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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
3R01AG011227-03S2
Application #
2542316
Study Section
Biochemical Endocrinology Study Section (BCE)
Program Officer
Bellino, Francis
Project Start
1993-01-01
Project End
1997-12-31
Budget Start
1997-05-15
Budget End
1997-12-31
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
Lavallee, B; Provost, P R; Kahwash, Z et al. (1997) Effect of insulin on serum levels of dehydroepiandrosterone metabolites in men. Clin Endocrinol (Oxf) 46:93-100
Jakubowicz, D J; Nestler, J E (1997) 17 alpha-Hydroxyprogesterone responses to leuprolide and serum androgens in obese women with and without polycystic ovary syndrome offer dietary weight loss. J Clin Endocrinol Metab 82:556-60
Nestler, J E (1997) Insulin regulation of human ovarian androgens. Hum Reprod 12 Suppl 1:53-62
Nestler, J E; Jakubowicz, D J (1996) Decreases in ovarian cytochrome P450c17 alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med 335:617-23
Beer, N A; Jakubowicz, D J; Matt, D W et al. (1996) Dehydroepiandrosterone reduces plasma plasminogen activator inhibitor type 1 and tissue plasminogen activator antigen in men. Am J Med Sci 311:205-10
Nestler, J E; Beer, N A; Jakubowicz, D J et al. (1995) Effects of insulin reduction with benfluorex on serum dehydroepiandrosterone (DHEA), DHEA sulfate, and blood pressure in hypertensive middle-aged and elderly men. J Clin Endocrinol Metab 80:700-6
Nestler, J E (1995) Regulation of human dehydroepiandrosterone metabolism by insulin. Ann N Y Acad Sci 774:73-81
Jakubowicz, D J; Beer, N A; Beer, R M et al. (1995) Disparate effects of weight reduction by diet on serum dehydroepiandrosterone-sulfate levels in obese men and women. J Clin Endocrinol Metab 80:3373-6
Jesse, R L; Loesser, K; Eich, D M et al. (1995) Dehydroepiandrosterone inhibits human platelet aggregation in vitro and in vivo. Ann N Y Acad Sci 774:281-90
Nestler, J E; Beer, N A; Jakubowicz, D J et al. (1994) Effects of a reduction in circulating insulin by metformin on serum dehydroepiandrosterone sulfate in nondiabetic men. J Clin Endocrinol Metab 78:549-54

Showing the most recent 10 out of 13 publications