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C. Ronald Kahn, M.D.

Research Summary

Research in the Kahn laboratory focuses in four related and highly integrated areas, which are central to both type 1 and type 2 diabetes:  1) mechanisms of insulin and IGF-1 signaling in control of metabolism; 2) how insulin signaling is altered in diabetes, obesity and insulin resistant states; 3) heterogeneity of adipose tissue and different adipose depots affect metabolism; and 4) the impact of genes, aging and the environment on these processes.

Since our discovery that the insulin receptor is an insulin-stimulated receptor tyrosine kinase, the Kahn lab has focused on understanding how this event activates the complex signaling network that leads to the multiple actions of insulin.  We showed that following activation of the receptor kinase, several insulin receptor substrates (IRS proteins) become tyrosine phosphorylated and serve as intracellular messengers by docking to other intracellular signaling proteins that link 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. These form the critical nodes in the insulin signaling network and are points of regulation in type 1 and 2 diabetes.

Using a wide range of genetic and biochemical approaches, including creation of genetically engineered mice and human iPS cells lines, the Kahn laboratory is working to define the specific pathways that lead to each of insulin’s actions and how they are modified in diabetes and other insulin resistant states. Through these approaches, we have defined the role of insulin in both classical target tissues for insulin action (liver, muscle and fat) and non-classical targets such as the brain, endothelial cell and β-cell. We also study mechanisms of insulin resistance and its impact on function of these tissues. These studies are being used as a platform for developing new therapeutics, including new types of insulins, as well as insulin sensitizers, which are critical for future treatments for type 1 and type 2 diabetic patients.  

Recently, we have shown how loss of insulin action in the brain in diabetes can affect brain cholesterol metabolism and brain function. These findings are critical for understanding the reason for the increased risk for neurodegenerative complications, which affect both type 1 and type 2 diabetic patients. To identify how genetic and environmental alterations might contribute to the development of diabetes in humans and rodents, we have assessed the effects of the gut microbiome in different strains of mice on development of obesity, insulin resistance and diabetes.
 
The biology of adipocytes and their special role in metabolism and insulin resistance is another major area of interest.  We have shown how various depots can affect metabolism and what determines fat distribution and the nature of adipocyte lineages, including the formation of brown vs. white fat and subcutaneous vs. intra-abdominal fat. We have found important roles for a variety of fundamental developmental genes, and are exploring these through the creation of knockout and knockdown mouse and cellular models. Recently, we have also studied the role of microRNAs as regulators of adipose biology and metabolism.

Finally, we are also interested in the problem of aging and the relationship between insulin action, obesity and lifespan. Again we have taken advantage of some of our genetic models to define better the physiological connections between these events.  We are now studying the insulin signaling pathway may from a connection between aging and metabolism at the molecular level.  In this area, we also have been studying the role of sirtuins, especially Sirt3 and Sirt5, and the role of miRNAs in adipose tissue in aging and metabolic control. This area is important for patients with type 1 and type 2 diabetes, as many are living longer with their disease, and age is a major risk factor for development of disease complications. 

Biography

C. Ronald Kahn is a world recognized expert in diabetes and obesity research, as well as a preeminent investigator in the area of insulin signal transduction and mechanisms of altered signaling in diabetes and metabolic disease. Dr. Kahn is Senior Investigator, Head of the Section on Integrative Physiology and Metabolism at Joslin Diabetes Center and the Mary K. Iacocca Professor of Medicine at Harvard Medical School. Dr. Kahn served as Research Director of the Joslin Diabetes Center from 1981 to 2000, and served as President of Joslin from 2001 to 2007. He is currently the Center’s Chief Academic Officer.

Dr. Kahn has received more than 70 awards and honors, including the highest honors of the American Diabetes Association, U.S. and British Endocrine Societies, Juvenile Diabetes Research Foundation, European Association for the Study of Diabetes and the American Association of Clinical Endocrinologists, and election to the National Academy of Science and Institute of Medicine. He has authored more than 600 original publications and 200 reviews and chapters.

Dr. Kahn holds undergraduate and medical degrees from the University of Louisville. He also holds an honorary Master of Science from Harvard University, honorary Doctor of Science degrees from the University of Paris, University of Louisville, University of Geneva and Washington University in St. Louis, an honorary Doctor of Medicine from the University of Copenhagen and is an honorary Professor and Director of the Diabetes Center at Peking University School of Medicine.

Page last updated: December 20, 2014