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DIABETIC ATHEROTHROMBOSIS AND ACCELERATED AGING: INTERVENTION STRATEGIES

DIABETIC ATHEROTHROMBOSIS AND ACCELERATED AGING: INTERVENTION STRATEGIES. Laurence Watkins, M.D., M.P.H., F.A.C.C. Healthy Heart Center Port St. Lucie, FL. Modernization Leads To Increased Prevalence of Diabetes. Intermittent Starvation + High-Protein Diet +  Physical Activity.

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DIABETIC ATHEROTHROMBOSIS AND ACCELERATED AGING: INTERVENTION STRATEGIES

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  1. DIABETIC ATHEROTHROMBOSIS AND ACCELERATED AGING:INTERVENTION STRATEGIES Laurence Watkins, M.D., M.P.H., F.A.C.C. Healthy Heart Center Port St. Lucie, FL

  2. Modernization Leads To Increased Prevalence of Diabetes Intermittent Starvation + High-Protein Diet + Physical Activity Genetic Selection Metabolic Efficiency = "Thrifty Genes" Acute Modernization (calories, dietary fat,physical activity) Obesity, Insulin Resistance, And Type 2 Diabetes

  3. GLUCOSE INTOLERANCE IN POPULATIONS OF WEST AFRICAN ORIGIN Age Standardized Prevalence of Diabetes MEN WOMEN 1.0 0.5 11.0 14.8 0.5 2.3 11.5 14.6 PREVALENCE (188) (138) (199) (181) (196) (157) (198) (224)

  4. AGE-ADJUSTED PREVALENCE OF DIABETES: ST. JAMES CARDIOVASCULAR STUDY

  5. PREVALENCE OF DIABETES IN MEN BY AGE AND ETHNIC GROUPST. JAMES CARDIOVASCULAR STUDY AGE GROUP

  6. PREVALENCE OF DIABETES IN WOMEN BY AGE AND ETHNIC GROUPST. JAMES CARDIOVASCULAR STUDY AGE GROUP

  7. DIABETES ESTIMATES AND PROJECTION Persons with Diabetes

  8. Two-Thirds of People with Diabetes Die of Cardiovascular Disease

  9. High Risk of Cardiovascular Events in Type 2 Diabetes

  10. DIABETES IN TRINIDAD AND TOBAGO MORTALITY STATISTICS • In 1980, highest death rates for DM in the Americas • In 1986, fourth leading cause of death, 52 per 100,000 • Greater contribution in women 8%, 25%, 14% for ages 25-44, 45-64, 65 and over

  11. Atherosclerosis Timeline Inter-mediate lesion Foam cells Complicated lesion / rupture Athe-roma Fatty streak Fibrous plaque

  12. Potential Mechanisms of Atherogenesis in Diabetes • Abnormalities in apoprotein and lipoprotein particle distribution • Glycosylation and advanced glycation of proteins in plasma and arterial wall • “Glycoxidation” and oxidation • Procoagulant state • Insulin resistance and hyperinsulinemia • Hormone, growth-factor, and cytokine-enhanced SMC proliferation and foam cell formation

  13. Angina and Coronary Artery Disease in Patients with Diabetes Mellitus

  14. Atherosclerosis: Lesion Initiation L-Selectin, Integrins Monocyte VCAM-1, ICAM-1 E-Selectin, P-Selectin LDL MCP-1 Intima OxLDL M-CSF Macrophage Activation & Division Media Smooth Muscle Cell Migration

  15. Atherosclerosis: An Inflammatory Disorder Adherence andentry of leukocytes VSMCmigration Adherence andaggregation of platelets T-cellactivation Foam-cellformation VSMC, vascular smooth muscle cell migration.

  16. Hyperglycemia-induced endothelial damage Increased Advanced Glycation End-product formation Activation of Proinflammatory Nuclear Factor Kappa B Overproduction of Reactive Oxygen Species causes Endothelial Dysfunction via Decreased bioavailability of NO, Increased synthesis of Endothelin Increased vascular permeability Increased production of VascularEndothelial Growth factor(promotes angiogenesis and microangiopathy) EARLY STAGES OF DIABETIC ATHEROSCLEROSIS

  17. Insulin Resistance induces in MACROPHAGES -upregulation of CD36 protein -increased uptake of Ox-LDL -increased Matrix Metalloproteinase production -infiltration into plaque Diabetes-induced Oxidative Stress stimulates -Adventitial Inflammation -Vasa vasorum neovascularization End Result -Intraplaque hemorrhage -Macrophage activation -Lipid core expansion Increased potential for plaque rupture ADVANCED STAGES OF DIABETIC ATHEROSCLEROSIS

  18. Nature of Coronary Artery Disease (CAD) in Diabetes Normal glycemia (n=291) Disease both mild and diffuse Impaired Fasting Glucose (IFG) (n=82) “Mild” diabetes (n=20) WHO-defined diabetes (n=73) P for linear trend=0.0001 ns P=0.06 P for linear trend=0.001 P=0.05 ns P for linear trend=0.05 ns ns Mean Number of Affected Segments Mean Number of Affected Segments Mean Number of Affected Segments Normal segments<25% Mildly diseased segments (26% to 50%) Severely diseased segments (76% to 99%) Ledru F, et al. J Am Coll Cardiol. 2001;37(6):1543-1550.

  19. Chronic Coronary Artery Disease in the Elderly

  20. Normal Type 2 Diabetes Visceral Fat Distribution:Normal vs Type 2 Diabetes

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