Repaglinide, a carbamoylmethyl benzoic acid (CMBA) derivative, belongs to a new class of antidiabetic agents structurally related to meglitinide (previously known as the non-sulphonylurea moiety of glibenclamide). Repaglinide and glibenclamide exert reciprocal competitive effects on their respective binding to insulinoma cells. Repaglinide does not affect the metabolism of D-glucose or endogenous nutrients or the biosynthesis of peptides in isolated rat pancreatic islets. Repeated intragastric administration of repaglinide to normal rats increases basal and glucose-stimulated peptide biosynthesis in isolated islets. The major primary action of repaglinide in islets is the closure of ATP-sensitive K+ channels. This agent decreases 86Rb outflow from prelabelled islets perifused in the absence of any exogenous nutrient and protects beta-cells against the inhibitory action of a diazoxide analogue on glucose-stimulated insulin release. The decrease in K+ conductance coincides with stimulation of Ca2+ influx into the islet cells. Meglitinide and its analogues stimulate insulin release more efficiently in the presence of D-glucose or other nutrient secretagogues than in their absence. They are efficient insulinotropic agents in animal models of Type 2 diabetes or in animals infused for 48 h with a hypertonic solution of D-glucose. Repaglinide augments somatostatin secretion, without affecting glucagon release, in isolated perfused rat pancreases exposed to D-glucose. The insulinotropic action of repaglinide was documented in vivo after intravenous or oral administration in normal or Goto-Kakizaki rats. These preclinical investigations suggest that these new insulin secretagogues are well suited as potential insulinotropic tools in the treatment of Type 2 diabetes.