Molecular mechanisms of Insulin resistance under chronic stress

慢性应激下胰岛素抵抗的分子机制

• 批准号: 10403478
• 负责人: YANG K XIANG
• 金额: --
• 依托单位: VA NORTHERN CALIFORNIA HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10403478
• 关键词: ADRBK1 gene; Address; Adipocytes; Adrenergic Agents; Adrenergic Receptor; Affect; Arrestins; Autonomic nervous system; Binding; Brain; Cardiac; Cardiovascular Diseases; Cardiovascular Physiology; Cartoons; Cell membrane; Cell surface; Chronic; Chronic Disease; Chronic stress; Complex; Data; Development; Diabetes Mellitus; Disease; Endocytosis; Fatty acid glycerol esters; Foxes; Functional disorder; GLUT 4 protein; Genes; Glucose; Glucose Intolerance; Goals; Health; Healthcare; High Fat Diet; Hyperinsulinism; Impairment; In Vitro; Insulin; Insulin Receptor; Insulin Resistance; Isoproterenol; Lead; Link; Liver; Mediating; Military Personnel; Molecular; Mus; Muscle Cells; Muscle Fibers; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Perfusion; Pharmaceutical Preparations; Pharmacotherapy; Play; Prevalence; Risk Factors; Role; Signal Transduction; Skeletal Muscle; Stress; System; Tissues; Transactivation; Vesicle; Veterans; Wild Type Mouse; adrenergic stress; comorbidity; diabetes management; feeding; fighting; glucose metabolism; glucose transport; glucose uptake; improved; inhibitor/antagonist; insulin regulation; insulin sensitivity; new therapeutic target; novel; preservation; public health relevance; response; skeletal

 DESCRIPTION (provided by applicant): Abstract Insulin resistance and the resultant glucose intolerance are central to the pathophysiology of acquired diabetes, common health issues among veterans. Insulin resistance is also a powerful independent risk factor and a common co-morbidity in cardiovascular diseases. The prevalence of insulin resistance in multiple tissues associated diabetes and other diseases suggest a potential common mechanism of impaired glucose transport. We believe that we have identified a critical missing link between impaired insulin regulation and diabetes. Our data suggest that poorly balanced input from the brain via the sympathetic branch of the autonomic nervous system may underlie disruption of both glucose metabolism and cardiovascular function. I will explore a novel mechanism by which insulin regulates glucose uptake in a beta2 adrenergic receptor (beta2AR)-dependent manner and elucidate the contribution of this mechanism to the development of insulin resistance, the fundamental cause of Type II diabetes. I hypothesize that activation of a newly characterized insulin receptor/ beta2AR complex by insulin traffics a specific subcellular pool of activated Akt via transactivation of a beta2AR/Gi/PI3K cascade, which is essential for translocation of GLUT4 to the cell surface for glucose uptake. Our evidence suggests that this novel IR/beta2AR complex may hold the key to understanding insulin resistance in diverse tissues associated with diabetes. My ultimate goal is to advance the understanding of the pathophysiology of insulin resistance by identifying previously unidentified mechanisms involved in insulin-induced mobilization of GLUT4. These studies have the potential to lead to entirely new therapeutic targets to increase insulin sensitivity, of which relatively few agents currently exist.

 描述（由申请人提供）： 抽象的胰岛素抵抗和由此产生的葡萄糖intlera是获得性糖尿病的病理生理学的核心，这是退伍军人中常见的健康问题。胰岛素抵抗也是强大的独立危险因素，也是心血管疾病中常见的合并症。多次胰岛素抵抗的患病率与糖尿病和其他疾病有关，这表明葡萄糖转运受损的常见机制。我们认为，我们已经确定了受损的胰岛素调节和糖尿病之间的严重缺失联系。我们的数据表明，通过自主神经系统的交感神经分支，大脑的平衡输入不足可能是葡萄糖代谢和心血管功能的破坏。我将探索一种新的机制，通过该机制，胰岛素可以调节BetA2肾上腺素受体（BetA2AR）依赖性方式中的葡萄糖摄取，并阐明了该机制对胰岛素抵抗发展的贡献，这是II型糖尿病型的基本原因。我假设通过胰岛素运输来激活新表征的胰岛素受体/β2AR复合物通过beta2AR/gi/gi/pi3k级联反式激活Akt的特异性亚细胞池，这对于将GLUT4转移到细胞表面上的细胞表面至关重要。我们的证据表明，这种新型的IR/Beta2AR复合物可能是了解与糖尿病相关的多样性组织中胰岛素抵抗的关键。我的最终目标是通过确定与胰岛素诱导的GLUT4动员有关的先前未鉴定的机制来提高对胰岛素抵抗的病理生理的理解。这些研究有可能导致全新的治疗靶标，以提高胰岛素敏感性，目前存在相对较少的药物。