FLOTILLINS AND INSULIN-STIMULATED GLUCOSE TRANSPORT

FLOTILLINS 和胰岛素刺激的葡萄糖转运

• 批准号: 7006950
• 负责人: PERRY E BICKEL
• 金额: $ 24.5万
• 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 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7006950
• 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.

随着肥胖症的流行和种群的衰老，2型糖尿病的患病率正在增加。胰岛素抵抗是2型糖尿病的标志。 该应用程序的长期目标是了解如何在细胞中传达胰岛素的信号以及该过程如何在胰岛素耐药状态下有缺陷。 脂肪细胞在胰岛素抵抗中起着核心作用，骨骼肌是饮食后葡萄糖处置的主要部位。 脂肪细胞的初步结果导致了以下假设：膜蛋白植物素-1募集特定的信号分子到质膜的区室，并且这种募集是为了使细胞表面葡萄糖转运蛋白的增加所必需，从而导致对胰岛素的反应发生。 这些事件构成了独立于磷脂酰肌醇3-激酶所需的第二个信号通路。具体目的1是通过操纵其在培养的脂肪细胞和肌肉细胞中的表达来定义氟替林-1在葡萄糖代谢中的功能。 将确定氟列蛋白-1表达水平与葡萄糖代谢和胰岛素作用的指标之间的关系。 具体目的2是定义氟替林-1在葡萄糖代谢中的功能，其基因工程小鼠的功能。 将会产生过表达脂肪组织中过表达浮球素-1的小鼠，而在骨骼肌和骨骼肌和无表达无功能性氟列赛-1的小鼠中将产生，其表型仔细地分析了葡萄糖和脂质代谢。 这些基因工程的小鼠将是研究全身葡萄糖稳态生理学的宝贵试剂。 特定目的3是通过鉴定在酵母两杂交系统中与之相互作用的蛋白质来调查氟列蛋白-1的调节。 这些目的的完成应提出可检验的假设，涉及植被-1在人类健康和疾病以及2型糖尿病的病理生理学中的作用。