This is a renewal of NIH grant DK031036, the original grant to the Kahn lab, which is now in its 38th year and was granted MERIT status at the last renewal. Since inception, this grant has focused on the insulin and IGF-1 receptors, their signaling pathways and their alterations in physiologic and pathologic states. Over the past decade, we have made tremendous progress in understanding the signaling and biological roles of these receptors through both in vitro and in vivo studies. These include extensive studies using gene targeting to create single and combinatorial knockouts of insulin and IGF-1 receptors (IR and IGF1R); combinatorial knockouts IR with post-receptors effectors of insulin action (IRS and FoxO proteins); and tissue-specific and inducible knockouts to determine the role of IR and IGF1R in individual tissues in normal physiology and the pathophysiology of diabetes. In addition, in vitro we have defined differential signaling by insulin and IGF-1 receptors, and unique actions of insulin and IGF-1 in different cell types. As a result, since the last competitive renewal, this grant has provided support for 88 published papers which have led to new insights into the complex nature of the insulin/IGF-1 signaling network, the contribution of insulin resistance in different organs to diabetes and metabolic syndrome, as well as evidence on how tissues communicate with one another in insulin resistant states. In addition, we have made novel observations regarding the role of insulin action in non-classical target tissues, like the brain, intestine, endothelial and iPS cells; the presence of novel insulin-like peptides in viruses, and potential for signaling by unoccupied IR and IGF1R. During the coming grant period, our aims are to continue to expand our understanding of insulin/IGF1 action by 1) defining the differential roles of the extra- and intra-cellular domains of IR and IGF1R in signaling in vitro and in vivo using three complementary strategies [mass spectroscopy based phosphoproteomic analysis of insulin/IGF-1 receptor mutants and chimeric receptors in vitro; creation of a new generation of knock-in mouse models in which IR is replaced by IGF1R, by chimeric insulin/IGF-1 receptors or by substitutions in the juxtamembrane domain of the receptor important in differences in IR vs IGF1R signaling, and use of newly discovered viral insulin-like peptides (VILPs) to explore differences in IR/IGF1R signaling]; 2) determine the nature of signaling by the unoccupied insulin and IGF-1 receptors involved in control of gene expression, autophagy and apoptosis and identify the domains of the receptors mediating these effects and the signaling proteins that interact with them and 3) continuing to define the role of insulin signaling in brain on astrocytes vs neurons using global and region-specific IR knockouts; insulin regulation of gene expression and metabolite levels in brain; and the interaction of insulin resistance in brain with genetic risks in pathogenesis of Alzheimer?s Disease. Together these studies will continue to help unravel new aspects in the mechanisms of insulin/IGF-1 receptor signaling and their alterations in diabetes, metabolic and neurodegenerative disease.

Public Health Relevance

This is a renewal of NIH grant DK031036 which is focused on the insulin and IGF-1 receptors, their signaling pathways and their alterations in physiologic and pathologic states. Over the past decade, we have made tremendous progress in understanding the signaling and biological roles of these receptors through both in vitro and in vivo studies, including extensive studies using gene targeting to create over a dozen models with single, combinatorial and tissue-specific knockouts of insulin and IGF-1 receptors to determine their role in normal physiology and the pathophysiology of disease. During the coming grant period, our aims are to continue to expand our understanding of insulin/IGF1 action by 1) defining the differential roles of the extra- and intra-cellular domains of IR and IGF1R in signaling in vitro and in vivo; 2) determining the nature of signaling by the unoccupied insulin and IGF-1 receptors involved in control of gene expression, autophagy and apoptosis and 3) continuing to determine the role of insulin signaling in brain on astrocytes vs neurons and the role insulin resistance in brain in pathogenesis of Alzheimer?s Disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK031036-40
Application #
10153752
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Silva, Corinne M
Project Start
1982-04-15
Project End
2025-02-28
Budget Start
2021-03-01
Budget End
2022-02-28
Support Year
40
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Joslin Diabetes Center
Department
Type
DUNS #
071723084
City
Boston
State
MA
Country
United States
Zip Code
02215
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
Viana-Huete, Vanesa; Guillén, Carlos; García, Gema et al. (2018) Male Brown Fat-Specific Double Knockout of IGFIR/IR: Atrophy, Mitochondrial Fission Failure, Impaired Thermogenesis, and Obesity. Endocrinology 159:323-340
Garcia-Castillo, Maria Daniela; Chinnapen, Daniel J-F; Te Welscher, Yvonne M et al. (2018) Mucosal absorption of therapeutic peptides by harnessing the endogenous sorting of glycosphingolipids. Elife 7:
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
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

Showing the most recent 10 out of 142 publications