Polycystic Ovary Syndrome: Role of Insulin Resistance

描述（由申请人提供）：这是K24面向患者研究的中期职业研究者奖的竞争性更新申请，旨在为John E. Nestler博士作为临床研究者，最重要的是，作为研究导师的发展提供持续的支持。Nestler博士是弗吉尼亚联邦大学医学院的医学教授，也是一位多产的以患者为导向的研究者，他的研究重点是胰岛素抵抗在多囊卵巢综合征（PCOS）中的病理生理作用，多囊卵巢综合征是一种影响6-10%育龄妇女的疾病。Nestler博士在指导年轻临床研究人员方面有着良好的记录，并在K24资助的4年任期内为年轻研究人员提供了非常成功的研究培训。Nestler博士研究的长期目标是开展机制和转化研究，探索胰岛素抵抗在多囊卵巢综合征中的作用。本申请中提出的具体研究，目前由NIH R01基金资助，旨在确定：1)是否通过二氮氧化合物抑制多囊卵巢综合征肥胖女性胰岛胰岛素释放直接降低循环胰岛素(i)降低d -手性肌醇（uCIDCI）的肾脏清除率（ii）增加循环DCI浓度；2)如果通过吡格列酮改善胰岛素敏感性间接降低循环胰岛素，肥胖的多囊卵巢综合征女性(i)降低uCIDCI， （ii）增加循环DCI浓度，（iii）在OGTT[口服葡萄糖耐量试验]中增加胰岛素刺激的假定DCI-肌醇磷酸聚糖介质的释放；3)非肥胖多囊卵巢综合征女性急性增加循环胰岛素是否会增加uCIDCI和/或DCI的代谢清除率。这些研究将在普通临床研究中心（GCRC）进行，使用最先进的方法，如改进的最小模型FSIVGTT[频繁采样静脉胰岛素耐量]来确定胰岛素敏感性。K24的更新将使Nestler博士能够继续他对年轻研究人员的指导，并促进他作为临床研究人员的个人成长。为此，它将继续为内斯特勒博士提供更多的受保护时间，并继续减少行政职责和临床服务责任。由于K24的更新，Nestler博士将能够将75-85%的精力投入到研究，临床研究中的个人发展，最重要的是，培训和指导年轻的研究人员。

DESCRIPTION (provided by applicant): This competitive renewal application for a K24 Mid-Career Investigator Award in Patient-Oriented Research is to provide continued support for the development of Dr. John E. Nestler as a clinical investigator and, most importantly, as a research mentor. Dr. Nestler is Professor of Medicine at Virginia Commonwealth University's Medical College of Virginia, and has been a productive patient-oriented investigator whose research focus has been the pathophysiologic role of insulin resistance in the polycystic ovary syndrome (PCOS), a disorder that affects 6-10% of women of childbearing age. Dr. Nestler has an established track record of mentorship of young clinical investigators, and has been highly successful in providing research training to young investigators during the 4 year tenure of the active K24 grant. The broad long-term objective of Dr. Nestler's studies has been to conduct both mechanistic and translational studies exploring the role of insulin resistance in PCOS. The specific studies proposed in this application, which are currently funded by an NIH R01 grant, are designed to determine: 1) if decreasing circulating insulin directly by inhibition of islet insulin release with diazoxide in obese women with PCOS (i) decreases renal clearance of D-chiro-inositol (uCIDCI) and (ii) increases the circulating concentration of DCI; 2) if decreasing circulating insulin indirectly, by improving insulin sensitivity with pioglitazone, in obese women with PCOS (i) decreases uCIDCI, (ii) increases the circulating concentration of DCI, and (iii) enhances the insulin-stimulated release of the putative DCI-inositolphosphoglycan mediator during an OGTT [oral glucose tolerance test]; and 3) if acutely increasing circulating insulin in non obese women with PCOS increases uCIDCI and/or the metabolic clearance rate of DCI. These studies will be conducted on the General Clinical Research Center (GCRC) using state of the art methodologies, such as the modified minimal model FSIVGTT [frequently-sampled intravenous insulin tolerance] to determine insulin sensitivity. The K24 renewal will allow Dr. Nestler to continue his increased mentorship of young investigators and to enhance his personal growth as a clinical investigator. It will do so by continuing to provide Dr. Nestler with increased protected time and to maintain decreases in administrative duties and clinical service responsibilities. As a result of the K24 renewal, Dr. Nestler will be able to devote 75-85% effort to research, personal development in clinical research, and, most importantly, the training and mentorship of young investigators.