Repaglinide preserves nutrient-stimulated biosynthetic activity in rat pancreatic islets

The meglitinide analogue repaglinide is a novel non-sulphonylurea insulinotropic agent which, like hypoglycaemic sulphonylureas, causes the closing of ATP-sensitive K+ channels in islet cells. We have now explored the effect of repaglinide upon proinsulin biosynthesis in rat pancreatic islets. Groups of eight islets each were incubated for 90 min in the presence of L-[4-(3)H]phenylalanine (4 microM) and glucose (2.8 or 16.7 mM), in the absence or presence of repaglinide (10 microM). A rise in glucose concentration caused a four-fold increase of the incorporation of L-[4-(3)H]phenylalanine into TCA-precipitable material. Repaglinide failed to adversely affect protein biosynthesis, whether at low or high glucose concentrations. Further characterization of the biosynthetic response was achieved by separation of the tritiated peptides by gel filtration. In the absence of repaglinide, the (pro)insulin/total ratio of tritiated peptides averaged 33.3 +/- 10.2 and 58.7 +/- 1.7% (n = 6 in both cases) at 2.8 and 16.7 mM D-glucose, respectively. Repaglinide again failed to significantly affect such ratios. In conclusion, repaglinide may offer the advantage over hypoglycaemic sulphonylureas of preserving nutrient-stimulated biosynthetic activity in pancreatic islet cells.