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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1-EMNR-G (02))
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Silva, Corinne M
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Children's Hospital Boston
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Copps, Kyle D; Hançer, Nancy J; Qiu, Wei et al. (2016) Serine 302 Phosphorylation of Mouse Insulin Receptor Substrate 1 (IRS1) Is Dispensable for Normal Insulin Signaling and Feedback Regulation by Hepatic S6 Kinase. J Biol Chem 291:8602-17
Hançer, Nancy J; Qiu, Wei; Cherella, Christine et al. (2014) Insulin and metabolic stress stimulate multisite serine/threonine phosphorylation of insulin receptor substrate 1 and inhibit tyrosine phosphorylation. J Biol Chem 289:12467-84
Sadagurski, Marianna; Dong, X Charlie; Myers Jr, Martin G et al. (2014) Irs2 and Irs4 synergize in non-LepRb neurons to control energy balance and glucose homeostasis. Mol Metab 3:55-63
Sadagurski, Marianna; Leshan, Rebecca L; Patterson, Christa et al. (2012) IRS2 signaling in LepR-b neurons suppresses FoxO1 to control energy balance independently of leptin action. Cell Metab 15:703-12
Cheng, Zhiyong; White, Morris F (2011) Targeting Forkhead box O1 from the concept to metabolic diseases: lessons from mouse models. Antioxid Redox Signal 14:649-61
Sadagurski, Marianna; Cheng, Zhiyong; Rozzo, Aldo et al. (2011) IRS2 increases mitochondrial dysfunction and oxidative stress in a mouse model of Huntington disease. J Clin Invest 121:4070-81
Zaret, Kenneth S; White, Morris F (2010) Diabetes forum: Extreme makeover of pancreatic alpha-cells. Nature 464:1132-3
Cheng, Zhiyong; Tseng, Yolanda; White, Morris F (2010) Insulin signaling meets mitochondria in metabolism. Trends Endocrinol Metab 21:589-98
Cheng, Zhiyong; White, Morris F (2010) Foxo1 in hepatic lipid metabolism. Cell Cycle 9:219-20
Norquay, Lisa D; D'Aquino, Katharine E; Opare-Addo, Lynn M et al. (2009) Insulin receptor substrate-2 in beta-cells decreases diabetes in nonobese diabetic mice. Endocrinology 150:4531-40

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