NICOTINAMIDE DECREASES NITRIC-OXIDE PRODUCTION AND PARTIALLY PROTECTSHUMAN PANCREATIC-ISLETS AGAINST THE SUPPRESSIVE EFFECTS OF COMBINATIONS OF CYTOKINES

It has been recently reported that human pancreatic islets in tissue c ulture produce nitric oxide (NO) and show a decreased function when ex posed for 6 days to combinations of cytokines (interleukin-1 beta (IL- 1 beta)+ tumor necrosis factor-alpha (TNF-alpha)+ interferon-gamma (IF N-gamma). Here we study the effects of nicotinamide (Nic; 10 or 20 mmo l/l) on these deleterious effects of cytokines (50 U/ml IL-1 beta + 10 00 U/ml TNF-alpha+ 1000 U/ml IFN-gamma). Islets were isolated from 8 h uman pancreata at the Central Unit of the P-cell Transplant, Brussels, sent to Uppsala and, after 3-5 days in culture, exposed for 6 additio nal days to the cytokines and/or Nic. The cytokines induced a 6-fold i ncrease in islet NO production (P < 0.001), and this effect was partia lly counteracted by Nic (50-60% decrease in NO production; P < 0.001). The cytokines severely decreased the islet insulin content and glucos e-induced insulin release (16.7 mmol/l glucose; 90% decrease; P < 0.00 1). Both these effects of cytokines were partially counteracted by Nic , especially at the highest concentration (20 mmol/l; 2-4-fold increas e compared to islets exposed to cytokines alone; P < 0.01). Nic by its elf did not affect the insulin content or insulin release by control i slets. In conclusion, the present data indicate that Nic counteracts t he deleterious effects of cytokines on human pancreatic islets. This e ffect of Nic may be relevant for the beneficial effects of the drug in early IDDM.