Administration of NF-κB decoy inhibits pancreatic activation of NF-κB and prevents diabetogenesis by alloxan in mice

Many risk factors can trigger the development of insulin-dependent diabetes mellitus (IDDM). The induction of IDDM in vivo is strongly associated not only with the generation of reactive oxygen species but also with the activation of the transcription factor nuclear factor-kappaB (NF-kappaB). The purpose of this study was to determine the role of NF-kappaB activation in diabetogenesis. Alloxan, a diabetogenic compound that causes diabetic conditions by selectively killing the insulin-producing pancreatic beta-cells, was used as a model chemical compound to induce diabetes. We show here that the injection of alloxan in mice rapidly and specifically induced the activation of NF-kappaB in the pancreas. Intravenous administration of synthetic oligodeoxynucleotides, which are exact copies of the DNA binding site of NF-kappaB (NF-kappaB decoy), given before the alloxan injection, effectively blocked pancreatic NF-kappaB activation in mice and subsequently prevented pancreatic cell death, restored insulin secretion, and abolished hyperglycemia. Injection of scrambled NF-kappaB decoy oligodeoxynucleotides to mice had no effect on alloxan-induced diabetic conditions, These results demonstrate that NF-kappaB activation in the pancreas is required for the induction of chemically induced diabetes by alloxan.