IRS2 function in beta cell physiology

描述（由申请人提供）：这是DK 55326 -05的竞争性更新，标题为“IRS 2在β细胞生理学中的功能”。“在过去的5年中，我们的工作确定了胰岛素/IGF信号级联的Irs 2-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，Irs 2信号整合下丘脑营养传感与外周胰岛素作用，以控制营养稳态。因此，β细胞和大脑（下丘脑）中Irs 2信号传导的部分失调可以解释肥胖、外周胰岛素抵抗和β细胞衰竭之间的密切联系，这是2型糖尿病的特征。糖尿病是世界范围内的一个主要健康问题，当胰腺β细胞不能足够快地分泌足够的胰岛素以维持葡萄糖稳态时，就会发生糖尿病。虽然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Irs 2信号级联失调可能是糖尿病发病途径中的一个容许步骤。现在我们面临的挑战是了解β细胞和下丘脑中Irs 2信号失调的机制，并确定如何利用Irs 2信号来预防肥胖和治疗糖尿病。在这一竞争性更新中，我们提出了四个具体目标来研究β细胞功能和营养稳态中Irs 1和Irs 2信号级联之间的串扰，并探索Irs 2信号转导可用于促进β细胞功能和再生的策略，以预防或治愈糖尿病： 1.揭示Irs 1和Irs 2信号在营养稳态和β细胞功能中的相互作用。2.研究IRS 1的常见变体（G972 Rlrs 1）在小鼠中失调β细胞功能和营养稳态的机制。 3.建立NOD小鼠β细胞中T细胞浸润和Irs 2信号传导之间的关系。 4.研究Irs 2依赖性β细胞再生的机制。

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.