Inhibition of poly (ADP‐ribose) synthetase by gene disruption or inhibition with 5‐iodo‐6‐amino‐1,2‐benzopyrone protects mice from multiple‐low‐dose‐streptozotocin‐induced diabetes

Activation of poly(ADP‐ribose) synthetase (PARS, also termed polyADP‐ribose polymerase or PARP) has been proposed as a major mechanism contributing to β‐cell destruction in type I diabetes. In the present study, we have investigated the role of PARS in mediating the induction of diabetes and β‐cell death in the multiple‐low‐dose‐streptozotocin (MLDS) model of type I diabetes. Mice genetically deficient in PARS were found to be less sensitive to MLDS than wild type mice, with a lower incidence of diabetes and reduced hyperglycemia. A potent inhibitor of PARS, 5‐iodo‐6‐amino‐1,2‐benzopyrone (INH 2 BP), was also found to protect mice from MLDS and prevent β‐cell loss, in a dose‐dependent manner. Paradoxically, in the PARS deficient mice, the compound increased the onset of diabetes.In vitro the cytokine combination; interleukin‐1β, tumor necrosis factor‐α and interferon‐γ inhibited glucose‐stimulated insulin secretion from isolated rat islets of Langerhans and decreased RIN‐5F cell viability. The PARS inhibitor, INH 2 BP, protected both the rat islets and the β‐cell line, RIN‐5F, from these cytokine‐mediated effects. These protective effects were not mediated by inhibition of cytokine‐induced nitric oxide formation. Inhibition of PARS by INH 2 BP was unable to protect rat islet cells from cytokine‐mediated apoptosis. Cytokines, peroxynitrite and streptozotocin were all shown to induce PARS activation in RIN‐5F cells, an effect suppressed by INH 2 BP. The present study provides evidence for in vivo PARS activation contributing to β‐cell damage and death in the MLDS model of diabetes, and indicates a role for PARS activation in cytokine‐mediated depression of insulin secretion and cell viability in vitro .British Journal of Pharmacology (2001) 133 , 909–919; doi: 10.1038/sj.bjp.0704156