Joslin Investigator Details

A Harvard Medical School Affiliate

Welcome to the Joslin Research Website


	Joslin Investigator:

C. Ronald Kahn, MD

NEW! Kahn Lab Website

Investigator Specifics:

Professional Details:

Member of Section:

Current Fellows, Students, or Lab Members:

Victoria Rotter Sopasakis, PhD

Past Fellows, etc.:

Katrine Almind

Sudha Biddinger

Matthias Bluher

Dong Chen

Lihong Chen

Steven Cohen

Kezia Frayjo

Jenny Gunton

Masa Katic

Tatsuya Kondo

Palle Laustsen

Choy Lewis

Laureen Mazzola

Aileen McGettrick

Pal Njolstad

Andrew Norris

Amelia Pearsall

Jane Pedersen, Ph. D.

Helge Rader

Jean-Paul Riou

Kohjiro Ueki

David Vicent-Lopez

Jesse Washington III

Vijay Yechoor

Investigators

Adjunct Investigators

Fellows & Team Members

DERC Cores

Research Sections

Joslin Resources

C. Ronald Kahn, MD

Vice Chairman/ Section Chief, Obesity

Joslin Diabetes Center

Professor of Medicine

Harvard Medical School

8/1/1981 -

Insulin Signaling and the Pathogenesis of Diabetes

Since our discovery that the insulin receptor is an insulin-stimulated enzyme with protein tyrosine kinase activity, my laboratory has focused its attention on how this early signal is converted to the final effects of insulin on metabolism and growth, how insulin signaling is altered in insulin resistant states such as type 2 diabetes and obesity, and what the impact of genetics is on these functions.

We have shown that following the activation of the receptor kinase, several intracellular substrates become tyrosine phosphorylated. The best studied of these are a family of high molecular weight proteins termed insulin receptor substrates-1, 2, 3 and 4 (IRS-1 thru -4). These phosphorylated IRS proteins serve as intracellular messangers by docking to other intracellular signaling proteins that contain SH2 domains. This links insulin to two major intracellular cascades - one mediated by the enzyme phosphatidylinositol 3-kinase (PI 3-kinase) and the other mediated by the Ras-MAP kinase pathway. This forms an important point of diversion in insulin signaling and several potential points of regulation in disease. Using a wide range of genetic, biochemical, and approaches, as well as cellular, animal and human systems, my laboratory is attempting to define the specific pathways that lead to specific insulin actions and how they are modified in insulin resistant states. We are also attempting to identify genetic alterations which might contribute to the development of type 2 diabetes in humans and rodents, by gene expression using Affymetrix microarray analysis, proteomics and other techniques.

Current projects in the laboratory fall into four areas: 1)Defining the roles of each of the IRS-proteins and and isoforms of PI 3-kinase in insulin signaling and insulin resistance through the creation of cell lines and animal models in which these proteins are either eliminated by a genetic "knock-out" or increased by overexpression. This also includes studies utilizing the technique of tissue specific gene inactivation to determine the role of insulin in various tissues of the body, including classical target tissues for insulin action such as liver, muscle and fat, as well as non-classical targets such as the brain and beta cell. 2) Mechanisms of insulin resistance, including the role of SOCS proteins and other molecules as inhibitors of insulin action. 3)The role of insulin signaling in control of gene expression utilizing microarray analysis and the genetic models we have created to dissect insulin vs diabetes regulated events. 4) The biology of adipocytes and their special role in insulin resistance.

NEW! Kahn Lab Website

Selected References:

Araki, E., Lipes, M.A., Patti, M.E., Bruning, J.C., Haag, B.L., Johnson, R.S., Kahn, C.R., Alternative Pathway of Insulin Signaling in Mice with Targeted Disruption of the IRS-1 Gene, Nature, 1994, 372: 186-190.

Bruning, J.C., Winnay, J., Bonner-Weir, S., Taylor, S.I., Accili, D., and Kahn, C.R., Development of a Novel Polygenic Model of NIDDM in Mice Heterozygous for IR and IRS-1 Null Alleles, Cell, 1997, 88: 561-572.

Almind, K., Inoue, G., Pedersen, O., Kahn, C.R., A Common Amino Acid Polymorphism in Insulin Receptor Substrate-1 Causes Impaired Insulin Signalling: Evidence from Transfection Studies, J Clin Invest., 1996, 97: 2569-2575.

Zhu J, Tseng YH, Kantor JD, Rhodes CJ, Zetter BR, Moyers JS, Kahn CR. Interaction of the ras-related protein associated with diabetes rad and the putative tumor metastasis suppressor NM23 provides a novel mechanism of GTPase regulation. Proc Natl Acad Sci. USA 1999; 96:14911-14918.

Velloso, L.A., Folli, F.B., Sun, X.J., White, M.F., Saad, M.J.A., Kahn, C.R., Cross-talk Between the Insulin and Angiotensin Signaling Systems. Proc. Natl. Acad. Sci., USA, 1996, 93: 12490-12495.

Brüning JC, Michael MD, Winnay J, Hayashi T, Hörsch D, Accili D, Goodyear LJ, Kahn CR. A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance. Mol Cell 1998; 2(5):559-569.

Kulkarni RN, Brüning JC, Winnay JN, Postic C, Magnuson MA, Kahn CR. Tissue-specific knockout of the insulin receptor in pancreatic beta-cells creates an insulin secretory defect similar to that in Type 2 diabetes. Cell 1999; 96:329-339.

Michael MD, Kulkarni RN, Postic C, Previs SF, Shulman Gl, Magnuson MA, Kahn CR. Loss of insulin signaling in liver leads to severe insulin resistance and progressive hepatic dysfunction. Molecular Cell 2000; 6:87-97.

Bruning JC, Gautam DC, Burks DJ, Gillette J, Schubert M, Orban P, Klein R, Krone W, Muller-Wieland D, Kahn CR, Role of brain insulin receptor in control of body weight and reproduction. Science. 2000 289:2122-5.

Zisman A, Peroni O, Abel ED, Michael MD, Mauvais-Jarvis F, Lowell BB, Wojtaszewski JFP, Hirshman MF, Virkamaki A, Goodyear LJ, Kahn CR, Kahn BB. Insulin resistance and glucose intolerance in mice with disruption of the GLUT4 glucose transporter selectivity in muscle. Nature Medicine 2000; 6:924-928.

Almind K, Doria A, and Kahn CR. Putting the genes for type 2 diabetes on the map. Nat. Med, 2001, 7:277-9

Bluher M, Kahn BB, Kahn CR. Extended longevity in mice lacking the insulin receptor in adipose tissue. Science. 2003; 299:572-574.

Almind K, Kulkarni RN, Lannon SM, Kahn CR. Identification of interactive Loci linked to insulin and leptin in mice with genetic insulin resistance. Diabetes. 2003;52: 35-43.

Patti ME, Butte AJ, Crunkhorn S, Cusi K, Berria R, Kashyap S, Miyazaki Y, Kohane I, Costello M, Saccone R, Landaker EJ, Goldfine AB, Mun E, DeFronzo R, Finlayson J, Kahn CR, Mandarino LJ. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1. Proc Natl Acad Sci U S A. 2003;100:8466-71

Ueki K, Fruman DA, Yballe CM, Fasshauer M, Klein J, Asano T, Cantley LC, Kahn CR.Positive and negative roles of p85 alpha and p85 beta regulatory subunits of phosphoinositide 3-kinase in insulin signaling. J Biol Chem. 2003; 278: 48453-66.

Chen D, Mauvais-Jarvis F, Bluher M, Fisher SJ, Jozsi A, Goodyear LJ, Ueki K, Kahn CR. p50alpha/p55alpha phosphoinositide 3-kinase knockout mice exhibit enhanced insulin sensitivity. Mol Cell Biol. 2004,(1):320-9.

Schubert M, Gautam D, Surjo D, Ueki K, Baudler S, Schubert D, Kondo T, Alber J, Galldiks N, Kustermann E, Arndt S, Jacobs AH, Krone W, Kahn CR, Bruning JC. Role for neuronal insulin resistance in neurodegenerative diseases. Proc Natl Acad Sci U S A. 2004, 101(9):3100-5.

Biographical Sketch:

Dr. Kahn received his B.S. and M.D. at the University of Louisville. After training in internal medicine at Washington University's Barnes Hospital, he went to the NIH for 11 years where he rose to head the Section on Cellular and Molecular Physiology of the Diabetes Branch of NIDDK. In 1981, he became the Research Director of the Joslin Diabetes Center. Since 1986 he has been the Mary K. Iacocca Professor of Medicine at Harvard Medical School. In 1997, he was named Executive Vice President and Director of Joslin. In 2000, he was named Joslin's President. He has received the major research awards of the American Federation of Clinical Research, ADA, JDF and IDF, and holds an honorary D.Sc. degrees from the University of Paris and the University of Geneva. He is a member of the National Academy of Science, the Institute of Medicine, and the American Academy of Arts and Sciences.