title: 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.
abstract: Activation of poly(ADP-ribose) synthetase (PARS, also termed polyADP-ribose polymerase or PARP) has been proposed as a major mechanism contributing to beta-cell destruction in type I diabetes. In the present study, we have investigated the role of PARS in mediating the induction of diabetes and beta-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 beta-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-1beta, tumor necrosis factor-alpha and interferon-gamma 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 beta-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 beta-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.
authors.affiliation: Inotek Corporation, Suite 419E, 100 Cummings Center, Beverly, Massachusetts MA 01915, USA. jmabley@inotekcorp.com
authors.forename: J G
authors.initials: JG
authors.lastname: Mabley
authors.forename: W L
authors.initials: WL
authors.lastname: Suarez-Pinzon
authors.forename: G
authors.initials: G
authors.lastname: Haskó
authors.forename: A L
authors.initials: AL
authors.lastname: Salzman
authors.forename: A
authors.initials: A
authors.lastname: Rabinovitch
authors.forename: E
authors.initials: E
authors.lastname: Kun
authors.forename: C
authors.initials: C
authors.lastname: Szabó
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003374:Coumarins / Q000494:pharmacology*; D016207:Cytokines / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005838:Genotype; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009154:Mutation; D009566:Nitrates / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics; D051381:Rats; D012720:Severity of Illness Index; D013311:Streptozocin / Q000008:administration & dosage; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000201:enzymology
chemical_list: D001786:Blood Glucose; D003374:Coumarins; D016207:Cytokines; D004791:Enzyme Inhibitors; D007328:Insulin; D009566:Nitrates; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C071383:5-iodo-6-amino-1,2-benzopyrone; C039642:peroxynitric acid; D009569:Nitric Oxide; D013311:Streptozocin; D011065:Poly(ADP-ribose) Polymerases