Steven E. Shoelson
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 obesity. Type 1 or insulin-dependent diabetes is caused by insulin deficiency, in most cases due to autoimmune destruction of pancreatic beta cells. Fewer than 1 in 10 diabetics have this more severe form of the disease. Type 2 diabetes is much more common, and its prevalence is rapidly rising. Type 2 diabetes or NIDDM, affects greater than 10% of our population. In type 2 diabetes insulin is present, often in excess, but target tissues fail to respond appropriately. This is referred to as insulin resistance, a problem in signal transduction.
Physiological studies identify acquired as opposed to genetic determinants of insulin resistance, particularly relationships between insulin resistance and obesity, Western diet and sedentary lifestyle. Due to its reversal by exercise and weight loss, we hypothesized a reversible defect in signal transduction. We recently showed that the inflammatory pathways leading to the transcription factor NF- κB, particularly those mediated by the IκB kinase, IKKβ , can mediate acquired insulin resistance. Insulin resistance leads to heightened Ser/Thr phosphorylation and decreased tyrosine-phosphorylation of the insulin receptor and its substrates, IRS1 and IRS2. We found that IKK inhibition reverses insulin resistance – either by reduced gene dosage (IKKβ +/- mice) or with high-dose salicylates. This accounts for aspirin's long-known but unexplained ability to lower blood glucose. Clinical studies are underway in obese subjects and patients with type 2 diabetes, and selected animal models, including tissue-specific knockouts and transgenics, are helping to identify primary target tissues and mechanisms of inter-organ cross-talk.
Structural biology efforts focus as well on diabetes. Current targets are subdivided into (1) genetic causes of diabetes, including MODY, lipodystrophy and obesity, (2) potential mediators of insulin resistance, and (3) autoantigens in type 1 diabetes. Recently solved structures include HNF-1 a , a new type of POU-homeodomain transcription factor; HNF-4α , a nuclear receptor that is linked to type 2 diabetes; the tail of nuclear Lamin A/C, which is mutated in patients with lipodystrophy and certain forms of muscular dystrophy; and the diabetes autoantigen, IA-2, against which antibodies and activated T cells are found in the majority of patients with newly-diagnosed type 1 diabetes.
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-kB activation causes severe muscle wasting in mice. Cell 119, 285-298 (2004).
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 (2004).
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-kB. Nature Medicine (in press).