PATHOBIOLOGY OF MACROVASCULAR DISEASE IN DIABETES

University Of Washington, Seattle WA

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Linked publications & trials

Abstract

The overall objective of this research program is to gain understanding of the genetic, cellular, biochemical and molecular nature of premature atherosclerosis in diabetes mellitus. There are five interrelated projects: (1) The role of hyperglycemia, diabetic nephropathy and the development of central obesity with intensive insulinization in determining the levels, distribution and composition of lipoproteins: It is proposed that part of the excess incidence of premature disease is related to the dyslipidemia that results from these variables in diabetes; (2) Therole of diabetes on the interaction between lilpoproteins and proteoglycans of the artery wall: It is hypothesized that alterations in lipoprotein and or proteoglycans as a results of diabetes will facilitate their interaction in such a manner that would result in the retention of lipoprotein in the artery wall in diabetes; (3) The effect of diabetes on HDL-mediated cholesterol efflux: This project will evaluate how modifications of lipoproteins affect two distinct pathways of cholesterol efflux from cells, passive desorption and apolipoprotein-mediated efflux, and will focus on how changes in HDL structure in diabetes affects HDL function; (4) The role of non-enzymatic glycation of endothelial cell matrix proteins on the signaling pathways activated by physiologic fluid flow: The major hypothesis is that nonenzymatic glycation of extracellular matrix proteins makes them "slippery" and unable to participate normally in the transduction of physico-chemical signals in response to fluid flow, which is the primary determinant of the production of endothelial-derived nitric oxide, a critical mediator of vascular homeostasis; (5) Molecular mechanisms of oxidation damage in diabetes: The hypothesis is that oxidant stress due to glucose autoxidation and/or protein glycation results in highly specific biologically active reaction products that can be used to detect glucose-mediated oxidative damage in vivo. This focus on the effects of diabetes on basic biological mechanisms of atherosclerosis should help establish which alteration are preventable or reversible, and will provide a rational basis for the prevention of this major complication of diabetes.