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: Charles Affourtit, Martin Jastroch, Martin D Brand
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 50 Issue 5 Pg. 609-16 (Mar 01 2011) ISSN: 1873-4596 [Electronic] United States
• PMID: 21172424 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: 2010 Elsevier Inc. All rights reserved.

Chemical References

• Antioxidants
• Insulin
• Ion Channels
• Metalloporphyrins
• Mitochondrial Proteins
• Mn(III) 5,10,15,20-tetrakis(N-methylpyridinium-2-yl)porphyrin
• Reactive Oxygen Species
• Ucp2 protein, mouse
• Ucp2 protein, rat
• Uncoupling Protein 2
• Glucose

Topics

• Animals
• Antioxidants (pharmacology)
• Cell Line, Tumor
• Diabetes Mellitus, Type 2 (metabolism)
• Energy Metabolism (physiology)
• Gene Knockdown Techniques
• Glucose (metabolism)
• Insulin (metabolism)
• Insulin Secretion
• Insulin-Secreting Cells (metabolism)
• Ion Channels (genetics, physiology)
• Metalloporphyrins (pharmacology)
• Mice
• Mitochondria (metabolism)
• Mitochondrial Proteins (genetics, physiology)
• Rats
• Reactive Oxygen Species (metabolism)
• Uncoupling Protein 2