CHROMIUM ENHANCES INSULIN & GLUT4 ACTION VIA LIPID RAFTS

描述（由申请人提供）：在胰岛素的里程碑式发现38年后，铬被确定为维持正常葡萄糖耐量所需的单独因素。与深入研究胰岛素信号传导的分子机制和对其与肥胖和2型糖尿病最显著相关的生物作用的抵抗不同，铬作用的分子基础多年来一直断断续续地研究。最近的数据与铬通过放大胰岛素受体的活性来增强胰岛素抵抗状态下胰岛素作用的理论是一致的。然而，鉴于胰岛素作用受损的病因是针对多个受体后信号传导步骤的一个或多个因素，铬增强信号的分子基础很可能超出了胰岛素受体。在质膜和胰岛素抵抗方面仔细选择最相关的胰岛素信号转导数据，促使我们问膜的变化是否在很大程度上代表了解释铬作用的共同点。在对3T3L1脂肪细胞培养系统的初步研究中，铬增加了质膜GLUT4的基础水平和胰岛素刺激水平，GLUT4是一种细胞内局部葡萄糖转运蛋白。铬还被发现能同时降低质膜上的胆固醇。丢失的质膜胆固醇的补充逆转了铬对GLUT4动员到细胞表面的增强作用。本提案将在这些发现的基础上进行扩展，并使用一种综合的方法来研究几种（不是相互排斥的）铬可以在细胞膜上发挥其GLUT4调节作用的方法。首先，我们将定义介导铬增强葡萄糖转运过程的质膜结构变化；这项工作的一个子集将测试细胞表面下依赖胆固醇的肌动蛋白网是否受到铬的影响。其次，我们将评估铬是否参与GL UT4信号分子的特定子集。证据支持这样一种观点，即几种胰岛素和胰岛素模拟信号成分存在或积聚在质膜的胆固醇依赖区域。我们的假设是关键的GLUT4效应物复杂地依赖于细胞表面的膜脂和/或肌动蛋白细胞骨架的活性。最后，我们将测试铬是否纠正胰岛素抵抗条件干扰的信号转导机制，这些信号转导机制针对胰岛素信号网络的近端或远端成分。这些结果将是重要的，因为它们有望为预防和治疗干预提供新的目标，这对这个国家越来越多的胰岛素抵抗个体尤其重要，这些个体表现出不同的生化特征，但胰岛素敏感性却共同丧失。

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.