Role of Adrenal and Gonadal Androgens in Insulin Action and Metabolism

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Abstract
In a previous report we found extreme hyperinsulinemia associated with high testosterone levels in patients with polycystic ovarian syndrome (PCO) and normal insulin levels in a small group of patients with elevated dehydroepiandrosterone (DHEA). From these observations, we hypothesized that DHEA and testosterone may have opposing actions on insulin sensitivity. To test this hypothesis, we studied insulin sensitivity in vivo and in vitro in a) obese PCO women with elevated testosterone, b) obese patients with adult-onset adrenal hyperplasia (AH) and high levels of DHEA, c) weight-matched obese controls, and d) lean controls. Insulin sensitivity was determined by insulin responses to a standard OGTT, hypoglycemic responses to an IV insulin tolerance test (ITT), red blood cell (RBC) insulin binding and receptor kinase activity, and phytohemagglutinin (PHA)-activated T-lymphocyte (T-cell) insulin binding and PDH insulin sensitivity. In PCO patients, we found that basal and glucose-challenged insulin levels were significantly greater than, and hypoglycemic responses to IV insulin, significantly lower than, weight-matched control values. However, AH patients had insulin values significantly below, and hypoglycemic responses significantly above, those of the weight-matched controls. Their values were, in fact, comparable to those observed for the lean control subjects. Similar findings were observed with insulin binding and PDH insulin sensitivity. Insulin sensitivity in all study subjects was found to be negatively correlated to testosterone and positively correlated to DHEA and, more significantly, to the ratio of DHEA/testosterone. These data would suggest that, in females, DHEA and T may have opposing actions on insulin sensitivity. We conclude that in females insulin sensitivity in vivo and in vitro is modulated, at least in part, by the ratios of DHEA to testosterone.

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