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Oxidative stress is thought to promote pancreatic -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 -cells express low levels of antioxidant enzymes, including catalase and GSH peroxidases, have supported a model in which -cells are ill-equipped to detoxify ROS. This hypothesis seems at odds with the essential role of -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 H 2 O 2 continuously over time and Amplex Red to measure extracellular H 2 O 2 concentration, we found here that -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 -cells to continuously generated H 2 O 2 . In contrast, when delivered as a bolus, H 2 O 2 induced the DNA damage response, depleted cellular energy stores, and decreased -cell viability independently of thioredoxin reductase inhibition. These findings show that -cells have the capacity to detoxify micromolar levels of H 2 O 2 through a thioredoxin reductase-dependent mechanism and are not as sensitive to oxidative damage as previously thought.
Stancill et al. (Fri,) studied this question.