INSULIN AND THE POLYCYSTIC OVARY SYNDROMEUWEIGHT REDUCTION STUDY

这个子项目是许多研究子项目中的一个 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来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 多囊卵巢综合征（PCOS）是美国女性不孕的主要原因，其特征是高雄激素血症和慢性无排卵。 这种疾病影响大约6-10%的育龄妇女。 患有多囊卵巢综合征的女性也有患2型糖尿病的高风险，可能是由于伴随该综合征的胰岛素抵抗。 胰岛素的某些作用可能受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，含有特定D-手性肌醇（DCI）的IPG的缺乏可能导致糖耐量受损或2型糖尿病患者的胰岛素抵抗。 DCI的缺乏也可能导致PCOS女性的胰岛素抵抗。 该研究小组先前的研究表明，与正常女性相比，PCOS女性的DCI肾脏清除率增加，伴随着DCI循环浓度的降低和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，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。 然而，在亚组分析中，尿DCI清除率增加仅在肥胖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（见初步进展）。 事实上，患有PCOS的肥胖女性与肥胖正常女性相比，DCI的肾脏清除率增加了14倍。 因此，似乎肥胖需要存在于PCOS中的DCI肾清除率异常，并且肥胖似乎对正常女性的DCI肾清除率没有影响。 我们的假设是，肥胖调节了多囊卵巢综合征女性DCI的肾脏清除率，但在正常女性中则不然。 该假设的推论是，增加的尿DCI清除率导致循环DCI和胰岛素刺激的DCI-IPG释放减少，并加重PCOS女性的胰岛素抵抗。 为了检验我们的假设，我们建议研究以下具体目标： 5. 具体目标 具体目标1：确定与年龄和体重匹配的正常肥胖女性相比，患有PCOS的肥胖女性的DCI肾清除率是否增加。 为此，我们将再次证实，与年龄和BMI匹配的肥胖正常女性相比，患有PCOS的肥胖女性（i）增加了DCI的肾脏清除率，（ii）降低了DCI的循环水平，（iii）减少了OGTT期间血液中DCI-IPG的释放。 具体目标2：确定体重减轻是否会降低肥胖PCOS女性的DCI肾清除率，但不会降低年龄和体重匹配的肥胖正常女性的DCI肾清除率。 这一目标确定了体重减轻是否逆转了PCOS中DCI处理的异常。 将在患有PCOS的肥胖女性与年龄和BMI匹配的肥胖正常女性之间比较体重减轻对（i）DCI的肾清除率、（ii）DCI的循环水平和（iii）OGTT期间血液中DCI-IPG释放的影响。 具体目标3：确定体重减轻导致的DCI肾清除率的变化（降低）是否与肥胖PCOS女性胰岛素敏感性的变化（改善）相关，而这种变化与体重减轻本身无关。 在我们以前的研究中，我们已经确定胰岛素敏感性与尿DCI清除率呈显著的负相关。 在这个目标中，我们将确定肥胖PCOS女性通过体重减轻降低DCI肾清除率是否会改善胰岛素敏感性和炎症风险标志物，而与体重减轻程度无关（通过以体重减轻程度作为协变量进行统计学调整）。 具体目标4：确定是否有相同程度的体重减轻肥胖妇女和无PCOS与（i）更大的减少DCI肾清除率，（ii）胰岛素敏感性的改善PCOS妇女相比，正常妇女。 为了进一步证明DCI处理改善导致的胰岛素敏感性改善是否与体重减轻本身无关，将根据体重减轻程度对女性进行分层。 对于每种程度的体重减轻，我们将确定与体重匹配的肥胖正常女性相比，肥胖PCOS女性是否具有（i）DCI的肾脏清除率更大的降低和（ii）由于体重减轻而导致胰岛素敏感性和炎症风险标志物的更大改善。 如果我们提出的研究证实肥胖在调节PCOS中DCI处理中的作用，它们将大大增强我们对PCOS发病机制的理解，并可能提供针对IPG系统及其功能正常化的新治疗策略的见解。

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 the leading cause of female infertility in the United States and is characterized by hyperandrogenism and chronic anovulation. The disorder affects approximately 6-10% of women of reproductive age. Women with PCOS are also at high risk for developing type 2 diabetes, presumably due to the insulin resistance that accompanies the syndrome. 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 (DCI)-containing IPG may contribute to insulin resistance in individuals with impaired glucose tolerance or type 2 diabetes mellitus. A deficiency in DCI may also contribute to the insulin resistance in women with PCOS. Previous studies of this research group demonstrated that women with PCOS, when compared to normal women, had an increase in the renal clearance of DCI, accompanied by a reduction in the circulating concentration of DCI and a 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. 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. However, in a subgroup analysis, increased urinary DCI clearance was only evident in obese women with PCOS, but not in obese normal women, or non-obese PCOS or normal women (see Preliminary Progress). In fact, obese women with PCOS had a 14 fold increase in renal clearance of DCI compared to obese normal women. Thus, it appears that obesity needs to be present for the abnormality in renal clearance of DCI to be present in PCOS, and obesity does not seem to have an effect in DCI renal clearance in normal women. Our hypothesis is that obesity modulates the renal clearance of DCI in women with PCOS, but not in normal women. A corollary of this hypothesis is that an increased urinary DCI clearance leads to a reduction in circulating DCI and insulin-stimulated DCI-IPG release, and aggravates insulin resistance in women with PCOS. To test our hypothesis, we propose to study the following specific aims: 5. Specific Aims Specific Aim 1: Determine if DCI renal clearance in obese women with PCOS is increased compared to age- and weight-matched, obese normal women. In this aim, we will reconfirm that obese women with PCOS have (i) increased renal clearance of DCI, (ii) decreased circulating levels of DCI, and (iii) decreased DCI-IPG release in blood during an OGTT, as compared to age- and BMI-matched, obese normal women. Specific Aim 2: Determine if weight loss reduces DCI renal clearance in obese women with PCOS, but not in age- and weight-matched obese normal women. This aim determines if weight loss reverses the abnormalities in DCI handling in PCOS. The effects of weight loss on (i) renal clearance of DCI, (ii) circulating levels of DCI, and (iii) DCI-IPG release in blood during an OGTT, will be compared between obese women with PCOS and age- and BMI-matched obese normal women. Specific Aim 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. In our previous studies, we have determined that insulin sensitivity has a significant inverse relationship with urinary DCI clearance. In this aim, we will determine if decreasing DCI renal clearance by weight loss in obese women with PCOS will improve insulin sensitivity and inflammatory risk markers independent of the degree of weight loss (via statistical adjustment with the degree of weight loss as a covariate). Specific Aim 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. To further demonstrate whether improvement in insulin sensitivity as a result of an improvement in DCI handling is independent of weight loss itself, women will be stratified by the degree of weight loss. For each degree of weight loss, we will determine if obese women with PCOS have (i) a greater reduction of renal clearance of DCI and (ii) a greater improvement in insulin sensitivity and inflammatory risk markers as a result of weight reduction, as compared to weight-matched obese normal women. If our proposed studies confirm a role for obesity in modulating DCI handling in PCOS, they will substantially enhance our understanding of the pathogenesis of PCOS and are likely to provide insights into novel treatment strategies directed specifically at the IPG system and normalization of its function.