Joslin Investigator Details

A Harvard Medical School Affiliate

Welcome to the Joslin Research Website


	Joslin Investigator:

Investigator Specifics:

Professional Details:

CV not available

Member of Section:

Current Fellows, Students, or Lab Members:

Tatjana Ignjatovic, PhD

Nozomu Kamei, M.D., Ph. D.

Souphatta Sasorith, PhD

Hagit Shapiro, PhD

Takeshi Shimada, M.D. Ph.D.

Takuhito Shoji, M.D., Ph. D.

Ju Rang Woo, PhD

Yasuhiko Yamamoto, MD, PhD

Past Fellows, etc.:

Andisheh Abedini, PhD

Dong-Sheng Cai

Young-In Chi

Sirano Dhe-Paganon

Karen Duda

Jane Yongjing Guo

Chandrashekaran Gurunathan, Ph. D.

Lone Hansen

Nadine Joseph, MS

Peter Melendez

Ali Nayer, MD

Peter Voshol, PhD

Eric Werner

Leanne Wilson-Fritch

Minsheng Yuan

Investigators

Adjunct Investigators

Fellows & Team Members

DERC Cores

Research Sections

Joslin Resources

Steven E Shoelson, MD, PhD

Section Head, Cellular & Molecular Physiology
Joslin Diabetes Center

Professor of Medicine, Harvard Medical School

Affiliated Member
Dept of Biological Chemistry and Molecular Pharmacology

Harvard Medical School

Faculty of the Committee on Higher Degrees in Biophysics

Harvard University

7/1/1988 -

Studies in the Shoelson laboratory are divided into two main areas:

Pathophysiology of insulin resistance and type 2 diabetes.
Structural biology of diabetes and insulin resistance.

Insulin resistance (the failure of tissues to respond to insulin) is a major pathogenic feature of type 2 diabetes. The triad of excess weight, Western diet and a sedentary lifestyle all promote insulin resistance and type 2 diabetes, and additional associated conditions referred to collectively as the metabolic syndrome, which includes elevated blood pressure and lipid levels and cardiovascular disease. Our laboratory is interested in identifying the molecular links to insulin resistance, diabetes and metabolic syndrome – and have focused squarely on inflammation. Epidemiologists have found that patients with type 2 diabetes and cardiovascular disease have slightly elevated levels of inflammatory markers in their bloodstream, raising the possibility that inflammation might be associated with the development of these diseases, and proinflammatory cytokines such as TNF-α and IL-6 promote insulin resistance in experimental models.

However, a third series of investigations really provided a breakthrough for our understanding. Drawing upon earlier studies suggesting that anti-inflammatory salicylates reverse hyperglycemia in diabetic patients, we identified the NF-κB pathway as a target of this effect and found that it to be activated by obesity. While NF-κB is well known as a master regulator of innate immunity, inflammation and apoptosis in host defense, its functions in fat and liver with respect to metabolic diseases had not been investigated previously. We found that activation of the inflammatory NF-κB pathway in fat and liver by weight gain leads to the production of inflammatory mediators that cause both local and systemic insulin resistance. By inhibiting this pathway with drugs we hope to develop new treatments for type 2 diabetes and the metabolic syndrome.

Our laboratory also uses the method of x-ray crystallography to solve three-dimensional structures of proteins and macromolecular complexes related to the diabetes and insulin resistance or related complications. Recently solved structures include elements of the insulin signaling cascade (IRS-1 and APS) and the MODY (Maturity Onset Diabetes of the Young) gene products, HNF-1α and HNF-4α.

Biographical Sketch:

Steve Shoelson, M.D., Ph.D., received his Ph.D. in chemistry and M.D. degrees from the University of Chicago. After training in internal medicine at the Brigham and Women's Hospital, he joined the faculty at the Joslin Diabetes Center in 1988. He currently heads the Section of Cellular and Molecular Physiology and is Professor of Medicine at Harvard Medical School. He has received numerous awards and honors, including a Burroughs-Wellcome Fund Scholar Award in Experimental Therapeutics, the Excellence in Diabetes Research Award of the Juvenile Diabetes Research Foundation and Boehringer Mannheim Corporation, and a MERIT award from the National Institutes of Health. Dr. Shoelson holds the Helen and Morton Adler Chair at the Joslin Diabetes Center.

Selected References:

Hof P, Pluskey S, Dhe-Paganon S, Eck MJ, and Shoelson SE (1998) Crystal structure of the tyrosine phosphatase SHP-2. Cell. 92, 441-450.

Dhe-Paganon S, Ottinger E, Nolte R, Eck MJ, and Shoelson SE (1999) Crystal structure of the PH-PTB targeting region of IRS-1. Proc Natl Acad Sci USA. 96, 8378-8383.

Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M, and Shoelson SE (2001) Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkb. Science 293, 1673-1677.

Dhe-Paganon, S., Duda, K., Iwamoto, M., Chi, Y. I., and Shoelson, S. E. (2002) Crystal structure of the HNF4α ligand binding domain in complex with endogenous fatty acid ligand. J Biol Chem. 277, 37973-37976.

Chi, Y. I., Frantz, J. D., Oh, B.-C., Hansen, L., Dhe-Paganon, S., and Shoelson, S. E. (2002) Diabetes mutations delineate an atypical POU domain in HNF-1α. Molecular Cell 10, 1129-1137.

Cai, D., Dhe-Paganon, S., Melendez, P.A., Lee, J. and Shoelson, S.E. (2003) Two new substrates in insulin signaling: IRS5/DOK5 and IRS6/DOK4. J Biol Chem. 278, 25323-25330.

Duda K, Chi YI, and Shoelson SE (2004) Structural basis for HNF-4α activation by ligand and coactivator binding. J Biol Chem. 279, 23311-23316.

Werner ED, Lee J, Hansen L, Yuan M and Shoelson SE. (2004) Insulin resistance due to phosphorylation of IRS-1 at serine 302. J Biol Chem. 279, 35298-35305.

Dhe-Paganon S, Werner ED, Nishi M, Hansen L, Chi Y-I and Shoelson SE (2004) A phenylalanine zipper mediates APS dimerization. Nature Struct Mol Biol. 11, 968-974.

Cai D, Frantz JD, Tawa NE, Melendez PA, Oh B-C, Lidov HGW, Hasselgren P-O, Frontera WR, Lee J, Glass DJ, Shoelson SE. (2004) IKKb/NF-κB activation causes severe muscle wasting in mice. Cell 119, 285-298.

Nishi M, Werner ED, Oh B-C, Frantz JD, Dhe-Paganon S, Hansen L, Lee J and Shoelson SE. Kinase activation through dimerization by SH2-B. (2005) Mol Cell Biol. 25, 2607-2621.

Cai D, Yuan M, Frantz JD, Melendez PA, Hansen L, Lee J, Shoelson SE. Local and systemic insulin resistance due to hepatic activation of IKKb and NF-κB. (2005) Nature Medicine 11, 183-190.