OXIDATIVE STRESS AND ANTHEROSCLEROTIC COMPLICATIONS OF DIABETES

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The role of the oxidant stress in the evolution of diabetic vascular complications is unclear. This reflects, in part, limitation of current methodology to access free radical generation in vivo. The isopstanes are a family of prostaglandin isomers formed in a free radical catalyzed manner from arachidonic acid, initially esterified in the phospholipid from which they are cleaved by phospholipases. A quantitative method for an F2 isoprostane, 8-epi-PGF2alpha, using gas chromatography / mass spectometry (GC/MS), will be utilized to address the hypothesis that oxidative stress is enhanced in diabetes and that this precedes the onset of micro or macrovascular disease. Urinary 8-epi-PGF2alpha and the diene conjugate ratio, will be measured in diabetics with and without retinopathy, with and without macrovascular disease and in appropriate controls. To address the hypothesis that oxidation of LDL in diabetes might be facilitated by accumulation of advanced glycosylation end products (AGEs), we will isolate LDL to access esterified 8-epi-PGF2alpha and both apo-B- and lipid-linked AGEs. Additionally, in these subjects we will access the formation of esterified isoprostanes in the LDL oxidized in vitro in response to copper. Finally, we will address the hypothesis that chronic administration of the antioxidants, vitamins E & C, will depress urinary 8-epi-PGF2alpha concomitantly with modulation of LDL susceptability to oxidation. These studies will provide the first information using a novel quantitative approach, on free radical generation in vivo in human diabetes. They will address the hypothesis that increased oxidative stress precedes the onset of clinically detectable vascular complications and that it is reflected both systematically and in LDL by isoprostane formation. Preliminary information will be obtained on the potential role of vitamin E and C antioxidant drugs in diabetes.