IRS2 function in beta cell physiology

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 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-分支在胰岛素/IGF信号级联中起着重要的作用。 在β-细胞生长、功能和存活中起中心作用，特别是在外周血细胞代偿期间， 胰岛素抵抗此外，Irs 2信号转导整合了下丘脑营养感测与外周神经系统。 胰岛素控制营养平衡作用。因此，β细胞中Irs 2信号传导的部分失调 和大脑（下丘脑）可以解释肥胖、外周胰岛素之间的密切联系 抵抗和β细胞衰竭，这是2型糖尿病的特征。糖尿病是一个主要的健康问题 当胰腺β细胞不能快速分泌足够的胰岛素时， 足以维持葡萄糖稳态尽管许多基因的多态性与 糖尿病，Irs 2信号级联调节异常通过环境，代谢或免疫 压力可能是导致糖尿病的一步。现在我们的挑战是了解 β细胞和下丘脑中Irs 2信号失调的机制，并确定如何 Irs 2信号可以用来预防肥胖和治疗糖尿病。在这场竞争性的复兴中，我们 提出了四个具体的目标，以调查在Irs 1和Irs 2信号级联之间的串扰， β细胞功能和营养稳态，并探索Irs 2信号转导可以被 用于促进β细胞功能和再生，预防或治疗糖尿病： 1.揭示Irs 1和Irs 2信号在营养稳态和β细胞中的相互作用 功能 2.研究IRS 1（G972 Rlrs 1）的常见变异体失调的机制 β-细胞功能和营养平衡。 3.建立NOD β细胞中T细胞浸润和Irs 2信号传导之间的关系 老鼠. 4.研究Irs 2依赖性β细胞再生的机制。

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.