Cellular Mechanisms for Insulin Resistance in Human Gestational Diabetes Mellitus

人类妊娠糖尿病胰岛素抵抗的细胞机制

• 批准号: 8003061
• 负责人: Kristen Elizabeth Boyle
• 金额: $ 4.76万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8003061
• 关键词: Adult; Biopsy; Cesarean section; Chronic; Controlled Study; Development; Diabetes Mellitus; Epigenetic Process; Fetus; Gestational Diabetes; High Prevalence; Human; Hyperinsulinism; Impairment; In Vitro; Incidence; Insulin Resistance; Knowledge; Mitochondria; Molecular; Morbidity - disease rate; Mothers; Muscle; Muscle Fibers; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Patients; Postpartum Period; Predisposition; Pregnancy; Prevalence; Research; Risk; Skeletal Muscle; Time; United States; Woman; impaired glucose tolerance; insulin signaling; mitochondrial dysfunction; obesity in children; offspring; pregnant; prospective; public health relevance

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.

描述（由申请人提供）：妊娠期糖尿病（GDM）占所有妊娠的3-10%，发病率正在增加，但对胰岛素抵抗的分子机制知之甚少。它导致母亲和胎儿的显著发病率，包括母亲患2型糖尿病的风险为50%，以及后代中儿童肥胖和成人2型糖尿病的高患病率。本研究将通过研究三组受试者的骨骼肌胰岛素信号传导和线粒体功能，研究GDM母亲与妊娠对照组相比的胰岛素抵抗机制。将在妊娠晚期和分娩后糖尿病和高胰岛素血症消退时再次研究瘦妊娠、肥胖妊娠和肥胖GDM患者。在选择性剖宫产时和产后6-8周再次收集重复肌肉活检，以检查产后胰岛素信号传导和线粒体功能的损伤是否持续存在。我们假设，产后持续糖耐量受损的妇女将表现出线粒体功能和胰岛素信号传导的慢性损害，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机制，增加2型糖尿病进展的风险。 公共卫生相关性：肥胖和胰岛素抵抗的流行在美国很普遍，而且只会增加。肥胖、胰岛素抵抗的妇女在怀孕期间更容易患妊娠糖尿病，产后患2型糖尿病的风险也大大增加。线粒体功能障碍与骨骼肌胰岛素抵抗的发生密切相关，但其细胞机制尚不清楚。通过检查妊娠期糖尿病和非妊娠期糖尿病的妇女在分娩期间和分娩后，我们可能能够更清楚地定义这些机制及其与胰岛素抵抗的关系。这些知识不仅将提供有关妊娠期胰岛素抵抗的有价值的信息，而且还将提供妊娠期糖尿病妇女患2型糖尿病的易感性。