INSULIN ACTION IN POLYCYSTIC OVARY SYNDROME

本研究的总体具体目标是确定 多囊卵巢综合征胰岛素抵抗的机制和发病机制 卵巢综合征（PCO）。 这项研究将提供深入了解 PCO和非胰岛素依赖型糖尿病的原因 （NIDDM）。 PCO是一种病因不明的高雄激素性疾病， 女性生殖系统最常见的内分泌疾病之一 年龄 患有PCO的女性明显存在胰岛素抵抗， 肥胖症。 但是PCO和肥胖有协同的有害作用， 对葡萄糖耐量的影响，20%的肥胖PCO女性 葡萄糖耐量受损或明显的NIDDM。 我们的初步 流行病学、家族和成纤维细胞胰岛素结合研究 强烈表明胰岛素有遗传成分 抗PCO。 此外，有一个惊人的增加， PCO女性家庭中NIDDM的患病率与 这些疾病的因果和/或遗传关联。 的 本建议的具体目的是：1）详细描述 PCO胰岛素抵抗的体内机制 这将是 通过定义对以下方面的敏感性和响应性来实现 胰岛素对葡萄糖利用和肝葡萄糖生成的影响 以及内源性胰岛素分泌的反馈抑制， 胰岛素 性腺类固醇对这些参数的影响将 通过回归分析确定。 序贯倍数 胰岛素剂量正葡萄糖钳夹技术将用于 定义对胰岛素的体内剂量-反应曲线， 将使用频繁采样的静脉葡萄糖耐量试验 来测定C肽代谢 2)确定细胞 PCO中胰岛素作用的缺陷。 这将通过 研究体外胰岛素结合和均匀标记的（14 C）- 分离的脂肪细胞中的葡萄糖转运。 性腺的作用 还将评估类固醇对这些参数的影响。 3)到 确定PCO中细胞胰岛素结合或作用是否降低 是后天的还是内在的（？遗传的）缺陷。 这将是 通过确定是否存在持续缺陷来完成 在胰岛素结合，胰岛素受体酪氨酸激酶活性， 和/或葡萄糖转运。

The Overall Specific Aims of this research are to determine the mechanisms and pathogenesis of insulin resistance in the polycystic ovary syndrome (PCO). This research will provide insight into the cause(s) of PCO and of non-insulin dependent diabetes mellitus (NlDDM). PCO, a hyperandrogenic disorder of unknown etiology, is one of the most common endocrine diseases of women of reproductive age. Women with PCO are markedly insulin resistant, independent of obesity. But PCO and obesity have a synergistic deleterious effect on glucose tolerance such that 20% of obese PCO women have impaired glucose tolerance or frank NIDDM. Our preliminary epidemiologic, family, and fibroblast insulin binding studies strongly suggest that there is a genetic component to the insulin resistance of PCO. Further, there is a strikingly increased prevalence of NIDDM in families of women with PCO consistent with a causal and/or genetic association of these disorders. The Specific Aims of this proposal are: 1) To Characterize in Detail the Mechanisms of Insulin Resistance In Vivo in PCO. This will be accomplished by defining the sensitivity and responsiveness to insulin of glucose utilization and hepatic glucose production as well as the feedback inhibition of endogenous insulin secretion by insulin. The effect of gonadal steroids on these parameters will be determined by regression analysis. The sequential multiple insulin dose euglycemic glucose clamp technique will be used to define the in vivo dose-response curve to insulin and the modified frequently sampled intravenous glucose tolerance test will be used to determine C-peptide metabolism. 2) To Determine the Cellular Defects in Insulin Action in PCO. This will be accomplished by investigating in vitro insulin binding and uniformly labeled (14C)- glucose transport in isolated adipocytes. The effect of gonadal steroids on these parameters will also be assessed. 3) To Determine if Decreased Cellular Insulin Binding or Action in PCO is an Acquired or Intrinsic (? Genetic) Defect. This will be accomplished by determining whether there are persistent defects in insulin binding, insulin receptor tyrosine kinase activity, and/or glucose transport in cultured fibroblasts from PCO women.