Glutathionylation state of uncoupling protein-2 and the control of glucose-stimulated insulin secretion

J Biol Chem. 2012 Nov 16;287(47):39673-85. doi: 10.1074/jbc.M112.393538. Epub 2012 Oct 3.


The role of reactive oxygen species (ROS) in glucose-stimulated insulin release remains controversial because ROS have been shown to both amplify and impede insulin release. In regard to preventing insulin release, ROS activates uncoupling protein-2 (UCP2), a mitochondrial inner membrane protein that negatively regulates glucose-stimulated insulin secretion (GSIS) by uncoupling oxidative phosphorylation. With our recent discovery that the UCP2-mediated proton leak is modulated by reversible glutathionylation, a process responsive to small changes in ROS levels, we resolved to determine whether glutathionylation is required for UCP2 regulation of GSIS. Using Min6 cells and pancreatic islets, we demonstrate that induction of glutathionylation not only deactivates UCP2-mediated proton leak but also enhances GSIS. Conversely, an increase in mitochondrial matrix ROS was found to deglutathionylate and activate UCP2 leak and impede GSIS. Glucose metabolism also decreased the total amount of cellular glutathionylated proteins and increased the cellular glutathione redox ratio (GSH/GSSG). Intriguingly, the provision of extracellular ROS (H(2)O(2), 10 μM) amplified GSIS and also activated UCP2. Collectively, our findings indicate that the glutathionylation status of UCP2 contributes to the regulation of GSIS, and different cellular sites and inducers of ROS can have opposing effects on GSIS, perhaps explaining some of the controversy surrounding the role of ROS in GSIS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Glucose / genetics
  • Glucose / metabolism*
  • Glutathione / genetics
  • Glutathione / metabolism*
  • Hydrogen Peroxide / metabolism
  • Insulin / genetics
  • Insulin / metabolism*
  • Insulin Secretion
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / metabolism*
  • Ion Channels / genetics
  • Ion Channels / metabolism*
  • Mice
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Mitochondrial Membranes / metabolism*
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Protein Processing, Post-Translational / physiology*
  • Uncoupling Protein 2


  • Insulin
  • Ion Channels
  • Mitochondrial Proteins
  • Ucp2 protein, mouse
  • Uncoupling Protein 2
  • Hydrogen Peroxide
  • Glutathione
  • Glucose