title: Uncoupling protein-2 attenuates glucose-stimulated insulin secretion in INS-1E insulinoma cells by lowering mitochondrial reactive oxygen species.
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.
authors.affiliation: Mitochondrial Biology Unit, Medical Research Council, Cambridge CB2 0XY, UK.charles.affourtit@plymouth.ac.uk
authors.forename: Charles
authors.initials: C
authors.lastname: Affourtit
authors.forename: Martin
authors.initials: M
authors.lastname: Jastroch
authors.forename: Martin D
authors.initials: MD
authors.lastname: Brand
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D045744:Cell Line, Tumor; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004734:Energy Metabolism / Q000502:physiology; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007473:Ion Channels / Q000235:genetics / Q000502:physiology*; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000502:physiology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000071246:Uncoupling Protein 2
chemical_list: D000975:Antioxidants; D007328:Insulin; D007473:Ion Channels; D008665:Metalloporphyrins; D024101:Mitochondrial Proteins; C502230:Mn(III) 5,10,15,20-tetrakis(N-methylpyridinium-2-yl)porphyrin; D017382:Reactive Oxygen Species; C000604390:Ucp2 protein, mouse; C000604391:Ucp2 protein, rat; D000071246:Uncoupling Protein 2; D005947:Glucose