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

基本信息

批准号：
8229902
负责人：
Kristen Elizabeth Boyle
金额：
$ 5.22万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
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/8229902
关键词：
Acetylation Adult Biopsy Cell Culture Techniques Cell Respiration Cesarean section Characteristics Chronic Controlled Study Data Development Diabetes Mellitus Enzymes Epigenetic Process Exposure to Fatty Acids Fetus Future Genes Genetic Gestational Diabetes Goals High Prevalence Human Hyperinsulinism Impairment In Vitro Incidence Individual Inflammation Insulin Resistance Knowledge Link Lipids Metabolic Mitochondria Modeling Molecular Morbid Obesity Morbidity - disease rate Mothers Muscle Muscle Cells Muscle Fibers Muscle Mitochondria Non-Insulin-Dependent Diabetes Mellitus Obesity Oxidative Stress Patients Pattern Population Postpartum Period Predisposition Pregnancy Prevalence Primary Cell Cultures Rectus Abdominis Research Research Design Risk Signaling Protein Skeletal Muscle Skeletal Muscle Satellite Cells Stream Testing Time United States Woman diabetic impaired glucose tolerance insulin signaling mitochondrial dysfunction obesity in children offspring oxidation pregnant prospective protein expression public health relevance satellite cell vastus lateralis

项目摘要

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) 使 3-10% 的妊娠变得复杂，并且发病率正在增加，但人们对胰岛素抵抗的分子机制知之甚少。它会导致母亲和胎儿显着发病，其中母亲患 2 型糖尿病的风险高达 50%，而后代儿童肥胖和成人 2 型糖尿病的患病率很高。这项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传导和线粒体功能，研究 GDM 母亲与怀孕对照者的胰岛素抵抗机制。瘦孕妇、肥胖孕妇和肥胖 GDM 患者将在妊娠后期以及分娩后糖尿病和高胰岛素血症消退时再次进行研究。将在选择性剖腹产时和产后 6-8 周再次收集肌肉活检，以检查产后胰岛素信号和线粒体功能是否持续受损。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机制，以增加潜在的风险进展为 2 型糖尿病。公共卫生相关性：肥胖和胰岛素抵抗在美国普遍存在，而且只会不断增加。肥胖、胰岛素抵抗的女性在怀孕期间更容易患妊娠糖尿病，并且产后患 2 型糖尿病的风险大大增加。尽管细胞机制仍不清楚，但线粒体功能障碍广泛涉及骨骼肌胰岛素抵抗的发展。通过在分娩期间和分娩后检查患有或不患有妊娠糖尿病的女性，我们也许能够更清楚地定义这些机制及其与胰岛素抵抗的关系。这些知识不仅可以提供有关妊娠期胰岛素抵抗的宝贵信息，还可以提供妊娠期糖尿病女性患 2 型糖尿病的倾向。