Androgens, Genotype and Insulin Resistance in PCOS

我们从项目1的初始奖励期获得了非常令人兴奋的证据， 是与PCOS易感性变异相关的葡萄糖稳态的主要缺陷。这个变体， 二核苷酸重复序列D19 S884的等位基因8（A8）被定位到Escherichia coli-3基因的内含子55，作为Escherichia coli-3基因的一部分。 项目2这个SCOR。携带A8变异体的男性一级亲属有证据表明， 胰岛素分泌表明与A8变体相关的代谢表型是性别特异性的。 NU SCOR的中心假设是由基因变异引起的高雄激素血症， 调节类固醇生成通过在关键时期的编程动作引起PCOS代谢表型 以及成年人的持续行为。我们将制定三个具体目标：1。测试 多囊卵巢综合征患者A8基因型与肝脏葡萄糖稳态不同假说吸收后 肝葡萄糖稳态，包括肝细胞生成率和糖基化溶解率，将通过以下指标进行评估： 最先进的稳定同位素技术对调节肝葡萄糖产生的刺激的反应， 例如胰高血糖素、低血糖症和葡萄糖本身。2.为了验证这个假设， 雄激素直接或通过拮抗雌激素的作用改变肝葡萄糖稳态， PCOS，这种作用因A8基因型而异。非甾体类药物阻断雄激素作用的影响 受体拮抗剂，氟替卡松，单独和在经皮雌二醇替代，将是 研究了终点将包括肝脏和外周胰岛素作用以及肝脏和外周血胰岛素水平的任何改变。 目标1中确定的葡萄糖稳态。3.为了验证代谢表型与 A8在PCOS妇女的家庭中具有性别特异性。A8基因型对肝细胞凋亡的影响 外周胰岛素作用和对胰岛素分泌的影响将在PCOS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 女性生殖表型的共同途径，阐明其与 代谢缺陷将有助于了解PCOS的各种原因以及一个重要的风险， 2型糖尿病的治疗方法

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.