Androgens, Genotype and Insulin Resistance in PCOS

我们从项目1的初始获奖期获得了非常令人兴奋的证据，证明肝脏胰岛素抵抗 是与PCOS易感变异相关的葡萄糖稳态的主要缺陷。这个变种， 二核苷酸重复序列D19S884的等位基因8(A8)被定位到纤毛素-3基因的55号内含子，作为 这一SCOR的项目2。携带A8变异的男性一级亲属有证据表明 胰岛素分泌表明与A8变异相关的代谢表型具有性别特异性。 NU SCOR的中心假设是高雄激素血症是由基因变异引起的(S) 调节类固醇合成导致PCOS代谢表型通过在关键期编程动作 以及成人正在进行的行动。我们将计划三个具体目标：1.测试 假设多囊卵巢综合征患者的肝脏葡萄糖稳态不同于A8基因。后吸收 肝糖稳态，包括糖异生和糖不裂解的速率，将用 最先进的稳定同位素技术。对调节肝脏葡萄糖产生的刺激的反应， 如高血糖素、低血糖和葡萄糖本身，将进行检查。2.检验假设 雄激素直接或通过拮抗雌激素作用改变女性高血压患者的肝脏葡萄糖稳态 这种作用因A8基因不同而不同。非甾体激素阻断雄激素作用的影响 受体拮抗剂氟他胺，单独和在经皮雌二醇替代期间，将被 调查过了。终点将包括肝脏和外周胰岛素的作用以及肝脏的任何变化 在目标1.3中确定了葡萄糖动态平衡。检验代谢表型与 在患有多囊卵巢综合征的女性家庭中，携带A8基因的患者具有性别特异性。A8基因对肝脏和肝脏的影响 外周胰岛素的作用和对胰岛素分泌的影响将在患有多囊卵巢综合征和多囊卵巢综合征的妇女的兄弟中进行检查 在年龄、体重和种族方面与对照组男性相似。因为高雄激素血症似乎是最终的 通向女性生殖表型的共同途径，阐明其与 代谢缺陷将与理解多囊卵巢综合征的各种原因以及一个重要的风险相关 2型糖尿病的致病因素。

We have extremely exciting evidence from the initial award period of Project 1 that hepatic insulin resistance is the major defect in glucose homeostasis associated with the PCOS susceptibility variant. This variant, allele 8 (A8) of the dinucleotide repeat D19S884, was mapped to intron 55 of the fibrillin-3 gene as part of Project 2 of this SCOR. Male first-degree relatives with the A8 variant have evidence for abnormalities in insulin secretion suggesting that the metabolic phenotypes associated with the A8 variant are sex-specific. The central hypothesis of the NU SCOR is that hyperandrogenemia resulting from variation in a gene(s) regulating steroidogenesis causes the PCOS metabolic phenotype by programming actions at critical periods of development as well as by ongoing actions in the adult. We will plan three Specific Aims: 1. To test the hypothesis that hepatic glucose homeostasis differs by A8 genotype in women with PCOS. Postabsorptive hepatic glucose homeostasis, including rates of gluconeogenesis and glycoge no lysis, will be assessed with state-of-the-art stable isotope techniques. Responses to stimuli that modulate hepatic glucose production, such as glucagon, hypoglycemia and glucose per se, will be examined. 2. To test the hypothesis that androgens alter hepatic glucose homeostasis, directly or by antagonizing estrogen action, in women with PCOS and that this action differs by A8 genotype. The impact of blocking androgen action with the nonsteroidal receptor antagonist, flutamide, alone and during transdermal estradiol replacement, will be investigated. Endpoints will include hepatic and peripheral insulin action as well as any alterations in hepatic glucose homeostasis identified in Aim 1. 3. To test the hypothesis that metabolic phenotypes associated with A8 are sex-specific in the families of women with PCOS. The impact of A8 genotype on hepatic and peripheral insulin action and on insulin secretion will be examined in the brothers of women with PCOS and in age, weight and ethnicity comparable control men. Since hyperandrogenemia appears to be a final common path to the female reproductive phenotype, elucidating the mechanisms for its association with metabolic defects will be relevant to understanding diverse causes of PCOS as well as an important risk factor for type 2 diabetes.