Acute and long-term effects of nateglinide on insulin secretory pathways

1. Acute and chronic effects of the insulinotropic drug nateglinide upon insulin release were examined in the BRIN-BD11 cell line. 2. Nateglinide (10-400 μM) stimulated a concentration-dependent increase (P<0.05-P<0.001) in insulin release at a non-stimulatory (1.1 mM) glucose concentration. The insulinotropic response to 200 μM nateglinide was increased at 30 mM (P<0.01), but not 5.6-16.7mM glucose concentrations. 3. In depolarized cells, nateglinide (50-200 μM) evoked K _ATP channel-independent insulin secretion (P<0.05-P<0.001) in the absence and presence of 5.6-30.0 mM glucose (P<0.001). 4. Exposure for 18h to 100 μM nateglinide abolished the acute insulinotropic effects of 200 μM nateglinide, tolbutamide or glibenclamide, but had no effect upon the insulinotropic effect of 200 μM efaroxan. 5. While 18 h exposure to 100 μM nateglinide did not affect basal insulin release or insulin release in the presence of 16.7 mM glucose, 25 μM forskolin or 10 nM PMA, significant inhibition of the insulinotropic effects of 20 mM leucine and 20 mM arginine were observed. 6. These data show that nateglinide stimulates both K _ATP channel-dependent and-independent insulin secretion. The maintained insulinotropic effects of this drug with increasing glucose concentrations support the antihyperglycaemic actions of nateglinide in Type II diabetes. 7. Studies of the long-term effects of nateglinide indicate that nateglinide shares signalling pathways with sulphonylureas, but not the imidazoline efaroxan. This may be significant when considering a nateglinide treatment regimen, particularly in patients previously treated with sulphonylurea.