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1. Pathophysiology of CVD in Type 2 Diabetes

5. The Vessel Wall Endothelial cell Internal elastic lamina Intimal smooth muscle cell Resident macrophage Medial smooth muscle cell Vasa vasorum Fibroblast External elastic lamina Intima Media Adventitia Sobel BE. Proc Assoc Am Physicians . 1999;111:313-318.

6. Atherosclerosis: Lesion Initiation Lusis AJ. Nature . 2000;407:233-241. Fluid shear stress Phospholipid Chol LDL ApoB ApoAII HDL PON1 ApoAI 12-LO ROS (HPETE) Permeability gene expression, EC NOS Matrix Seeding, oxidation Trapping Transport Transport (–) Minimally oxidized LDL Specific ApoB interaction

7. Human Plaque Progression Davies MJ. Br Heart J . 1993;69(suppl):S3-S11. Fatty streak Complicated plaque with thrombus formation Transitional plaque Advanced fibrolipid plaque Foam cell (Intracellular lipid) Extracellular lipid Smooth muscle cell Thrombus

8. Glagov’s Coronary Remodeling Concept Glagov S et al. N Engl J Med . 1987;316:1371-1375. Normal vessel Minimal CAD Moderate CAD Severe CAD Compensatory expansion maintains constant lumen Expansion overcome: lumen narrows

9. Vulnerable and Stable Plaques Libby P. Circulation . 1995;91:2844-2850. “ Stable” plaque Lumen Lumen - T-lymphocyte - Macrophage foam cell (Tissue Factor + ) - “Activated” intimal SMC (HLA-DR + ) - Normal medial SMC Lipid core Lipid core Area of detail “ Vulnerable” plaque Fibrous cap Media

10. Robust VSM Cell Accumulation Yielding an Obstructive, Stable Plaque Endothelial cell VSM Cell Macrophage T-lymphocyte Sobel BE. Proc Assoc Am Physicians . 1999;111:313-318. VSM=vascular smooth muscle.

11. Matrix Skeleton of Unstable Coronary Artery Plaque Fissures in the fibrous cap Davies MJ. Circulation . 1996;94:2013-2020.

12. PAI-1 Activity in Patients With Type 2 Diabetes McGill JB et al. Diabetes. 1994;43:104-109. PAI-1 activity (AU/mL) Lean Obese 0 5 10 15 20 No diabetes Diabetes PAI-1=plasminogen activator inhibitor type 1.

13. Fibrinolytic System Variables From Young Survivors of MI Hamsten A et al. N Engl J Med . 1985;313:1557-1563. Patients Controls (n=71) (n=50) Patients Controls (n=71) (n=50) t-PA inhibitor (PAI-1) t-PA activity 0.0 1.5 3.0 4.5 6.0 4 3 2 1 0 * * * P <0.001. MI=myocardial infarction. t-PA=tissue plasminogen activator. U/mL U/mL

14. PAI-1 in Internal Mammary Arteries Pandolfi A et al. Arterioscler Thromb Vasc Biol . 2001;21:1378-1382. No Diabetes Diabetes No Diabetes Diabetes

15. PAI-1 Is Increased in Atheroma From Patients With Diabetes 0 15 30 45 60 75 0 10 20 30 40 Urokinase PAI-1 Pixel intensity Pixel intensity Sobel BE. Circulation . 1998;97:2213-2221. * * No diabetes Diabetes * P <0.05.

17. Plaque Vulnerability Plaque Evolution Plaque Rupture Sobel BE. Circulation . 1999;99:2496-2498. Decreased proteolysis secondary to increased PAI-1 Decreased vascular smooth muscle cell migration and matrix metalloproteinase activation Extracellular matrix accumulation Increased lipid:vascular smooth muscle cell ratio Thin fibrous cap Increased proteolysis secondary to cytokines Shoulder macrophage activation, increase in matrix metalloproteinases Extracellular matrix degradation Lipid peroxidation Rupture

18. Insulin Resistance: Causes and Associated Conditions PCOS=polycystic ovary syndrome. Medications Aging Atherosclerosis Genetics Obesity and inactivity Rare disorders PCOS Dyslipidemia Hypertension Type 2 diabetes INSULIN RESISTANCE

20. Insulin Resistance and Atherosclerosis: Proposed Relationships Accelerated atherosclerosis Clinical diabetes Hyperinsulinemia Impaired glucose tolerance Hypertriglyceridemia Decreased HDL-C Essential hypertension Insulin resistance

23. Odds Ratios for IHD According to Plasma Insulin and Lipids Després J-P et al. N Engl J Med . 1996;334:952-957. <12 12-15 >15 Total:HDL-C ratio Insulin (  U/mL) 1.0 3.4 ‡ 4.3 § 7.1 † 10.3 † 9.6 † Low High 0 3 6 9 12 <12 12-15 >15 Apo B Insulin (  U/mL) Odds ratio 1.0 1.8 3.0* 3.2* 9.7 † 11.0 † * P =0.04; † P <0.001; ‡ P =0.05; § P =0.01. IHD=ischemic heart disease. Low High 0 3 6 9 12

24. IRAS: Negative Association Between Insulin Sensitivity and Atherosclerosis Howard G et al. Circulation . 1996;93:1809-1817. Reduction in mean ICA IMT (  m  per 1-unit increase in S i After adjustment for demographics. IRAS=Insulin Resistance Atherosclerosis Study. 20 10 0 -10 -20 -30 -40 Non-Hispanic White Hispanic African American -30.1 -29.9 6.1

25. Framingham Offspring Study: Lipid Levels in Men No diabetes Diabetes Siegel RD et al. Metabolism . 1996;45:1267-1272. * P <0.001. 9.3 4.9 22.6* 11.7* 27 22.8 20.3 22.4 18.3 43.9* 0 5 10 15 20 25 30 35 40 45 50 HDL-C <35 TC >240 LDL-C >160 TG >250 HDL-C <35 TG >250 %

26. Framingham Offspring Study: Lipid Levels in Women Siegel RD et al. Metabolism . 1996;45:1267-1272. No diabetes Diabetes * P <0.001. 3 1 29.3* 23.4* 9.3 22.7 22.2 37.7* 41.1* 35 0 5 10 15 20 25 30 35 40 45 HDL-C <35 TC >240 LDL-C >160 TG >250 HDL-C <35 TG >250 %

27. Dyslipidemia and Insulin Resistance: Mechanisms (CETP) (lipoprotein or hepatic lipase) Fat cells Insulin IR FFA Liver (CETP) CE TG Apo A-I CE TG LDL TG Apo B VLDL Kidney (hepatic lipase) CE=cholesterol ester; CETP=cholesterol ester transfer protein. VLDL HDL SD LDL

33. Nitric Oxide–Mediated Vasodilation Is Impaired in Type 2 Diabetes 0 2 4 6 8 10 12 Baseline 0.3 1 3 10 Methacholine chloride (  g/min) No diabetes (23) Diabetes (21) Difference in forearm blood flow (mL/min/100 mL) Modified from Williams SB et al. J Am Coll Cardiol . 1996;27:567-574. * P <0.005. *

34. Impaired Macrovascular Reactivity in People at Risk for Type 2 Diabetes Caballero AE et al. Diabetes. 1999;48:1856-1862. *C vs R, IGT, and D, P <0.01. 13.7* 10.5 9.8 8.4 Increase over baseline after cuff occlusion (%) Controls (C) Relatives (R) IGT Diabetes (D)

35. Impaired Microvascular Reactivity in People at Risk for Type 2 Diabetes Caballero AE et al. Diabetes. 1999;48:1856-1862. *C vs R, IGT, and D, and R vs D, P <0.001. Increase over baseline after cuff occlusion (%) 0 100 200 Acetylcholine Sodium nitroprusside 126* 98* 94 74 123* 85* 83 65 Controls (C) Relatives (R) IGT Diabetes (D)

36. Oxidative Stress in the Development of CVD in Diabetes Rösen P et al. Diabetes Metab Res Rev . 2001;17:189-212. LDL Oxidized LDL Macrophages overloaded with oxidized LDL Increased MI rate Decreased plaque stability Atherogenic plaques Foam cells in arterial walls Modulation of transcription factors Hyperglycemia Free radicals

37. IRAS: Relation of C-Reactive Protein to Insulin Sensitivity Festa A et al. Circulation . 2000;102:42-47. Low Middle High Insulin sensitivity tertile 0.05 0.25 1.22 6.05 30.0 Log CRP (mean values) IRAS = Insulin Resistance Atherosclerosis Study.

38. Relation of C-Reactive Protein to Insulin Sensitivity Festa A et al. Circulation . 2003;108:1822-1830. CRP (mg/L) High resistance Low secretion Non-converters High resistance vs low secretion, P =0.005 High resistance vs nonconverters, P <0.0001 Low secretion vs nonconverters, P =NS

43. AGEs and the Severity of Coronary Arteriosclerosis in Diabetes 0 4 8 12 Single vessel Two vessel Three vessel AGE (mU/mL) P <0.017 P <0.017 Kiuchi K et al. Heart . 2001;85:87-91. AGE=advanced glycation end-products.