Spatial distribution and temporal onset of NF-kB activation and inducible nitric oxide synthase within pancreatic islets in the pre-diabetic stage of genetic, diabetic-prone BB rats: attenuation by drug intervention decreases inflammatory cell infilt

摘要

OBJECTIVE AND DESIGN: To document in vivo immunolocalization and activation of nuclear factor-kappaB (NF-kappaB) and inducible nitric oxide synthase (iNOS) expression in prediabetic stages of diabetes mellitus. MATERIAL OR SUBJECTS: Genetic, diabetic-prone or diabetic-resistant BB rats (total = 189). TREATMENT: Various doses of an oral dithiocarbamate derivative, NOX-700, or cyclosporine (2.5 mg/kg) starting at 30 or 60 days of age. METHODS: Immunohistochemistry, electrophoretic mobility shift assays, plasma glucose. RESULTS: NF-kappaB and iNOS was increased in pancreas of hyperglycemic, diabetic-prone rats but not normoglycemic, diabetic-resistant rats. Immunostaining for NF-kappaB and iNOS was largely confined to islets and occurred in diabetic-prone rats prior to overt hyperglycemia. NOX-700 decreased cell infiltration, delayed the onset of disease and decreased the incidence of hyperglycemia to levels achieved by immunosuppressant therapy. NOX-700 also decreased the intensity of immunoreactive NF-kappaB and iNOS within pancreatic islets. CONCLUSIONS: These studies support a role of NF-kB and iNOS in diabetogenesis in vivo.