Tetrahydrobiopterin Synthesis Precedes Nitric Oxide-Dependent Inhibition of Insulin Secretion in INS-1 Rat Pancreatic β-Cells

Abstract

Interleukin 1 (IL-1) induces pancreatic β-cell dysfunction mainly due to overproduction of nitric oxide (NO). Since tetrahydrobiopterin (BH4) is a obligatory cofactor of NO synthases, we examined the temporal relationship of BH4synthesis, NO production and insulin secretion in a pancreatic β-cell line (INS-1) which was exposed to IL-1. IL-1 affected BH4synthesis in a time- and concentration-dependent manner. At a concentration of 10ng/ml IL-1 caused an increase in intracellular BH4with peak levels being observed at 6 hours followed by a steady decline in the cellular BH4content. The increase in BH4synthesis was followed by enhanced NO production and, consecutively, inhibition of insulin secretion. The concentration-dependent regulation of BH4synthesis, NO production and suppression of insulin secretion indicate a functional link between these parameters in pancreatic β-cells.