CHROMIUM ENHANCES INSULIN & GLUT4 ACTION VIA LIPID RAFTS

铬增强胰岛素

• 批准号: 6820666
• 负责人: JEFFREY S ELMENDORF
• 金额: $ 30.79万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6820666
• 关键词: actins; adipocytes; biological signal transduction; cell line; cell membrane; chemical structure function; cholesterol; chromium; cytoskeleton; disease /disorder model; glucose transport; glucose transporter; hormone regulation /control mechanism; hyperglycemia; hyperinsulinism; insulin; insulin sensitivity /resistance; intermolecular interaction; membrane activity; membrane structure; molecular pathology; noninsulin dependent diabetes mellitus; obesity; protein localization

DESCRIPTION (provided by applicant): Thirty-eight years after the landmark discovery of insulin, chromium was identified to be a separate factor required to maintain normal glucose tolerance. Unlike the intensive research in pursuit of understanding the molecular mechanisms of insulin signaling and resistance to its biological action associated most significantly with obesity and type 2 diabetes, the molecular basis of chromium action has been intermittently studied over the years. Recent data is consistent with the theory that chromium enhances insulin action during the insulin resistant state by amplifying the activity of the insulin receptor. However, given that the etiology of impaired insulin action results from one or more factors that target multiple post-receptor signaling steps, the molecular basis of signal enhancement by chromium most likely extends beyond the insulin receptor. Careful selection of most relevant insulin signal transduction data in terms of plasma membrane and insulin resistance prompted us to ask if membrane changes largely represent a common denominator explaining chromium action. In preliminary studies on the 3T3L1 adipocyte cell culture system, chromium increased the basal and insulin-stimulated level of plasma membrane GLUT4, an intracellular localized glucose transporter. Chromium also was found to concomitantly diminish cholesterol from the plasma membrane. Replenishment of the lost plasma membrane cholesterol reversed the potentiating action of chromium on GLUT4 mobilization to the cell surface. This proposal will extend upon these findings and use an integrated approach to study several (not mutually exclusive) means by which chromium could exert its GLUT4 regulatory action at the cell membrane. First, we will define plasma membrane architectural changes mediating the chromium enhanced glucose transport process; a subset of that work will test if the cholesterol-dependent actin mesh beneath the cell surface is affected by chromium. Second, we will assess if chromium engages a specific subset of GL UT4 signaling molecules. Evidence supports the idea that several insulin and insulin mimetic signaling components reside or accumulate at cholesterol-dependent regions of the plasma membrane. Our postulate is that key GLUT4 effectors intricately rely upon the activity of membrane lipids and/or actin cytoskeleton at the cell surface. Finally, we will test if chromium corrects signal transduction mechanisms disturbed by insulin resistant conditions that target proximal or distal components of the insulin signaling network. These results will be significant, because they are expected to provide new targets for the preventative and therapeutic interventions that will be particularly important to the growing numbers of insulin resistant individuals in this country who display different biochemical signatures but a shared loss in insulin sensitivity.

描述（由申请人提供）：地标发现胰岛素后的三十八年，铬被确定为维持正常葡萄糖耐受性所需的单独因素。与追求了解胰岛素信号传导的分子机制以及对其生物学作用的耐药性最显着相关的大量研究不同，多年来，铬作用的分子基础是多年来的分子基础。最近的数据与以下理论一致：铬通过扩增胰岛素受体的活性来增强胰岛素抵抗状态期间的胰岛素作用。然而，鉴于胰岛素作用受损的病因是靶向多个受感受器后信号步骤的一个或多个因素，因此铬的信号增强的分子基础很可能延伸到胰岛素受体之外。仔细选择最相关的胰岛素信号转导数据，以质膜和胰岛素耐药性促使我们询问膜变化是否在很大程度上代表了解释铬作用的共同点。在3T3L1脂肪细胞培养系统的初步研究中，铬增加了质膜GLUT4的基础和胰岛素刺激水平，质膜Glut4是一种细胞内局部葡萄糖转运蛋白。还发现铬同时减少了质膜的胆固醇。丢失的质膜胆固醇的补充逆转了铬对GLUT4动员至细胞表面的增强作用。该建议将扩展这些发现，并使用综合方法研究铬可以在细胞膜上发挥其GLUT4调节作用的几种（不是相互排斥的）手段。首先，我们将定义质膜结构变化，介导铬增强的葡萄糖转运过程。该工作的一个子集将测试细胞表面下方的胆固醇依赖性肌动蛋白网格是否受铬的影响。其次，我们将评估铬是否参与了GL UT4信号分子的特定子集。证据支持了以下观点：几种胰岛素和胰岛素模拟信号成分位于质膜的胆固醇依赖性区域或积聚。我们的假设是，关键的GLUT4效应子杂乱地依赖于细胞表面上膜脂质和/或肌动蛋白细胞骨架的活性。最后，我们将测试铬是否纠正靶向胰岛素信号网络近端或远端成分的胰岛素耐药条件干扰的信号转导机制。这些结果将是重要的，因为它们有望为预防和治疗性干预措施提供新的目标，这些干预措施对于越来越多的胰岛素抵抗个体尤为重要，这些胰岛素耐药性具有不同的生化特征，但在胰岛素敏感性方面具有共同的损失。