The objective of this application is to define the role of sex hormone balance in the association between body fat distribution and hyperinsulinemia, glucose intolerance and insulin resistance in premenopausal women. We propose to validate a metabolic sequence in which increased androgenic activity could lead to localization of fat in the upper body and to a decline in hepatic insulin extraction and insulin sensitivity. We postulate that the female liver and regional adipocyte precursors are highly sensitive to the androgenic:estrogenic balance. The sensitivity to androgens in the female is exacerbated by aberrant sexual dimorphism and the disturbance in insulin and glucose metabolism is further exacerbated by the presence of obesity. We first evaluate mechanisms relating sex hormone profiles and body fat distribution to defects in glucose-insulin homeostasis independent of obesity. For this purpose, normal, obese and ex-obese premenopausal women of varying body fat distribution are examined to determine: i) prehepatic production and hepatic extraction of insulin, ii) insulin-regulated glucose production; peripheral glucose utilization, oxidation and storage; and lipolysis, and iii) skeletal muscle morphology and sensitivity. We then assess the contribution of hyperandrogenicity to defects in splanchnic insulin metabolism and insulin action, independent of obesity by studying normal weight and moderately obese hyperandrogenized women before and after amelioration of the hyperandrogenic state. Finally, we unravel the cellular mechanisms by which androgenes could influence regional adipose tissue growth and hepatic insulin metabolism. The relationship of androgenic activity to regional preadipocyte differentiation and hepatocyte insulin metabolism is examined in sexually dimorphic rats, female rats with experimentally induced aberrant sexual dimorphism, and rats lacking the androgen receptor. This direction extends the current body of scientific data from our group and should reveal the complex pathophysiologic mechanisms underlying the relationship of body fat distribution, to glucose intolerance and non-insulin dependent diabetes mellitus.
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