Role of Rab GAPs AS160 and Tbc1d1 in GLUT4 translocation and glucose homeostasis

Rab GAP AS160 和 Tbc1d1 在 GLUT4 易位和葡萄糖稳态中的作用

• 批准号: 7623638
• 负责人: SUSANNA R KELLER
• 金额: $ 18.94万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7623638
• 关键词: Adipocytes; Brain; Cell surface; Condition; Data; Disease; Drug Delivery Systems; Exercise; Fasting; Fatty acid glycerol esters; GLUT4 gene; GTPase-Activating Proteins; Glucose; Glucose Transporter; Insulin; Insulin Resistance; Knock-out; Knockout Mice; Maintenance; Metabolic syndrome; Mus; Muscle; Muscle Cells; Non-Insulin-Dependent Diabetes Mellitus; Numbers; Obesity; Play; Process; Regulation; Relative (related person); Research; Role; Skeletal Muscle; Validation; abstracting; blood glucose regulation; cell type; feeding; glucose uptake; improved; in vivo; insight; prevent; rab GTP-Binding Proteins; response

Project Summary/Abstract Major diseases including obesity, the metabolic syndrome, and type 2 diabetes, are associated with insulin resistance and consequently impaired glucose homeostasis. A key to the maintenance of glucose homeostasis under fasting and fed conditions is the proper control of the subcellular distribution of the glucose transporter GLUT4 in muscle and fat cells. Under fasting conditions a low number of GLUT4 at the cell surface limits the uptake of glucose into muscle and fat cells and thus allows the circulating glucose to be available as fuel for the brain. After a meal, in response to insulin, the number of GLUT4 at the cell surface is dramatically increased, through a process known as GLUT4 translocation. This facilitates glucose uptake and promotes the disposal of 80-90% of the ingested glucose into muscle and fat. In addition, GLUT4 translocation is also responsible for increased glucose uptake in skeletal muscles in response to exercise. AS160, a Rab GTPase activating protein (Rab GAP), and its recently identified relative Tbc1d1, play important roles in the regulation of the subcellular distribution of GLUT4, as established in cultured fat and muscle cells and specific skeletal muscles in mice. They are responsible for the efficient intracellular retention of GLUT4 under basal conditions, as well as the release of GLUT4 from retention and translocation of GLUT4 to the cell surface in response to insulin and exercise. The roles of AS160 and Tbc1d1 have not yet been evaluated in vivo. Preliminary data with mice in which AS160 had been deleted (AS160 knockout mice), suggest an essential role for AS160 in the regulation of glucose uptake in adipocytes, but not in skeletal muscles. Tbc1d1 knockout mice are being generated and no preliminary results are yet available from these mice. Considering that Tbc1d1 is expressed at higher levels in some skeletal muscle types, it is possible that Tbc1d1 is the major regulator of GLUT4 translocation in skeletal muscles. Our hypothesis is that AS160 and Tbc1d1 play important and possibly unique roles in the regulation of the subcellular distribution of GLUT4 in different cell types. The specific aims of the proposed research are to determine the roles of AS160 and Tbc1d1 by analyzing glucose homeostasis and the regulation of the subcellular distribution of GLUT4 in muscle and fat cells under basal conditions and in response to insulin and exercise in AS160 knockout, Tbc1d1 knockout, and double AS160/Tbc1d1 knockout mice. Our research will thus elucidate fundamental mechanisms contributing to the maintenance of glucose homeostasis. It will further provide crucial information towards the validation of AS160 and Tbc1d1 as drug targets to improve glucose homeostasis and prevent ensuing complications of insulin resistance.

项目摘要/摘要 包括肥胖，代谢综合征和2型糖尿病在内的主要疾病是相关的 具有胰岛素抵抗，因此葡萄糖稳态受损。维护的关键 在禁食和喂养条件下的葡萄糖稳态是亚细胞的适当控制 在肌肉和脂肪细胞中葡萄糖转运蛋白glut4的分布。在禁食条件下 细胞表面的GLUT4数量限制了葡萄糖对肌肉和脂肪细胞的吸收，因此 允许循环葡萄糖作为大脑的燃料可用。饭后，回应胰岛素， 通过称为Glut4的过程，细胞表面的GLUT4数量大大增加 易位。这有助于葡萄糖吸收，并促进了80-90％的摄入的处置 葡萄糖成肌肉和脂肪。此外，GLUT4易位还负责增加葡萄糖 骨骼肌肉响应运动。 AS160，Rab GTPase激活蛋白（RAB） GAP）及其最近确定的相对TBC1D1，在亚细胞的调节中起重要作用 Glut4的分布，如培养的脂肪和肌肉细胞以及特定的骨骼肌中所建立的分布 老鼠。他们负责在基础条件下有效的GLUT4细胞内保留率 以及GLUT4从保留和glut4转移到细胞表面的响应的释放 进行胰岛素和运动。 AS160和TBC1D1的作用尚未在体内评估。 使用AS160删除的小鼠的初步数据（AS160敲除小鼠），建议 AS160在脂肪细胞中葡萄糖摄取的调节中的重要作用，但在骨骼肌中却没有。 TBC1D1淘汰小鼠正在生成，并且尚无初步结果 老鼠。考虑到TBC1D1在某些骨骼肌类型中以较高的水平表达，这是 TBC1D1可能是骨骼肌中GLUT4易位的主要调节剂。我们的假设 AS160和TBC1D1在亚细胞的调节中扮演着重要且可能独特的角色 GLUT4在不同细胞类型中的分布。拟议研究的具体目的是 通过分析葡萄糖稳态和调节，确定AS160和TBC1D1的作用 在基础条件下，肌肉和脂肪细胞中GLUT4的亚细胞分布以及响应 AS160淘汰赛，TBC1D1敲除和双AS160/TBC1D1敲除小鼠中的胰岛素和运动。 因此，我们的研究将阐明有助于维持葡萄糖的基本机制 稳态。它将进一步提供至关重要的信息，以验证AS160和TBC1D1作为 药物靶标可改善葡萄糖稳态并防止随之而来的胰岛素抵抗并发症。