Interleukin 1 beta increases arginine accumulation and activates the citrulline-NO cycle in rat pancreatic beta cells

Nitric oxide (NO) may contribute to pancreatic beta cell damage during the development of type 1 diabetes;lts formation can be triggered by cytokines which induce the expression of the inducible form of nitric oxide synthase (iNOS) in pancreatic islets, In the iNOS-catalyzed reaction, arginine is co nverted into citrulline and NO, Cellular NO formation may be regulated by t he availability of arginine, Arginine can be provided extracellularly, ente ring the cell mainly through the cationic amino acid transporter system y()CAT, and intracellularly, by protein degradation or synthesis from citrull ine (the citrulline-NO cycle). This study demonstrates for the first time t hat the citrulline-NO cycle is induced in FAGS-purified rat beta cells expo sed to interlenkin-1 beta (IL-1 beta) and that extracellular arginine or ci trulline is required for NO production by beta cells, Moreover, the accumul ation of arginine was higher in IL-1 beta-treated beta cells than in contro l cells, beta cells expressed mRNAs for the two y+CAT transporters CAT-2A a nd CAT-2B with no change in transporter expression after exposure to IL-1 b eta, It is concluded that the activation of the citrulline-NO cycle and an increase in arginine accumulation may be adaptive responses in cytokine-exp osed beta-cells to assure an adequate arginine supply for continuous NO pro duction in the presence of low extracellular arginine levels which may prev ail during insulitis. (C)1999 Academic Press.