The “not-so-vulnerable” β-cell

Oxidative stress, mediated by reactive oxygen species (ROS) like superoxide and H2O2, is thought to promote pancreatic β-cell dysfunction and contribute to type 1 and type 2 diabetes. When blood glucose is chronically elevated, it is thought that increased oxidative phosphorylation results in accumulation of ROS in β-cells due to electron leak from the mitochondrial electron transport chain. However, early reports that β-cells express low levels of detoxifying enzymes, including catalase and glutathione peroxidases, suggested that β-cells are ill-equipped to detoxify ROS. This notion has been propagated by the common use of bolus H2O2 delivery to cells. However, the logic supporting the “vulnerable β-cell” model is unclear when considering the importance of β-cells to survival of the organism as well as the tight coupling of oxidative phosphorylation to insulin secretion. Here, using glucose oxidase to deliver H2O2 continuously over time, rather than the more traditional bolus delivery, we found that β-cells are capable of detoxifying micromolar levels of this oxidant. Treatment with H2O2 bolus, but not glucose oxidase, results in DNA damage, activation of the DNA damage response, and depletion of cellular energy stores. We find that β-cells readily express peroxiredoxins, thioredoxins, and thioredoxin reductase, essential components of the peroxiredoxin/thioredoxin antioxidant system. Either inhibition or specific knockdown of thioredoxin reductase or peroxiredoxins 1 or 3 sensitizes β-cells to continuously-generated H2O2, suggesting that this mechanism is essential for β-cells to detoxify this ROS. Finally, inhibition of thioredoxin reductase sensitizes β-cells to peroxynitrite, a potent RNS generated by the reaction of superoxide and nitric oxide. Together, these studies, which directly contradict the current dogma, suggest that β-cells are able to detoxify H2O2 and peroxynitrite through a peroxiredoxin-dependent mechanism, and may not be so vulnerable after all.