The broad objective of this research program is to gain under-standing of the nature of the disorder diabetes mellitus, particularly with respect to etiology, and to mechanisms of pathological, physiological, and biochemical changes. The proposed approach to the pathobiology of diabetes mellitus focuses on three major interrelated areas: (1) insulin secretion and action; (2) primary cellular abnormalities; and (3) pathophysiological abnormalities. Projects are proposed to study the regulation of insulin and glucagon secretion in pancreatic islet cell cultures, abnormalities of insulin and glucagon secretory products, molecular and cellular mechanisms of insulin action including interaction of insulin with its receptors and enzyme induction (hexokinase II), role of cyclic nucleotide metabolism in insulin action, abnormalities of growth and metabolism of cultured skin fibroblasts and arterial smooth muscle cells in diabetes, and mechanisms of hypertriglyceridemia in diabetes involving the regulation of human adipose tissue lipoprotein lipase. A common project involving all investigators is focused on the effect of insulin on the proliferation of cultured human arterial smooth muscle cells, which may be relevant to accelerated atherosclerosis in diabetes.