Mechanisms of Insulin Resistance in GDM

描述（由申请人提供）：妊娠期糖尿病（GDM）使高达10%的妊娠并发症，并导致胎儿高胰岛素血症、巨大儿和分娩期间的母体并发症。母亲和胎儿的发病率在妊娠后并没有结束，因为最近的数据表明，GDM女性的成年后代患肥胖症和葡萄糖耐受不良的风险较高，而既往GDM女性患II型糖尿病的风险极高。我们的人体研究表明，GDM的一个主要缺陷是胰岛素不能刺激葡萄糖转运到骨骼肌中。这种严重胰岛素抵抗的机制尚不清楚，但可能涉及胰岛素受体IRS-1的缺陷和GLUT 4易位水平的未知受体后缺陷。该项目的长期目标是阐明引起GDM女性胰岛素抵抗的潜在分子信号机制。在这个建议中，我们将剖析怀孕激素的作用，包括TNF α，作为胰岛素信号传导的负调节剂，特别强调使用人类肌纤维和L 6肌管的IR和IRS-1丝氨酸磷酸化的机制。具体目标1将检验以下假设：PI 3-激酶重新分布至胰岛素受体通过触发丝氨酸激酶活性增加以抑制IR酪氨酸磷酸化并触发IRS-1降解来介导妊娠期胰岛素抵抗。在具体目标2中，我们将确定胎盘衍生激素如何使用L 6肌细胞下调IR和IRS-1信号传导。在具体目标3中，我们将研究骨骼肌TNF α的产生作为GDM女性胰岛素抵抗增加的机制。在具体目标4中，我们将探讨新的CAP/Cbl信号通路作为独立于PI 3-激酶的GLUT 4易位的潜在介体的作用。这些研究的结果将为妊娠如何触发人类骨骼肌胰岛素抵抗以及胰岛素信号转导下调的新机制提供重要的新见解。最终，这些研究将使我们更好地了解触发人类GDM的细胞因素。

DESCRIPTION (provided by applicant): Gestational Diabetes Mellitus (GDM) complicates up to 10% of all pregnancies and results in fetal hyperinsulinemia, macrosomia, and maternal complications during delivery. The morbidity to the mother and fetus does not end after pregnancy as recent data demonstrate a higher risk of obesity and glucose intolerance in adult offspring from GDM women and extremely high risk for type II DM in former GDM women. Our human studies have shown that a major defect in GDM involves the inability of insulin to stimulate glucose transport into skeletal muscle. The mechanisms for this severe insulin resistance are unknown, but likely involve a defect in the insulin receptor, IRS-1, and an unknown post-receptor defect at the level of GLUT4 translocation. The long-term goal of this project is to elucidate the underlying molecular signaling mechanisms that provoke insulin resistance in women with GDM. In this proposal we will dissect the roles of hormones of pregnancy, including TNFalpha, as negative regulators of insulin signaling, with a special emphasis on mechanisms for serine phosphorylation of IR and IRS-1 using human muscle fibers and L6 myotubes. Specific Aim 1 will test the hypothesis that re-distribution of PI 3-kinase to the insulin receptor mediates insulin resistance in pregnancy by triggering increased serine kinase activity to inhibit IRtyrosine phosphorylation and trigger IRS-1 degradation. In Specific Aim 2, we will determine how placental derived hormone(s) down-regulate IR and IRS-1 signaling using L6 muscle cells. In Specific Aim 3, we will investigate the contribution of skeletal muscle TNFalpha production as a mechanism for greater insulin resistance in women with GDM. In Specific Aim 4, we will explore the role of the novel CAP/Cbl signaling pathway as a potential mediator of GLUT4 translocation independent of PI 3-kinase. The outcome of these studies will provide important new insights into how pregnancy triggers insulin resistance in human skeletal muscle, and novel mechanisms for the down-regulation of insulin signaling. Ultimately, these studies should provide us with a better understanding of the cellular factors that trigger human GDM.