Molecular mechanisms of Insulin resistance under chronic stress

 描述(由申请人提供)： 摘要胰岛素抵抗和由此导致的糖耐量异常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。胰岛素抵抗也是一个强大的独立危险因素，也是心血管疾病常见的共同发病率。胰岛素抵抗在与糖尿病和其他疾病相关的多个组织中的流行表明了葡萄糖转运受损的潜在共同机制。我们认为，我们已经确定了胰岛素调节受损和糖尿病之间一个关键的缺失环节。我们的数据表明，通过自主神经系统的交感神经分支从大脑输入的不平衡可能是导致葡萄糖代谢和心血管功能中断的原因。我将探索胰岛素以β2肾上腺素能受体(Beta2AR)依赖的方式调节葡萄糖摄取的新机制，并阐明这一机制在胰岛素抵抗发展中的作用，胰岛素抵抗是II型糖尿病的根本原因。我假设，胰岛素激活一个新鉴定的胰岛素受体/β2AR复合体，通过反式激活β2AR/GI/PI3K级联通路，运输特定的激活Akt的亚细胞池，这对于GLUT4移位到细胞表面以摄取葡萄糖是必不可少的。我们的证据表明，这种新的IR/Beta2AR复合体可能是理解与糖尿病相关的不同组织中胰岛素抵抗的关键。我的最终目标是通过确定以前未知的涉及胰岛素诱导的GLUT4动员的机制来促进对胰岛素抵抗的病理生理学的理解。这些研究有可能带来提高胰岛素敏感性的全新治疗靶点，目前存在的药物相对较少。

 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.