Type 1 diabetes in humans arises from the autoimmune destruction of pancreatic beta-cells and typically presents in childhood. Genetic susceptibility is an underlying cause, but environmental agents, that is, toxins and viruses, are postulated to be initiating factors. The underlying role of beta-cell death in response to environmental or physiologic events has been investigated as a critical event in diabetes onset. A well-studied rodent model for type 1 diabetes utilizes streptozotocin (STZ) to induce beta-cell death. STZ is a selective beta-cell genotoxicant, and when administered in a single high dose it induces rapid onset of diabetes by generating DNA adducts, including N3-methyladenine and O(6)-methylguanine adducts, and subsequently beta-cell death by necrosis. In the present work, we have extended previous studies in which mice deficient in the repair of N3-methyladenine adducts, 3-methyladenine DNA glycosylase (alkyladenine DNA glycosylase [Aag]) null mice, were reported to be resistant to the direct cytotoxic effect of STZ, but later developed autoimmune diabetes (J. W. Cardinal et al., 2001, Mol. Cell. Biol. 231, 5605-5613). We found that Aag(-/-) mice treated with a single high dose of STZ were protected from widespread beta-cell necrosis and diabetes. However, moderate levels of beta-cell apoptosis were observed in the Aag(-/-) STZ-treated mice. While mice became glucose impaired for the duration of study (14 months after STZ injection), overt diabetes did not develop. We conclude that an autoimmune response is not initiated in Aag(-/-) mice in response to beta-cell apoptosis. Furthermore, tumor development is not observed in Aag(-/-) treated mice, suggesting that N3-methyladenine adducts that accumulate in the genome may not be promutagenic in beta-cells.