Jongsoon Lee, Ph.D.
Dr. Lee is an Assistant Investigator in the Section on Pathophysiology and Molecular Pharmacology, and an Assistant Professor at Harvard Medical School. He received his doctoral degree in Biochemistry from Boston University and completed postdoctoral training in the laboratory of Steven Shoelson, M.D., Ph.D., at Joslin. He has been on the faculty at Harvard Medical School since 1999.
Dr. Lee has been working with Dr. Shoelson in 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.
Dr. Lee's research has focused on studies of insulin signaling and insulin resistance, with his doctoral thesis centered on elucidating the mechanism of insulin receptor activation. One of his findings is called “asymmetric phosphorylation,” referring to his observation that the binding of insulin to its receptor and the Tyr phosphorylation of the insulin receptor involve different receptor subunits. This finding is considered to be a highly significant contribution to our understanding of the mechanism by which the insulin receptor is activated.
Since joining the Joslin staff, Dr. Lee has been studying the biochemistry of insulin signaling. One goal of this research is to understand the intracellular signaling involved so that the signaling defects that underlie insulin resistance, and that impair glucose tolerance and induce type 2 diabetes, can be identified. Through his collaboration with Dr. Shoelson, Dr. Lee identified IKKbeta as being an important protein in tissue inflammation, which is related to insulin resistance. In fact, their research demonstrates that this enzyme is also involved in the development of insulin resistance, especially in obesity. When IKKbeta is blocked experimentally, insulin resistance can be reversed. Drs. Shoelson and Lee first successfully produced this response in animal models and then in small human clinical studies.
Dr. Lee is now studying a different enzyme, GSK3. By using animal models, Dr. Lee seeks to determine whether GSK3, like IKKbeta, is also involved in the development of insulin resistance. His preliminary data with mouse models show that if activity of the GSK3beta isoform of the enzyme is decreased, the mouse is protected from the development of insulin resistance. In female mice, obesity is also decreased as the enzyme activity is reduced. Dr. Lee is currently using similar approaches to study the role of the GSK3alpha isoform in the development of insulin resistance. Ultimately Dr. Lee’s goal with his current line of research is to determine whether GSK3 is a suitable target for the treatment of insulin resistance and type 2 diabetes.
Pilch PF, Lee J. Insulin receptor family. Encyclopedia of Biological Chemistry Lennarz W, Lane MD (eds). San Diego: Elsevier Science. Vol 2; pp. 436-440, 2004.
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, Konstantopoulos 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.