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 infiltration and incidence of diabetes

Abstract

Objective and Design: To document in vivo immunolocalization and activation of nuclear factor-κB (NF-κB) 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-κB and iNOS was increased in pancreas of hyperglycemic, diabetic-prone rats but not normoglycemic, diabetic-resistant rats. Immunostaining for NF-κB 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-κB and iNOS within pancreatic islets.

Conclusions: These studies support a role of NF-kB and iNOS in diabetogenesis in vivo.