Diabetes is associated with an increased risk of coronary artery disease, cerebrovascular, and peripheral vascular disease, and 70-80% of diabetic patients die of these conditions. Diabetes also accounts for almost half of all end stage renal disease, and is the most common cause of adult-onset blindness in the Western world. Epidemiologic studies suggest that poor glycemic control, hypertension, dyslipidemia (including low HDL), and oxidative stress are contributory, but markers and mediators of vascular disease in diabetes are not clearly established. To address this issue, cohorts from the DCCT/EDIC (Type 1 diabetes, n=1,416) and a new VA Cooperative Study (Type 2 diabetes, n=1,700) will be studied prospectively. Dyslipidemia, including quantitative and qualitative lipoprotein abnormalities, which can now be assessed in greater detail than ever before, may promote vascular damage. Nuclear Magnetic Resonance (NMR) lipoprotein profiles,apolipo-proteins A1, B, E, and Lp(a), and activities of the lipoprotein-related enzymes paraoxonase (PON), Lecithin Cholesterol Acyl Transferase (LCAT), and Platelet Activating Factor Acetyl Hydrolase (PAFAH) will be determined. Oxidative stress, inflammation, and elevated homocysteine levels may also mediate endothelial injury and accelerated atherosclerosis in diabetes. products of free radical oxidation and antioxidant reserves in plasma, C-reactive protein and serum amyloid A as measures of inflammatory processes, and homocysteine levels will be measured in both cohorts. Data will be related cross-sectionally and prospectively to vascular complication status, insulin resistance, and interventions, including diabetes management randomization groups. Related studies to address underlying mechanisms of vascular damage in diabetes will be conducted. Plasma will be incubated with purified enzymes in vitro and effects on lipoprotein subclasses determined by NMR. Functional characteristics of LDL, HDL, and their subclasses from Type 1 and Type 2 diabetic and control subjects will be determined. effects of LDL subclasses on endothelial cell modulators of fibrinolysis and vascular tone, adhesion molecules, intracellular calcium flux and matrix binding will be evaluated. HDL subfractions will be tested for potentially anti-atherogenic functions, including suppression of cytokin-induced endothelial cell adhesion molecule expression, prevention of LDL and cell membrane oxidation, and break down of lipid oxidation products in membranes. These studies, in collaboration with the other Projects and Cores and the Clinical Coordinating Centers of both studies, will enable us to dissect the complex mechanisms underlying vascular disease in both types of diabetes. Our studies may provide guidelines for identification and treatment of high-risk subjects, and rationale for new preventive or interventive strategies, which will improve the lives of people with diabetes.