Department of Medicine
Joslin Diabetes Center
One Joslin Place
Boston, MA 02215
10 postdoctoral fellows, 1 student
Our studies can be divided into two main areas, (1) pathophysiological mechanisms of insulin resistance and type 2 diabetes, and (2) 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-? 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-?B pathway as a target of this effect and found that it to be activated by obesity. While NF-?B 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-?B 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-1? and HNF-4?.
- 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-?B 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. Mol Cell Biol. 2004 Oct;11(10):968-74.
- 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-?B. Nature Medicine 2005 Feb;11(2):183-90.
BBS webpage updated 12/02/2009