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A Harvard Medical School Affiliate
Welcome to the Joslin Research Website
Joslin Investigator:
Jongsoon Lee, PhD
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Cellular and Molecular Physiology
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Jongsoon Lee, PhD
Investigator
Joslin Diabetes Center
Instructor
Harvard Medical School
1/1/2001 -
Jongsoon Lee, Ph.D., has been working with Steven E. Shoelson, M.D., Ph.D., studying the biochemistry of insulin signaling. One goal of their research is to understand intracellular signaling in order to identify the defects that underlie insulin resistance, which impairs glucose tolerance and is a root cause of type 2 diabetes.
Dr. Lee’s current work focuses on insulin resistance (also referred to as pre-diabetes syndrome), a condition in which certain tissues of the body—notably muscle, liver and fat—no longer respond to normal levels of insulin in the body. To compensate, the pancreatic beta cells must express insulin in ever-increasing quantities. Over time, the heavy demand for insulin production causes “beta-cell burnout.” The pancreas cannot produce enough insulin to overcome insulin resistance, causing the development of type 2 diabetes.
During post-doctoral training with Dr. Shoelson, Dr. Lee and his colleagues identified IkappaB kinase (IKK) as an important enzyme involved in the process of tissue inflammation, which is related to insulin resistance. Their research demonstrated that this enzyme also is involved in the development of insulin resistance, especially in obesity. In experiments in which IKK is blocked, it is possible to reverse insulin resistance. Drs. Shoelson and Lee first successfully produced this response in animal models and then in small clinical studies.
The relationships among obesity, cellular inflammation and insulin resistance are significant.
More than 20 percent of Americans are considered obese, and this number rises to 50 percent if people who are overweight are included in the total. About 40 percent of people who are obese eventually develop diabetes. Over the past few years, the number of people with diabetes has increased to 10 percent of the population, largely due to the epidemic of obesity. Understanding obesity on the molecular level—including intracellular signaling defects—and how obesity promotes diabetes will make it possible to design treatments to reverse insulin resistance and prevent the development of the disease.
Dr. Lee is now studying another enzyme, glycogen synthase kinase 3 beta (GSK3beta). Using animal models, he is investigating whether GSK3beta also is involved in the development of insulin resistance.
Preliminary data with mouse models show that if activity of the GSK3beta enzyme is decreased, the mouse is protected from developing insulin resistance. In female mice, obesity also decreases as enzyme activity decreases. If the enzyme is knocked out completely, however, the mouse dies. Dr. Lee hopes that his studies can identify GSK3beta as a therapeutic target for the treatment of insulin resistance and type 2 diabetes.
Selected References
Pilch PF, Lee J. Insulin receptor family. Encyclopedia of Biological Chemistry. Lennarz W, Lane MD (eds). San Diego: Elsevier Science. In press.
Cai D, Dhe-Paganon S, Melendez PA, Lee J, Shoelson SE. Two new substrates in insulin signaling: IRS5/DOK4 and IRS6/DOK5. J Biol Chem 278:25323-25330, 2003.
Yuan M, Konstantopoulis N, Lee J, Hansen L, Li ZW, Karin M, Shoelson SE. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science 293:1673-1677, 2001.
Lee J, Pilch PF, Shoelson SE, Scarlata SF. Conformational changes of the insulin receptor upon insulin binding and activation as monitored by fluorescence spectroscopy. Biochemistry 36:2701-2708, 1997.
Lee J, O’Hare T, Pilch PF, Shoelson SE. Insulin receptor autophosphorylation occurs asymmetrically. J Biol Chem 268:4092-4098, 1993.
