INTERLEUKIN 1βINCREASES ARGININE ACCUMULATION AND ACTIVATES THE CITRULLINE–NO CYCLE IN RAT PANCREATICβCELLS

Abstract

Nitric oxide (NO) may contribute to pancreatic β cell damage during the development of type 1 diabetes. Its 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 converted into citrulline and NO. Cellular NO formation may be regulated by the availability of arginine. Arginine can be provided extracellularly, entering the cell mainly through the cationic amino acid transporter system y+CAT, and intracellularly, by protein degradation or synthesis from citrulline (the citrulline–NO cycle). This study demonstrates for the first time that the citrulline–NO cycle is induced in FACS-purified rat βcells exposed to interleukin-1β(IL-1β) and that extracellular arginine or citrulline is required for NO production byβcells. Moreover, the accumulation of arginine was higher in IL-1β-treatedβcells than in control cells.β cells expressed mRNAs for the two y+CAT transporters CAT-2A and CAT-2B with no change in transporter expression after exposure to IL-1β. It is concluded that the activation of the citrulline–NO cycle and an increase in arginine accumulation may be adaptive responses in cytokine-exposed β-cells to assure an adequate arginine supply for continuous NO production in the presence of low extracellular arginine levels which may prevail during insulitis.