The polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age in the U.S. The PCOS present with hyperandrogenism accompanied by chronic inflammation, insulin resistance and type 2 diabetes (T2DM). Evidence presented in this proposal suggests that in women and mice, excess testosterone production generates inflammation which alters fat biology and insulin production, thus contributing to insulin resistance, the metabolic syndrome and T2DM. Despite these observations, the evidence that testosterone directly alters insulin secretion from pancreatic ?-cells is lacking and the role of testosterone in disrupting fat biology, thus provoking insulin resistance, has not been investigated. The goal of this application is to demonstrate that excess testosterone in females predisposes to the metabolic syndrome and T2DM by acting on AR and provoking oxidative stress in pancreatic ?-cells and in fat-cells.
The specific aims of this application are: To demonstrate, through use of the ?-cell AR knockout mouse (?ARKO) that in females, excess testosterone activation of AR in ?-cells provokes insulin-deficient diabetes. We will test the hypothesis that excess testosterone activation of AR in ?-cells provokes oxidative stress. We will use a fat-cell AR knockout mouse (FARKO) to establish that, in females, excess testosterone activation of AR in adipocytes alters adipocytokines secretion and provokes systemic inflammation and insulin resistance. Finally, we will test the hypothesis using FARKO female mice and adipocytes that excess testosterone action on AR in adipocytes provokes oxidative stress and disrupts adipocytokines production. Successful completion of these studies will help define the AR as a target in hyperandrogenic women. This will help this center program in achieving its goal of supporting research to improve women's health.
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