This is a competitive renewal of NIH grant DK31036. This grant is now completing 28 years and a 10-year cycle since receiving a merit extension by NIDDK. Since its inception, the grant has been focused on the insulin receptor, and to a lesser extent IGF-1 receptor, and their signaling capabilities and their alterations in physiologic and pathologic states. Since the last renewal, we have made very substantial progress in understanding the signaling and biological roles of these receptors through both in vitro and in vivo studies. The largest body of studies derived from the use of homologous recombination gene targeting to study the role of the insulin receptor in insulin action in vivo. This has included the use of single gene knockouts of the insulin and IGF-1 receptors;combinatorial homozygous and heterozygous knockouts as polygenic models of Type 2 diabetes;and tissue-specific knockouts using the Cre-lox approach to determine the role of the insulin and IGF-1 receptors in individual tissues in the physiology of glucose and lipid homeostasis and the pathophysiology of diabetes and metabolic syndrome. In addition, we have performed a series of in vitro studies focusing on differential signaling by the insulin and IGF-1 receptors in the actions of insulin and IGF-1. As a result, since the last competitive renewal, this grant has provided support for a total of 90 published papers (including 48 original articles, 26 collaborative articles and 16 reviews). This work has led to development of new hypotheses about the nature of the insulin/IGF-1 signaling network, the contribution of insulin resistance in different organs to diabetes and the metabolic syndrome, as well as new evidence on how tissues communicate with one another in insulin resistant states, a role for insulin signaling in fat in longevity and a role for insulin signaling in the brain in neurodegeneration. In unpublished studies, we have also developed data on the role of the insulin receptor in brain in the control of CNS cholesterol metabolism and a novel role of signaling from the unoccupied insulin and IGF-1 receptors in control of apoptosis which appears to be kinase independent.
The specific aims for the next grant period are: 1) Explore the role of insulin and IGF-1 signaling in increased longevity, stress resistance and mitochondrial metabolism in mice with selective insulin resistance in fat or brain. 2) Study the role of insulin signaling in the brain on regulation of brain cholesterol metabolism and the relationship of CNS insulin resistance and altered cholesterol metabolism to neurodegeneration. 3) Determine the nature of tyrosine kinase independent signaling by the unoccupied insulin and IGF-1 receptors involved in control of apoptosis. 4) Define the differential nature of insulin and IGF-1 receptor signaling in vivo by creation of a new generation of mouse models in which the insulin receptor is replaced by knocking of the IGF1 receptor or a chimeric insulin/IGF-1 receptor to produce mice and cell lines that express each receptor or chimeric receptor in the tissue and temporal pattern of the other receptor.

Public Health Relevance

This grant, now completing 28 years and a merit extension, is focused on the insulin receptor, and to a lesser extent the highly related IGF-1 receptor, their signaling capabilities and their alterations in physiologic and pathologic states such as diabetes and metabolic syndrome. Since the last renewal, we have made very substantial progress in understanding the roles of these receptors through creation and characterization of a large number of mice genetically engineered to have insulin or IGF-1 resistance in only one tissue at a time. This work has led an integrated view of the role of insulin resistance in diabetes and metabolic syndrome, as well as a number of new insights into previously unrecognized aspects of insulin signaling, which form the basis of the proposed experiments going forward.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK031036-33
Application #
8638937
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Silva, Corinne M
Project Start
1982-04-01
Project End
2015-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
33
Fiscal Year
2014
Total Cost
$548,325
Indirect Cost
$207,985
Name
Joslin Diabetes Center
Department
Type
DUNS #
071723084
City
Boston
State
MA
Country
United States
Zip Code
02215
Wang, X; Häring, M-F; Rathjen, T et al. (2017) Insulin resistance in vascular endothelial cells promotes intestinal tumour formation. Oncogene 36:4987-4996
Sakaguchi, Masaji; Fujisaka, Shiho; Cai, Weikang et al. (2017) Adipocyte Dynamics and Reversible Metabolic Syndrome in Mice with an Inducible Adipocyte-Specific Deletion of the Insulin Receptor. Cell Metab 25:448-462
Ussar, Siegfried; Haering, Max-Felix; Fujisaka, Shiho et al. (2017) Regulation of Glucose Uptake and Enteroendocrine Function by the Intestinal Epithelial Insulin Receptor. Diabetes 66:886-896
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
Boucher, Jeremie; Softic, Samir; El Ouaamari, Abdelfattah et al. (2016) Differential Roles of Insulin and IGF-1 Receptors in Adipose Tissue Development and Function. Diabetes 65:2201-13
Palsgaard, Jane; Emanuelli, Brice; Winnay, Jonathon N et al. (2016) Cross-talk between insulin and Wnt signaling in preadipocytes. ROLE OF Wnt CO-RECEPTOR LDL RECEPTOR-RELATED PROTEIN-5 (LRP5). J Biol Chem 291:16878
Softic, Samir; Boucher, Jeremie; Solheim, Marie H et al. (2016) Lipodystrophy Due to Adipose Tissue-Specific Insulin Receptor Knockout Results in Progressive NAFLD. Diabetes 65:2187-200
Fujisaka, Shiho; Ussar, Siegfried; Clish, Clary et al. (2016) Antibiotic effects on gut microbiota and metabolism are host dependent. J Clin Invest 126:4430-4443
Ussar, Siegfried; Fujisaka, Shiho; Kahn, C Ronald (2016) Interactions between host genetics and gut microbiome in diabetes and metabolic syndrome. Mol Metab 5:795-803
O'Neill, Brian T; Lee, Kevin Y; Klaus, Katherine et al. (2016) Insulin and IGF-1 receptors regulate FoxO-mediated signaling in muscle proteostasis. J Clin Invest 126:3433-46

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