Insulin resistance and beta cell failure play key roles in the pathogenesis of diabetes. Targeted mutagenesis in mice suggests that both abnormalities can be ascribed to impaired insulin signaling. Over the past funding cycle, the PI has endeavored to meet three goals: i, to define the contribution of different insulin target tissues to the pathogenesis of insulin resistance; ii, to understand whether different IRS proteins play separate or overlapping roles in insulin action; and Hi, to examine the role of insulin and IGF signaling in pancreatic beta cells to the pathogenesis of beta cell failure. These studies have led to a reassessment of the site(s) of onset of insulin resistance, by emphasizing the contribution to this process by tissues that do not display insulin dependent glucose uptake, such brain and liver. The studies have also contributed to establishing the idea that pancreatic beta cells are an """"""""insulin-sensitive"""""""" cell type. Building on these lessons, the PI proposes studies of the integrated physiology of insulin action that will focus primarily on the contribution of liver, brain and pancreatic betaa cells to insulin resistance. These studies will be carried out using a genetic approach in which mutations affecting insulin signaling are introduced in mice and the consequences analyzed by thorough metabolic phenotyping. There are three aims in this proposal.
In Aim 1, the PI will analyze the role of different organs in insulin action. Studies during the past cycle have established that insulin signaling in liver, as well as atypical target tissues, such as brain and pancreatic acells, is sufficient to restore metabolic control in insulin receptor (InsR)-deficient mice. The PI now wishes to test whether restoring InsR function at sites of insulin-dependent glucose uptake and disposal, such as skeletal muscle and adipocytes, would also have a similar effect. This question will be addressed using a locus knock-in approach to express InsR in mice.
In Aim 2, the PI will use transgenic knockout mice expressing InsR solely in brain, liver and beta cells to study the role of direct and indirect mechanisms in insulin control of hepatic glucose production. To this end, the PI will employ conditional tissue knock-ins to restore InsR function at additional sites, with an emphasis on the arcuate and paraventricular hypothalamic nuclei.
In Aim 3, the PI will study the role of insulin resistance in the regulation of beta cell mass. The PI will perform lineage tracing experiments of Neurogenin3-expressing endocrine progenitor cells in insulin-resistant mice and introduce mutations affecting insulin/IGF signaling in the same cell type to study the function of these pathways in endocrine cell differentiation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK058282-07
Application #
7093041
Study Section
Special Emphasis Panel (ZRG1-EMNR-G (02))
Program Officer
Blondel, Olivier
Project Start
2000-08-15
Project End
2010-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
7
Fiscal Year
2006
Total Cost
$437,518
Indirect Cost
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Accili, Domenico (2018) Insulin Action Research and the Future of Diabetes Treatment: The 2017 Banting Medal for Scientific Achievement Lecture. Diabetes 67:1701-1709
Haeusler, Rebecca A; McGraw, Timothy E; Accili, Domenico (2018) Biochemical and cellular properties of insulin receptor signalling. Nat Rev Mol Cell Biol 19:31-44
Langlet, Fanny; Haeusler, Rebecca A; Lindén, Daniel et al. (2017) Selective Inhibition of FOXO1 Activator/Repressor Balance Modulates Hepatic Glucose Handling. Cell 171:824-835.e18
Kim-Muller, Ja Young; Kim, Young Jung R; Fan, Jason et al. (2016) FoxO1 Deacetylation Decreases Fatty Acid Oxidation in ?-Cells and Sustains Insulin Secretion in Diabetes. J Biol Chem 291:10162-72
Cinti, Francesca; Bouchi, Ryotaro; Kim-Muller, Ja Young et al. (2016) Evidence of ?-Cell Dedifferentiation in Human Type 2 Diabetes. J Clin Endocrinol Metab 101:1044-54
Pajvani, Utpal B; Accili, Domenico (2015) The new biology of diabetes. Diabetologia 58:2459-68
Bouchi, Ryotaro; Foo, Kylie S; Hua, Haiqing et al. (2014) FOXO1 inhibition yields functional insulin-producing cells in human gut organoid cultures. Nat Commun 5:4242
Ren, Hongxia; Yan, Shijun; Zhang, Baifang et al. (2014) Glut4 expression defines an insulin-sensitive hypothalamic neuronal population. Mol Metab 3:452-9
Haeusler, Rebecca A; Hartil, Kirsten; Vaitheesvaran, Bhavapriya et al. (2014) Integrated control of hepatic lipogenesis versus glucose production requires FoxO transcription factors. Nat Commun 5:5190
Tsuchiya, Kyoichiro; Westerterp, Marit; Murphy, Andrew J et al. (2013) Expanded granulocyte/monocyte compartment in myeloid-specific triple FoxO knockout increases oxidative stress and accelerates atherosclerosis in mice. Circ Res 112:992-1003

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