Insulin and the Polycystic Ovary Syndrome

描述(由申请人提供)：本提案描述了一项为期5年的培训计划，旨在发展以患者为中心的研究的学术生涯。张凯，帕姆。博士，寻求对这项研究培训的支持，以确立自己作为女性健康中胰岛素抵抗的独立临床研究员的地位。约翰·E·内斯特勒医学博士将指导首席研究员的科学发展。内斯特勒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，一个由备受尊敬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。候选人所在的学院为跨学科研究提供了良好的环境，并将把张博士至少75%的精力投入到她的研究和培训活动中，以获得这一奖项。研究重点将集中在假定的肌醇磷酸多糖(IPG)在多囊卵巢综合征中胰岛素作用的中介作用上。先前对申请人导师的研究表明，含有IPG的D-肌醇(DCI)缺乏，伴随着DCI肾脏清除量的增加，可能导致多囊卵巢综合征患者的胰岛素抵抗。然而，只有患有多囊卵巢综合征的肥胖女性才能明显增加DCI的肾脏清除量，而在肥胖的正常女性、非肥胖的多囊卵巢综合征或正常女性中并不明显。巧合的是，肥胖与多囊卵巢综合征女性胰岛素敏感度降低5倍有关，但在正常女性中仅降低2倍。由于胰岛素敏感性与DCI肾清除量呈负相关，我们认为肥胖的PCOS妇女和正常妇女之间的DCI肾清除量的差异可以部分解释肥胖的PCOS妇女与肥胖的正常妇女相比胰岛素敏感性的不成比例降低。我们的假设是，肥胖调节了多囊卵巢综合征女性DCI的肾脏清除，但在正常女性中不是。我们进一步提出，增加DCI的肾脏清除量会导致PCOS女性患者DCI的可用性降低，并加重胰岛素抵抗。具体目标包括：(1)确定与年龄和体重匹配的肥胖正常女性相比，患有PCOS的肥胖女性的DCI肾脏清除量是否增加；(2)确定体重减轻是否降低了患有PCOS的肥胖女性的DCI肾脏清除量，但在年龄和体重匹配的肥胖正常女性中没有；(3)确定由于体重减轻而导致的DCI肾脏清除量的变化(减少)是否与患有PCOS的肥胖女性的胰岛素敏感性的变化(改善)相关，该变化(改善)独立于体重减轻本身；以及(4)确定患有和不患有PCOS的肥胖女性的体重减轻程度是否与(I)与正常女性相比，(I)DCI肾脏清除率更大的降低，以及(Ii)PCOS女性的胰岛素敏感性的更大改善有关。相关性：多囊卵巢综合征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。这项研究具有重要意义，因为它将促进对多囊卵巢综合征胰岛素抵抗本质的理解，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.