Mechanisms of Insulin Resistance in GDM

描述(由申请人提供)：妊娠期糖尿病(GDM)合并高达10%的妊娠，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不会在怀孕后结束，因为最近的数据表明，妊娠期糖尿病妇女的成年后代患肥胖症和葡萄糖不耐受的风险更高，而前妊娠期糖尿病妇女患II型糖尿病的风险极高。我们的人体研究表明，妊娠期糖尿病的一个主要缺陷涉及胰岛素无法刺激葡萄糖运输到骨骼肌。这种严重的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，以及GLUT4易位水平的未知受体后缺陷。该项目的长期目标是阐明引发妊娠期糖尿病妇女胰岛素抵抗的潜在分子信号机制。在这项提案中，我们将剖析妊娠激素，包括肿瘤坏死因子α，作为胰岛素信号的负调节因子的作用，特别强调使用人类肌肉纤维和L6肌管对IR和IRS-1进行丝氨酸磷酸化的机制。具体目标1将验证这一假说，即PI 3-激酶重新分布到胰岛素受体上，通过触发增加的丝氨酸激酶活性来抑制IR酪氨酸的磷酸化和触发IRS-1的降解，从而介导妊娠期间的胰岛素抵抗。在特定的目标2中，我们将确定胎盘衍生激素(S)如何通过L6肌细胞下调IR和IR-1信号。在具体目标3中，我们将研究骨骼肌产生肿瘤坏死因子α作为妊娠期糖尿病患者胰岛素抵抗增强的机制的作用。在特定的目标4中，我们将探索新的CAP/Cbl信号通路作为GLUT4转位的潜在媒介的作用，而不依赖于PI 3-激酶。这些研究的结果将为了解怀孕如何触发人类骨骼肌中的胰岛素抵抗以及下调胰岛素信号的新机制提供重要的新见解。最终，这些研究应该会让我们更好地了解引发人类妊娠期糖尿病的细胞因素。

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.