A dithiocarbamate analogue decreases intraislet cell infiltration and the incidence of diabetes mellitus in the genetic diabetes-prone BB rat

SUMMARY: Dithiocarbamates are a class of agents that have interesting biologic properties including the ability to limit the production and/or action of nitric oxide (NO). These agents are also potential immunosuppressant agents. Since immunosuppressant agents have been examined for remission of disease in clinical trials, we wanted to examine whether a dithiocarbamate analogue, NOX-200, might inhibit diabetogenesis in the genetic diabetes-prone BB rat model. Immunohistochemical analysis revealed inducible NO synthase (iNOS) gene expression in pancreatic islets of both normoglycemic and hyperglycemic diabetes-prone BB rats but not in diabetes-prone BB rats at the early age of 30 days or in diabetes-resistant BB rats. A qualitative decrease in immunostaining for iNOS was also observed in the pancreata of drug-treated animals. Long-term treatment with NOX-200, used alone or in combination with low-dose cyclosporine (CsA), significantly reduced the incidence of diabetes mellitus. In the subset of animals that became diabetic, NOX-200 did not alter either the time to onset of hyperglycemia or the level of hyperglycemia, insulinopenia, or lymphocytic cell infiltration into the pancreas. In contrast, in animals that did not develop hyperglycemia, treatment with NOX-200 decreased inflammatory cell infiltration into the pancreas equipotent to that seen using CsA. These studies demonstrate the potential therapeutic efficacy of dithiocarbamates to oppose the development of autoimmune insulin-dependent diabetes mellitus by limiting inflammatory cell activation/infiltration.