We have shown previously that H2O2 inhibits insulin secretion due to opening of KATP channels. Now we evaluated whether loss of functional KATP channels renders b-cells less sensitive to oxidative stress. In islets from WT mice insulin secretion was inhibited by addition of H2O2 at a low concentration (25 mM). By contrast, hormone secretion from islets of SUR1-KO mice was only affected by concentrations of H2O2 larger than 250 mM. To elucidate the underlying mechanism, we examined the effects of H2O2 on Vm and [Ca2+ ]c. In WT b-cells the addition of 10 and 100 mM H 2O2 resulted in a reversible hyperpolarisation of Vm consistent with the opening of KATP channels. In b-cells from SUR1-KO mice application of 10 or 100 mM H 2O2 did not hyperpolarise Vm. [Ca2+ ]c was decreased to basal levels in WT b-cells after exposure to 10 mM H 2O2. In SUR1-KO b-cells [Ca2+ ]c remained elevated due to Ca2+ -influx through L-type Ca2+ -channels. The data show that loss of KATP channel function renders b-cells less sensitive to oxidative stress. Thus, modulation of KATP channel activity may be an interesting possibility to protect b-cells against an oxidative insult.