Cellular Mechanisms for Insulin Resistance in Human Gestational Diabetes Mellitus

描述（由申请人提供）：妊娠期糖尿病（GDM）并发症占所有妊娠的3-10%，并且发病率正在增加，但对胰岛素抵抗的分子机制知之甚少。它对母亲和胎儿的发病率都很高，包括母亲患2型糖尿病的风险为50%，后代患儿童肥胖和成人2型糖尿病的风险很高。本研究将通过纵向前瞻性研究三组受试者的骨骼肌胰岛素信号和线粒体功能来研究GDM母亲与妊娠对照组相比的胰岛素抵抗机制。瘦孕妇、肥胖孕妇和肥胖GDM患者将在妊娠后期进行研究，并在分娩后糖尿病和高胰岛素血症消退后再次进行研究。在选择性剖宫产时和产后6-8周再次进行肌肉活检，以检查产后胰岛素信号和线粒体功能的损害是否持续存在。我们假设，产后糖耐量持续受损的女性将表现出线粒体功能和胰岛素信号的慢性损害，其中一些特征将在体外骨骼肌肌管中持续存在，这使我们能够研究潜在的表观遗传机制，以增加进展为2型糖尿病的风险。

DESCRIPTION (provided by applicant): Gestational diabetes mellitus (GDM) complicates 3-10% of all pregnancies and is increasing in incidence, yet little is known about the molecular mechanisms of the insulin resistance. It results in significant morbidity to both the mother and the fetus, including a 50% risk of developing type 2 diabetes mellitus in the mother, and a high prevalence of childhood obesity and adult type 2 diabetes in the offspring. This research will examine mechanisms of insulin resistance in mothers with GDM compared to pregnant controls by studying skeletal muscle insulin signaling and mitochondrial function in a longitudinal prospective manner in three groups of subjects. Lean pregnant, obese pregnant, and obese GDM patients will be studied during late pregnancy and again after delivery when diabetes and hyperinsulinemia subsides. Repeat muscle biopsies will be collected at the time of elective cesarean section and again at 6-8 weeks post-partum in order to examine whether or not impairments in insulin signaling and mitochondrial function persist postpartum. We hypothesize that women who continue to have impaired glucose tolerance postpartum will demonstrate a chronic detriment in mitochondrial function and insulin signaling, some features of which will persist in skeletal muscle myotubes in-vitro, allowing us to investigate potential epigenetic mechanisms for increased risk underlying the progression to type 2 diabetes. PUBLIC HEALTH RELEVANCE: The prevalence of obesity and insulin resistance is widespread in the United States, and only increasing. Obese, insulin resistant women are more susceptible to developing gestational diabetes during pregnancy and have greatly increased risk of developing type 2 diabetes post-partum. Mitochondrial dysfunction has been widely implicated in the development of skeletal muscle insulin resistance, although the cellular mechanisms remain unknown. By examining women with and without gestational diabetes during and following delivery, we may be able to more clearly define these mechanisms and their association with insulin resistance. This knowledge will not only provide valuable information regarding the insulin resistance of pregnancy but also the predisposition to type 2 diabetes in women who develop gestational diabetes.