UCSF DIABETES, ENDOCRINOLOGY & METABOLISM TRAINING PROGRAM FACULTY RESEARCH SUMMARIES

My research interests concern the signaling mechanisms for insulin and insulin-related receptors and the role of these receptors in human diseases. One area of interest has been the regulation of the insulin receptor gene. We are investigating the nature of a unique nuclear binding protein for the insulin receptor gene that increases during differentiation. This protein binds to an AT rich tract in the insulin receptor promoter. A second area of research has been the purification of insulin receptor tyrosine kinase inhibitors from fibroblasts of insulin-resistant patients. We have found an unusual plasma membrane protein, PC-1, which is present both in very insulin-resistant patients and in more routine patients with type 2 diabetes mellitus. PC-1 blocks the ability of insulin to activate its receptor. A third area of our work is in the elucidation of the intracellular signaling mechanisms induced by oxidative stress that cause insulin resistance. We have data indicating that the potent antioxidant alpha lipoic acid can prevent the effects of oxidative stress. A fourth area is the role of the insulin receptor in the biology of breast and other cancers. We find that insulin receptors, especially the fetal insulin receptor, are over-expressed in both human breast cancers and animal models of breast cancer, suggesting that this receptor may control cancer growth.

Selected References

Pender C. Goldfine ID, Manchem VP, Evans JL, Spevak WR, Shi S, Rao S, Bajjalaeih S, Maddux BA, Youngren JF. Regulation of insulin receptor function by a small molecule insulin receptor activator. J Biol Chem. 277: 43565-71, 2002.

Dong, H., Maddux, B.A., Altomonte, J., Meseck, M., Accili, D., Terkeltaub, R., Johnson, K., Youngren, J., Goldfine, I.D. Increased Hepatic Levels of the Insulin Receptor Inhibitor, PC-1/NPP1, Induce Glucose Intolerance. Diabetes. 54:267-72, 2005.

Meyre D, Maddux B, Goldfine ID, Froguel P, et al. Variants of ENPP1 are associated with childhood and adult obesity and increase the risk o glucose intolerance and type 2 diabetes. Nat Genet 2005 Aug; 37(8): 863-7.

Youngren J, Gable K, Peñaranda C, Maddux BA, Zavodovskaya M, Lobo M, Campbell M, Goldfine ID. Nordihydroguaiaretic Acid (NDGA) Inhibits the IGF-1 and C-Erbb2/Her2/Neu Receptors And Suppresses Growth in Breast Cancer Cells . Breast Cancer Research Treatment. 2005 Nov; 94(1) : 37-46

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