Pancreatic β-cells detoxify H 2 O 2 through the peroxiredoxin/thioredoxin antioxidant system

J Biol Chem. 2019 Mar 29;294(13):4843-4853. doi: 10.1074/jbc.RA118.006219. Epub 2019 Jan 18.

Abstract

Oxidative stress is thought to promote pancreatic β-cell dysfunction and contribute to both type 1 and type 2 diabetes. Reactive oxygen species (ROS), such as superoxide and hydrogen peroxide, are mediators of oxidative stress that arise largely from electron leakage during oxidative phosphorylation. Reports that β-cells express low levels of antioxidant enzymes, including catalase and GSH peroxidases, have supported a model in which β-cells are ill-equipped to detoxify ROS. This hypothesis seems at odds with the essential role of β-cells in the control of metabolic homeostasis and organismal survival through exquisite coupling of oxidative phosphorylation, a prominent ROS-producing pathway, to insulin secretion. Using glucose oxidase to deliver H2O2 continuously over time and Amplex Red to measure extracellular H2O2 concentration, we found here that β-cells can remove micromolar levels of this oxidant. This detoxification pathway utilizes the peroxiredoxin/thioredoxin antioxidant system, as selective chemical inhibition or siRNA-mediated depletion of thioredoxin reductase sensitized β-cells to continuously generated H2O2 In contrast, when delivered as a bolus, H2O2 induced the DNA damage response, depleted cellular energy stores, and decreased β-cell viability independently of thioredoxin reductase inhibition. These findings show that β-cells have the capacity to detoxify micromolar levels of H2O2 through a thioredoxin reductase-dependent mechanism and are not as sensitive to oxidative damage as previously thought.

Keywords: ROS detoxification; diabetes; hydrogen peroxide; metabolic dysfunction; oxidative phosphorylation; oxidative stress; reactive oxygen species (ROS); thioredoxin reductase; β-cell.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Survival
  • DNA Damage
  • Hydrogen Peroxide / metabolism*
  • Insulin Secretion
  • Insulin-Secreting Cells / metabolism*
  • Male
  • Oxidation-Reduction
  • Peroxiredoxins / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Thioredoxin-Disulfide Reductase / metabolism
  • Thioredoxins / metabolism*

Substances

  • Thioredoxins
  • Hydrogen Peroxide
  • Peroxiredoxins
  • Thioredoxin-Disulfide Reductase