Role of the citrulline-nitric oxide cycle in the functional response of adult human and rodent pancreatic islets to cytokines.

The present study aims to characterize the role of the citrulline-nitric oxide cycle in the response of adult human and rat pancreatic islets to cytokines. Citrulline (0.1-1.0 mM) or arginine (0.1-1.0 mM) led to a similar dose dependent nitric oxide (NO) production by rat islets exposed to interleukin 1 beta (IL-1 beta) or human islets exposed to IL-1 beta + tumour necrosis factor alpha (TNF-alpha) + interferon gamma (IFN-gamma). In the absence of citrulline or arginine cytokines failed to induce NO production. Cytokines induced argininosuccinate synthetase activity in both species. Studies of IL-1 beta exposed rat islets revealed both NO-dependent and NO-independent effects: (1) IL-1 beta inhibits glucose-induced insulin release even in the absence of NO synthesis, but this inhibition is more severe when the presence of citrulline or arginine enables NO production; (2) NO formation in the presence of arginine or citrulline is necessary for cytokine-induced inhibition of protein biosynthesis. In conclusion, the citrulline-NO cycle enables rodent and human islet of Langerhans to regenerate arginine from citrulline and maintain NO production, thus contributing to islet functional inhibition. Considering that arginine availability may be limiting for NO production in vivo, the citrulline-NO cycle may be important for the regulation of NO production during insulitis in early insulin-dependent diabetes mellitus.