Vesicle Translocation and the Metabolic Syndrome

葡萄糖动态平衡的调节是一个复杂的过程，在2型糖尿病等疾病状态下会被破坏。胰岛素是调节血糖动态平衡的主要激素。胰岛素通过引起含有GLUT4葡萄糖转运体的细胞膜的运动来刺激肌肉和脂肪中的葡萄糖摄取，GLUT4转运体融合并插入细胞表面的GLUT4。胰岛素的这种作用在营养过剩、缺乏活动和遗传易感性的情况下受到损害，导致胰岛素抵抗，并导致糖尿病的发展。因此，为了了解代谢性疾病的发病机制，有必要了解GLUT4在细胞内膜之间转运的分子机制，以及这种转运受胰岛素调节并在胰岛素抵抗中被破坏的分子机制。该项目之前的工作发现，TUG蛋白是肌肉和脂肪细胞中GLUT4运输和葡萄糖摄取的主要调节因子。这些数据支持一种模型，在该模型中，TUG介导GLUT4和选定的其他蛋白质在未受刺激的细胞内的特定膜小泡中的滞留。然后，胰岛素通过触发TRAG内切蛋白分解来动员这些小泡。裂解使葡萄糖摄取与其他生理效应相协调，这些效应来自与GLUT4共同调节的蛋白质的作用，以及对能量消耗的可能影响。在胰岛素抵抗的个体中，这种膜转运机制的改变可能导致代谢综合征的多个方面。然而，目前尚不清楚TUG和GLUT4在细胞中的定位，这种定位在胰岛素抵抗中是如何受到影响的，以及减弱的TUG切割是否会在体内导致胰岛素抵抗。为了解决这些问题，将实现三个目标。目标1将描述TUG如何能够捕获未受刺激的细胞中含有GLUT4的囊泡，以及它如何将这些囊泡保持在胰岛素响应的配置中。目标2将研究TRAG将这些囊泡锚定到细胞内结构的位置和机制，以及这可能如何在胰岛素抵抗中受到影响。。目的3研究肌肉中TUG蛋白分解对整体胰岛素作用和葡萄糖稳态的重要性。我们预计，这些研究将有助于更好地理解调节葡萄糖代谢和能量消耗的分子机制，并对糖尿病和代谢综合征的预测、预防和治疗产生影响。

The regulation of glucose homeostasis is a complex process, which is disrupted in disease states such as type 2 diabetes. Insulin is the primary hormone that regulates glucose homeostasis. Insulin stimulates glucose uptake in muscle and fat by causing the movement of intracellular membranes containing GLUT4 glucose transporters, which fuse and insert GLUT4 at the cell surface. This effect of insulin is impaired in the setting of overnutrition, inactivity, and genetic predisposition, resulting in insulin resistance and contributing to the development of diabetes. Therefore, to understand the pathogenesis of metabolic disease, it is necessary to understand the molecular mechanisms that specify the trafficking of GLUT4 among intracellular membranes, and by which this trafficking is modulated by insulin and disrupted in insulin resistance. Previous work by this project identified the TUG protein as a major regulator of GLUT4 trafficking and glucose uptake in muscle and fat cells. The data support a model in which TUG mediates the intracellular retention of GLUT4, together with selected other proteins, in specific membrane vesicles within unstimulated cells. Insulin then mobilizes these vesicles by triggering TUG endoproteolytic cleavage. Cleavage coordinates glucose uptake with other physiologic effects, resulting from the action of proteins that are co-regulated with GLUT4 by this mechanism, as well as with possible effects on energy expenditure. In insulin resistant individuals, alterations in this membrane trafficking mechanism may contribute to multiple aspects of the metabolic syndrome. Yet, it remains unknown where TUG and GLUT4 are localized in cells, how this localization is affected in insulin resistance, and whether attenuated TUG cleavage can cause insulin resistance in vivo. To address these questions, three Aims will be undertaken. Aim 1 will characterize how TUG is able to trap the GLUT4-containing vesicles in unstimulated cells, and how it maintains these vesicles in an insulin-responsive configuration. Aim 2 will study the location and mechanism by which TUG anchors these vesicles to intracellular structures, and how this may be affected in insulin resistance. . Aim 3 will study the importance of TUG proteolysis in muscle for overall insulin action and glucose homeostasis. We anticipate that, together, these studies will result in an improved understanding of molecular mechanisms regulating glucose metabolism and energy expenditure, with implications for the prediction, prevention, and treatment of diabetes and the metabolic syndrome.