Complications of atherosclerosis are the leading cause of morbidity and mortality in subjects with diabetes mellitus. Epidemiologic research has indicated that the traditional risk factors for cardiovascular disease are not sufficient in and of themselves to account for this increased risk. Therefore, efforts to define factors that play a role in the increase of morbidity associated with diabetes is warranted. The overall objective of this research proposal is to identify the role of glucosylated plasma apoproteins in the lipoprotein abnormalities frequently observed in diabetic patients. Because we identified that each of the apoproteins in the plasma of patients with diabetes can be glucosylated, the first specific aim of this renewal is to identify the functional consequences of this glucosylation. So that the physiologic significance of apoprotein glucosylation can be understood, these studies will be performed on lipoproteins isolated from the plasma of diabetic subjects. These isolated lipoproteins will be assayed in four discrete biological systems, which are either regulated by lipoproteins or directly reflect lipoprotein metabolism including lymphocyte proliferation, ovarian steroidogenesis, macrophage cholesterol ester accumulation and an assessment of lipoprotein metabolism in vivo. When a functional defect is identified, apoprotein glucosylation will be biochemically and immunochemically characterized. Therefore, the second specific aim is to characterize and quantitate physiologically important apoprotein glucosylation. This will be accomplished by identifying which peptides or amino acid residues are modified in apoproteins isolated from hyperglycemic diabetic subjects so that specific structural changes can be related directly to functional changes. The third specific aim is to identify the prevalence and degree of physiologically significant lipoprotein glucosylation. Immunoassays will be developed to measure lipoprotein glucosylation in the plasmas of large numbers of diabetic subjects so that the extent and prevalence of functionally significant apoprotein glucosylation can be documented. The development of these assays will provide an important diagnostic tool for clinically assessing protein glucosylation. When completed, these studies will provide a comprehensive biochemical and functional assessment of apoprotein glucosylation as it occurs in diabetics.
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