Role of GPR40 in the regulation of insulin secretion

GPR40在胰岛素分泌调节中的作用

• 批准号: 6899458
• 负责人: VINCENT POITOUT
• 金额: $ 7.35万
• 依托单位: PACIFIC NORTHWEST RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6899458
• 关键词: blood chemistry; cell surface receptors; dietary lipid; disease /disorder onset; enzyme linked immunosorbent assay; gene induction /repression; glucose metabolism; glucose tolerance test; homeostasis; insulin; insulin sensitivity /resistance; laboratory mouse; long chain fatty acid; metabolism disorder; noninsulin dependent diabetes mellitus; pancreatic islet function; pathologic process; polymerase chain reaction; receptor binding; receptor expression; transfection /expression vector

DESCRIPTION (provided by applicant): Fatty acids acutely stimulate insulin secretion, but chronically impair pancreatic beta-cell function, a phenomenon likely to play a role in the pathogenesis of type 2 diabetes mellitus. Recently, a G-protein-coupled receptor specifically expressed on the surface of beta cells has been proposed as a long-chain fatty acid receptor. This challenges the current dogma that the effects of fatty acids on insulin secretion are mediated by their transmembrane transport and intracellular metabolism. The overall objective of the work described in this proposal is to define the role of the G-protein coupled receptor GPR40 in pancreatic beta-cell function. We have obtained preliminary data showing that gpr40 -/- mice develop glucose intolerance, and that islets isolated from these mice have defective fatty-acid potentiation of insulin secretion. Based on these preliminary findings, our hypothesis is that GPR40 plays an essential role in the regulation of insulin secretion by long-chain fatty acids. Specific aim 1 is to assess whether targeted deletion of gpr40 affects glucose homeostasis and insulin secretion in mice and precipitates the onset of diabetes upon high-fat feeding. We hypothesize that the lack of GPR40 will impair glucose homeostasis in vivo. Our preliminary findings support this hypothesis, but need to be further substantiated by measuring insulin secretion in response to various secretagogues as well as insulin sensitivity in vivo at different ages. We further hypothesize that the absence of GPR40 will precipitate the onset of diabetes in the context of high-fat diet-induced insulin resistance. Specific aim 2 is to determine whether loss of function of GPR40 impairs fuel metabolism and insulin secretion in isolated mouse islets. We hypothesize that islets isolated from gpr40 KO mice will have defective insulin secretion in response to FA. Our preliminary data showing impairment of FA-induced insulin release support this hypothesis, but need to be further substantiated by measuring insulin secretion in response to a variety of nutrient and non-nutrient stimuli and performing a comprehensive assessment of glucose and FA metabolism in islets from gpr40 -/- mice. As an alternative approach, we will knock down GPR40 expression in isolated adult mouse islets by RNA silencing using adenoviral technology.

描述（由申请人提供）：脂肪酸急性刺激胰岛素的分泌，但长期损害胰腺β细胞功能，这种现象可能在2型糖尿病的发病机理中发挥作用。最近，已经提出了一种在β细胞表面表达的G蛋白偶联受体，已被提出为长链脂肪酸受体。这挑战了当前的教条，即脂肪酸对胰岛素分泌的作用是由它们的跨膜转运和细胞内代谢介导的。该提案中描述的工作的总体目的是定义G蛋白偶联受体GPR40在胰腺β细胞功能中的作用。我们已经获得了初步数据，表明GPR40 - / - 小鼠会出现葡萄糖不耐症，并且从这些小鼠中分离出的胰岛具有胰岛素分泌的脂肪酸性增强。基于这些初步发现，我们的假设是GPR40在长链脂肪酸对胰岛素分泌的调节中起着至关重要的作用。具体目标1是评估GPR40的靶向缺失是否会影响小鼠的葡萄糖稳态和胰岛素分泌，并在高脂喂养时沉淀糖尿病的发作。我们假设缺乏GPR40会损害体内葡萄糖稳态。我们的初步发现支持了这一假设，但需要通过测量胰岛素分泌来响应各种促分泌物以及在不同年龄的体内胰岛素敏感性来进一步证实。我们进一步假设，在高脂饮食诱导的胰岛素抵抗的背景下，GPR40的不存在会导致糖尿病的发作。具体目标2是确定GPR40功能的丧失是否会损害孤立小鼠胰岛中燃料代谢和胰岛素分泌。我们假设从GPR40 KO小鼠中分离出来的胰岛将对FA响应有缺陷的胰岛素分泌。我们的初步数据显示了FA诱导的胰岛素释放损害支持了这一假设，但需要通过测量胰岛素分泌来进一步证实，以响应各种营养和非营养刺激，并对GPR40-/ - / - / - - - / - - - / - - / - - / - - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - /）进行全面评估。作为另一种方法，我们将使用腺病毒技术通过RNA沉默来击败孤立的成年小鼠胰岛中的GPR40表达。