Uncoupling protein-2 attenuates glucose-stimulated insulin secretion in INS-1E insulinoma cells by lowering mitochondrial reactive oxygen species.

TitleUncoupling protein-2 attenuates glucose-stimulated insulin secretion in INS-1E insulinoma cells by lowering mitochondrial reactive oxygen species.
Publication TypeJournal Article
Year of Publication2011
AuthorsAffourtit, C, Jastroch, M, Brand, MD
JournalFree Radic Biol Med
Volume50
Issue5
Pagination609-16
Date Published2011 Mar 01
ISSN1873-4596
KeywordsAnimals, Antioxidants, Cell Line, Tumor, Diabetes Mellitus, Type 2, Energy Metabolism, Gene Knockdown Techniques, Glucose, Insulin, Insulin Secretion, Insulin-Secreting Cells, Ion Channels, Metalloporphyrins, Mice, Mitochondria, Mitochondrial Proteins, Rats, Reactive Oxygen Species, Uncoupling Protein 2
Abstract

Glucose-stimulated insulin secretion (GSIS) by pancreatic β 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 β 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.

DOI10.1016/j.freeradbiomed.2010.12.020
Alternate JournalFree Radic. Biol. Med.
Citation Key10.1016/j.freeradbiomed.2010.12.020
PubMed ID21172424
PubMed Central IDPMC3036803
Grant ListPL1 AG032118 / AG / NIA NIH HHS / United States
P01 AG025901 / AG / NIA NIH HHS / United States
R01 AG033542-02 / AG / NIA NIH HHS / United States
/ / Medical Research Council / United Kingdom
R01 AG033542 / AG / NIA NIH HHS / United States
P30 AG025708 / AG / NIA NIH HHS / United States