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后38年，铬被确定为维持正常葡萄糖耐量所需的单独因素。与追求理解胰岛素信号传导的分子机制和对与肥胖和2型糖尿病最显著相关的生物作用的抵抗的深入研究不同，铬作用的分子基础多年来一直在间歇性研究。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期间的胰岛素作用的理论一致。然而，考虑到胰岛素作用受损的病因是由靶向多个受体后信号传导步骤的一种或多种因素引起的，铬增强信号的分子基础很可能超出胰岛素受体。仔细选择最相关的胰岛素信号转导数据质膜和胰岛素抵抗促使我们问，如果膜的变化在很大程度上代表了一个共同的分母解释铬的作用。在对3 T3 L1脂肪细胞培养系统的初步研究中，铬增加了质膜GLUT 4（一种细胞内定位的葡萄糖转运蛋白）的基础和胰岛素刺激水平。铬也被发现同时减少从质膜胆固醇。补充丢失的质膜胆固醇逆转了铬对GLUT 4动员到细胞表面的增强作用。该提案将扩展这些发现，并使用综合方法来研究几种（不相互排斥）铬可以在细胞膜上发挥其GLUT 4调节作用的方法。首先，我们将定义质膜结构的变化介导的铬增强葡萄糖转运过程，该工作的一个子集将测试，如果胆固醇依赖的肌动蛋白网格下的细胞表面是铬的影响。其次，我们将评估铬是否与GL UT 4信号分子的特定子集结合。有证据支持以下观点：几种胰岛素和胰岛素模拟信号传导组分存在于或积累在质膜的胆固醇依赖性区域。我们的假设是，关键GLUT 4效应错综复杂地依赖于膜脂和/或肌动蛋白细胞骨架在细胞表面的活动。最后，我们将测试铬是否能纠正胰岛素抵抗条件下靶向胰岛素信号网络近端或远端组件的信号转导机制。这些结果将是重要的，因为它们有望为预防和治疗干预提供新的靶点，这对该国越来越多的胰岛素抵抗个体特别重要，这些个体显示出不同的生化特征，但胰岛素敏感性共同丧失。

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.