In Subproject 5, Metabolic and Genetic Factors in IDDM Vascular Disease, W. Timothy Garvey subproject principal investigator, investigates whether metabolic and genetic factors are associated with the development of macrovascular disease or albuminuria in approximately 60 IDDM patients. The investigators have developed the concept, based on published and pre-data, that patients with upper body fat distribution who become diabetic exhibit primary abnormalities in fatty acid metabolism which secondarily exacerbate insulin resistance via alterations in fatty acid composition of skeletal muscle membranes, vascular reactivity via functional and structural changes in the vessel wall, and consequently vascular disease risk. They are testing the hypothesis that, in patients with vascular complications, poor glycemic control alters both circulating free fatty acids and fatty acid composition of muscle membranes to enhance vascular reactivity and induce insulin resistance. They are performing hyperinsulinemic glucose clamps in three IDDM subgroups (without complications, with albuminuria, and with macrovascular disease) under conditions of poor glycemic control and after intensive therapy to asses both glycemia-dependent and independent components of insulin resistance. They are also testing the hypothesis that insulin resistance and candidate gene polymorphisms determine in part which IDDM patients develop macrovascular disease and albuminuria. They are assessing candidate gene polymorphisms in all DCCT patients, and testing for linkage/association with macro- and microvascular disease outcomes, as well as for abnormalities in encoded proteins.