Pancreatic beta-cell K-ATP channel activity and membrane-binding studies with nateglinide: A comparison with sulfonylureas and repaglinide

Nateglinide (A-4166) is an amino acid derivative with insulinotrophic actio n in clinical development for treatment of type 2 diabetes. The aim of this study was to determine whether nateglinide's interaction at the K-ATP chan nel/sulfonylurea receptor underlies its more rapid onset and shorter durati on of action in animal models. Binding studies were carried out with membra nes prepared from RIN-m5F cells and HEK-293 cells expressing recombinant hu man sulfonylurea receptor 1 (SUR1). The relative order for displacement of [H-3]glibenclamide in competitive binding experiments with RIN-m5F cell mem branes was glibenclamide > glimepiride > repaglinide > glipizide > nateglin ide > L-nateglinide > tolbutamide. The results with HEK-293/recombinant hum an SUR1 cells were similar with the exception that glipizide was more poten t than repaglinide. Neither nateglinide nor repaglinide had any effect on t he dissociation kinetics for [H-3]glibenclamide, consistent with both compo unds competitively binding to the glibenclamide-binding site on SUR1. Final ly, the inability to measure [H-3]nateglinide binding suggests that nategli nide dissociates rapidly from SUR1. Direct interaction of nateglinide with K-ATP channels in rat pancreatic beta-cells was investigated with the patch -clamp method. The relative potency for inhibition of the K-ATP channel was repaglinide. glibenclamide. nateglinide. Kinetics of the inhibitory effect on K-ATP current showed that the onset of inhibition by nateglinide was co mparable to glibenclamide but more rapid than that of repaglinide. The time for reversal of channel inhibition by nateglinide was also faster than wit h glibenclamide and repaglinide. These results suggest that the unique char acteristics of nateglinide are largely the result of its interaction at the K-ATP channel.