INSULIN-INDUCED TRANSLOCATION OF GLUCOSE TRANSPORTER

描述(摘自申请人的摘要) 胰岛素通过刺激肌肉在血糖稳态中发挥重要作用 和脂肪细胞来吸收葡萄糖。胰岛素通过激活一种信号来实现这一点 最终导致葡萄糖转运体GLUT4募集的途径 从细胞内隔间到细胞表面。这条路 显然与磷脂酰肌醇3-激酶(PI)的激活有关 3-激酶)。然而，PI3-激酶的信号靶点仍然不清楚， 而转移GLUT4的效应器机制仍然难以捉摸。 这一胰岛素信号通路具有重大的医学意义，因为 它的损伤可能导致肥胖、糖尿病的发生。 糖尿病和多囊卵巢综合征。该计划的长远目标 申请者需要从分子方面了解胰岛素是如何起作用的。是这样的 知识可能会为上述疾病带来新的治疗方法。 申请人建议在培养脂肪中解决以下问题 单元格： 1.胰岛素诱导的GLUT4易位是否涉及通过 PI3-激酶的建议靶点，如蛋白激酶B及其异构体 蛋白激酶C？这些动因的作用将由 激活或阻断它们并观察其对GLUT4的影响 易位。 2.胰岛素诱导的GLUT4易位可以用假设的 细胞内GLUT4伴侣？这个监护人将起到锚定GLUT4的作用 在细胞内没有胰岛素的情况下。在胰岛素存在的情况下， 伴侣会释放GLUT4，并允许它跟随胞外流向 细胞表面。为了克隆这个假定的伴侣，提出了两种策略。 3.胰岛素诱导的GLUT4易位是否涉及GLUT4的分类 通过组装蛋白(AP)进入笼状蛋白包裹的囊泡？AP与以下各项交互 其他与GLUT4具有相似分类基序的蛋白质，并将它们分类为 包被网状蛋白的囊泡。这些囊泡已经被提出用来调节 GLUT4易位。AP在GLUT4贩运中的作用将是 通过确定AP是否与GLUT4交互以及是否 相互作用受胰岛素调节。

DESCRIPTION (Taken from the applicant's Abstract) Insulin plays an important role in glucose homeostasis by stimulating muscle and fat cells to take up glucose. Insulin does so by activating a signaling pathway that culminates in the recruitment of the glucose transporter GLUT4 from an intracellular compartment to the cell surface. This pathway apparently involves the activation of phosphatidylinositol 3-kinase (PI 3-kinase). However, the signaling target of PI 3-kinase remains unclear, and the effector machinery that translocates GLUT4 remains elusive. This insulin signaling pathway has significant medical implications, since its impairment may contribute to the development of obesity, diabetes mellitus, and polycystic ovarian syndrome. The long-term objective of the applicant is to understand in molecular terms how insulin works. Such knowledge may engender new treatments for the aforementioned diseases. The applicant proposes to address the following questions in cultured fat cells: 1. Does insulin-induced GLUT4 translocation involve the activation by PI 3-kinase of its proposed targets, such as protein kinase B and isoforms of protein kinase C? The role of these kineses will be investigated by activating or blocking them and observing the resultant effect on GLUT4 translocation. 2. Can insulin-induced GLUT4 translocation be explained by a putative intracellular GLUT4 chaperon? This chaperon would serve to anchor GLUT4 intracellularly in the absence of insulin. In the presence of insulin, the chaperon would release GLUT4 and allow it to follow the exocytic flow toward cell surface. To clone this putative chaperon, two strategies are proposed. 3. Does insulin-induced GLUT4 translocation involve sorting of GLUT4 into clathrin-coated vesicles by assembly proteins (APs)? APs interact with other proteins bearing similar sorting motifs as GLUT4, and sort them into clathrin-coated vesicles. These vesicles have been proposed to mediate GLUT4 translocation. The role of APs in GLUT4 trafficking will be investigated by determining if APs interact with GLUT4 and if the interaction is modulated by insulin.