ATHEROGENIC TRIGLYCERIDE RICH LIPOPROTEINS IN DIABETES

Diabetes mellitus is associated with a 2-4 fold increase in risk for atherosclerotic cardiovascular disease (ASCVD). ASCVD, particularly coronary artery disease (CAD), is the leading cause of death in diabetics. The goal of Project 3 is to better understand the excess cardiovascular disease associated with diabetes mellitus. In particular, the studies proposed in this project will examine the atherogenicity of hypertriglyceridemia in subjects with NIDDM. Project 3 will test hypotheses concerning the impact of the size and number of triglyceride- rich lipoproteins (TGRL) on risk for ASCVD in several human populations. A case-control study of diabetics with or without CAD will determine if TGRL size and number differ between the groups. In this study, Whites, Blacks and Hispanics with documented CAD or with less than 50% coronary stenosis by angiography will be recruited at our medical center and affiliates. We will test the hypothesis that increased apoB in small TGRL is associated with CAD. Fasting and postprandial blood samples will be obtained for measurement of TGRL apoB level, TGRL TG:apoB ratio, the amount of apoB in apoE-rich TGRL, and retinyl palmitate clearance. Allelic differences in the apoB, apoE, LPL, and apoCIII genes will be examined for effects on the size and number of TGRL: specific hypotheses will be tested regarding the impact of these alleles. TGRL size and number will also be compared in diabetics with and without carotid atherosclerosis in the ARIC study, in Sioux and Pima Indian tribes that differ in ASCVD rates, and in Blacks, Whites and Hispanics with a range of insulin levels and insulin resistance in the IRAS study. These studies will serve both to confirm findings in our case-control study and to provide the opportunity to investigate diverse populations. Our collaboration with IRAS will allow determination of the effects of insulin resistance and insulin secretory capacity on TGRL size and number. Finally, experiments with cultured endotheliaI cells will be performed to determine if small TGRL can cause endothelial dysfunction. PMI-1 and VCAM-1 will be markers of TGRL effects. In the case-control study, plasma PMI and VCAM-1 will be measured to examine their relationship to CAD and to TGRL size and number. Project 3 interacts with projects 1 and 2 in tissue culture experiments of the effects of different size TGRL, and in studies of plasma markers of endothelial dysfunction in diabetics with different size TGRL. The Lipoprotein and Apoprotein Core will be essential for efficient endpoint measurements.