Cellular Mechanisms for Insulin Resistance in Human Gestational Diabetes Mellitus

描述(申请人提供)：妊娠期糖尿病(GDM)合并3-10%的妊娠，发病率正在增加，但对胰岛素抵抗的分子机制知之甚少。它对母亲和胎儿都造成了严重的发病率，包括母亲患2型糖尿病的风险高达50%，以及儿童肥胖症和成人2型糖尿病在子女中的高患病率。这项研究将通过对三组受试者的骨骼肌胰岛素信号和线粒体功能的纵向前瞻性研究，与妊娠对照组相比，研究妊娠期糖尿病母亲的胰岛素抵抗机制。精瘦孕妇、肥胖孕妇和肥胖的妊娠期糖尿病患者将在妊娠晚期和糖尿病和高胰岛素血症消退后再次进行研究。重复的肌肉活检将在选择性剖宫产时收集，并在产后6-8周再次收集，以检查胰岛素信号和线粒体功能的损害是否在产后持续存在。我们假设，产后继续糖耐量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，使我们能够研究潜在的表观遗传学机制，增加发展为2型糖尿病的风险。 与公共健康相关：肥胖和胰岛素抵抗的流行在美国很普遍，而且还在增加。肥胖、胰岛素抵抗的妇女在怀孕期间更容易患妊娠期糖尿病，产后患2型糖尿病的风险大大增加。线粒体功能障碍被广泛认为与骨骼肌胰岛素抵抗的发生有关，尽管其细胞机制尚不清楚。通过在分娩期间和分娩后检查患有和不患有妊娠期糖尿病的妇女，我们可能能够更清楚地确定这些机制及其与胰岛素抵抗的关联。这一知识不仅将提供关于妊娠胰岛素抵抗的有价值的信息，而且还将提供患妊娠期糖尿病的妇女患2型糖尿病的易感性。

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.