IRS2 function in beta cell physiology

这是DK55326-05的竞争性更新，标题为“IRS2在β细胞生理学中的功能”。在.期间 在过去的5年里，我们的工作证实了胰岛素/胰岛素样生长因子信号级联的irs2分支在 在β细胞生长、功能和存活中的中心作用，特别是在外周细胞的代偿过程中 胰岛素抵抗。此外，irs2信号整合了下丘脑的营养感知和外周。 胰岛素控制营养动态平衡的作用。因此，β细胞中irs2信号的部分失调 和大脑(下丘脑)可以解释肥胖和外周胰岛素之间的密切联系 抵抗力和β细胞衰竭是2型糖尿病的特征。糖尿病是一个主要的健康问题。 在世界各地，当胰岛β细胞无法迅速分泌足够的胰岛素时，就会出现这种疾病 足以维持葡萄糖的稳态。尽管许多基因的多态与 糖尿病，由环境、代谢或免疫引起的irs2信号级联失调 压力可能是糖尿病道路上允许的一步。现在我们的挑战是理解 在β细胞和下丘脑中失调irs2信号的机制，并确定如何 IRS2信号可以用来预防肥胖和治疗糖尿病。在这场竞争性的更新中，我们 提出四个具体目标来研究IRS1和IRS2信令级联之间的串扰 β细胞功能和营养动态平衡，并探索Irs2信号转导的策略 用来促进β细胞功能和再生，以预防或治疗糖尿病： 1.揭示IRS1和Irs2信号在营养动态平衡和β细胞中的相互作用 功能。 2.研究IRS1(G972Rlrs1)常见变异体的调控机制 小鼠的β细胞功能和营养动态平衡。 3.建立结节β细胞中T细胞浸润与Irs2信号转导的关系 老鼠。 4.探讨IRS2依赖的胰岛β细胞再生机制。

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.