MULTIFACTORIAL ORIGINS OF DYSLIPIDEMIA IN IDDM

University Of Washington, Seattle WA

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Abstract

Description (taken directly from the application): The overall objective of this proposal is to determine the mechanisms accounting for the increase in the levels of atherogenic lipoproteins and the marked lipoprotein heterogeneity seen in insulin treated patients with insulin dependent diabetes mellitus (IDDM), and to determine which changes in lipoprotein distribution and composition predict premature death due to coronary artery disease. Early in the course of IDDM, lipoprotein distribution and composition are nearly normal. However, they frequently become abnormal later in the course of the disease. and hyperglycemia represent cardiovascular disease (CVD) risk factors for both IDDM and NIDDM. Typically, insulin resistance and central obesity usually are regarded as indicators of CVD risk in NIDDM. However, with intensive diabetes therapy for IDDM, individuals genetically predisposed to develop central obesity should express the components of this syndrome as they gain weight with intensive therapy. Thus, they will be expected to develop CVD risk factors similar to those that occur in NIDDM. Individuals recruited from the Diabetes Control and Complications Trial (DCCT) into the Epidemiology of Diabetes Intervention and Complications (EDIC) study will be studied at the national level (n=1,300) and in more detail in the Seattle cohort (n=80). It is hypothesized that 1) hyperglycemia will continue to be associated with gender specific changes in lipoprotein distribution and composition, and will predispose to glycoxidation as measured by appearance of coronary oxidation markers. The costs for the GGE on whole plasma is estimated to be $36 each an is included in the supply budget, 2) intensive diabetes therapy will lead to expression of the central obesity and the insulin resistance syndrome in genetically predisposed individuals, and will lead to the atherogenic lipid phenotype similar to that seen in MDDM, and 3) nephropathy will cause specific changes in lipoprotein distribution and composition leading to marked excess CAD in a subset of susceptible patients. Results from these studies will provide rationale for treatment to prevent or to treat the dyslipidemia seen in diabetes and diminished risk for atherosclerosis.