IRS2 function in beta cell physiology

描述（由申请人提供）：这是DK55326-05的竞争性更新，标题为“β细胞生理学中的IRS2功能”。在过去的5年里，我们的工作确定了胰岛素/IGF信号级联的irs2分支在β细胞生长、功能和存活中起着核心作用，特别是在外周胰岛素抵抗的补偿过程中。此外，Irs2信号将下丘脑的营养感知与外周胰岛素的作用结合起来，以控制营养稳态。因此，β细胞和大脑（下丘脑）中Irs2信号的部分失调可以解释肥胖、外周胰岛素抵抗和β细胞衰竭（2型糖尿病的特征）之间的密切联系。糖尿病是世界范围内的一个主要健康问题，当胰腺细胞不能快速分泌足够的胰岛素来维持葡萄糖稳态时，就会发展成糖尿病。尽管许多基因的多态性与糖尿病有关，但环境、代谢或免疫应激导致的irs2信号级联失调可能是糖尿病发生的一个有利条件。现在我们的挑战是了解β细胞和下丘脑中Irs2信号失调的机制，并确定如何利用Irs2信号来预防肥胖和治疗糖尿病。在这一竞争更新中，我们提出了四个特定的目标来研究Irs1和Irs2信号级联在β细胞功能和营养稳态中的串扰，并探索Irs2信号可以用来促进β细胞功能和再生的策略，从而预防或治疗糖尿病：

DESCRIPTION (provided by applicant): This is a competing renewal of DK55326-05 entitled "IRS2 function in beta-cell physiology." During the past 5 years, our work established that the Irs2-branch of the insulin/IGF signaling cascade plays a central role in beta-cell growth, function and survival, especially during compensation for peripheral insulin resistance. Moreover, Irs2 signaling integrates hypothalamic nutrient sensing with peripheral insulin action to control nutrient homeostasis. Thus, partial dysregulation of Irs2 signaling in beta-cells and brain (hypothalamus) can explain the close association between obesity, peripheral insulin resistance, and beta-cell failure that characterizes type 2 diabetes. Diabetes is a major health problem around the world that develops when pancreatic beta-cells fail to secrete sufficient insulin quickly enough to maintain glucose homeostasis. Although polymorphisms in many genes are implicated in diabetes, dysregulation of the Irs2-signaling cascade-by environmental, metabolic or immunologic stress-can be a permissive step on the path to diabetes. Now our challenge is to understand the mechanisms that dysregulate Irs2 signaling in beta-cells and the hypothalamus, and determine how Irs2 signaling can be exploited to prevent obesity and cure diabetes. In this competing renewal, we propose four Specific Aims to investigate the crosstalk between Irs1 and Irs2 signaling cascades in beta-cell function and nutrient homeostasis, and explore strategies by which Irs2 signaling can be employed to promote beta-cell function and regeneration that prevents or cures diabetes: 1. Reveal the interaction between Irs1 and Irs2 signaling in nutrient homeostasis and beta-cell function. 2. Investigate the mechanism by which the common variant of IRS1 (G972Rlrs1) dysregulates beta-cell function and nutrient homeostasis in mice. 3. Establish the relation between T-cell infiltration and Irs2 signaling in beta-cells of the NOD mouse. 4. Investigate the mechanism of Irs2-dependent beta-cell regeneration.