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-nitr ic oxide cycle in the response of adult human and rat pancreatic islet s to cytokines. Citrulline (0.1-1.0 mM) or arginine (0.1-1.0 mM) led t o a similar dose dependent nitric oxide (NO) production by rat islets exposed to interleukin 1 beta (IL-1 beta) or human islets exposed to I L-1 beta + tumour necrosis factor alpha (TNF-alpha) + interferon gamma (IFN-gamma). In the absence of citrulline or arginine cytokines faile d to induce NO production, Cytokines induced argininosuccinate synthet ase activity in both species, Studies of IL-1 beta exposed Pat islets revealed both NO-dependent and NO-independent effects: (1) IL-1 beta i nhibits glucose-induced insulin release even in the absence of NO synt hesis, but this inhibition is more severe when the presence of citrull ine or arginine enables NO production; (2) NO formation in the presenc e of arginine or citrulline is necessary for cytokine-induced inhibiti on of protein biosynthesis. In conclusion, the citrulline-NO cycle ena bles rodent and human islet of Langerhans to regenerate arginine from citrulline and maintain NO production, thus contributing to islet func tional inhibition, Considering that arginine availability may be limit ing for NO production in vivo, the citrulline-NO cycle mag be importan t for the regulation of NO production during insulitis in early insuli n-dependent diabetes mellitus. (C) 1996 Academic Press Limited