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A Harvard Medical School Affiliate
Welcome to the Joslin Research Website
Joslin Investigator:
Andrew W. Norris, MD, PhD
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Andrew W. Norris, MD, PhD
Investigator
Joslin Diabetes Center
Instructor in Pediatrics
Harvard Medical School
1/10/2003 - 8/1/2005
One issue that impacts people with type 2 diabetes, in addition to higher glucose levels, is higher levels of fat molecules in the blood. As the disease develops, these circulating fat molecules often get deposited where they do not belong, for example, within muscles, arteries or the liver. In fact, excess fat within muscle tissue is one of the best predictors of insulin resistance. This is important because muscle is the primary tissue that takes up circulating glucose from the blood in response to insulin.
Andrew W. Norris, M.D., Ph.D., is studying the molecular process underlying the connection between excess muscle fat and insulin resistance in type 2 diabetes, with a view to developing targeted treatments. He has focused on a transcription factor called PPAR-gamma as a possible link between excess muscle fat and insulin resistance. (A transcription factor is a protein that controls gene expression.) Several years ago, work at Joslin helped show that (1) people with certain mutations in PPAR-gamma accumulate excess fat and (2) drugs that activate PPAR-gamma improve blood glucose in people with insulin resistance.
Currently, several powerful medications that target PPAR-gamma are on the market and taken regularly by many patients with type 2 diabetes. But the drugs are not perfect, causing weight gain even as they reduce fat in muscle tissue.
To find better treatments for type 2 diabetes, Dr. Norris collaborated with C. Ronald Kahn, M.D., to produce a mouse model that lacks the PPAR-gamma protein in skeletal muscles. The scientists then studied these mice to determine the role that PPAR-gamma plays in insulin resistance. The results were unexpected: While the protein does appear to control the amount of fat found in tissues, it does not appear to play much of a role in how the muscle responds to insulin. This finding led the scientists to postulate that current drugs targeting this protein must be working indirectly, first acting on fat tissue, which contains high amounts of PPAR-gamma, instead of directly on muscle tissue, where fat deposits are creating an issue.
These findings may lead to refinement of the medications to reduce type 2 diabetes insulin resistance, producing the desired effect of reducing fat in muscle without causing side effects such as weight gain.
Dr. Norris also plans to study the mechanisms by which exercise causes the muscle to burn fuel (fat) more efficiently, improving the muscle’s ability to respond to insulin.
Selected References:
Norris AW, Chen L, Fisher SJ, Szanto I, Ristow M, Jozsi AC, Hirshman MF, Rosen ED, Goodyear LJ, Gonzalez FJ, Spiegelman BM, Kahn CR. Muscle-specific PPAR-gamma deficient mice develop increased adiposity and hepatic insulin resistance but respond to thiazolidinediones.
J Clin Invest 112:608-618, 2003.
Widstrom RL, Norris AW, van der Veer J, Spector AA. Fatty acid-binding proteins inhibit hydration of epoxyeicosatrienoic acids by soluble epoxide hydrolase. Biochemistry 42:11762-11767, 2003.
Wolfrum C, Shih DQ, Kuwajima S, Norris AW, Kahn CR, Stoffel M. Role of foxa-2 in adipocyte metabolism and differentiation. J Clin Invest 112:345-356, 2003.
Norris AW, Spector AA. Very long chain n-3 and n-6 polyunsaturated fatty acids bind strongly to liver fatty acid-binding protein. J Lipid Res 43:646-653, 2002.
Widstrom RL, Norris AW, Spector AA. Binding of cytochrome P450 monooxygenase and lipoxygenase pathway products by heart fatty acid-binding protein. Biochemistry 40:1070-1076, 2001.
