TESTOSTERONE-INDUCED INSULIN INSENSITIVITY

Hyperandrogenism and insulin resistance frequently coexist, although the cause and effect relationship of this association is not clear. The possibility that hyperandrogenism may induce insulin insensitivity, with resultant hyperinsulinemia, has become of increased clinical importance. This heightened significance stems from epidemiologic reports suggesting a link of hyperinsulinism with atherosclerosis and coronary vascular disease. Examination of the effect of androgens on insulin sensitivity has primarily utilized glucose tolerance testing. Our preliminary studies have utilized "clamp" methodologies which fix glucose or glucose and insulin concentrations at predetermined levels, thereby minimizing homeostatic responses and allowing evaluation of the effect of each individual parameter. In our studies, methyltestosterone administration resulted in a reduction in insulin sensitivity in normal women, when assessed either by the euglycemic, hyperinsulinemic clamp technique or the hyperglycemic clamp technique. Furthermore, testosterone administration markedly reduced glucose uptake in dogs during euglycemic, hyperinsulinemic clamp studies. This protocol will test the hypothesis suggested by these three studies, namely that testosterone induces insulin insensitivity. The proposal will evaluate insulin sensitivity after elevation or reduction of testosterone levels in humans and animals. The techniques to be utilized are l) euglycemic, hyperinsulinemic clamp studies in association with 3-3H-glucose and L-[l-13C)leucine infusion and the performance of indirect calorimetry, 2) hyperglycemic clamp procedures, and 3) 24h whole body calorimetry studies. The mechanism of testosterone action will be assessed by indirect calorimetry to determine the fate of glucose and leucine taken up by muscle (either oxidation or storage). Lastly, this proposal will examine the sexual dimorphism that exists with regard to the ability of testosterone to reduce insulin sensitivity in women, but not in men in whom testosterone levels are several-fold higher.