guntram schernthaner · kaplan-meier curves for remaining free of chd and stroke during 22-year...
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Insulin resistance and Beta cell failure:
Relevance for diabetes development, prognosis and treatment decisions
Guntram Schernthaner
Medical University of Vienna, Austria
The “classic” concept:Development of T2DM depends on interplay between insulin resistance and beta-cell dysfunction
Gerich JE. Mayo Clin Proc. 2003;78:447-56.
Insulin resistance
Insulin resistance
Abnormalbeta-cell function
Relative insulin
deficiencyT2DM
Compensatory hyperinsulinaemia
No diabetes
Genes and environment
Normalbeta-cell function
Genes and environment
Beta cell dysfunction is a critical determinant for type 2 diabetes
Kasuga et al. Clin Invest. 2006;116 :1756-1760.
Adipokines InflammationFFAs
Insulin
resistance
Obesity
Adipocytes
Vasculature
Pancreatic islets beta cell compensation beta cell failure
Insulin secretion
by beta cells
Normal Increased Decreased
Blood glucose Normal Normal or impaired
glucose tolerance
Diabetes mellitus
Causes of beta-cell dysfunction in T2DM
DeFronzo RA. Diabetes. 2009;58:773-95.
Beta-celldysfunction
Amyloid(islet amyloidpolypeptide)deposition
Insulinresistance
Genetics(e.g. TCF 7L2)
Age
↓ Incretin effect
Glucose toxicityLipotoxicity
↑ Free fatty acids
ß-cell Volume Is Reduced by 40% in Patients with IFG and Up to 60% with Type 2 Diabetes Mellitus (DM)
Data derived from Butler AE et al. Diabetes 2003;52(1):102-110.
0
0.5
1
1.5
2
2.5
3ß
-cell v
olu
me (
%)
Lean
40% reduction
p<0.05
63% reduction
p<0.001
Nondiabetic
IFG
Type 2 DM
42% reduction
p<0.05
Obese
N=124 autopsies
IFG: Impaired Fasting Glucose
-cell function decline in DM2 regardless of intervention:
the need of early intervention
UKPDS Group. Diabetes 1995;44:1249-58
0
20
40
60
80
100
–5 –4 –3 –2 –1 0 1 2 3 4 5 6
Years Since Diagnosis
Sulfonylurea
Diet
Metformin
β-C
ell F
un
cti
on
(%
)*
Progressive loss of beta-cell function
occurs prior to diagnosis
*beta-cell function measured by HOMA
Which treatment options do we have to stop
or even reverse the progression of ß-cell
dysfunction in patients with type 2 diabetes?
QUARTET: Mean changes of FPG over two years from baseline
after addition of Pioglitazone or Gliclazide to Metformin
Weeks
-3
-2,5
-2
-1,5
-1
-0,5
0
10 20 30 40 50 60 70 80 90 100 110
Changes
from
baselin
ein
fasting
pla
sm
aglu
cose
(mm
ol/l) *
Pioglitazone
Gliclazide
* p<0.003a
*
a in patients treated for a minimum of 18 months
Charbonnel B, Schernthaner G et al: Diabetologia 2005;48:1093-1104
Fasting Plasma Glucose over Time in ADOPT Study
Rosiglitazone vs. Metformin: 9,8 (P<0,001)
Rosiglitazone vs. Glyburide: 17,4 mg/dl (P<0,001)m
g/d
l
0
120
160
140
130
150
0 1 2 3 4 5
Time (years)
Glyburide
Rosiglitazone
Metformin
Kahn SE et al. N Engl J Med 2006; 355:2427–2443
RCT of 4.360 newly diagnosed patients with type 2 diabetes followed up for a median of 4.0 years
Functional defect: Deterioration of β-cell function over time
Kahn SE, et al. N Engl J Med. 2006;355:2427-43.
−6.1% per year
−2.0% per year
−3.1% per year
0
60
70
80
90
100
0 1 2 3 4 5
Rosiglitazone vs metformin; 5.8%, p = 0.003Rosiglitazone vs glyburide; −0.8%, p = 0.67
Glyburide
Rosiglitazone
Metformin
Time (years)
HO
MA
%B
Durability of Glycemic Control with Glitazones
-2
-1
0
1
50 1 2 3 4 6
Ch
an
ge
in
Hb
A1
c (
%)
TIME (years)
ROSI...Rosiglitazone
PIO......Pioglitazone
Periscope (n=178)
RECORD (n=301) Tan (n=249)
PIO
Chicago (n=232)
PIO
Hanefeld (n=250)
PIO
Rosestock (n=115)
ROSI
Charbonnel (n=317)
PIO
ADOPT (n=1,456)
Rosiglitazone
DeFronzo (Diabetes 2009; 58:773-795)
No Durability of Glycemic Control with Sulfonylureas
Ch
an
ge
in
Hb
A1
c (
%)
DeFronzo (Diabetes 2009; 58:773-795)
TIME (years)
50 1 2 3 4 106
-2
-1
0
1
Periscope (n=178)
Glyburide
Tan (n=249)
Gliclazide
Alvarsson (n=39)GLYAlvarsson (n=48)x
Charbonnel (n=317)
x
x
x
xx
Gliclazide
SU
RECORD (n=301)
SU
Chicago (n=232)
Glimpepiride
Hanefeld (n=250)Glyburide
ADOPT (n=1,456)
Glyburide
UKPDS (n=1,573)
Glyburide
EUREXA: Exenatide BID was associated with Lower
A1C Levels Over Time Compared to Glimepiride
Gallwitz B, Guzman J, Dotta F, Guerci B, Simó R, Basson BR, Festa A, Kiljański j, Sapin H, Trautmann M, Schernthaner G. Lancet 2012; 379:2270-8
ITT Efficacy Population Time on Randomized Treatment (months)
A1C
(%
)
3 18 30 42
Exenatide BID Glimepiride
0
486
480
6
440
471
12
331
371
24
230
264
36
182
197
Patient number:
Exenatide BID
Glimepiride
EXE 6.85
GLIM 6.94
P = 0.141
EXE 6.95
GLIM 7.13
P = 0.008
EXE 7.10
GLIM 7.26
P = 0.035
6.6
6.7
6.8
6.9
7.0
7.1
7.2
7.3
7.4
7.5
7.6
EUREXA: Treatment Failure (HbA1c >7.0%) in Patients
dependent from by Baseline A1C and Study Drug
Pro
po
rtio
n o
f P
ati
en
ts N
ot
Meeti
ng
Tre
atm
en
t F
ailu
re C
rite
ria
Exenatide BID (n = 235)
Exenatide BID (n = 189)
Exenatide BID (n = 66)
Glimepiride (n = 257)
Glimepiride (n = 166)
Glimepiride (n = 64)
A1C ≤7.3%
A1C >7.3-≤8.2%
A1C >8.2%
Baseline strata Randomized treatment
Time on Randomized Treatment (months)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 6 12 18 24 30 36 42 48
Gallwitz B, Guzman J, Dotta F, Guerci B, Simó R, Basson BR, Festa A, Kiljański j, Sapin H, Trautmann M, Schernthaner G. Lancet 2012; 379:2270-8
After 4 years about 35% of patients
in both groups showed similar
treatment failure even when
started from low HbA1c levels
(<7.3%)
(A) fasting plasma glucose level
(B) basal hepatic glucose production (HGP)
(C) hepatic triacylglycerol content
For comparison, data for a matched
nondiabetic control group are shown as o
• Eleven people with type 2 diabetes (49.5 years, BMI
33.6±1.2 kg/m2, were studied before and after 1, 4 and 8
weeks of a (600 kcal)/day diet.
• Normalisation of both beta cell function and hepatic
insulin sensitivity in type 2 diabetes was achieved by
dietary energy restriction alone.
• This was associated with decreased pancreatic and
liver triacylglycerol stores.
• The abnormalities underlying type 2 diabetes are
reversible by reducing dietary energy intake.
Effect of an 8-week very-low-calorie diet in type 2 diabetes on
Lim et al. Diabetologia 2011;54:2506
Restoring normoglycaemia by use of a very low calorie
diet in short- and long-duration Type 2 diabetes
Short duration
Long duration
• 87% of the short-duration group and 50% of the
long-duration group achieved nondiabetic fasting
plasma glucose levels at week 8
• In people with Type 2 diabetes of > 8 years’ duration,
a therapeutic trial of a very-low-calorie diet may be
undertaken with a 50% chance of achieving non-diabetic
fasting glucose levels off all antidiabetic therapies.
Steven S & Taylor R. Diabet. Med. 2015; 32, 1149–1155
The progression of ß-cell dysfunction in
Type 2 Diabetes has many negative conseqences
• Significant increase of HbA1c due to deterioration of
fasting and postprandial glucose control
• More complex glucose lowering strategies are needed
(second line, thirdline, combination of 4 and more),
whereby evidence for the best combination is missing
• All vascular complications start to develop with
deterioration of glycemic control
Death from Cardiovascular Causes among Patients with Type 2 Diabetes
versus Controls is related to Mean Glycated Hemoglobin Level*
Tancredi M et al. N Engl J Med 2015; 373:1720-1732
* P values for the interaction term between time-updated mean glycated hemoglobin or renal disease status and time-updated age categories were less than 0.001 in all models.
In the Swedish National Diabetes Register
435,369 patients with type 2 diabetes were
followed up for 4.6 years (mean age 65.8 yrs.)
Mean HbA1c was 7.1% and the mean duration
of diabetes was 5.7 years at baseline.
2,117,483 controls had the same follow up
Historical Assessment of Insulin Resistance
Plasma Glucose
0 1 2 3
Time in hours
0
50
100
150
200
250
300
350
400
450
Pla
sm
a g
lucose in m
g/d
L
FPG>150
FPG: 110-150
Chemical DM
Normal
Plasma Insulin
0 1 2 3
Time in hours
0
20
40
60
80
100
120
140
160
Pla
sm
a insulin
in
mU
/mL
OGTT in 95 Subjects
Reaven GM, et al. Am J Med 1976;60:80
Aetiology of Insulin Resistance
Henry RR. Ann Int Med 1996;124:97-103.
Olefsky JM. In: Ellenberg and Rifkin’s Diabetes Mellitus. 5th Ed. 1997:513-552.
Olefsky JM. In: Endocrinology. 2nd Ed. 1989;1:1369-1388.
An interplay between genetics and environment
Genetics (Inherited)
Abnormal Insulin Receptor
Abnormal Insulin
Abnormal Signaling Proteins
Type 2 Diabetes:
Hyperglycaemia
Adipocytokines
Free Fatty Acids
Environment (Acquired)
Obesity
Aging
Medications
Glucose (G)
Defective insulin secretion
Carbohydrate
Resistance to the action of insulin
Insulin (I)
G
G
G G
G
G
G
G
I
I
I
I
I
I
I
Excessive fatty acid release
Reduced glucoseuptake
Excessive glucoseproduction
What is Insulin resistance? A reduced response to circulating insulin in target tissues
DeFronzo RA. Diabetes 2009; 58:773-95
Defective insulinsecretion
Defective insulin action in T2DM
DeFronzo RA, et al. J Clin Invest. 1979;63:939-46. DeFronzo RA, et al. J Clin Invest. 1985;76:149-55.
Leg
glu
co
se u
pta
ke
(m
g/
kg
leg
weig
ht/
min
)
Time (minutes)
0
p < 0.01
12
1801401006020
8
4
0
To
tal
bo
dy g
luco
se u
pta
ke
(m
g/
kg
/m
in)
T2DMNormal0
7
6
5
4
3
2
1
Normal
T2DM-30%
-45%
Conditions associated with insulin resistance
Centralobesity
Physicalactivity
Insulin
resistanceHyperinsulinemia
HDL
Platelet
hyperactivation
Blood pressure
Microalbuminuria
PPG
Impaired glucose tolerance
Diabetes mellitus
Small dense
LDL Fibrinogen
PAI-1 Triglycerides
Chronic inflammation Proinsulin
Thrombus
Inflammatory atherosclerotic process
Small dense LDL
ox-LDL
Monocyte
chemotaxis
mf
O2
Foam cell
differentiation
fatty streakComplex
(vulnerable)
plaque
Lumen of
blood vessel
Artery wall
Endothelium
ROS
Vascular smooth
muscle cells
PLAQUE
RUPTURE
CRP: C-reactive protein
MCP-1: monocyte chemoattractant protein-1
IL-6: interleukin-6
TNFα: tumour necrosis factor alpha
MMP-9: matrix metalloproteinase-9
PAI-1: plasminogen activator inhibitor-1
Inflammatory
cytokines
IL-6, TNF
Inflammatory
markers
CRP
MMP-9
MCP-1
PAI-1
0.75
0.8
0.85
0.9
0.95
1
0 5 10 15 20 25
Years
Pro
port
ion w
ithout
Majo
r C
HD
Event
Pyörälä M et al. Circulation 1998;98:398-404
P=0.001
Q1
Q2
Q3
Q4
Q5
Kaplan-Meier survival curves for remaining free of major CHD
events during 22-year follow-up by quintiles of AUC insulin
0.75
0.8
0.85
0.9
0.95
1
0 5 10 15 20 25
Years
Pro
port
ion w
ithout
CH
D E
vent
P<0.001
T1
T2
T3
Pyörälä M et al. Circulation 1998;98:398-404
0.75
0.8
0.85
0.9
0.95
1
0 5 10 15 20 25
Years
Pro
port
ion w
ithout
Str
oke
P<0.001
T1
T2
T3
Kaplan-Meier curves for remaining free of CHD and stroke during
22-year follow-up by tertiles of insulin resistance factor score
Coronary heart disease Stroke
The association between insulin resistance and risk for stroke has been examined in
4 case-control studies and 5 prospective observational cohort studies. Six of the 9
studies provide evidence that insulin resistance is associated with risk for strokeKernan & Inzucchi, Neurology 2002; 59:809-15
Insulin resistance is an independent predictor of CVD in type 2 diabetesThe Verona Diabetes Complications Study
Bonora E, et al. Diabetes Care 2002; 25:1135*P < 0.001; n = 627 Error bars = 95% CI
0.0
0.5
1.0
1.5
2.0
2.5
Insulinresistance(per unit)
Smoking (yes vs. no)
TC:HDL(per unit)
Age(per year)
Od
ds r
ati
o (
95%
) fo
r
incid
en
t C
VD
*
*
*
*
Can Insulin Resistance Be Treated?
• Weight Reductíon
• Physical Exercise
• Improved glucose control per se
• Specific glucose lowering drugs
• Bariatric Surgery
Franssila-Kallunki A, et al. Am J Clin Nutr 1992;55:356
50
40
30
20
10
Before weight loss
Glucose
disposal
(mmol/min•kg
of lean mass)
After weight
loss
0
*P<0.05
*
Weight Reduction Improves Insulin Sensitivity
Sato Y. Horm Met Res 1984;16:483
Physical Activity Reduces Insulin Resistance
Hyperinsulinaemic Euglycaemic Clamp
5
7
9
11
45%Glucose
Infusion
Rate
(mg/kg•min)
Controls Physical Training
p< 0.05
Garvey WT, et al. Diabetes 1985;34:222
Diabetes
good control
Diabetes
poor control
Normal
Glucose
disposal
(mg/min/m2)
400
300
200
100
0
Insulin Resistance may be improved with Treatment
Some forms of insulin resistance may be reversible
Insulin Sensitivity over 2 Years: Pioglitazone vs Gliclazide
0 8 16 24 32 42 52 65 78 91 104
Weeks
110
100
90
80
50
60
70
Insulin Sensitivity (HOMA-S%)
Tan MG et al: Diabetes Care 2005; 28:544-50
Gliclazide
* p < 0,001
Pioglitazone
* ** *
* ** * * * * *
β-Zell-Acivity over 2 Years: Pioglitazone vs Gliclazide
0 8 16 24 32 42 52 65 78 91 104
80
70
60
30
40
50
*
β-Cell-Activity (HOMA-B%)
Tan MG et al: Diabetes Care 2005; 28:544-50
* p < 0,001‡ p < 0,01† p < 0.05
Pioglitazone
* * * * * *
‡
‡
‡
* *
Gliclazide
Effect of PIO versus GLIC on CISI
Change from baseline at 52 weeksChange from baseline at 52 weeks
0
0,5
1
1,5
-1
0
1
2
Effect of PIO versus MET on CISI
N=113, baseline CISI = 2,53GLIC
GLIC Gliclazide; MET Metformin; PIO Pioglitazone; SU Sulfonylurea
N=187, baseline CISI = 2,68MET
**
N=129, baseline CISI = 2,72
p<0.0001 between treatments
PIO
**
*p<0.05 between treatments
N=194, baseline CISI = 2,76PIO
*
Composite Insulin Sensitivity Index (CISI) for 3 different Monotherapies
Effect of PIO+SU vs MET+SU on CISI Effect of PIO+MET vs GLIC+MET on CISI
-0,5
0
0,5
1
1,5
Change from baseline at 52 weeks
0
0,5
1
1,5
Change from baseline at 52 weeks
GLIC Gliclazide; MET Metformin; PIO Pioglitazone; SU Sulfonylurea
N=62, baseline CISI = 2,73GLIC + METN=95, baseline CISI = 2,49MET + SU
**
N=54, baseline CISI = 2,61
p<0.0001 between treatments
PIO + MET
**
* p<0.05 between treatments
N=105, baseline CISI = 2,51PIO + SU
*
Composite Insulin Sensitivity Index for 2 different Combination Therapies
Ceriello et al (Diabetes Care 2005; 28:266)
Treatment-induced changes in Insulin-mediated Glucose Uptake (M value) with Metformin and Thiazolidinediones
Metformin Thiazolidinediones
50
40
30
20
10
0
-10
-20Open Double-blind/
placebo-controlled
Open
Insu
lin
-med
iate
d g
luc
ose u
pta
ke
(% c
han
ge
)
Double-blind/placebo-controlled
+ 34 %
+ 36 %
+ 11 %
+ 18 %
Effect of Weight Loss induced by Gastroplastic Surgery
on Diabetes and Glucose Intolerance
0
10
20
30
40
50
60
70
Diabetes (DM) Impaired GT Normal GT
37 % 40 %
Preoperative BMI (49±7 kg/m2)
Weight 136±23 kg
23 %
Prevalence
of DM, IGT,
NGT (%)
33 %
64 %
3 %
Postoperative BMI (33±6 kg/m2) Weight 92±17 kg
Kopp HP, Kopp CW, Festa A, Krzyzanowska K, Kriwanek S, Minar E, Roka R, Schernthaner G
Kopp HP, Kopp CW, Festa A, Krzyzanowska K, Kriwanek S, Minar E, Roka R, Schernthaner G. Arterioscler Thromb Vasc Biol. 2003;23:1042-1047
Postoperative
33± 6
Preoperative
BMI:49±7Glu
co
se,
mg
/dL
Insu
lin
, m
U/m
L
HOMA-insulin resistance
Glucose and insulin levels and HOMA-insulin resistance in morbidly obese patients before and after bariatric surgery
0
1
2
3
4
5
6
7
Preoperative Postoperative
8
9
10
0
50
100
150
200
Fasting 1-Hour 2-Hour
*
**
*p=0.0001
Fasting 1-Hour 2-Hour0
30
60
90
120
150
*
*p=0.0001
*
*
p=0.0001
Kopp HP, Kopp CW, Festa A, Krzyzanowska K, Kriwanek S, Minar E, Roka R, Schernthaner G. Arterioscler Thromb Vasc Biol. 2003;23:1042-1047
Adipose tissue: A major secretory organ
Triglycerides
Free fatty Acids
Lipoprotein lipase
Vascular endothelial growth factor
MCP 1
Resistin
Adiponectin
Adipsin (Complement D)
Leptin
Visfatin RBP4
IGF-1
TNF-
Angiotensinogen
PAI-1 IL-6 IL-18
Adipose tissue, adipokines and atherogenesisTNF, IL6, PAI-1, angiotensinogen, CRP, adiponectin, leptin, resistin
MMP activity
EC and SMC apoptosis
Platelet adhesion
Thrombosis
Plaque progression:
Plaque destabilisation:
Endothelial dysfunction:
Plaque initiation:
Foam cell formation
SMC proliferation and migration
ICAM-1 and VCAM-1
MCP-1
CD40/CD40L
Leukocyte adhesion and transmigration
NO
ET-1
ATII
oxLDL
ADMA
Effects of weight reduction induced by bariatric surgery
Before weight loss After weight loss1. Kopp CW, Obesity Research 2003;11:950; 2. Kopp HP, Internat J Obes 005:766;
3. Schernthaner GH, IDF 2006; 4. Krzyzanowska K, Obesity 2006;14:1886;
5. Kopp HP, Obes Surg 2006;16;1214; 6. Kopp HP, ATVB 2003;23:1042; 7.
Schernthaner GH, Obes Surg 2006;16:709; 8. Krzyzanowska K, JCEM
2004;89:6277; 9. Schernthaner GH, EJCI 2006; 36:333
Visfatin 4Leptin 1 Adiponectin 2 Resistin 3 RBP-4 3
0
5
10
15
20
25
0
5
10
15
20
25
0
20
40
60
80
100
0
20
40
60
80
100
0
20
40
60
80
100
µg/mlng/ml µg/ml ng/mlµg/ml
16
12
87
7771
p=0.0005
61
p=0.001
24
p=0.0001
29
p=0.01
11
p=0.007
86
-62 %
+100 %-31 %
-30 %
+ 21 %
On adipokines On hemostasis
µMng/mlpg/l ng/ml
Free TFPI 1 Fibrinogen 1Total TFPI 1TF 1
ng/ml
F VIII 1
nMPTF 1.2 1
p=0.041 p=0.023 p=0.036p=0.039 p=0.019p=0.0370
50
100
150
200
250
300
350 314
235
-71 %
0
20
40
60
80
100
120
140 130
113
-13 %
0
0.5
1.0
1.5
2.0
2.5
3.0
2.4
1.1
-53 %
0
10
20
30
40
50
60
70
8069
64
-7 %
0
10
20
30
40
50
60
4844
-8 %
0
2
4
6
8
10
12 11.010.3
-6 %µM
On sexual hormones On vascular inflammation
µMng/ml nmol/l
Index Free Androgene 5
Cortisol 5Testosterone 5Androstendione 5
µg/ml
DHEA-S 5
nmol/lSHBG 1.2 5
p>0.001 p=0.01 p<0.001p<0.001 p=0.001p<0.001
µg/dl
0
0.5
1.0
1.5
2.0
2.5
2.05
1.40
-32 %
0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.01.72
1.49
-13 %
0
10
20
30
40
50
60
70
80
17
70
+311 %
0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0 1.88
1.16
-38 %
0
0.02
0.04
0.06
0.08
0.10
0.12
0.14
0.16 0.15
0.02
-87 %
0
5
10
15
20
25
20
15
-25 %3.7
0
1
2
3
4
ng/ml
1.06
0
0,2
0,4
0,6
0,8
1
mmol/l
0
1
2
3
4
5
6
7
8
9
mg/l
581
0
100
200
300
400
500
600
pg/ml
8.6
ADMA 8 sCD40L 9MCP-1 7CRP 6
5.1
1
2
3
4
5
pg/ml
IL-6 6
6
0
51,210 7001526
0
200
400
600
800
1000
1200
1400
pg/ml
IL-18 7
1600
p<0.006
2.5
-71 %
p<0.02
3.9
-24 %
p<0.001
309
-47 %
p<0.001
960
-37 %
2.2
p<0.001
-41 %
p<0.00001
0.81
-24 %
Complex Pathophysiology of Type 2 Diabetes:
Hyperglycaemia is the result of multiple organ dysfunction
High
blood
glucose
Pancreas
Insulin secretion
Glucagon secretion
Muscle
Glucose uptakev
Adipose tissue
FFA
Adiponectin
Inflammatory cytokines
Kidneys
Gluconeogenesis
Glucose reabsorption
Liver
Gluconeogenesis
Gut
GLP-1 secretion
Brain
Satiety
1. International Diabetes Federation Diabetes Atlas 2015. 2. Cornell Ther Clin Risk Manag 2015;11:621–32. 3. DeFronzo RA et al. Diabetes Care 2013;36:3169–76.
Summary and Conclusion
• ß-cell dysfunction and Insulin resistance are the key players in the
development and progression of type 2 diabetes
• Decline of ß-cell function increases the severity of diabetes with the need
of complex glucose lowering therapies
• The Insulin resistant state is a life long problem of type 2 diabetes, which
is associated with many abnormalities believed to be involved in the
development/and or progression of macrovascular disease
• Effective therapeutic strategies should focus to improve both ß-cell
dysfunction and insulin resistance