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

PCOS 女性中 D-手性肌醇与胰岛素的偶联

• 批准号: 6668732
• 负责人: MARIA J IUORNO
• 金额: $ 7.5万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6668732
• 关键词: clinical research; diazoxide; dosage; enzyme linked immunosorbent assay; female; glucose clamp technique; glucose tolerance test; hormone regulation /control mechanism; human subject; inositol phosphates; insulin; insulin inhibitor; insulin receptor; insulin sensitivity /resistance; pancreatic islet function; patient oriented research; pharmacokinetics; polycystic ovary syndrome; receptor coupling; receptor expression; statistics /biometry

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.

描述（由申请人提供）：多囊卵巢综合征（PCOS）的特征是高雄激素血症和慢性无排卵，是美国女性不孕症的最常见形式。已证明胰岛素抵抗伴代偿性高胰岛素血症是这种疾病的高雄激素血症和无排卵的部分原因。PCOS胰岛素抵抗的细胞机制仍不清楚。D-手性肌醇磷酸聚糖（DCI-IPG）是胰岛素作用的非经典介体，已被证明可增加葡萄糖利用。先前的研究表明，给予PCOS女性类似于天然介质的药物可增加胰岛素敏感性，减少卵巢雄激素的产生并改善这些女性的排卵。因此，患有PCOS的女性似乎可能在DCI-IPG细胞活性方面存在缺陷，导致胰岛素抵抗。 本申请的目的是确定D-手性肌醇磷酸聚糖和胰岛素之间的偶联缺陷是否在PCOS的胰岛素抵抗中起作用。我们建议在PCOS女性和正常女性中评估DCI-IPG与胰岛素的偶联：1）通过向这些女性施用二氮嗪以暂时抑制她们的胰腺胰岛素分泌，并测量在胰岛素抑制后这些女性的血浆中DCI-IPG活性的变化，和2）通过在施用二氮嗪后使用胰岛素钳夹恢复胰岛素，并测量DCI-IPG活性降低的程度。在正常女性与PCOS女性的钳夹期间，IPG活性也恢复。因此，将评价PCOS女性和正常对照女性的胰岛素与DCI-IPG活性的关系。我们的假设是，PCOS中至少有一种胰岛素抵抗机制是由于胰岛素和DCI-IPG活性之间的偶联缺陷。 这些研究的结果将1）描述正常女性中胰岛素和DCI-IPG之间的生理学体内关系; 2）提供PCOS中胰岛素抵抗的机制，因为它与DCI-IPG胰岛素信号级联相关; 3）为进一步的临床研究提供基础，以探索偶联缺陷在其他胰岛素抵抗人类疾病中的作用（如肥胖或2型糖尿病）;和4）导致PCOS的胰岛素抵抗的新的特异性疗法。