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产生的葡萄糖耐受不良是获得性糖尿病的病理生理学核心，是退伍军人常见的健康问题。胰岛素抵抗也是心血管疾病的一个重要的独立危险因素和常见的合并症。胰岛素抵抗在多种组织中的流行与糖尿病和其他疾病相关，提示葡萄糖转运受损是一种潜在的共同机制。我们相信，我们已经确定了胰岛素调节受损和糖尿病之间的关键缺失环节。我们的数据表明，通过自主神经系统的交感分支从大脑输入的不平衡可能导致葡萄糖代谢和心血管功能的破坏。我将探索胰岛素以β 2肾上腺素能受体（β 2AR）依赖性方式调节葡萄糖摄取的新机制，并阐明这种机制对胰岛素抵抗（II型糖尿病的根本原因）发展的贡献。我推测，一个新的特点胰岛素受体/β 2 AR复合物的激活胰岛素运输一个特定的亚细胞池的激活Akt通过β 2 AR/Gi/PI 3 K级联反应的反式激活，这是必不可少的葡萄糖转运到细胞表面的葡萄糖摄取。我们的证据表明，这种新的IR/β 2AR复合物可能是了解糖尿病相关的各种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确定的参与胰岛素诱导的GLUT 4动员的机制来促进对胰岛素抵抗的病理生理学的理解。这些研究有可能导致全新的治疗靶点，以增加胰岛素敏感性，其中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.