Vesicle Translocation and the Metabolic Syndrome

摘要 葡萄糖动态平衡的调节是一个复杂的过程，在疾病状态下会被破坏，如 2糖尿病。胰岛素是调节血糖动态平衡的主要激素。胰岛素刺激血糖 通过动员细胞内含有GLUT4葡萄糖转运体的囊泡来摄取肌肉和脂肪，GLUT4葡萄糖转运体可以融合 并在细胞表面插入GLUT4。这一过程的损害会导致胰岛素抵抗，并导致 糖尿病的发展。因此，要了解代谢性疾病的发病机制，就有必要 了解控制GLUT4贩运的分子机制，并了解这种贩运是如何 受到胰岛素的调节，并在胰岛素抵抗中被破坏。以前的工作发现TUG蛋白是一种 肌肉和脂肪细胞中GLUT4转运和葡萄糖摄取的主要调节因子。数据支持中的模型 它介导GLUT4在未受刺激的细胞内的特定囊泡中的细胞内滞留。胰岛素 触发拉动内蛋白分解，将这些小泡动员到细胞表面。拖带劈理 协调葡萄糖摄取与其他生理效应，这是由共同运输的蛋白质的作用引起的 与GLUT4结合，以及通过TUG C-末端产物调节基因表达的作用。在胰岛素中 对于耐药个体，这种机制的受损可能导致代谢综合征和肥胖。 然而，这一机制在胰岛素抵抗中是如何受到影响的尚不清楚，是否减弱了TRAG。 乳沟导致肌肉中的胰岛素抵抗，或者是否拖拽乳沟参与了运动刺激 葡萄糖摄取。此外，完整的TRAG将GLUT4保留在胰岛素中的分子机制- 对反应性小泡池的了解尚不清楚。为了解决这些问题，将实现两个目标。 目的1将研究肌肉特异性干扰的小鼠的胰岛素抵抗和葡萄糖稳态。 TUG或TUG内切蛋白分解，并将研究这一途径在运动诱导中的潜在作用 葡萄糖摄取。目标2将研究TRAG捕获含有GLUT4的囊泡的分子机制 胰岛素响应池，在胰岛素抵抗状态下，这一过程可能会改变。我们期待着 总之，这些研究将导致对葡萄糖代谢和能量的更好理解 用于预防和治疗糖尿病和代谢综合征的支出。

Abstract 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 mobilizing intracellular vesicles containing GLUT4 glucose transporters, which fuse and insert GLUT4 at the cell surface. Impairment of this process results in insulin resistance and contributes to the development of diabetes. Therefore, to understand the pathogenesis of metabolic disease, it is necessary to understand the molecular mechanisms that control GLUT4 trafficking, and to understand how this trafficking is modulated by insulin and disrupted in insulin resistance. Previous work 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 in specific vesicles within unstimulated cells. Insulin triggers TUG endoproteolytic cleavage to mobilize these vesicles to the cell surface. TUG cleavage coordinates glucose uptake with other physiologic effects, resulting from the action of proteins that co-traffic with GLUT4, as well as from action of the TUG C-terminal product to modulate gene expression. In insulin resistant individuals, impairment of this mechanism may contribute to the metabolic syndrome and obesity. Yet, it remains unknown how this mechanism is affected in insulin resistance, whether attenuated TUG cleavage causes insulin resistance in muscle, or whether TUG cleavage participates in exercise-stimulated glucose uptake. As well, the molecular mechanisms by which intact TUG retains GLUT4 in an insulin- responsive pool of vesicles are not understood. To address these questions, two Aims will be undertaken. Aim 1 will characterize insulin resistance and glucose homeostasis in mice with muscle-specific disruption of TUG or of TUG endoproteolytic cleavage, and will study the potential role of this pathway in exercise-induced glucose uptake. Aim 2 will study molecular mechanisms by which TUG traps GLUT4-containing vesicles in an insulin-responsive pool, and by which this process may be altered in insulin-resistant states. We anticipate that, together, these studies will result in an improved understanding of glucose metabolism and energy expenditure, with implications for the prevention and treatment of diabetes and the metabolic syndrome.