Development of autoimmune diabetes in NOD mice is associated with the formation of peroxynitrite in pancreatic islet beta-cells.
Peroxynitrite (ONOO-) is a highly reactive oxidant species produced by the reaction of the free radicals superoxide (O(2).-) and nitric oxide (NO.). Here we report a marked increase in nitrotyrosine (NT), a marker of peroxynitrite, in islet cells from NOD mice developing spontaneous autoimmune diabetes. By using specific antibodies and immunohistochemical methods, we found that NT-positive cells were significantly more frequent in islets from acutely diabetic NOD mice (22 +/- 6%) than in islets from normoglycemic NOD mice (7 +/- 1%) and control BALB/c mice (2 +/- 1%). The NT+ cells in islets were identified to be macrophages and also beta-cells. Most of the beta-cells in islets from acutely diabetic NOD mice were NT+ (73 +/- 8%), whereas significantly fewer beta-cells were NT+ in islets from normoglycemic NOD mice (18 +/- 4%) and BALB/c mice (5 +/- 1%). Also, the percentage of beta-cells in islets from NOD mice (normoglycemic and diabetic) correlated inversely with the frequency of NT+ beta-cells. This study demonstrates for the first time that peroxynitrite, a reaction product of superoxide and nitric oxide, is formed in pancreatic islet beta-cells of NOD mice developing autoimmune diabetes. This suggests that both oxygen and nitrogen free radicals contribute to beta-cell destruction in IDDM via peroxynitrite formation in the islet beta-cells.
Suarez-Pinzon
W L
WL
Department of Medicine, University of Alberta, Edmonton, Canada.
Szabó
C
C
Rabinovitch
A
A
D000818:Animals; D002452:Cell Count; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced*; D005260:Female; D007515:Islets of Langerhans / Q000737:chemistry / Q000378:metabolism*; D007962:Leukocytes / Q000737:chemistry / Q000166:cytology; D008264:Macrophages / Q000737:chemistry / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D009566:Nitrates / Q000378:metabolism*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis
D009566:Nitrates; C039642:peroxynitric acid; C002744:3-nitrotyrosine; D014443:Tyrosine