Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8020, USA.
Annu Rev Biochem. 2012;81:507-32. doi: 10.1146/annurev-biochem-060109-094246. Epub 2012 Apr 5.
To enhance glucose uptake into muscle and fat cells, insulin stimulates the translocation of GLUT4 glucose transporters from intracellular membranes to the cell surface. This response requires the intersection of insulin signaling and vesicle trafficking pathways, and it is compromised in the setting of overnutrition to cause insulin resistance. Insulin signals through AS160/Tbc1D4 and Tbc1D1 to modulate Rab GTPases and through the Rho GTPase TC10α to act on other targets. In unstimulated cells, GLUT4 is incorporated into specialized storage vesicles containing IRAP, LRP1, sortilin, and VAMP2, which are sequestered by TUG, Ubc9, and other proteins. Insulin mobilizes these vesicles directly to the plasma membrane, and it modulates the trafficking itinerary so that cargo recycles from endosomes during ongoing insulin exposure. Knowledge of how signaling and trafficking pathways are coordinated will be essential to understanding the pathogenesis of diabetes and the metabolic syndrome and may also inform a wide range of other physiologies.
为了增强肌肉和脂肪细胞对葡萄糖的摄取，胰岛素会刺激 GLUT4 葡萄糖转运蛋白从细胞内膜向细胞表面转位。这种反应需要胰岛素信号和囊泡运输途径的交叉，而在营养过剩的情况下，这种反应会受到损害，导致胰岛素抵抗。胰岛素通过 AS160/Tbc1D4 和 Tbc1D1 信号来调节 Rab GTPases，并通过 Rho GTPase TC10α 作用于其他靶标。在未受刺激的细胞中，GLUT4 被整合到含有 IRAP、LRP1、sortilin 和 VAMP2 的特殊储存囊泡中，这些囊泡被 TUG、Ubc9 和其他蛋白质隔离。胰岛素将这些囊泡直接动员到质膜上，并调节运输途径，使货物在持续的胰岛素暴露期间从内体中循环回收。了解信号和运输途径如何协调对于理解糖尿病和代谢综合征的发病机制至关重要，也可能为广泛的其他生理学提供信息。
