Coupling of D-chiro-inositol to insulin in PCOS women

描述（由申请人提供）：多囊卵巢综合征（PCOS）以高雄激素和慢性无排卵为特征，是美国最常见的女性不孕症。研究表明，胰岛素抵抗伴代偿性高胰岛素血症是多囊卵巢综合征高雄激素和无排卵的部分原因。多囊卵巢综合征胰岛素抵抗的细胞机制在很大程度上仍然未知。d -氨基肌醇磷酸聚糖（DCI-IPG）是胰岛素作用的非经典介质，已被证明可以增加葡萄糖的利用。先前的研究表明，对多囊卵巢综合征妇女使用类似于天然介质的药物可增加这些妇女的胰岛素敏感性，减少卵巢雄激素的产生并改善排卵。因此，多囊卵巢综合征的女性似乎有DCI-IPG细胞活性缺陷，导致胰岛素抵抗。本应用的目的是确定d -氨基肌醇磷酸聚糖与胰岛素之间偶联的缺陷是否在多囊卵巢综合征的胰岛素抵抗中起作用。我们建议评估PCOS女性和正常女性DCI-IPG与胰岛素的耦合：1)给这些女性服用二氮氧化合物，以暂时抑制她们的胰腺胰岛素分泌，并测量这些女性在胰岛素抑制后血浆中DCI-IPG活性的变化；2)使用胰岛素钳钳给药后恢复胰岛素，并测量正常女性与多囊卵巢综合征女性在夹钳期间DCI-IPG活性的恢复程度。因此，PCOS女性和正常对照女性都将评估胰岛素与DCI-IPG活性的关系。我们的假设是，PCOS中胰岛素抵抗的至少一种机制是由于胰岛素和DCI-IPG活性之间的偶联缺陷。这些研究结果将1)描述正常女性胰岛素与DCI-IPG之间的生理和体内关系；2)提供PCOS胰岛素抵抗的机制，可能与DCI-IPG胰岛素信号级联有关；3)为进一步的临床研究提供基础，探讨偶联缺陷在其他胰岛素抵抗人类疾病（如肥胖或2型糖尿病）中的作用；4)为多囊卵巢综合征胰岛素抵抗提供新的特异性治疗方法。

DESCRIPTION (provided by applicant): Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and chronic anovulation and it is the most common form of female infertility in the U.S. It has been demonstrated that insulin resistance accompanied by compensatory hyperinsulinemia is, in part, responsible for the hyperandrogenism and anovulation of this disorder. The cellular mechanisms of insulin resistance in PCOS are still largely unknown. D-chiro-inositol phosphoglycan (DCI-IPG) is a nonclassical mediator of insulin action that has been demonstrated to increase glucose utilization. Previous studies have shown that administering a drug similar to the native mediator to women with PCOS increases insulin sensitivity, reduces ovarian androgen production and improves ovulation in these women. Therefore, it seems likely that women with PCOS have a defect in DCI-IPG cellular activity that leads to insulin resistance. The aim of this application is to determine whether a defect in coupling between D-chiro-inositol phosphoglycan and insulin plays a role in the insulin resistance of PCOS. We propose to assess the coupling of the DCI-IPG to insulin in women with PCOS and normal women: 1) by administering diazoxide to these women in order to temporarily suppress their pancreatic insulin secretion and measure a change in activity in DCI-IPG in plasma of these women following suppression of insulin and 2) by restoring insulin following diazoxide administration using an insulin clamp and measuring the degree to which DCI-IPG activity is also restored during the clamp in normal women versus women with PCOS. Hence, both PCOS women and normal control women will be evaluated for this insulin to DCI-IPG activity relationship. It is our hypothesis that at least one mechanism of insulin resistance in PCOS is due to defective coupling between insulin and DCI-IPG activity. The results of these studies will 1) describe the physiologic, in vivo relationship between insulin and DCI-IPG in normal women; 2) provide a mechanism for insulin resistance in PCOS as it relates to the DCI-IPG insulin signaling cascade; 3) provide the groundwork for further clinical studies to explore the role of defective coupling in other insulin resistant human conditions (such obesity or type 2 diabetes); and 4) lead to novel specific therapies for the insulin resistance of PCOS.