INSULIN ACTION IN THE POLYCYSTIC OVARY SYNDROME

多囊卵巢综合征是最常见的内分泌疾病 在育龄妇女中。它与深层胰岛素有关 抵抗导致非胰岛素风险显著增加 依赖性糖尿病（NIDDM）在惊人的早期（第3 - 4 十年）。本提案的具体目标是：1）确定 胰岛素受体丝氨酸磷酸化在糖尿病发病机制中的作用 PCOS胰岛素抵抗我们假设增加的胰岛素- 独立的胰岛素受体丝氨酸磷酸化抑制胰岛素- 在PCOS中诱导受体介导的信号传导。这将被调查 通过检测去磷酸化对 从肌肉和脂肪中部分纯化的胰岛素受体， 丝氨酸特异性的（例如，磷酸盐2A型）以及非特异性 (e.g.,碱性磷酸酶）磷酸盐。2)以确定是否 胰岛素的非胰岛素依赖性丝氨酸磷酸化增加 受体与胰岛素受体介导的 PCOS中的体内信号传导。这将通过评估进行调查 胰岛素在体内和完整脂肪细胞中的胰岛素刺激 受体底物-1（IRS-1）磷酸化和磷脂酰肌醇 3-激酶（PtdIns 3-激酶）活性。肌肉胰岛素反应性葡萄糖 还将检查转运蛋白（GLUT 4）含量，以确定 胰岛素信号传导的异常影响其丰度。3)到 确定PCOS中胰岛素作用的缺陷是否是遗传性的。如果 PCOS胰岛素抵抗是一种遗传缺陷，一级亲属 应该受到影响。这将通过测定全身来研究 以及PCOS先证者兄弟的细胞胰岛素作用。我们将 筛查PCOS患者胰岛素受体和IRS-1基因突变 变性梯度凝胶电泳或单链 确认多态性。

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. It is associated with profound insulin resistance resulting in a markedly increased risk for non-insulin dependent diabetes mellitus (NIDDM) at a strikingly early age (3rd-4th decades). The Specific Aims of this proposal are 1) To determine the role of insulin receptor serine phosphorylation in the pathogenesis of insulin resistance in PCOS. We hypothesize that increased insulin- independent insulin receptor serine phosphorylation inhibits insulin- induced receptor-mediated signaling in PCOS. This will be investigated by examiningthe effects of dephosphorylation on the kinase activity of insulin receptors partially purified from muscle and from fat, using serine specific (e.g., phosphate type 2A) as well as nonspecific (e.g., alkaline phosphatase) phosphates. 2) To determine whether increased insulin-independent serine phosphorylation of the insulin receptor is associated with decreased insulin-receptor mediated signaling in vivo in PCOS. This will be investigated by assessing insulin stimulation, in vivo and in intact adipocytes, of insulin receptor substrate-1 (IRS-1) phosphorylation and phosphatidylinositol 3-kinase (PtdIns 3-kinase) activity. Muscle insulin-responsive glucose transporter (GLUT4) content will also be examined to determine if abnormalities in insulin signaling affect its abundance. 3) To determine whether defects in insulin action in PCOS are genetic. If insulin resistance in PCOS is a genetic defect, first degree relatives should be affected. This will be investigated by determining total body and cellular insulin action in brothers of PCOS probands. We will screen for mutations in the insulin receptor and IRS-1 genes of PCOS women with denaturing gradient gel electrophoresis or single-stranded confirmation polymorphisms.