Effectiveness of Nateglinide on In Vitro Insulin Secretion from Rat Pancreatic Islets Desensitized to Sulfonylureas

Chronic exposure of pancreatic islets to sulfonylureas (SUs) is known to impair the ability of islets to respond to subsequent acute stimulation by SUs or glucose. Nateglinide (NAT) is a novel insulinotropic agent with a primarily site of action at beta-cell K(ATP) channels, which is common to the structurally diverse drugs like repaglinide (REP) and the SUs. Earlier studies on the kinetics, glucose-dependence and sensitivity to metabolic inhibitors of the interaction between NAT and K(ATP) channels suggested a distinct signaling pathways with NAT compared to REP, glyburide (GLY) or glimepiride (GLI). To obtain further evidence for this concept, the present study compared the insulin secretion in vitro from rat islets stimulated acutely by NAT, GLY, GLI or REP at equipotent concentrations during 1-hr static incubation following overnight treatment with GLY or tolbutamide (TOL). The islets fully retained the responsiveness to NAT stimulation after prolonged pretreatment with both SUs, while their acute response to REP, GLY, and GLI was markedly attenuated, confirming the desensitization of islets. The insulinotropic efficacy of NAT in islets desensitized to SUs may result from a distinct receptor/effector mechanism, which contributes to the unique pharmacological profile of NAT.