This is a grant application, which focuses on studying the role of tyrosine phosphorylation in the mechanism of insulin action. Under this grant over the past 4 years, the PI and colleagues have studied the role of IRS-1 in insulin signaling, used homologous recombinant gene targeting to produce mice and cell lines deficient in this protein, identified IRS-2, defined several of the molecules which interact with IRS-1 and IRS-2 to produce the diverse down-stream signals generated by insulin action, studied the regulation of IRS-1 and IRS-2 in animal models of diabetes and produced a novel polygenic model of NIDDM heterozygous for defects in the insulin receptor and IRS-1. These findings have lead to the hypothesis that insulin signaling is not a simple linear cascade, but a complex network with both alternative and complementary signals generated by families of molecules interacting in the three dimensional space of the cell. The major goal of this grant over the next 5 years will be to further dissect this multi-dimensional network focusing on the potentially complementary, and possibly unique, roles of the various insulin receptor substrates in insulin action. The PI and colleagues will also explore how these components interact with each other and with other signaling molecules to produce both normal patterns of insulin action and alterations in pathophysiologic states.
The specific aims of this grant are to: 1) Study the similarities, differences and potentially complementary roles of various insulin receptor substrates in insulin action by creating and characterizing models of altered insulin signaling using homologous recombination to knockout IRS-2, IRS-3, and IRS-4 with both global and conditional/tissue specific strategies. These mice will be crossbred with IRS-1 knockout mice and with each other to determine the nature of the complementary signaling created by multiple insulin receptor substrates. 2) Characterize insulin and IGF-1 action in 3T3 cells derived from knockout animal models lacking IRS-1 and/or other insulin receptor substrates. These cells will be studied before and after reconstitution with different insulin receptor substrates and chimerical molecules produced from the substrates. Metabolic actions will be studied before and after conversion to adipocyte-like cell lines with PPARg. 3) Determine the subcellular compartmentalization, differential partnering and differences in regulation of the major IRS family members in disease states. Together these studies should provide important insights into the complex network of insulin signaling and its alternations in diabetes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Study Section
Metabolism Study Section (MET)
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Blondel, Olivier
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Joslin Diabetes Center
United States
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Rabiee, Atefeh; Krüger, Marcus; Ardenkjær-Larsen, Jacob et al. (2018) Distinct signalling properties of insulin receptor substrate (IRS)-1 and IRS-2 in mediating insulin/IGF-1 action. Cell Signal 47:1-15
Soto, Marion; Herzog, Clémence; Pacheco, Julian A et al. (2018) Gut microbiota modulate neurobehavior through changes in brain insulin sensitivity and metabolism. Mol Psychiatry 23:2287-2301
Altindis, Emrah; Cai, Weikang; Sakaguchi, Masaji et al. (2018) Viral insulin-like peptides activate human insulin and IGF-1 receptor signaling: A paradigm shift for host-microbe interactions. Proc Natl Acad Sci U S A 115:2461-2466
Cai, Weikang; Xue, Chang; Sakaguchi, Masaji et al. (2018) Insulin regulates astrocyte gliotransmission and modulates behavior. J Clin Invest 128:2914-2926
Fujisaka, Shiho; Avila-Pacheco, Julian; Soto, Marion et al. (2018) Diet, Genetics, and the Gut Microbiome Drive Dynamic Changes in Plasma Metabolites. Cell Rep 22:3072-3086
Wang, X; Häring, M-F; Rathjen, T et al. (2017) Insulin resistance in vascular endothelial cells promotes intestinal tumour formation. Oncogene 36:4987-4996
Thomou, Thomas; Mori, Marcelo A; Dreyfuss, Jonathan M et al. (2017) Adipose-derived circulating miRNAs regulate gene expression in other tissues. Nature 542:450-455
Ferris, Heather A; Perry, Rachel J; Moreira, Gabriela V et al. (2017) Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism. Proc Natl Acad Sci U S A 114:1189-1194
Giles, Daniel A; Moreno-Fernandez, Maria E; Stankiewicz, Traci E et al. (2017) Erratum: Thermoneutral housing exacerbates nonalcoholic fatty liver disease in mice and allows for sex-independent disease modeling. Nat Med 23:1241
Merry, Troy L; Kuhlow, Doreen; Laube, Beate et al. (2017) Impairment of insulin signalling in peripheral tissue fails to extend murine lifespan. Aging Cell 16:761-772

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