Pancreatic beta cells release insulin in response to increased concentrations of serum glucose and its metabolites. Increasing concentrations of ATP (adenosine triphosphate), a product of glucose metabolism in mitochondria, cause beta cells to secrete insulin. Zhang et al. found that UCP2 (uncoupling protein-2), a protein that decreases the efficiency of ATP production in mitochondria by allowing protons to leak out through the mitochondrial membrane, negatively influences insulin secretion by controlling glucose-dependent ATP synthesis. Isolated pancreatic islet cells from ucp2-deficient mice produced larger amounts of ATP and secreted more insulin, and ucp2-deficient mice had lower serum concentrations of glucose. In hyperglycemic, insulin-resistant, obese (ob/ob) mice, amounts of both UCP2 protein and mRNA were greatly increased, suggesting that increased UCP2 might contribute to impaired beta cell function, leading to diabetes. Zhang et al. crossed ob/ob mice and ucp2-deficient mice and found that although the double-mutant mice were still obese, they were no longer hyperglycemic and secreted greater amounts of insulin compared with ob/ob mice, indicating that these double-mutant mice had improved beta cell function resulting from the absence of UCP2. Thus, these data indicate that UCP2 may link beta cell dysregulation to diabetes.
C.-Y. Zhang, G. Baffy, P. Perret, S. Krauss, O. Peroni, D. Grujic, T. Hagen, A. J. Vidal-Puig, O. Boss, Y.-B. Kim, X. X. Zheng, M. B. Wheeler, G. I. Shulman, C. B. Chan, B. B. Lowell, Uncoupling Protein-2 negatively regulates insulin secretion and is a major link between obesity, cell dysfunction, and type 2 diabetes. Cell 105, 745-755 (2001). [Online Journal]