The “not-so-vulnerable” β-cell

Oxidative stress, mediated by reactive oxygen species (ROS) like superoxide and H 2 O 2 , 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 H 2 O 2 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 H 2 O 2 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 H 2 O 2 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 H 2 O 2 , 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 H 2 O 2 and peroxynitrite through a peroxiredoxin-dependent mechanism, and may not be so vulnerable after all.