FLOTILLINS AND INSULIN-STIMULATED GLUCOSE TRANSPORT

随着肥胖的流行和人口的老龄化，2型糖尿病的患病率越来越高。胰岛素抵抗是2型糖尿病的标志。这个应用程序的长期目标是了解胰岛素的信号是如何在细胞内沟通的，以及这个过程在胰岛素抵抗状态下是如何缺陷的。脂肪细胞在胰岛素抵抗中起着核心作用，而骨骼肌是饭后葡萄糖处理的主要部位。脂肪细胞的初步结果提出了一种假设，即膜蛋白flotilin -1将特定的信号分子招募到质膜的一个隔室，这种招募是胰岛素反应中细胞表面葡萄糖转运蛋白增加所必需的。这些事件构成了独立于磷脂酰肌醇3-激酶的胰岛素刺激葡萄糖运输所需的第二信号通路。特异性目的1是通过调控flotilin -1在培养脂肪细胞和肌肉细胞中的表达来确定其在葡萄糖代谢中的功能。flotilin -1表达水平与糖代谢指标和胰岛素作用的关系将被确定。特异性目的2是确定flotilin -1在基因工程小鼠葡萄糖代谢中的功能。将产生在脂肪组织和骨骼肌中过度表达flotilin -1的小鼠和不表达功能性flotilin -1的小鼠，并仔细分析其葡萄糖和脂质代谢的表型。这些基因工程小鼠将成为研究全身葡萄糖稳态生理学的有价值的试剂。具体目的3是通过鉴定酵母双杂交系统中与flotilin -1相互作用的蛋白来研究flotilin -1的调控。这些目标的完成将产生关于flotilin -1在人类健康和疾病以及2型糖尿病病理生理学中的作用的可测试的假设。

With the epidemic of obesity and the population's aging the prevalence of type 2 diabetes mellitus is increasing. Insulin resistance is a hallmark of type 2 diabetes. This application's long-term objectives are to understand how insulin's signals are communicated within cells and how this process is defective in insulin resistant states. The adipocyte plays a central role in insulin resistance, and skeletal muscle is the major site of glucose disposal after a meal. Preliminary results in adipocytes lead to the hypothesis that the membrane protein flotillin-1 recruits specific signaling molecules to a compartment of the plasma membrane and that this recruitment is required for the increase in cell surface glucose transporters that occurs in response to insulin. These events constitute a second signaling pathway required for insulin-stimulated glucose transport that is independent of phosphatidylinositol 3-kinase. Specific Aim 1 is to define the function of flotillin-1 in glucose metabolism by manipulating its expression in cultured adipocytes and muscle cells. Relationships between flotillin-1 expression level and indices of glucose metabolism and insulin action will be determined. Specific Aim 2 is to define the function of flotillin-1 in glucose metabolism with genetically engineered mice. Mice that overexpress flotillin-1 in adipose tissue and in skeletal muscle and mice that express no functional flotillin-1 will be generated and their phenotypes carefully analyzed with respect to glucose and lipid metabolism. These genetically engineered mice will be valuable reagents to study the physiology of whole body glucose homeostasis. Specific Aim 3 is to investigate the regulation of flotillin-1 by identifying the proteins that interact with it in the yeast two-hybrid system. Completion of these aims should yield testable hypotheses about the role of flotillin-1 in human health and disease and in the pathophysiology of type 2 diabetes.