期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 50, 期 5, 页码 609-616出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2010.12.020
关键词
Pancreatic beta cells; Glucose-stimulated insulin secretion; Uncoupling protein 2; Mitochondrial respiration; Reactive oxygen species; Coupling efficiency of oxidative phosphorylation; Type 2 diabetes; Metabolic syndrome; Free radicals
资金
- Medical Research Council
- National Institutes of Health [P01 AG025901, PL1 AG032118, P30 AG025708, R01 AG033542]
- W.M. Keck Foundation
- Ellison Medical Foundation [AG-SS-2288-09]
- Deutsche Forschungsgemeinschaft [JA 1884/2-1]
Glucose-stimulated insulin secretion (GSIS) by pancreatic beta cells is regulated by mitochondrial uncoupling protein-2 (UCP2), but opposing phenotypes, GSIS improvement and impairment, have been reported for different Ucp2-ablated mouse models. By measuring mitochondrial bioenergetics in attached INS-1E insulinoma cells with and without UCP2, we show that UCP2 contributes to proton leak and attenuates glucose-induced rises in both respiratory activity and the coupling efficiency of oxidative phosphorylation. Strikingly, the GSIS improvement seen upon UCP2 knockdown in INS-1E cells is annulled completely by the cell-permeative antioxidant MnTMPyP. Consistent with this observation. UCP2 lowers mitochondrial reactive oxygen species at high glucose levels. We conclude that UCP2 plays both regulatory and protective roles in beta cells by acutely lowering GSIS and chronically preventing oxidative stress. Our findings thus provide a mechanistic explanation for the apparently discrepant findings in the field. (C) 2010 Elsevier Inc. All rights reserved.
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