. Groenier.
Logtenberg S.J.J. (2010) Intensive insulin therapy and glucose management. Studies with the
implantable pump and a glucose sensor. Promotores: prof. dr. H.J.G. Bilo, prof. dr. R.O.B. Gans.
Lutgers H.L. (2008) Skin autofluorescence in diabetes mellitus. Promotores: prof. dr. R.O.B.
Gans, prof. dr. H.J.G. Bilo. Copromotores: dr. A.J. Smit, dr. Ir. R. Graaff, dr. T.P. Links.
Van der Horst I.C. (2005) Metabolic interventions in acute myocardial infarction.
Promotoreres: prof. dr. F. Zijlstra, prof. dr. R.O.B. Gans. Copromotor: dr. H.J.G. Bilo.
Houweling S.T. (2005) Taakdelegatie in de eerste- en tweedelijns diabeteszorg; Resultaten
van de DISCOURSE studies. Promotor: prof. dr. B. Meyboom-de Jong. Copromotor: dr. H.J.G.
Bilo.
Ubink-Veltmaat L.J. (2004) Type 2 diabetes mellitus in a Dutch region. Epidemiology and
shared care. Promotor: prof. dr. B. Meyboom-de Jong. Copromotor: dr. H.J.G. Bilo.
Hart H.E. (2004) Health related quality of life in patients with diabetes mellitus type I.
Promotoreres: prof. dr. M. Berg, prof. dr. B. Meyboom-de Jong. Copromotor: dr. H.J.G. Bilo.
De Visser C.L. (2003) Health and health risk on Urk. A study about cardiovascular disease and
type 2 diabetes. Promotor: prof. dr. B. Meyboom-de Jong. Copromotor: dr. H.J.G. Bilo.
Assink J.H. (1998) Oxidative stress and health status in patients with insulindependent
diabetes mellitus. Promotor: prof. dr. D. Grobbee. Copromotor: dr. H.J.G. Bilo.
Goddijn P.P.M. (1997) Improving metabolic control in NIDDM patients referred for
insulin therapy. Promotor: prof. dr. B. Meyboom-de Jong. Copromotor: dr. H.J.G. Bilo.
previous dissertations
previous dissertationsprevious dissertations
200 201
This thesis is published within the Diabetes Centre of the Isala in Zwolle. Previous dissertations
at the Diabetes Centre:
Drion I. (2014) Renal function estimation: the implications for clinical practice. Promotores:
prof. dr. H.J.G. Bilo, prof. dr. J.F.M. Wetzels Copromotor: dr. N. Kleefstra.
Joosten J.M.H. (2014) Defining risk factors associated with renal and cognitive dysfunction.
Promotores: prof. dr. H.J.G. Bilo, prof. dr. J.P.J. Slaets. Copromotores: dr. R.T. Gansevoort, dr.
G.J. Izaks.
Hortensius J. (2013) Self-monitoring of blood glucose in insulin-treated patients with
diabetes. Promotores: prof. dr. H.J.G. Bilo, prof. dr. R.O.B. Gans. Copromotores: dr. J.J. van der
Bijl, dr. N. Kleefstra.
Alkhalaf A. (2013) Novel approaches in Diabetic Nephropathy. Promotores: prof. dr. G.J.
Navis, prof. dr. H.J.G. Bilo. Copromotores: dr. S.J.L. Bakker, dr. N. Kleefstra.
Hateren K.J.J. (2013) Diabetes care in old age. Promotores: prof. dr. H.J.G. Bilo, prof. dr. K. van
der Meer. Copromotores: dr. N. Kleefstra, dr. S.T. Houweling.
Gerrits E.G. (2013) Cardiovascular risk and its determinants in high risk patients. Promotores:
prof. dr. H.J.G. Bilo, prof. dr. R.O.B. Gans. Copromotores: dr. A.J. Smit, dr. H.L. Lutgers.
Landman G.W.D. (2012) Mortality predictors in patients with type 2 diabetes. Promotores:
prof. dr. H.J.G. Bilo, prof. dr. R.O.B. Gans. Copromotores: dr. N. Kleefstra, dr K.H. Groenier.
Lenters-Westra W.B. (2011) Hemoglobin A1c: Standardisation, analytical performance and
interpretation. Promotores: prof. dr. H.J.G. Bilo, prof. dr. R.O.B. Gans. Copromotores: dr. R.J.
Slingerland.
Kleefstra N. (2010) Self-care interventions in type 2 diabetes. Promotores: prof. dr. H.J.G. Bilo,
prof. dr. R.O.B. Gans. Copromotores: dr. S.T. Houweling, dr. K.H. Groenier.
Logtenberg S.J.J. (2010) Intensive insulin therapy and glucose management. Studies with the
implantable pump and a glucose sensor. Promotores: prof. dr. H.J.G. Bilo, prof. dr. R.O.B. Gans.
Lutgers H.L. (2008) Skin autofluorescence in diabetes mellitus. Promotores: prof. dr. R.O.B.
Gans, prof. dr. H.J.G. Bilo. Copromotores: dr. A.J. Smit, dr. Ir. R. Graaff, dr. T.P. Links.
Van der Horst I.C. (2005) Metabolic interventions in acute myocardial infarction.
Promotoreres: prof. dr. F. Zijlstra, prof. dr. R.O.B. Gans. Copromotor: dr. H.J.G. Bilo.
Houweling S.T. (2005) Taakdelegatie in de eerste- en tweedelijns diabeteszorg; Resultaten
van de DISCOURSE studies. Promotor: prof. dr. B. Meyboom-de Jong. Copromotor: dr. H.J.G.
Bilo.
Ubink-Veltmaat L.J. (2004) Type 2 diabetes mellitus in a Dutch region. Epidemiology and
shared care. Promotor: prof. dr. B. Meyboom-de Jong. Copromotor: dr. H.J.G. Bilo.
Hart H.E. (2004) Health related quality of life in patients with diabetes mellitus type I.
Promotoreres: prof. dr. M. Berg, prof. dr. B. Meyboom-de Jong. Copromotor: dr. H.J.G. Bilo.
De Visser C.L. (2003) Health and health risk on Urk. A study about cardiovascular disease and
type 2 diabetes. Promotor: prof. dr. B. Meyboom-de Jong. Copromotor: dr. H.J.G. Bilo.
Assink J.H. (1998) Oxidative stress and health status in patients with insulindependent
diabetes mellitus. Promotor: prof. dr. D. Grobbee. Copromotor: dr. H.J.G. Bilo.
Goddijn P.P.M. (1997) Improving metabolic control in NIDDM patients referred for
insulin therapy. Promotor: prof. dr. B. Meyboom-de Jong. Copromotor: dr. H.J.G. Bilo.
previous dissertations
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