Increased susceptibility to streptozotocin-induced beta-cell apoptosis anddelayed autoimmune diabetes in alkylpurine-DNA-N-glycosylase-deficient mice

Type I diabetes is thought to occur as a result of the loss of insulin-prod ucing pancreatic beta cells by an environmentally triggered autoimmune reac tion. In rodent models of diabetes, streptozotocin (STZ), a genotoxic methy lating agent that is targeted to the beta cells, is used to trigger the ini tial cell death. High single doses of STZ cause extensive beta -cell necros is, while multiple low doses induce limited apoptosis, which elicits an aut oimmune reaction that eliminates the remaining cells. We now show that in m ice lacking the DNA repair enzyme alkylpurine-DNA-N-glycosylase (APNG), bet a -cell necrosis was markedly attenuated after a single dose of STZ. This i s most probably due to the reduction in the frequency of base excision repa ir-induced strand breaks and the consequent activation of poly(ADP-ribose) polymerase (PARP), which results in catastrophic ATP depletion and cell nec rosis. Indeed, PARP activity was not induced in A-PNG(-/-) islet cells foll owing treatment with STZ in vitro. However, 48 h after STZ treatment, there was a peak of apoptosis in the beta cells of APNG(-/-) mice. Apoptosis was not observed in PARP-inhibited APNG(+/+) mice, suggesting that apoptotic p athways are activated in the absence of significant numbers of DNA strand b reaks. Interestingly, STZ-treated APNG(-/-) mice succumbed to diabetes 8 mo nths after treatment, in contrast to previous work with PARP inhibitors, wh ere a high incidence of beta -cell tumors was observed. In the multiple-low -dose model, STZ induced diabetes in both APNG(-/-) and APNG(-/-) mice; how ever, the initial peak of apoptosis was 2.5-fold greater in the APNG(-/-) m ice. We conclude that APNG substrates are diabetogenic but by different mec hanisms according to the status of APNG activity.