# INSULIN REGULATION OF HUMAN ADRENAL ANDROGEN METABOLISM

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 1993 · $110,059

## Abstract

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.

## Key facts

- **NIH application ID:** 3123202
- **Project number:** 1R01AG011227-01
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **SAM.gov UEI:** MLQFL4JSSAA9
- **Principal Investigator:** JOHN E NESTLER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1993
- **Award amount:** $110,059
- **Award type:** 1
- **Project period:** 1993-01-01 → 1995-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3123202

## Citation

> US National Institutes of Health, RePORTER application 3123202, INSULIN REGULATION OF HUMAN ADRENAL ANDROGEN METABOLISM (1R01AG011227-01). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3123202. Licensed CC0.

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