An inhibitor of inducible nitric oxide synthase and scavenger of peroxynitrite prevents diabetes development in NOD mice

J Autoimmun. 2001 Jun;16(4):449-55. doi: 10.1006/jaut.2001.0507.


Peroxynitrite (ONOO(-)) is a highly reactive oxidant produced by the interaction of the free radicals superoxide (O*-2) and nitric oxide (NO(*)). In a previous study, we found that peroxynitrite is formed in islet beta-cells of nonobese diabetic (NOD) mice. Here, we report that guanidinoethyldisulphide (GED), a selective inhibitor of inducible nitric oxide synthase (iNOS) and scavenger of peroxynitrite prevents diabetes in NOD mice. GED treatment of female NOD mice, starting at age 5 weeks, delayed diabetes onset (from age 12 to 22 weeks) and significantly decreased diabetes incidence at 30 weeks (from 80% to 17%). GED did not prevent pancreatic islet infiltration by leukocytes; however, beta-cells that stained positive for nitrotyrosine (a marker of peroxynitrite) were significantly decreased in islets of GED-treated mice (1+/-1%) compared with vehicle-treated mice (30+/-9%). In addition, GED significantly inhibited nitric oxide and nitrotyrosine formation and decreased destruction of beta-cells in NOD mouse islets incubated in vitro with the combination of proinflammatory cytokines interleukin 1-beta (IL-1beta), tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). These findings indicate that both superoxide and nitric oxide radicals contribute to islet beta-cell destruction in autoimmune diabetes via peroxynitrite formation in the beta-cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cells, Cultured
  • Diabetes Mellitus, Type 1 / metabolism
  • Diabetes Mellitus, Type 1 / prevention & control*
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Free Radical Scavengers / administration & dosage
  • Free Radical Scavengers / pharmacology*
  • Guanidines / administration & dosage
  • Guanidines / pharmacology*
  • Islets of Langerhans / cytology
  • Islets of Langerhans / drug effects
  • Male
  • Mice
  • Mice, Inbred NOD
  • Nitric Oxide Synthase / antagonists & inhibitors*
  • Nitric Oxide Synthase Type II
  • Oxidants / metabolism*
  • Pancreas / metabolism
  • Pancreas / pathology
  • Peroxynitrous Acid / metabolism*


  • Enzyme Inhibitors
  • Free Radical Scavengers
  • Guanidines
  • Oxidants
  • bis(2-guanidinoethyl)disulfide
  • Peroxynitrous Acid
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse