FLOTILLINS AND INSULIN-STIMULATED GLUCOSE TRANSPORT

FLOTILLINS 和胰岛素刺激的葡萄糖转运

• 批准号: 6436962
• 负责人: PERRY E BICKEL
• 金额: $ 25.16万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6436962
• 关键词: adipocytes; biological signal transduction; cardiac myocytes; cell membrane; gene expression; gene targeting; genetically modified animals; glucose metabolism; glucose tolerance; glucose transport; glucose transporter; homeostasis; insulin; insulin sensitivity /resistance; laboratory mouse; lipid disorder; lipid metabolism; membrane proteins; muscle cells; noninsulin dependent diabetes mellitus; obesity; phenotype; protein localization; protein structure function; striated muscles; tissue /cell culture; yeast two hybrid system

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.

随着肥胖的流行和人口老龄化，2型糖尿病的患病率呈上升趋势。胰岛素抵抗是2型糖尿病的一个特征。这项应用的长期目标是了解胰岛素的信号在细胞内是如何传递的，以及这一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，而骨骼肌是餐后葡萄糖的主要代谢部位。在脂肪细胞中的初步结果导致了一种假设，即膜蛋白Flotillin-1将特定的信号分子招募到质膜的一个隔室，并且这种招募是细胞表面葡萄糖转运蛋白增加所必需的，这种增加发生在对胰岛素的反应中。这些事件构成了胰岛素刺激的葡萄糖运输所需的第二个信号通路，该信号通路独立于磷脂酰肌醇3-激酶。目的1是通过调控Flotillin-1在培养的脂肪细胞和肌肉细胞中的表达来确定Flotillin-1在葡萄糖代谢中的作用。Flotillin-1的表达水平与糖代谢指标和胰岛素作用的关系将被确定。具体目标2是确定Flotillin-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表达fltillin-1的小鼠，以及不表达功能性fltillin-1的小鼠，并仔细分析它们在葡萄糖和脂肪代谢方面的表型。这些基因工程小鼠将是研究全身葡萄糖动态平衡的生理学的有价值的试剂。具体目标3是通过鉴定酵母双杂交系统中与之相互作用的蛋白质来研究Flotillin-1的调节。完成这些目标应该会产生关于fltillin-1在人类健康和疾病中的作用以及在2型糖尿病的病理生理学中的作用的可检验的假设。