Steven E. Shoelson, M.D., Ph.D.
Dr. Steven E. Shoelson is an internationally recognized leader in diabetes research, the Head of the Section on Pathophysiology and Molecular Pharmacology at Joslin and a Professor of Medicine at Harvard Medical School. He received a Ph.D. in chemistry and his medical degree from the University of Chicago. After training in Internal Medicine at Brigham and Women’s Hospital in Boston, he joined the Joslin faculty. 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 a MERIT award from the National Institutes of Health. Dr. Shoelson holds the Helen and Morton Adler Chair in Structural Biology at Joslin.
Inflammation most commonly refers to the body’s efforts to combat infection and is accompanied by dysfunction in the involved organs and four cardinal signs: redness, heat, swelling and pain. Dr. Shoelson and his lab have found that inflammation also accompanies obesity, and growing evidence indicates that inflammation is what links obesity to the development of insulin resistance, type 2 diabetes and cardiovascular disease. Although inflammation’s cardinal signs are not associated with the low-grade, subacute inflammation in obesity, evidence surely exists for chronic dysfunction in the involved organs.
As fat tissue expands with stored lipid, the number and activity of infiltrating immune cells that mediate inflammation also increase. Changes in macrophages are readily apparent, but other immune cells, including T-cell subtypes, also respond. Ongoing studies being conducted with Joslin’s Section on Immunology and Immunogenetics aim to more fully characterize the immunological accompaniments to obesity and the roles of a repertoire of immune cells in insulin resistance and diabetes.
Proinflammatory cytokines and other substances produced in fat and liver appear to propagate the inflammation systemically, which induces insulin resistance in other tissues including muscle. Similar mechanisms appear to increase risk of diabetes complications, including cardiovascular disease and possibly diabetic nephropathy. Chronic inflammation in the walls of atherosclerotic blood vessels is accepted as a pathological mediator, but how adipose tissue and liver are involved is another area of ongoing study and another of the Shoelson lab’s contributions to the field. Systemic inflammation and hyperglycemia induce inflammation in the kidney, which may have a role in diabetic nephropathy.
A Holy Grail in biomedical research is the translation of basic biomedical discoveries into new treatments or cures that improve patients’ lives. Dr. Shoelson’s lab has been fortunate to see their basic discoveries rapidly transition to clinical trials, which are either under way or planned in each of the aforementioned areas. Dr. Allison B. Goldfine from the Section on Clinical Research closely collaborates on these clinical trials—the first to determine whether inflammation is tractable as a primary target for treating chronic metabolic diseases and associated complications.
TINSAL-T2D (Targeting Inflammation with Salsalate in Type 2 Diabetes) is an NIH-sponsored trial being conducted at 16 sites nationwide to determine whether an anti-inflammatory drug effectively treats patients with type 2 diabetes. A second NIH-sponsored clinical trial, conducted with researchers at Beth IsraelDeaconess Medical Center, targets inflammation in cardiovascular disease (TINSAL-CVD). A third trial with the Veterans Administration hospital system targets inflammation in subjects with impaired glucose tolerance (TINSAL-IGT) to determine whether anti-inflammatory strategies prevent type 2 diabetes in subjects at risk.
The Shoelson lab also has a long interest in structural biology. The goals are to solve crystal structures of proteins and complexes relevant to diabetes and insulin resistance and use the information to better understand pathophysiology and for additional efforts in drug discovery.
Shoelson SE, Lee J, Goldfine AB. Inflammation in insulin resistance. J Clin Invest 116:1793-1801, 2006.
Cai D, Yuan M, Frantz JD, Melendez PA, Hansen L, Lee J, Shoelson SE. Local and systemic insulin resistance resulting from hepatic activation of IKKb and NF-kB. Nat Med 11:183-190, 2005.
Dhe-Paganon S, Werner ED, Nishi M, Hansen L, Chi YI, Shoelson SE. A phenylalanine zipper mediates APS dimerization. Nat Struct Mol Biol 11:968-974, 2004.
Cai D, Frantz JD, Tawa NE Jr, Melendez PA, Oh BC, Lidov HGW, Hasselgren PO, Frontera WR, Lee J, Glass DJ, Shoelson SE. IKKb/NF-kB activation causes severe muscle wasting in mice. Cell 119:285-298, 2004.
Chi YI, Frantz JD, Oh BC, Hansen L, Dhe-Paganon S, Shoelson SE. Diabetes mutations delineate an atypical POU domain in HNF-1a. Mol Cell 10:1129-1137, 2002.
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 IKKb. Science 293:1673-1677, 2001.