The studies outlined in this proposal may provide a theoretical mechanism for the epidemiologic association between hyperinsulinemia and macrovascular disease. Evidence suggests that the adrenal androgens DHEA and DHEA-sulfate protect against the development of atherosclerosis. This proposal is based on the hypothesis that insulin exerts significant modulatory effects on human adrenal androgen metabolism (both decreased production and increased clearance), such that hyperinsulinemia lowers serum adrenal androgen levels. Since serum insulin levels steadily risk with aging (as a result of increasing insulin resistance and decreasing clearance), we advance insulin-mediated suppression of serum adrenal androgens as a mechanism for the as yet unexplained age-related dissociation of serum adrenal androgens from other adrenal steroids -- i.e., serum DHEA and DHEA-sulfate levels fall by >90% with aging while serum glucocorticoid and mineralocorticoid levels remain stable. We invoke this mechanism t explain as well the increased clearance of adrenal androgens and reduction in serum levels observed in obesity (another hyperinsulinemic state). The putative regulation of serum adrenal androgen levels by insulin is potentially of great importance, since a lowering of serum DHEA and DHEA-sulfate by hyperinsulinemia could contribute to the development of atherosclerosis in the elderly and the obese. In support of this hypothesis, we have demonstrated in vivo acute inhibition of human adrenal 17,20-lyase activity by insulin. We also have shown that insulin acutely decreases the secretion of DHEA-sulfate in cultured human adrenocortical carcinoma (SW-13) cells, establishing SW-13 cells as an ideal model for pursuing our clinical observations. We will confirm in vitro specific inhibition of 17,20-lyase by insulin, and determine whether this is mediated by a reduction in intrinsic catalytic activity or alteration in P45017alpha gene expression. Furthermore, we will localize the site of insulin cell surface interaction subserving insulin's inhibition of adrenal androgen biosynthesis, and establish whether inositolglycan mediators serve as the signal transduction system for insulin action. Collectively, our proposed studies should yield important new information on insulin's role as a physiologic regulator of human androgen metabolism, and on a possible mechanism for the atherogenic action of hyperinsulinemia in man.
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