Pancreatic β-cells detoxify H2O2 through the peroxiredoxin/thioredoxin antioxidant system

Oxidative stress is thought to promote pancreatic beta-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 beta-cells express low levels of antioxidant enzymes, including catalase and GSH peroxidases, have supported a model in which beta-cells are ill-equipped to detoxify ROS. This hypothesis seems at odds with the essential role of beta-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 beta-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 beta-cells to continuously generated H2O2. In contrast, when delivered as a bolus, H2O2 induced the DNA damage response, depleted cellular energy stores, and decreased beta-cell viability independently of thioredoxin reductase inhibition. These findings show that beta-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.