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

Jon G. Mabley, Wilma L. Suarez-Pinzon, György Haskó, Andrew L. Salzman, Alex Rabinovitch, Ernest Kun, Csaba Szabo

Research output: Contribution to journalArticle

63 Citations (Scopus)

Abstract

1 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. 2 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. 3 A potent inhibitor of PARS, 5-iodo-6-amino-1,2-benzopyrone (INH 2BP), 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. 4 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 2BP, 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. 5 Inhibition of PARS by INH 2BP was unable to protect rat islet cells from cytokine-mediated apoptosis. 6 Cytokines, peroxynitrite and streptozotocin were all shown to induce PARS activation in RIN-5F cells, an effect suppressed by INH 2BP. 7 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.

Original languageEnglish
Pages (from-to)909-919
Number of pages11
JournalBritish Journal of Pharmacology
Volume133
Issue number6
StatePublished - 2001
Externally publishedYes

Fingerprint

Poly Adenosine Diphosphate Ribose
Experimental Diabetes Mellitus
Ligases
Streptozocin
Cytokines
Islets of Langerhans
Genes
Type 1 Diabetes Mellitus
Cell Survival
Cell Death
Insulin
Peroxynitrous Acid
Ribose
Poly(ADP-ribose) Polymerases
Interleukin-1
Hyperglycemia
Interferons
5-iodo-6-amino-1,2-benzopyrone
Nitric Oxide
Tumor Necrosis Factor-alpha

Keywords

  • Diabetes
  • DNA single strand break
  • Inducible nitric oxide synthase
  • Inflammation
  • Islets of Langerhans
  • Nitric oxide
  • Peroxynitrite
  • Poly (ADP-ribose) synthetase
  • Superoxide

ASJC Scopus subject areas

  • Pharmacology

Cite this

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. / Mabley, Jon G.; Suarez-Pinzon, Wilma L.; Haskó, György; Salzman, Andrew L.; Rabinovitch, Alex; Kun, Ernest; Szabo, Csaba.

In: British Journal of Pharmacology, Vol. 133, No. 6, 2001, p. 909-919.

Research output: Contribution to journalArticle

Mabley, Jon G. ; Suarez-Pinzon, Wilma L. ; Haskó, György ; Salzman, Andrew L. ; Rabinovitch, Alex ; Kun, Ernest ; Szabo, Csaba. / 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. In: British Journal of Pharmacology. 2001 ; Vol. 133, No. 6. pp. 909-919.
@article{55ec7b9fe864456094c231fa23ce040a,
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 = "1 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. 2 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. 3 A potent inhibitor of PARS, 5-iodo-6-amino-1,2-benzopyrone (INH 2BP), 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. 4 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 2BP, 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. 5 Inhibition of PARS by INH 2BP was unable to protect rat islet cells from cytokine-mediated apoptosis. 6 Cytokines, peroxynitrite and streptozotocin were all shown to induce PARS activation in RIN-5F cells, an effect suppressed by INH 2BP. 7 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.",
keywords = "Diabetes, DNA single strand break, Inducible nitric oxide synthase, Inflammation, Islets of Langerhans, Nitric oxide, Peroxynitrite, Poly (ADP-ribose) synthetase, Superoxide",
author = "Mabley, {Jon G.} and Suarez-Pinzon, {Wilma L.} and Gy{\"o}rgy Hask{\'o} and Salzman, {Andrew L.} and Alex Rabinovitch and Ernest Kun and Csaba Szabo",
year = "2001",
language = "English",
volume = "133",
pages = "909--919",
journal = "British Journal of Pharmacology",
issn = "0007-1188",
publisher = "Wiley-Blackwell",
number = "6",

}

TY - JOUR

T1 - 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

AU - Mabley, Jon G.

AU - Suarez-Pinzon, Wilma L.

AU - Haskó, György

AU - Salzman, Andrew L.

AU - Rabinovitch, Alex

AU - Kun, Ernest

AU - Szabo, Csaba

PY - 2001

Y1 - 2001

N2 - 1 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. 2 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. 3 A potent inhibitor of PARS, 5-iodo-6-amino-1,2-benzopyrone (INH 2BP), 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. 4 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 2BP, 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. 5 Inhibition of PARS by INH 2BP was unable to protect rat islet cells from cytokine-mediated apoptosis. 6 Cytokines, peroxynitrite and streptozotocin were all shown to induce PARS activation in RIN-5F cells, an effect suppressed by INH 2BP. 7 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.

AB - 1 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. 2 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. 3 A potent inhibitor of PARS, 5-iodo-6-amino-1,2-benzopyrone (INH 2BP), 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. 4 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 2BP, 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. 5 Inhibition of PARS by INH 2BP was unable to protect rat islet cells from cytokine-mediated apoptosis. 6 Cytokines, peroxynitrite and streptozotocin were all shown to induce PARS activation in RIN-5F cells, an effect suppressed by INH 2BP. 7 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.

KW - Diabetes

KW - DNA single strand break

KW - Inducible nitric oxide synthase

KW - Inflammation

KW - Islets of Langerhans

KW - Nitric oxide

KW - Peroxynitrite

KW - Poly (ADP-ribose) synthetase

KW - Superoxide

UR - http://www.scopus.com/inward/record.url?scp=0034885522&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034885522&partnerID=8YFLogxK

M3 - Article

VL - 133

SP - 909

EP - 919

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 6

ER -