Insulin and the Polycystic Ovary Syndrome

描述（由申请人提供）：本提案描述了一个为期5年的培训计划，用于发展以患者为导向的研究的学术生涯。凯岛Cheang，Pharm. D.，寻求对这项研究培训的支持，以使自己成为妇女健康中胰岛素抵抗的独立临床研究者。John E. Nestler，医学博士将指导首席研究员的科学发展Nestler博士是多囊卵巢综合征（PCOS）胰岛素抵抗领域公认的领导者。此外，一个由德高望重的科学家和统计学家组成的咨询委员会将提供科学和职业建议。候选人所在的机构为跨学科研究提供了良好的环境，并将至少75%的郑博士的努力投入到她的研究和培训活动中。 研究将集中在一个假定的肌醇磷酸聚糖（IPG）介导的胰岛素作用在PCOS中的作用。申请人导师的既往研究表明，含有IPG的D-手性肌醇（DCI）缺乏，伴随DCI肾清除率增加，可能导致PCOS的胰岛素抵抗。然而，增加的DCI肾清除率仅在肥胖PCOS女性中明显，而在肥胖正常女性或非肥胖PCOS或正常女性中不明显。巧合的是，肥胖与PCOS妇女胰岛素敏感性降低5倍有关，但正常妇女仅降低2倍。由于胰岛素敏感性与DCI肾清除率呈负相关，我们认为肥胖PCOS和正常女性之间DCI肾清除率的差异可以部分解释肥胖PCOS女性与肥胖正常女性相比胰岛素敏感性的不成比例降低。我们的假设是肥胖调节PCOS女性DCI的肾脏清除率，但在正常女性中则不然。我们进一步提出，增加DCI肾清除率导致DCI可用性降低，并加重PCOS妇女的胰岛素抵抗。具体目标包括：（1）确定患有PCOS的肥胖女性中的DCI肾清除率与年龄和体重匹配的肥胖正常女性相比是否增加;（2）确定体重减轻是否降低患有PCOS的肥胖女性中的DCI肾清除率，但在年龄和体重匹配的肥胖正常女性中不降低;（3）确定是否有变化体重减轻导致的DCI肾清除率（降低）与以下变化相关：（改善）肥胖PCOS妇女的胰岛素敏感性，这与体重减轻本身无关;和（4）确定患有和不患有PCOS的肥胖妇女中同等程度的体重减轻是否与（i）DCI肾清除率的更大降低相关，和（ii）与正常妇女相比，PCOS妇女的胰岛素敏感性有更大的改善。 相关性：PCOS是女性不孕的主要原因。胰岛素抵抗在这种疾病中起着重要作用。这项研究意义重大，因为它将促进对多囊卵巢综合征胰岛素抵抗本质的了解，并为新的治疗策略提供见解。

DESCRIPTION (provided by applicant): This proposal describes a 5-year training program for the development of an academic career in Patient-Oriented Research. Kai I. Cheang, Pharm. D., seeks support for this research training in order to establish herself as an independent clinical investigator in insulin resistance in women's health. John E. Nestler, M.D. will mentor the principal investigator's scientific development. Dr. Nestler is a recognized leader in the field of insulin resistance in the polycystic ovary syndrome (PCOS). In addition, an advisory committee of highly regarded scientists and statistician will provide scientific and career advice. The candidate's institution provides an excellent environment for interdisciplinary research, and will commit at least 75% of Dr. Cheang's efforts to her research and training activities for this award. Research will focus on the role of a putative inositol phosphoglycan (IPG) mediator of insulin action in PCOS. Previous studies of the applicant's mentor demonstrated that a deficiency in D-chiro-inositol (DCI) containing IPG, accompanied by an increase in DCI renal clearance, may contribute to insulin resistance in PCOS. However, increased DCI renal clearance was only evident in obese women with PCOS, but not in obese normal women, or in non-obese PCOS or normal women. Coincidentally, obesity was associated with a 5-fold reduction in insulin sensitivity in PCOS women, but only a 2-fold reduction in the normal women. Since insulin sensitivity is inversely correlated with DCI renal clearance, we propose that the difference in DCI renal clearance between obese PCOS and normal women could partially explain the disproportionate reduction in insulin sensitivity in obese PCOS women compared to obese normal women. Our hypothesis is that obesity modulates the renal clearance of DCI in women with PCOS, but not in normal women. We further propose that increased DCI renal clearance leads to a reduction in DCI availability and aggravates insulin resistance in women with PCOS. The specific aims include: (1) Determine if DCI renal clearance in obese women with PCOS is increased compared to age- and weight-matched, obese normal women; (2) Determine if weight loss reduces DCI renal clearance in obese women with PCOS, but not in age- and weight-matched obese normal women; (3) Determine if a change (reduction) in DCI renal clearance as a result of weight loss is correlated with a change (improvement) in insulin sensitivity in obese women with PCOS that is independent of weight loss itself; and (4) Determine if an equivalent degree of weight loss in obese women with and without PCOS is associated with (i) a greater reduction in DCI renal clearance, and (ii) a greater improvement in insulin sensitivity in the PCOS women compared to the normal women. Relevance: PCOS is a major cause of female infertility. Insulin resistance plays an important role in the disorder. The research proposed is significant, because it will advance the understanding of the nature of the insulin resistance in PCOS and provide insights into new treatment strategies.