DETERMINATION IF PHARMACOLOGIC BLOCKADE OF ANDROGEN ACTION DECREASES RENAL

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 多囊卵巢综合征（PCOS）是一种知之甚少的疾病，影响大约6-10%的育龄妇女。 PCOS的特征是慢性无排卵和高雄激素血症，是美国女性不孕的主要原因。 大多数患有PCOS的女性还具有胰岛素抵抗的特征，胰岛素抵抗在PCOS的发病机制中起着关键作用，并且还使受影响的女性患2型糖尿病的风险增加。 我们的长期目标是阐明胰岛素抵抗和PCOS之间的关系。 胰岛素的某些作用可能受到胰岛素作用的假定肌醇磷酸聚糖（IPG）介导剂的影响，有证据表明，特定的含D-手性肌醇的IPG（DCI-IPG）的缺乏可能导致PCOS女性的胰岛素抵抗，以及其他以胰岛素抵抗为特征的疾病，如葡萄糖耐量受损或2型糖尿病。 特别是在PCOS中，三项独立的研究表明，向肥胖和非肥胖PCOS女性给予D-手性肌醇（DCI）（DCI-IPG的前体）可改善葡萄糖耐受不良，同时降低循环胰岛素，改善排卵功能，并降低血清雄激素。 在一些研究中，血清甘油三酯、高密度脂蛋白胆固醇和血压也有所改善。 总的来说，这些发现强烈表明，给予DCI改善了PCOS女性的胰岛素敏感性，并且PCOS中的胰岛素抵抗部分是由于胰岛素刺激的DCI-IPG释放受损。 我们的目的是在目前的资助周期，以确定是否DCI代谢改变PCOS，如果改变导致DCI缺陷和减少胰岛素刺激释放的假定DCI-IPG介导的胰岛素作用。 为此，我们成功地完善和验证了DCI-IPG的生物活性测定，并评估了PCOS女性和一组正常对照女性的DCI代谢和胰岛素敏感性。 我们发现，与正常女性相比，PCOS女性1）DCI的肾脏清除率增加5倍以上，2）DCI的循环浓度降低50%，3）口服葡萄糖耐量试验（OGTT）期间胰岛素刺激的DCI-IPG释放减少。 此外，在所有女性中，胰岛素敏感性（通过频繁采样的静脉葡萄糖耐量试验[FSIVGTT]测定）与DCI的肾脏清除率呈负相关。 这些发现与PCOS中DCI的异常处理一致，其导致DCI-IPG介体的释放受损，从而导致胰岛素抵抗。 目前的建议试图通过测试DCI代谢本身受胰岛素调节的假设来扩展这些发现，使得高胰岛素血症增加DCI的肾清除率，并且这发生在PCOS中而不是正常女性中。 如果是这种情况，在患有PCOS的女性中产生胰岛素抵抗/高胰岛素血症的初始“损伤”将被“恶性循环”放大，其中肾DCI清除增加，导致循环DCI、细胞内DCI-IPG介体和胰岛素刺激的DCI-IPG释放的缺陷。 后者反过来又会进一步降低胰岛素敏感性。 这种机制可以解释PCOS女性的胰岛素抵抗明显大于年龄和BMI匹配的健康女性。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The polycystic ovary syndrome (PCOS) is a poorly understood disorder that affects approximately 6-10% of women of reproductive age. PCOS is characterized by chronic anovulation and hyperandrogenism, and is a leading cause of female infertility in the United States. Most women with PCOS are also characterized by insulin resistance, which plays a key role in the pathogenesis of PCOS and also places affected women at increased risk for developing type 2 diabetes. Our long-term goal is to elucidate the relationship between insulin resistance and PCOS. Some actions of insulin may be effected by putative inositolphosphoglycan (IPG) mediators of insulin action, and evidence suggests that a deficiency in a specific D-chiro-inositol-containing IPG (DCI-IPG) may contribute to insulin resistance in women with PCOS, as well as in other disorders characterized by insulin resistance such as impaired glucose tolerance or type 2 diabetes mellitus. Specifically in PCOS, three separate studies have shown that administration of D-chiro-inositol (DCI), the precursor to DCI-IPG, to both obese and non-obese women with PCOS improved glucose intolerance while reducing circulating insulin, improved ovulatory function, and decreased serum androgens. Serum triglycerides, HDL cholesterol and blood pressure improved in some of the studies as well. Collectively, these findings strongly suggest that administration of DCI improved insulin sensitivity in women with PCOS, and that insulin resistance in PCOS is due in part to impaired insulin-stimulated release of DCI-IPG. Our aim during the present grant cycle was to determine if DCI metabolism is altered in PCOS, and if that alteration leads to DCI deficiency and diminished insulin-stimulated release of the putative DCI-IPG mediator of insulin action. To this end we successfully refined and validated a bioactivity assay for DCI-IPG, and assessed DCI metabolism and insulin sensitivity in both women with PCOS and a group of normal control women. We found that women with PCOS, when compared to normal women, had a 1) greater than 5-fold increase in the renal clearance of DCI, 2) 50% reduction in the circulating concentration of DCI, and 3) decreased insulin-stimulated release of DCI-IPG during an oral glucose tolerance test (OGTT). Moreover, insulin sensitivity (as determined by frequently sampled intravenous glucose tolerance test [FSIVGTT]) correlated inversely with renal clearance of DCI in all women. These findings are consistent with abnormal handling of DCI in PCOS that results in impaired release of the DCI-IPG mediator and, consequently, insulin resistance. The present proposal seeks to extend these findings by testing the hypothesis that DCI metabolism itself is regulated by insulin, such that hyperinsulinemia increases renal clearance of DCI, and that this occurs in PCOS but not in normal women. If this were the case, an initial "insult" producing insulin resistance/hyperinsulinemia in a woman with PCOS would be amplified by a "vicious cycle" in which renal DCI clearance is increased, yielding deficiencies in circulating DCI, intracellular DCI-IPG mediator, and insulin-stimulated DCI-IPG release. The latter, in turn, would further decrease insulin sensitivity. Such a mechanism could account for the observation that insulin resistance in women with PCOS is substantially greater than that of age- and BMI-matched healthy women.