DIABETES_ LECTUREDIABETES_ LECTURE

PROF. DR. DOINA CATRINOIUPROF. DR. DOINA CATRINOIU

Diabetes MellitusDiabetes Mellitus One of the most common non-One of the most common non-

communicable diseasescommunicable diseases

Fourth leading cause of death in most Fourth leading cause of death in most developed countriesdeveloped countries

More than 194 million people with More than 194 million people with diabetes worldwidediabetes worldwide

Incidence of diabetes is increasing – Incidence of diabetes is increasing – estimated to rise to 333 million by 2025estimated to rise to 333 million by 2025

• To more than double in Africa, the Eastern To more than double in Africa, the Eastern Mediterranean and Middle East, and South-East AsiaMediterranean and Middle East, and South-East Asia

• To rise by 50% in North America, To rise by 50% in North America, 20% in Europe, 20% in Europe, 85% in South and Central Americas and 75% in the 85% in South and Central Americas and 75% in the Western PacificWestern Pacific

: International Diabetes Federation website

Types of Diabetes MellitusTypes of Diabetes Mellitus Type 1 diabetes (insulin-dependent Type 1 diabetes (insulin-dependent

diabetes)diabetes)• mainly in childhood/early adult lifemainly in childhood/early adult life• 10-20% of cases10-20% of cases

Type 2 diabetes (non-insulin-dependent Type 2 diabetes (non-insulin-dependent diabetes)diabetes)• usually develops in the middle-age/elderlyusually develops in the middle-age/elderly• incidence increasing at a younger ageincidence increasing at a younger age• 80-90% of cases80-90% of cases

At least 50% of all people with diabetes At least 50% of all people with diabetes are unaware of their conditionare unaware of their condition

: International Diabetes Federation website

CLASSIFICATION OF DIABETESCLASSIFICATION OF DIABETESImpaired glucose tolerance without Impaired glucose tolerance without

diabetes (IGT)diabetes (IGT)

Primary diabetes mellitusPrimary diabetes mellitus• Insulin dependent (IDDM or Type 1)Insulin dependent (IDDM or Type 1)• Noninsulin dependent (NIDDM or Type 2)Noninsulin dependent (NIDDM or Type 2)

Malnutrition-related diabetes mellitus Malnutrition-related diabetes mellitus (MRDM)(MRDM)

Secondary diabetes mellitusSecondary diabetes mellitus• Pancreatic diseasePancreatic disease• Endocrine disordersEndocrine disorders• Drug therapyDrug therapy• Inherited disordersInherited disorders

Secretia de insulinaSecretia de insulinaSynthesis of insulin

ESR10-08

S

S

S

S

HOOC

SS

NH2

Proinsulin (86aa)

Synthesis of insulin

ESR10-09

S

S

S

S

HOOC

SS

NH2

Insulin (21 + 30aa)HOOC

NH2

- chain

- chain

C - peptide (35aa)

Glucose

Basal-bolus therapy attempts to re-Basal-bolus therapy attempts to re-create physiological insulin secretioncreate physiological insulin secretion

Pre

dic

ted p

lasm

a insu

lin c

once

ntr

ati

on

pro

file

(m

U/l)

Time of day

Rapid-acting insulin

Basal insulin

Total

Diabetes is defined biochemically Diabetes is defined biochemically by the following criteriaby the following criteria

A fastingA fasting venous plasma glucose venous plasma glucose level greater than level greater than 7.8 mmol/litre 7.8 mmol/litre (126 mg/dl)(126 mg/dl) on more than one on more than one occasion; occasion;

oror A 2-hour A 2-hour (plus one other) venous (plus one other) venous plasma glucose level in excess of plasma glucose level in excess of 11.1 mmol/litre (200 mg/dl)11.1 mmol/litre (200 mg/dl) in a in a formal formal 75 g oral 75 g oral glucose tolerance glucose tolerance test test (GTT).(GTT).

Clinical features of diabetes at Clinical features of diabetes at diagnosisdiagnosis  

Type 1 Type 2 Type 1 Type 2

Polyuria and thirst ++ +Polyuria and thirst ++ +

Weakness or fatigue ++ +Weakness or fatigue ++ +

Polyphagia with weight loss++ –Polyphagia with weight loss++ –

Recurrent blurred vision + ++Recurrent blurred vision + ++

Vulvovaginitis or pruritus + ++Vulvovaginitis or pruritus + ++

Peripheral neuropathy + ++Peripheral neuropathy + ++

Nocturnal enuresis ++ –Nocturnal enuresis ++ –

Often asymptomatic – ++Often asymptomatic – ++

DIABETES

Fasting plasma glucose 109-125 mg/dl

postprandial plasma glucose > 200mg/dl

Classical Symptoms* +

Blood glucose > 200 mg/dl

Fasting plasma glucose> 126 mg/dl

2-h Plasma glucose after "OGTT" > 200 mg/dl

and/orFasting plasma glucose >

126 mg/dl

Blood glucose 100 -200 mg/dl

A diagnostic algorithm for diabetes mellitus

Blood glucose > 200 mg/dl "occasionally"

ASYMPTOMATIC

INVESTIGATIONSINVESTIGATIONS

Blood glucoseBlood glucose is the key to diagnosis in is the key to diagnosis in diabetes.diabetes.

Glycosylated haemoglobinGlycosylated haemoglobin and other and other proteins: measurement of these proteins proteins: measurement of these proteins reflects the degree of diabetic control in reflects the degree of diabetic control in the previous 4-6 weeks and is of value in the previous 4-6 weeks and is of value in long-term management and control .long-term management and control .

INVESTIGATIONSINVESTIGATIONS

Urine testing for glucose-Urine testing for glucose-glucose will glucose will be found in the urine only when it rises be found in the urine only when it rises above the renal threshold (usually about above the renal threshold (usually about 10 mmol/l10 mmol/l

Urine testing for ketone bodiesUrine testing for ketone bodies the the presence of ketones suggests loss of presence of ketones suggests loss of control.control.

ProteinuriaProteinuria is a reflection of the is a reflection of the development of renal complications and development of renal complications and is an early indicator of diabetic renal is an early indicator of diabetic renal disease Multiple test strips allow rapid disease Multiple test strips allow rapid testing for all these substancesin urine.testing for all these substancesin urine.

INVESTIGATIONSINVESTIGATIONS

ProteinuriaProteinuria is a reflection of the is a reflection of the development of renal complications and development of renal complications and is an early indicator of diabetic renal is an early indicator of diabetic renal disease Multiple test strips allow rapid disease Multiple test strips allow rapid testing for all these substancesin urine.testing for all these substancesin urine.

MicroalbuminuriaMicroalbuminuria is a very sensitive is a very sensitive marker of early and potentially reversible marker of early and potentially reversible renal impairment; it is the term given to renal impairment; it is the term given to the presence of protein below the level of the presence of protein below the level of detection with the stick methods, that is detection with the stick methods, that is 200 mg/litre.200 mg/litre.

INVESTIGATIONSINVESTIGATIONS

Serum electrolytes, blood gases, Serum electrolytes, blood gases, osmolality and anion gaposmolality and anion gap are all are all of value in metabolic crises if there is of value in metabolic crises if there is loss of water, sodium and potassium loss of water, sodium and potassium and acidosis is developing, or if there and acidosis is developing, or if there is a hyperosmolar state.is a hyperosmolar state.

Lipid profileLipid profile: elevations in serum : elevations in serum cholesterol are common, and cholesterol are common, and elevation of serum triglycerides is a elevation of serum triglycerides is a reflection of poor glycaemic control, reflection of poor glycaemic control, which usually reverts to normal when which usually reverts to normal when euglycaemia is achieved. euglycaemia is achieved.

PRESENTING FEATURES OF DIABETESPRESENTING FEATURES OF DIABETES

AcuteAcute: the typical presentation of the young : the typical presentation of the young patient with IDDM; features include polyuria, patient with IDDM; features include polyuria, polydipsia and weight loss of short duration, polydipsia and weight loss of short duration, often associated with, or apparently often associated with, or apparently precipitated by, a viral infection;visual precipitated by, a viral infection;visual disturbance or impairment of the conscious disturbance or impairment of the conscious level associated with severe ketoacidosis level associated with severe ketoacidosis

ChronicChronic: the typical presentation of a patient : the typical presentation of a patient with NIDDM; the symptoms have usually been with NIDDM; the symptoms have usually been present for some months and often include present for some months and often include weight loss, thirst, excess urine volume, genital weight loss, thirst, excess urine volume, genital and skin infectionsand skin infections

PRESENTING FEATURES OF DIABETESPRESENTING FEATURES OF DIABETES

Coincidental discoveryCoincidental discovery: routine : routine screening for urine or blood glucose as screening for urine or blood glucose as part of a pre-employment medical, during part of a pre-employment medical, during pregnancy or in local campaignspregnancy or in local campaigns

ComplicationsComplications: visual disturbance or : visual disturbance or overt retinopathy, neuropathy, overt retinopathy, neuropathy, nephropathy or after major thrombotic nephropathy or after major thrombotic events such as premature stroke or events such as premature stroke or myocardial infarction myocardial infarction

PRESENTING FEATURES OF DIABETESPRESENTING FEATURES OF DIABETES

Drug-relatedDrug-related diabetes may develop in diabetes may develop in patients on long-term steroids or thiazide patients on long-term steroids or thiazide diureticsdiuretics

Disease-related Disease-related as in acromegaly, as in acromegaly, Cushing's syndrome, Cushing's syndrome, phaeochromocytoma, thyrotoxicosis, phaeochromocytoma, thyrotoxicosis, pancreatitis, haemochromatosis, cystic pancreatitis, haemochromatosis, cystic fibrosis, carcinoma or surgical removal of fibrosis, carcinoma or surgical removal of the pancreasthe pancreas

GestationalGestational: pregnancy may unmask : pregnancy may unmask diabetes in a woman who is predisposed. A diabetes in a woman who is predisposed. A full history and clinical examination are full history and clinical examination are essential to detect any of the causative essential to detect any of the causative diseases and document the consequences.diseases and document the consequences.

PRESENTING FEATURES OF DIABETESPRESENTING FEATURES OF DIABETES

Patients with type 2 diabetes may Patients with type 2 diabetes may or may not have characteristic or may not have characteristic features. The presence of features. The presence of obesity or a strongly positive obesity or a strongly positive family history for mild diabetes family history for mild diabetes suggests a high risk for the suggests a high risk for the development of type 2 diabetes.development of type 2 diabetes.

DM Kendall et al. Eur J Intern Med 20, ( 2009) S329–S339 Prin amabilitatea Prof. Dr. N. Hâncu

Adapted from IDC, MinneapolisDiabetes duration (years)

-20 -10 0 10 20 30

Obesitate IGT Diabet [necontrolat]

Postprandial

Fasting

insulinorezistenta

Insulin Level

Treatmentul DZ tip 2: „inlocuirea deficitului“Treatmentul DZ tip 2: „inlocuirea deficitului“

Glicemia(mg/dl)

Functia ß-celulara

(%)

126

100

The Progression from CV Risk Factors to The Progression from CV Risk Factors to Endothelial Injury and Clinical EventsEndothelial Injury and Clinical Events

The Progression from CV Risk Factors to The Progression from CV Risk Factors to Endothelial Injury and Clinical EventsEndothelial Injury and Clinical Events

Risk factors

Oxidative stress

Endothelial dysfunction

NO Local mediators Tissue ACE-Ang II

PAI-1 VCAM

ICAM cytokines

Endothelium Growth factors matrix

Proteolysis

LDL-C BP Heart failureSmokingDiabetes

Vasoconstriction Vascular lesion and remodelling

Plaque ruptureInflammationThrombosis

Clinical endpoints

NO Nitric oxideGibbons GH, Dzau VJ. N Engl J Med 1994;330;1431-1438.

The Metabolic Syndrome andThe Metabolic Syndrome andAssociated CVD Risk FactorsAssociated CVD Risk Factors

Insulin Resistance

AtherosclerosisAtherosclerosis

Endothelial Dysfunction

Hypertension

Abdominal obesity

Hyperinsulinaemia

Dyslipidaemia• high TGs

• small dense LDL• low HDL-C

Diabetes

Hypercoagulability

Deedwania PC. Am J Med 1998;105(1A);1S-3S.

NCEP ATP III: The Metabolic NCEP ATP III: The Metabolic SyndromeSyndrome

<40 mg/dL (1.0 mmol/L)<40 mg/dL (1.0 mmol/L)<50 mg/dL (1.3 mmol/L)<50 mg/dL (1.3 mmol/L)

MenMenWomenWomen

>102 cm (>40 in)>102 cm (>40 in)>88 cm (>35 in)>88 cm (>35 in)

MenMenWomenWomen

110 mg/dL (6.0 mmol/L)110 mg/dL (6.0 mmol/L)Fasting glucoseFasting glucose130/130/85 mm Hg85 mm HgBlood pressureBlood pressure

HDL-CHDL-C150 mg/dL (1.7 mmol/L)150 mg/dL (1.7 mmol/L)TGTG

Abdominal obesity Abdominal obesity (Waist circumference)(Waist circumference)

Defining LevelDefining LevelRisk FactorRisk Factor

Recommends a diagnosis when 3 of these risk factors are present

NCEP, Adult Treatment Panel III, 2001. JAMA 2001:285;2486-2497.

WHO: The Metabolic SyndromeWHO: The Metabolic Syndrome

A working definition is glucose intolerance, IGT or diabetes mellitus and/or insulin resistance together with two or more of the following:

• Raised arterial pressure 160/90 mmHg

• Raised plasma triglycerides (1.7 mmol/L, 150 mg/dL) and/or low HDL-C (men <0.9 mmol/L, 35 mg/dL; women <1.0 mmol/L, 39 mg/dL)

• Central obesity

• Microalbuminuria (UAER 20 g/min or albumin: creatinine ratio 20 mg/g)

Alberti KGMM for the WHO. Diabet Med 1998:15;539-553.

TREATMENTTREATMENT

Type 1 diabetes ONLY INSULIN – is a Type 1 diabetes ONLY INSULIN – is a replacement therapyreplacement therapy

Type 2 diabetes ORAL DRUGS+/- Type 2 diabetes ORAL DRUGS+/- INSULIN THERAPYINSULIN THERAPY

Human insulins do not closely match the endogenous insulin response

Adapted from: Polonsky et al. J Clin Invest 1988;81:442–8

Insulin analogues address the limitations of human insulin

Adapted from: Polonsky et al. J Clin Invest 1988;81:442–8

Defining glucose variability• Hypoglycaemic events

• Postprandial glucose excursions

• Minor fluctuations in blood glucose levels

Monnier and Colette. Diabetes Care 2008;31(Suppl.2):S150–4

Nonglycemic effects of oral therapyCardiovascular Cardiovascular risk factorrisk factor

SulfonilSulfonilureaurea

Rapid-Rapid-acting acting insulin insulin secretagosecretagoguesgues

MetforMetforminmin

ThiazolidindiThiazolidindionesones

--glucosidaglucosidase se inhibitorsinhibitors

Insulin resistanceInsulin resistance

HyperinsulinemiaHyperinsulinemia

LDL chol levelsLDL chol levels

LDL particle patternLDL particle pattern

HDL chol levelsHDL chol levels

TriglyceridesTriglycerides

LP (a)LP (a)

PAI-1PAI-1

Endothelial functionEndothelial function

Body weightBody weight

Visceral adiposityVisceral adiposity

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Modified fromHE Lebovitz, Endocrinol clin North Am, 2001, 30: 909-933

Potential down-sides of pharmacological treatment modalities in patients with

T2DMPotential problemPotential problem Avoid or reconsiderAvoid or reconsider

Unwanted weight gainUnwanted weight gain

Gastrointestinal symptomsGastrointestinal symptoms

Hypoglycemia Hypoglycemia

Impaired kidney functionImpaired kidney function

Impaired liver functionImpaired liver function

Impaired cardio-pulmonary Impaired cardio-pulmonary functionfunction

Sulphonylureas, glinides, Sulphonylureas, glinides, glitazones, insulinglitazones, insulin

Biguanides, alpha-glucosidase Biguanides, alpha-glucosidase inhibitorsinhibitors

Sulphonylureas, glinides, Sulphonylureas, glinides, insulininsulin

Biguanides, sulphonylureasBiguanides, sulphonylureas

Glinides, glitazones, Glinides, glitazones, biguanides, alpha-glucosidase biguanides, alpha-glucosidase

Biguanides, glitazonesBiguanides, glitazones

ESC, EASD Guidelines, 2007

Suggested policy for the selection of glucose-lowering therapy according to the glucometabolic

situation

Post-prandial Post-prandial hyperglycemiahyperglycemia

Fasting hyperglycemiaFasting hyperglycemia

Insulin resistanceInsulin resistance

Insulin deficiencyInsulin deficiency

alpha-glucosidase inhibitors, short-alpha-glucosidase inhibitors, short-acting SU, glinides, short-acting acting SU, glinides, short-acting regular insulin or insulin analogsregular insulin or insulin analogs

Biguanides, long-acting SU, glitazones, Biguanides, long-acting SU, glitazones, long-acting insulin or insulin analogslong-acting insulin or insulin analogs

Biguanides, glitazones, alpha-Biguanides, glitazones, alpha-glucosidase inhibitorsglucosidase inhibitors

SU, glinides, insulinSU, glinides, insulin

ESC, EASD Guidelines, 2007

Adapted from Rosenstock J, Riddle MC. Chapter 9: Insulin therapy in type 2 diabetes. In: Cefalu WT, Gerich JE, LeRoith D (eds). The CADRE Handbook of Diabetes Management. New York: Medical Information Press; 2004:145―68.

Persistent HbA1c

>7%

Revisit T2DM treatment strategies: the evolving HbA1c position

Achieving and maintaining HbA1c at target may require

incremental and combination therapies

Treat-to-target concept

Realistic target: lowest HbA1c possible without

unacceptable hypoglycaemia

Healthy individual HbA1c 4–6%

ACTION

Summary of antidiabetic interventions as monotherapy

InterventionsInterventions Expected Expected decrease decrease

in A1c in A1c (%)(%)

AdvantagesAdvantages DisadvantagesDisadvantages

Step 1: initialStep 1: initial Lifestyle to decrease weight Lifestyle to decrease weight and increase activityand increase activity MetforminMetformin

Step 2: additional therapyStep 2: additional therapy InsulinInsulin

SulphonylureasSulphonylureas TZDsTZDs

Other drugsOther drugs -glucosidase inhibitors-glucosidase inhibitors

ExenatideExenatide

GlinidesGlinides PramlintidePramlintide

1-21-2

1.51.5

1.5-2.51.5-2.5

1.51.50.5-1.40.5-1.4

0.5-0.80.5-0.8

0.5-1.00.5-1.0

1-1.51-1.50.5-1.00.5-1.0

Low cost, many Low cost, many benefitsbenefitsWeight neutral, Weight neutral, inexpensiveinexpensive

No dose limit, No dose limit, inexpensive, inexpensive, improved lipid profileimproved lipid profileInexpensiveInexpensiveImproved lipid Improved lipid profileprofile

Weight neutralWeight neutral

Weight lossWeight loss

Short durationShort durationWeight lossWeight loss

Fails for most in first yearFails for most in first yearGI side effects, rare lactic GI side effects, rare lactic acidosisacidosis

Injections, monitoring, Injections, monitoring, hypoglycemia, weight gainhypoglycemia, weight gain

Weight gain, hypoglycemiaWeight gain, hypoglycemiaFluid retention, weight Fluid retention, weight gain, expensivegain, expensive

Frequent GI side effects, Frequent GI side effects, expensiveexpensiveInjections, frequent GI side Injections, frequent GI side effects, expensive, little effects, expensive, little experienceexperience3x/ day dosing, expensive3x/ day dosing, expensiveInjections, frequent GI side Injections, frequent GI side effects, expensive, little effects, expensive, little experienceexperience

A consensus statement from ADA and EASD. Diabetologia, 2006, 49: 1711-21

Diagnosis

Lifestyle intervention + metformin

Add basal insulin

-most efective

Add sulfonylurea-least expensive

Add glitazone-no hypoglycamia

HbA1C≥7%HbA1C≥7%HbA1C≥7%

HbA1C≥7%

Intensify insulin Add glitazone Add basal insulin Add sulfonylurea

HbA1C≥7% HbA1C≥7%

Add basal or intensify insulin

Intensive insulin + metformin +/- glitazone

A consensus statement from ADA and EASD. Diabetologia, 2006, 49: 1711-21

Algorithm for the metabolic management of T2DMStrategii si algoritmuri

Management of hyperglycemia in type 2 diabetesHow do I establish and sustain glycemic control?

Lifestyle change: an option?

Is metformin still the first line drug?

Which drugs after metformin?

Sulphonylureas, TZDs or insulin?

And then? Three oral agents, insulin as add-on or insulin alone?

What is the evidence for the proposed algorithm?

Will new drugs be able to halt the decline of beta-cell function?

Q & A

RJ Heine et al. BMJ, 9 december 2006, 333: 1200-1204

Contraindications can damage your health—is metformin a case in point?

Standard contraindications to the use of metformin should be relaxed, and that the benefits of reducing the number of patients excluded from using it would by far outweigh the potential risks

propose removal of the following contraindications from the list:

1. old age

2. chronic renal insufficiency (as long as GFR>40 ml/min)

3. chronic heart failure (NYHA stages I and II)

4. discontinuation of metformin therapy 2 days before surgery and i.v. contrast medium administration

A clear re-definition of metformin contraindications will enable more physicians to prescribe within the guidelines

The main effect of revising these contraindications and precautions will be to bring the official guidelines into harmony with day-to-day clinical practice

A Holstein, M. Stumwoll. Doiabetologia, 2005, 48:2454-59

Chacra RA et al. Diabetes, Obesity, Metab, 2005, 7: 148-160

Insulin

Oral agents

SIOFOR 1000

Management ofType 2 Diabetes

Glycemic controlDiet / LifestyleExerciseMedication

Treat associatedconditions

DyslipidemiaHypertensionObesityCoronary heartdisease

Screen for/managecomplications of

diabetesRetinopathyCardiovasculardiseaseNephropathyNeuropathyOther complications

Dyslipidemia in Diabetes

Triglycerides HDL

HMG CoAreductase inhibitor

Triglycerides HDL LDL

LDL

Medical nutritional therapy, increased physical activity

Improve glycemiccontrolHMG CoAreductase inhibitor

Improve glycemiccontrol

GLP-1GLP-1

Baggio LL, Drucker DJ. Gastroenterology. 2007;132:2131-2157 Reprodus cu permisiune Elsevier© 2007.

Ţesut

adipos

SNC

Ficat

Pancreas

Muşchi

Stomac

Preluarea şi stocarea glucozei

Sensibilitate la insulină Secreţia de insulină

Secreţia de glucagon

Sinteza de insulină

Proliferarea beta-celulară

Apoptoza celulelor beta

Evacuarea conţinutului gastric

ApetitulNeuroprotecţie

Cardioprotecţie

Funcţia cardiacă

Producţia de glucoză

Cord

GLP-1

Intestinul

Efects ofGLP-1 in healthy Efects ofGLP-1 in healthy subjectssubjects

50

Eliberare de insulină

Insulină

Exenatid is not Exenatid is not iinactivatednactivated by by DPP-4DPP-4

51Insulină

Eliberare de insulină

Basal insulinBasal insulin• Suppresses glucose production between Suppresses glucose production between

meals and overnightmeals and overnight

• 40% to 50% of daily needs40% to 50% of daily needs

Bolus insulin (mealtime)Bolus insulin (mealtime)• Limits hyperglycaemia after mealsLimits hyperglycaemia after meals

• Immediate rise and sharp peak at 1 hour Immediate rise and sharp peak at 1 hour

• 10% to 20% of total daily insulin10% to 20% of total daily insulin requirement requirement at each meal at each meal

The basal/bolus insulin conceptThe basal/bolus insulin concept