Alloxan is used to induce diabetes in animals; however, the underlying mechanisms are still a matter of debate. Alloxan evoked a rapid hyperpolarization of the plasma membrane potential and suppressed electrical activity elicited by 15mM glucose, thus terminating voltage-dependent Ca2+ influx. Accordingly, glucose-induced oscillations in intracellular free Ca2+ concentration were abolished. The effect of alloxan on membrane potential could not be reversed by glucose but was reversed by tolbutamide. However, the sensitivity to tolbutamide was decreased after treatment of the cells with alloxan. These effects closely resemble those described earlier for H2O2. H2O2 and alloxan decreased the mitochondrial membrane potential, indicating a decrease in ATP production and thus interference with cell metabolism. A decrease in ATP synthesis would explain the plasma membrane hyperpolarization observed in intact islets, reflecting the activation of ATP-dependent K+ channels. Surprisingly, alloxan inhibited the whole-cell K+ATP current measured in single cells and the single-channel K+ATP current registered in excised patches. This inhibitory effect of alloxan is not mediated by changes in cell metabolism but seems to be due to direct interactions with the K+ATP channels via thiol-group oxidation. We have monitored the appearance of reactive oxygen species in single cells and islets treated with alloxan and H2O2 for comparison. In contrast to H2O2, alloxan induced the appearance of measurable reactive oxygen species only in islets but not in single cells. The results show that alloxan evokes different effects in islets and single cells, giving a possible explanation for inconsistent results reported in the past. It is concluded that alloxan exerts its diabetogenic effect by the production of H2O2 in intact islets.

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