Suppressive effects of glucagon-like pepticle-1 on interferon-γ-induced nitric oxide production in insulin-producing cells is mediated by inhibition of tumor necrosis factor-α production

During the development of Type 1 diabetes, inflammatory cytokines are known to induce the expression of inducible nitric oxide synthase (iNOS) in pancreatic islets, and subsequent production of nitric oxide (NO) contributes to P cell destruction. Glucagon-like peptide-1 (GLP-1) has been shown to reduce cytokine-incluced apoptosis of P cells. In this study, we investigated whether GLP-1 affects cytokine-incluced NO production, resulting in the inhibition of beta cell apoptosis. We treated MIN6N8a mouse P cells with interferon (IFN)-gamma in the presence or absence of GLP-1 and found that IFN-gamma treatment induced iNOS mRNA expression and NO production, which was significantly inhibited by treatment with GLP-1. Blocking of GLP-1 receptor signaling via the cyclic AMP and phosphatidylinositol 3-kinase pathway did not directly affect the suppressive effect of GLP-1 on IFN-gamma-induced iNOS mRNA expression. Further studies revealed that IFN-gamma induced the expression of TNF-alpha mRNA and protein, which synergistically induced NO production, and GLP-1 treatment inhibited this induction of TNF-a. To examine whether the reduction of TNF-alpha by GLP-1 treatment plays a role in suppressing NO production, we treated MIN6N8a cells with IFN-y in the presence of anti-TNF-alpha neutralizing antibody and found that NO production was reduced. In addition, treatment of mouse islets with GLP-1 inhibited the expression of iNOS and TNF-alpha mRNA. These results suggest that GLP-1 inhibits IFN-gamma-induced NO production by suppression of TNF-a production.