IRS2 function in beta cell physiology

描述(由申请人提供)：这是DK55326-05的竞争性续订，标题为“IRS2在β细胞生理学中的功能”。在过去的五年中，我们的工作证实了胰岛素/胰岛素样生长因子信号级联中的irs2分支在胰岛细胞的生长、功能和存活中起着核心作用，特别是在外周胰岛素抵抗的代偿过程中。此外，Irs2信号整合了下丘脑的营养感知和外周胰岛素的作用，以控制营养动态平衡。因此，β细胞和脑(下丘脑)中irs2信号的部分失调可以解释肥胖症、外周胰岛素抵抗和表现为2型糖尿病特征的β细胞衰竭之间的密切联系。糖尿病是世界各地的一个主要健康问题，当胰岛β细胞不能足够快地分泌足够的胰岛素来维持血糖稳态时，糖尿病就会发展。虽然许多基因的多态与糖尿病有关，但由于环境、代谢或免疫压力，irs2信号级联的失调可能是糖尿病发展道路上的一个允许步骤。现在我们的挑战是了解β细胞和下丘脑中irs2信号失控的机制，并确定如何利用irs2信号来预防肥胖和治疗糖尿病。在这个相互竞争的更新中，我们提出了四个具体的目标来研究IRS1和IRS2信号之间的串扰在β细胞功能和营养动态平衡中的串扰，并探索利用IRS2信号来促进β细胞功能和再生以预防或治疗糖尿病的策略： 1.揭示IRS1和Irs2信号在营养动态平衡和β细胞功能中的相互作用。2.探讨IRS1常见变异体(G972Rlrs1)对小鼠胰岛β细胞功能和营养动态平衡的影响机制。 3.建立NOD小鼠胰岛β细胞内T细胞浸润与Irs2信号转导的关系。 4.探讨IRS2依赖的胰岛β细胞再生机制。

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.