TETRAHYDROBIOPTERIN SYNTHESIS PRECEDES NITRIC OXIDE-DEPENDENT INHIBITION OF INSULIN-SECRETION IN INS-1 RAT PANCREATIC BETA-CELLS

Interleukin 1 (IL-1) induces pancreatic beta-cell dysfunction mainly d ue to overproduction of nitric oxide (NO). Since tetrahydrobiopterin ( BH4) is a obligatory cofactor of NO synthases, we exacted the temporal relationship of BH4 synthesis, NO production and insulin secretion in a pancreatic beta-cell line (INS-1) which was exposed to IL-1. IL-1 a ffected BH4 synthesis in a time- and concentration-dependent manner. A t a concentration of 10ng/ml IL-1 caused an increase in intracellular BH4 with peak levels being observed at 6 hours followed by a steady de cline in the cellular BH4 content. The increase in BH4 synthesis was f ollowed by enhanced NO production and, consecutively, inhibition of in sulin secretion. The concentration-dependent regulation of BH4 synthes is, NO production and suppression of insulin secretion indicate a func tional link between these parameters in pancreatic beta-cells. (C) 199 7 Academic Press.