INSULIN AND THE POLYCYSTIC OVARY SYNDROMEUWEIGHT REDUCTION STUDY

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 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。这种疾病影响了大约6%-10%的育龄妇女。患有多囊卵巢综合征的女性患2型糖尿病的风险也很高，可能是因为伴随着这种综合征的胰岛素抵抗。 胰岛素的某些作用可能受假定的肌醇磷酸聚糖(IPG)介导的胰岛素作用的影响，有证据表明，在糖耐量减退或2型糖尿病患者中，含有D-环肌醇(DCI)的特定IPG的缺陷可能导致胰岛素抵抗。DCI缺陷也可能是多囊卵巢综合征患者胰岛素抵抗的原因之一。该研究小组以前的研究表明，与正常女性相比，多囊卵巢综合征患者肾脏对DCI的清除量增加，同时DCI循环浓度降低，口服葡萄糖耐量试验(OGTT)中胰岛素刺激的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的肾脏清除量呈负相关。这些发现与PCOS患者对DCI的异常处理是一致的，这会导致DCI-IPG介体的释放受损，从而导致胰岛素抵抗。然而，在一项亚组分析中，只有患有多囊卵巢综合征的肥胖女性的尿中DCI清除量增加是明显的，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没有明显的增加(见初步进展)。事实上，患有多囊卵巢综合征的肥胖女性与肥胖的正常女性相比，肾脏对DCI的清除量增加了14倍。因此，在PCOS中，似乎需要肥胖才能使DCI的肾脏清除异常出现，而肥胖似乎对正常女性的DCI肾脏清除没有影响。 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，但在正常女性中不是。这一假设的一个推论是，尿中DCI清除量的增加导致循环DCI和胰岛素刺激的DCI-IPG释放减少，并加剧了PCOS女性的胰岛素抵抗。为了验证我们的假设，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肥胖正常肥胖女性相比，患有多囊卵巢综合征的肥胖女性的DCI肾脏清除量是否增加。为此，我们将再次确认，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的肾脏清除量，(Ii)降低了循环DCI水平，(Iii)在OGTT期间血液中DCI-IPG释放减少。 具体目标2：确定体重减轻是否会降低患有多囊卵巢综合征的肥胖女性的DCI肾脏清除率，但在年龄和体重匹配的正常肥胖女性中不会。这一目标决定了体重减轻是否逆转了多囊卵巢综合征患者在DCI处理方面的异常。我们将在患有多囊卵巢综合征的肥胖女性和年龄和体重指数匹配的正常肥胖女性之间，比较体重减轻对(I)DCI的肾脏清除量、(Ii)DCI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肾脏清除量的改变(减少)是否与患有多囊卵巢综合征的肥胖女性胰岛素敏感性的改变(改善)相关，而这种改变(改善)与体重减轻本身无关。在我们之前的研究中，我们已经确定胰岛素敏感性与尿DCI清除量呈显著负相关。为此，我们将确定在患有PCOS的肥胖女性中，通过体重减轻来降低DCI肾脏清除量是否会改善胰岛素敏感性和炎症风险标记物，而不依赖于体重减轻的程度(通过以体重减轻程度为协变量进行统计调整)。 具体目标4：确定患有和不患有多囊卵巢综合征的肥胖女性的体重减轻程度是否与(1)多囊卵巢综合征患者的DCI肾脏清除率显著降低，以及(2)与正常女性相比，多囊卵巢综合征患者的胰岛素敏感性显著改善有关。为了进一步证明改善DCI治疗导致的胰岛素敏感性改善是否独立于体重减轻本身，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正常肥胖女性相比，患有PCOS的肥胖女性是否(I)肾脏对DCI的清除量有更大的降低，(Ii)由于体重减轻，胰岛素敏感性和炎症风险标记物有更大的改善。 如果我们提出的研究证实肥胖在调节PCOS的DCI处理中所起的作用，它们将极大地增强我们对PCOS发病机制的理解，并可能为专门针对IPG系统及其功能正常化的新的治疗策略提供见解。

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.