1 PRE PRE OVERWEIGHT PATIENT WITH VISCERAL ADIPOSITY DIABETES - - PDF document

1

LE PREDIABETE

DIABETOLOGIST

• Pr. Selim Jambart

Chef du Service d’Endocrinologie et des Maladies Métaboliques Hotel Dieu de France

Type 2 diabetes: Type 2 diabetes: vascular vascular complications complications a at diagnosis t diagnosis

• 20–30% diabetic retinopathy
• 10–20% microalbuminuria
• 30–40% hypertension
• 50–80% dyslipidaemia

Adapted from Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789

Macrovascular complications Microvascular complications

Insulin resistance Insulin resistance Insulin secretion Insulin secretion Postprandial glucose Fasting glucose Fasting glucose

INSULIN INSULIN DEFICIENCY DEFICIENCY

Adapted from Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789

Natural History of Type 2 Diabetes Natural History of Type 2 Diabetes

Macrovascular complications Microvascular complications

Insulin resistance Insulin resistance Impaired Impaired glucose tolerance glucose tolerance Undiagnosed Undiagnosed diabetes diabetes Known diabetes Known diabetes Insulin secretion Insulin secretion Postprandial glucose Fasting glucose Fasting glucose Adapted from Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789

Macrovascular complications Microvascular complications

Insulin resistance Insulin resistance Insulin secretion Insulin secretion Postprandial glucose Fasting glucose Fasting glucose

INSULIN INSULIN RESISTANCE RESISTANCE

2

Adapted from Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789

Macrovascular complications Microvascular complications

Insulin resistance Insulin resistance Insulin secretion Insulin secretion Postprandial glucose Fasting glucose Fasting glucose

PRE PRE DIABETES DIABETES

OVERWEIGHT PATIENT WITH VISCERAL ADIPOSITY

Mokdad AH et al, JAMA. January 2003;289:76-79

DIABESITY GLOBAL PROJECTIONS FOR THE GLOBAL PROJECTIONS FOR THE DIABETES EPIDEMIC: 2003 DIABETES EPIDEMIC: 2003-

• 2025

2025

23.0 36.2 57% 14.2 26.2 84% 48.4 58.6 21% 0.85 1.3 53% 7.1 15.0 111% World World 2003 = 194 million 2003 = 194 million 2025 = 333 million 2025 = 333 million Increase 72% Increase 72% 82.3 157.4 91% 19.2 39.4 105%

SURVIVAL SURVIVAL VISCERAL VISCERAL O OBESITY BESITY OVERLOADED ADIPOCYTE ENERGY STORAGE FOR MAXIMUM METABOLIC EFFICIENCY

“ “The Thrifty Gene Hypothesis" The Thrifty Gene Hypothesis"

Hunter Hunter-

• gatherer

gatherer Modern Modern society society FAMINE FEAST

INADEQUACY BETWEEN OUR GENES AND THE ENVIRONMENT

3

Pima Indians Thrifty Genes

THE 10 LEADING COUNTRIES FOR DIABETES PREVALENCE

0% 5% 10% 15% 20% 25% 30% 35% Nauru UAE Qatar Bahrain Cuba Puerto Rico Singapore Reunion Kuwait Seychelles

CRUDE PREVALENCE %*

*for 20-79 year population

Lower body:gynoid Abdominal:android Jean Vague (1948) Lower body:gynoid Pear-shape Abdominal:android Apple-shape Jean Vague (1948) METABOLIC DISORDERS Lower body:gynoid Pear-shape Abdominal:android Apple-shape Jean Vague (1948) CORONARY HEART DISEASE

Multiple secretory products Liver Pancreas Muscle Vasculature

Current View: secretory/endocrine organ Old View: inert storage depot Fatty acids Glucose Fatty acids Glycerol Fed Fasted Tg Tg Tg

The evolving view of adipose tissue: an endocrine organ

Lyon CJ et al 2003

4

Angiotensinogen Angiotensinogen Leptin Leptin

Adipocyte Adipocyte

Plasminogen activator Plasminogen activator inhibitor (PAI inhibitor (PAI-1) 1) Adipsin (ASP) Adipsin (ASP) IL IL-6 TNF TNF-α Adiponectin Adiponectin

Adipose Tissue as Endocrine Cells Adipose Tissue as Endocrine Cells

Resistin Resistin

OVERLOADED VISCERAL ADIPOSE TISSUE BECOMES INSULIN RESISTANT

PPARγ

I am the culprit OVERLOADED ADIPOCYTE INSULIN RESISTANCE TNFα IL-6 These amplifying signals increasingly impair adipocyte insulin signaling and eventually cause systemic insulin resistance in liver and muscles

Adverse cardiometabolic effects of products of adipocytes

Adipose

tissue

↑ IL-6 ↓ Adiponectin ↑ Leptin ↑ TNFα ↑ Adipsin (Complement D) ↑ Plasminogen activator inhibitor-1 (PAI-1) ↑ Resistin ↑ FFA ↑ Insulin ↑ Agiotensinogen ↓ Lipoprotein lipase ↑ Lactate Inflammation Type 2 diabetes Hypertension Atherogenic dyslipidaemia Thrombosis Atherosclerosis

Lyon 2003; Trayhurn et al 2004; Eckel et al 2005

The inflammatory The inflammatory atherosclerotic atherosclerotic process process

sdLDL sdLDL

• x-LDL

monocyte

chemotaxis m φ O2 foam cell

differentiation

fatty streak Complex (vulnerable) plaque

Lumen of blood vessel Artery wall endothelium

Inflamm cytokines, IL-6, TNFα ROS Inflamm markers, CRP MMP-9

• Smooth muscle

cells

MCP-1

PLAQUE RUPTURE

PAI-1 TF

TL

platelets

5

Features of the Metabolic Syndrome Features of the Metabolic Syndrome

Genetics + lifestyle Inflammation Liver fat Adiponectin Prothrombotic state Abdominal obesity Insulin resistance Hypertension Dyslipidemia

CVD

Type 2 DM

Insulin Resistance Genetics Glucose Toxicity Other (??) Amylin (IAPP) Age Incretin Effect Lipotoxicity FFA TG

Beta Cell Failure

Hexosamines TNFα

β-cell function in the natural history of T2DM

Adapted from UKPDS 16. Diabetes 1995;44:1249–58

Years from diagnosis Beta-cell function (%) –10 –8 –6 –4 –2 2 4 6 100 80 60 40 20 –12 12 IGT

Loss of early Loss of early-

• phase insulin secretion

phase insulin secretion in type 2 diabetes leads to harmful in type 2 diabetes leads to harmful mealtime glucose spikes mealtime glucose spikes

Normal 120 100 80 60 40 20 Time (minutes) Plasma insulin (µU/ml) –30 30 60 90 120 Type 2 diabetes –30 30 60 90 120 Time (minutes) 120 100 80 60 40 20

20 g glucose

Plasma insulin (µU/ml) Pattern of insulin secretion is altered early in type 2 diabetes

Ward WK et al. Diabetes Care 1984;7:491–502

20 glucose

Loss of early phase insulin secretion

Duration of daily Duration of daily glycaemic glycaemic conditions conditions in non in non-

• diabetics

diabetics

Monnier L. Eur J Clin Invest 2000;30(Suppl 2):3–11 Breakfast Lunch Dinner 0:00am 4:00am Breakfast

Post-mealtime Post-absorptive Fasting

6

DECODE: risk for all DECODE: risk for all-

• cause mortality

cause mortality

Adjusted for age, center, sex, cholesterol, body mass index (BMI), systolic blood pressure (SBP), smoking

<110 110–125 ≥126 ≥200 140–199 <140 Fasting plasma glucose (mg/dl) 2-hour plasma glucose (mg/dl) 2.5 2.0 1.5 1.0 0.5 0.0 Hazard ratio

Adapted from DECODE Study Group. Lancet 1999;354:617–21 Hyperglycaemia Oxidative stress Endothelial dysfunction Thrombosis Beta-cell Insulin resistance

Hyperglycemia: the role of oxidative stress?

Breakfast Lunch Dinner H y p e r g l y c a e m i a Endothelium Adhesion molecules Oxidative stress Thrombosis E n d

• t

h e l i a l D y s f u n c t i

• n

Atherosclerosis

Need for early detection of type 2 diabetes and for a strict control of blood glucose in diabetic patients in order to avoid vascular events

Glucose Tolerance Categories

American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S5-S10 FPG 2-h PPG (OGTT) 126 60 80 100 120 140 160 180 200 Plasma glucose (mg/dL) Normal Diabetes Mellitus 240 220 Diabetes Mellitus Normal IGT IFG

AT LEAST THREE OF THE FOLLOWING

• Waist circumference

– Men > 102 cm – Women > 88 cm

• Triglycerides

= > 150 mg/dl

• HDL-Cholesterol

– Men < 40 mg/dl – Women < 50 mg/dl

• Blood pressure

= >130/ = >85 mm Hg

• Fasting glucose

= >110 mg/dl

Clinical identification

• f the metabolic syndrome (ATP III)

7

VISCERAL OBESITY

• Waist circumference (ethnic specific)

– Men > 94 cm – Women > 80 cm

+

AT LEAST TWO OF THE FOLLOWING

• Triglycerides

= > 150 mg/dl

• HDL-Cholesterol

– Men < 40 mg/dl – Women < 50 mg/dl

• Blood pressure

= >130/ = >85 mm Hg

• Fasting glucose

= >100 mg/dl

Clinical identification

• f the metabolic syndrome (IDF- April 2005)

Waist circumference is a surrogate Waist circumference is a surrogate marker of visceral fat marker of visceral fat

Women Women

>80 cm = Increased risk

Men Men

>94 cm = Increased risk

cm

IDF; 2005

WAIST CIRCUMFERENCE - LEBANON

> 102 cm 35% < 94 cm 34 % 94 -102 cm 31% 80 - 88 cm 26 % < 80 cm 32% > 88 cm 42%

MEN (444) WOMEN (415)

NATURAL HISTORY OF IGT NATURAL HISTORY OF IGT

After 10 years After 10 years

33% 33% 33% 33% 33% 33% Normal Normal Diabetes Diabetes IGT IGT

IGT IGT

Can type 2 diabetes be prevented ?

100% 50% O% 10 15 years hyperglycemia IR IFG IGT TRIGGERING Genes & Environement Insulin Production

20% Insulin

Goals behind treating pre-diabetes

• Avoiding β

β– –cell dysfunction will allow a delayed cell dysfunction will allow a delayed progression from pre diabetes to diabetes progression from pre diabetes to diabetes

• Treating individuals at risk of developing

diabetes will translate into improved CVD

• utcomes and mortality rate

8

PRE DIABETES INTERVENTIONAL TRIALS

• Lifestyle intervention
• Pharmacotherapy

Prevention of type 2 diabetes by lifestyle changes in 522 persons with IGT

Tuomilehto J et al. NEJM 2001;344:1343 1.0 0.9 0.8 0.7 0.6 0.5 0.4 Cumulative probability of remaining free of diabetes 1 2 3 4 5 6 Study year Intervention group Control group Subjects at risk Total no. 507 471 374 167 53 27 Cumulative no. with diabetes: Intervention group 5 15 22 24 27 27 Control group 16 37 51 53 57 59

Prevention of Type 2 Diabetes

Pharmacotherapy for IGT

Reduction in progression to diabetes (%) Diabetes Prevention Program N=3234, 2.8 years Metformin 850 mg bid 31 STOP-NIDDM trial N=1429, 3.3 years Acarbose 100 mg tid 25 TRIPOD study N=236, 2.5 years Troglitazone 400 mg qd >50

DPP Research Group. N Engl J Med. 2002;346:393-403; Chiasson J-L et al.

• Lancet. 2002;359:2072-2077; Buchanan TA et al. Diabetes. 2002;51:2796-2803

WOSCOPS: Effect of WOSCOPS: Effect of Pravastatin Pravastatin

• n Development of Diabetes
• n Development of Diabetes

Percent Diabetic Years in Study 30% RRR p<0.036

1 2 3 4 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 Pravastatin Placebo

Freeman DJ et al. Circulation 2001;103:357-362.

HOPE – onset of new diabetes

Yusuf S AHA 72nd Session, Atlanta, USA, November 1999.

Patients developing diabetes (%) Follow-up (years) Ramipril Placebo 1 2 3 4 1 2 3 4 5 6 Intention-to-Treat

LIFE: LIFE: New New-

• Onset Diabetes

Onset Diabetes

Losartan Atenolol

Atenolol (N=3979) Losartan (N=4019)

Study Month 6 12 18 24 30 36 42 48 54 60 66 0.00 0.01 0.02 0.03 0.04 0.05 0.06 0.07 0.08 0.09 0.10

Adjusted Risk Reduction 25 %, p<0.001 Unadjusted Risk Reduction 25 %, p<0.001

• B. Dahlöf at the American College of Cardiology, Atlanta, GA, March 17-20, 2002.

Endpoint Rate

9

Potential Underlying Mechanisms of Benefit

• Modulation of inflammatory cytokines

– By reducing IL-6 & TNF-α, lipoprotein lipase activity is increased & lipolysis in adipose tissue decreased – Interruption of natural progression from central obesity to insulin resistance

• Improvement of endothelial function

– Improved capillary recruitment & insulin resistance – Improved tissue perfusion & glucose & insulin transport

• Improvement of beta cell function

– Decreased gluco and lipo toxicity – Decreased oxidative stress – Decreased beta cell apoptosis

Freeman DJ et al. Circulation 2001;103:357-362.

• «chronic hyperglycemia

suspected by the presence of excessive thirst and polyuria » Type 2 Diabetes Mellitus: the classical approach

• Goals of management :

avoid symptoms related to this hyperglycaemia

• Goals

Goals of

• f management:

management: prevent, delay, arrest vascular complications

• atherosclerotic

vascular disease,with a high blood glucose Type 2 Diabetes Mellitus: the new approach

• Le prédiabète est un état d’obésité viscérale

et de l’insulinorésistance qui en découle

• Le risque vasculaire est présent dès ce stade

à cause de la sécrétion d’adipokines inflammatoires et pro-thrombotiques, et de la dyslipidémie et de l’hypertension, souvent déjà présentes

• L’évolution vers l’hyperglycémie est un

épiphénomène qui dépend de la performance des cellules béta

Le concept de syndrome métabolique ne doit pas être perçu comme:

• Une anomalie supplémentaire par rapport

aux différents éléments qui le composent

• Un plus dans la prise en charge des

désordres métaboliques

Mais comme

• Un moyen de dépister au plus tôt dans une

population donnée les personnes à risque et leur proposer une prévention adéquate Merci de votre attention