Efficacy of 1400 W, a novel inhibitor of inducible nitric oxide synthase, in preventing interleukin-1b-induced suppression of pancreatic islet function in vitro and multiple low-dose streptozotocin-induced diabetes in vivo

Objective: Nitric oxide (NO), generated by inducible nitric oxide synthase (iNOS), has been implicated in b-cell destruction in type 1 diabetes. In the present study, we tested a highly selective iNOS inhibitor, 1400 W, against interleukin-1b (IL-1b) induced suppression of rat pancreatic islets, and investigated whether 1400 W could prevent multiple low-dose streptozotocin (MLDS) induced diabetes in mice. Furthermore, we studied if 1400 W affected lipopolysaccharide (LPS) induced increase in plasma nitrite þ nitrate (NOx) in mice. Design and methods: Precultured rat pancreatic islets were exposed for 48 h to 0, 1, 10 or 50mmol/l 1400 W in the presence or absence of 25 U/ml IL-1b, whereupon islet functions were analyzed. MLDS-treated mice were given 5.9 mg/kg body weight of 1400 W intraperitoneally daily or 14 mg/kg body weight twice a day. Blood glucose was monitored and degree of pancreatic mononuclear infiltration was determined. Mice previously injected intraperitoneally with LPS (500mg) were given 1400 W (14 mg/kg body weight) intraperitoneally and plasma NOx was determined after 3, 6 and 10 h. Results: The inhibitor alone did not affect islet functions. 1400 W (50mmol/l) fully counteracted both the suppression of glucose oxidation rate, (pro)insulin biosynthesis and nitrite accumulation caused by IL-1b. Cytokine-induced decrease in medium insulin accumulation and glucose-stimulated insulin release was partly counteracted by 1400 W, suggesting that inhibition of insulin release was partially NO independent. LPS-induced increase in plasma NOx was markedly inhibited for up to 10 h after 1400 W administration. Irrespective of 1400 W treatment, animals treated with MLDS developed hyperglycemia and pancreatic insulitis. Conclusions: 1400 W counteracted IL-1b-induced suppression of rat islets in vitro and LPS induction of NOx in vivo, however, it failed to protect against MLDS diabetes in vivo. The latter might be due to a failure by 1400 W in vivo to inhibit NO formation at the level of the pancreatic islet. European Journal of Endocrinology 147 543–551