The role of the Akt/PKB signaling in insulin action

描述（由申请人提供）：II型糖尿病是西方世界最常见的疾病之一，在老年人群中患病率为10-50%。II型糖尿病的一个重要组成部分是胰岛素抵抗，即不能达到最大浓度的胰岛素来刺激肌肉葡萄糖运输，抑制肝脏葡萄糖输出和其他生理反应。一种合理的策略导致新的胰岛素增敏药物的发展，从系统分析胰岛素信号开始。经过30多年对相关蛋白激酶的深入研究，Akt/PKB已成为唯一被确定为胰岛素调节重要代谢靶标的丝氨酸/苏氨酸蛋白激酶。Akt/PKB的活性取决于磷脂酰肌醇3'-激酶的脂质产物，这种酶被认为是几乎所有胰岛素代谢作用所必需的。Akt/PKB激酶代表了一个由三个密切相关的蛋白组成的家族，这些蛋白与细胞凋亡、细胞生长、细胞周期进程、分化、血管生成以及代谢等多种过程的调控有关。最近的研究表明，缺乏Akt2/ pkbβ的小鼠模拟了糖尿病的几个特征，包括肝脏、肌肉和脂肪组织的胰岛素抵抗。有趣的是，Akt1/PKBalpha缺失的小鼠代谢完全正常，但尺寸减少了约20%。Akt1/PKBalpha和Akt2/ β敲除小鼠之间的表型差异是由于同种异型特异性表达模式以及蛋白质固有的不同信号特性。这些拟议研究的基本原理是，通过研究Akt2/PKBbeta向葡萄糖转运发出信号的优先能力的生化基础，将在理解胰岛素作用的基本机制方面取得重大进展。特异性将通过几种相关策略来实现：1)Akt/PKB赋予异构体特异性信号的结构域将通过使用嵌合蛋白来绘制；2)分析两种异构体在细胞内定位上的差异；3)寻找akt2特异性底物。预计这些研究将显著扩展对生理胰岛素非依赖性信号的认识，并最终确定糖尿病治疗干预的潜在靶点。

DESCRIPTION (provided by applicant): Type II Diabetes Mellitus is one of the most common diseases in the Western world, with prevalence ranging from 10-50% in elderly populations. An integral component of Type II diabetes mellitus is insulin resistance, i.e. the inability of maximal concentrations of the hormone to stimulate appropriately muscle glucose transport, suppression of hepatic glucose output and other physiological responses. A plausible strategy leading to the development of novel insulin-sensitizing drugs begins with the systematic analysis of insulin signaling. After over 30 years of intensive research in the pursuit of relevant protein kinases, Akt/PKB has emerged as the only serine/threonine protein kinases definitively established as a mediator of insulin's regulation of important metabolic targets. The activity of Akt/PKB depends on the lipid products of phosphotidylinositol 3'- kinase, an enzyme known to be required for virtually all of the metabolic actions of insulin. The Akt/PKB kinases represent a family of three closely related proteins that have been implicated in the regulation of processes as diverse as apoptosis, cell growth, cell cycle progression, differentiation and angiogenesis as well as metabolism. Recent work has shown that mice deficient in Akt2/PKBbeta mimic several features of diabetes, including insulin resistance in liver, muscle and adipose tissue. Interestingly, Akt1/PKBalpha null mice are absolutely normal metabolically, but are about 20% reduced in size. The differences in phenotype between Akt1/PKBalpha and Akt2/beta knockout mice are due to both to isoform-speciflc patterns of expression as well as distinct signaling properties intrinsic to the proteins. The underlying rationale of these proposed studies is that by investigating the biochemical basis of the preferential ability of Akt2/PKBbeta to signal to glucose transport, significant progress will be made in understanding the fundamental mechanism of insulin action. Specificity will be approached using several related strategies: 1) the domains of Akt/PKB conferring isoform specific signaling will be mapped by the use of chimeric proteins; 2) the two isoforms will be analyzed for differences in intracellular localization; and 3) a search will be conducted for Akt2-specific substrates. It is anticipated that these studies will significantly extend the knowledge of physiological insulin-independent signaling and ultimately lead to the identification of potential targets for therapeutic intervention in diabetes mellitus.