The expression meglitinide analogs was introduced in 1995 to cover new molecules proposed as non-sulfonylurea insulinotropic agents and displaying structural analogy with meglitinide, such as repaglinide, nateglinide, and mitiglinide. Meglitinide analogs display, as judged by conformation analysis, a U-shaped configuration similar to that of antihyperglycemic sulfonylureas such as glibenclamide (glyburide) and glimepiride. In rat pancreatic islets incubated in the presence of 7.0 mmol/L D-glucose, repaglinide and mitiglinide demonstrate comparable concentration-response relationships for stimulation of insulin release, with a threshold value < 10 nmol/L and a maximal secretory response at about 10 nmol/L. Several findings indicate that meglitinide analogs provoke the closing of adenosine triphosphate-sensitive potassium channels, with subsequent gating of voltage-sensitive calcium channels. The effects of meglitinide analogs upon the binding of [3H]glibenclamide to islet cells membranes reinforces this concept. At variance, however, with other meglitinide analogs, the ionic and secretory response to repaglinide (10 micromol/L) is not rapidly reversible in perifused rat islets. In experiments conducted in vivo in control and diabetic rats, repaglinide provokes a greater and more rapid increase in plasma insulin concentration and an earlier fall in glycemia than glibenclamide or glimepiride. Onset of effect is also more rapid and duration of effect shorter with nateglinide versus glibenclamide. In clinical studies, single or repeated daily administration of repaglinide increased plasma insulin concentration in a dose-dependent manner, with an incremental peak reached about 2 hours after repaglinide intake. Plasma concentrations of repaglinide are about 5.0 microg/L 2-2.5 hours after oral intake of the drug. Despite the slow reversibility of repaglinide action in vitro, this drug offers advantages over glibenclamide in terms of the possible occurrence of hypoglycemia if a meal is missed. In volunteers receiving a single oral dose of nateglinide (120mg) 10 minutes before a standardized 800 Kcal breakfast, the plasma insulin concentration was higher 5, 10, and 20 minutes after meal intake than when they received a single dose of repaglinide (0.5 or 2.0mg) or placebo 10 minutes before breakfast. Peak plasma concentrations of nateglinide were reached within 2 hours in most volunteers. Peak plasma concentrations of mitiglinide were reached 30 minutes after a single oral dose in a representative volunteer. Mitiglinide significantly suppressed meal-induced elevations in blood glucose concentrations in a study of patients with type 2 diabetes. In conclusion, two obvious differences among these meglitinide analogs should be underlined. First, on a molar basis, nateglinide is somewhat less potent than repaglinide or mitiglinide, as an insulinotropic agent. The maximal secretory responses evoked by these three meglitinide analogs are, however, identical to one another. Secondly, and as already mentioned, the functional effects of nateglinide and mitiglinide are more rapidly reversible than those of repaglinide, for instance in perifused rat islets. The meglitinide analogs offer the advantage over the long-acting antihyperglycemic sulfonylurea glibenclamide of minimizing the risk of undesirable hypoglycemia.