Development of Autoimmune Diabetes in NOD Mice Is Associated With the Formation of Peroxynitrite in Pancreatic Islet β-Cells

Wilma L Suarez-Pinzon; Casaba Szabó; Alex Rabinovitch

doi:10.2337/diab.46.5.907

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Development of Autoimmune Diabetes in NOD Mice Is Associated With the Formation of Peroxynitrite in Pancreatic Islet β-Cells

Wilma L Suarez-Pinzon,
Casaba Szabó and
Alex Rabinovitch

Department of Medicine (W.L.S.-R, A.R.), University of Alberta, Edmonton, Alberta, Canada; and the Children's Hospital Medical Center, Division of Critical Care (C.S.) Cincinnati, Ohio

Address correspondence and reprint requests to Alex Rabinovitch, MD, 430 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada, T6G 2S2. ws3{at}gpu.srv.ualberta.ca.

Diabetes 1997 May; 46(5): 907-911. https://doi.org/10.2337/diab.46.5.907

Abstract

Peroxynitrite (ONOO⁻) is a highly reactive oxidant species produced by the reaction of the free radicals superoxide (O₂^·–) 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 β-cells. Most of the β-cells in islets from acutely diabetic NOD mice were NT⁺ (73 ± 8%), whereas significantly fewer β-cells were NT⁺ in islets from normoglycemic NOD mice (18 ± 4%) and BALB/c mice (5 ± 1%). Also, the percentage of β-cells in islets from NOD mice (normoglycemic and diabetic) correlated inversely with the frequency of NT⁺ β-cells. This study demonstrates for the first time that peroxynitrite, a reaction product of superoxide and nitric oxide, is formed in pancreatic islet β-cells of NOD mice developing autoimmune diabetes. This suggests that both oxygen and nitrogen free radicals contribute to β-cell destruction in IDDM via peroxynitrite formation in the islet β-cells.