Alloxan-induced DNA strand breaks in pancreatic islets. Evidence for H2O2 as an intermediate.

Alloxan exhibits the most potent diabetogenicity and has been used for induction of experimental diabetes mellitus. Understanding the mechanisms of action of the typical diabetogenic agent is important for elucidating the causes of diabetes. Okamoto (Okamoto, H. (1985) BioEssays 2, 15-21) proposed a model in which DNA fragmentation plays an important role for the development of diabetes. This DNA fragmentation is supposed to result from the accumulation of superoxide or hydroxyl radicals. However, direct evidence for this accumulation is lacking. Using rat pancreatic islets, we demonstrated that alloxan stimulated H2O2 generation, which induced DNA strand breaks. These findings support Okamoto's proposal that alloxan induces diabetes through the following biochemical events: alloxan----H2O2 generation----DNA strand breaks----diabetes mellitus. Perhaps this report constitutes the first demonstration of alloxan-stimulated H2O2 generation which could conceivably act as an intermediate for alloxan-induced DNA strand breaks.