Women with polycystic ovary syndrome (PCOS) are characteristically hyperinsulinemia and insulin resistant. The hyperinsulinemia appears to play a pathogenetic role in PCOS both in terms of its effects upon ovarian androgen production an the increased prevalence of non-insulin dependent diabetes mellitus (NIDDM). An increased frequency of NIDDM in insulin resistant subjects is predictable whether insulin resistance induces NIDDM or is a necessary but insufficient predisposing factor. Yet, additional genetic and/or environmental factors are likely to be necessary to account for the increased prevalence of NIDDM in PCOS since only a subset of these insulin resistant women goes on to develop frank NIDDM. Our preliminary studies suggest that 1) beta cell dysfunction is more prevalent among women with PCOS than among similarly insulin resistant controls; 2) parents of women with PCOS have NIDDM or impaired glucose tolerance (IGT) at higher than population level frequencies. Thus, the apparent increased frequency of NIDDM in women with PCOS and their first- degree relatives may be attributable to high frequencies of both insulin resistance and beta cell dysfunction. We hypothesize a genetic basis for the beta cell dysfunction in PCOS. To test this hypothesis, we propose to quantitate insulin sensitivity and beta cell function in a large and readily accessible population of women with PCOS, their first degree relatives, and controls. This will then allow us to perform segregation analyses to characterize the transmission of insulin resistance and beta cell dysfunction in PCOS families and to determine the extent to which beta cell dysfunction contributes tot he risk imparted by insulin resistance to the development of NIDDM in PCOS. The following specific aims are addressed in this revised application;
Specific Aim 1. To determine if beta cell secretory dysfunction is more prevalent among insulin resistant women with PCOS compared to similarly insulin resistant controls Specific Aim 2. To determine if first-degree relative sof women with PCOS are at increased risk of a) impaired glucose tolerance of NIDDM; b) insulin resistance; c) beta cell secretory dysfunction Specific Aim 3 To a) characterize the transmission of beta cell function and insulin sensitivity in families of women with PCOS; b) determine whether the transmission of insulin sensitivity is independent of the transmission of beta cell function: c) characterize the extent to which beta cell dysfunction contributes to the risk impaired by insulin resistance tot he development of NIDDM.
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