Stimulation of insulin release by repaglinide and glibenclamide involves both common and distinct processes.

Abstract

The action of repaglinide, a novel insulin secretagogue, was compared with the sulfonylurea glibenclamide with regard to the hypoglycemic action in vivo, binding to betaTC-3 cells, insulin secretion from perifused mouse islets, and capacity to stimulate exocytosis by direct interaction with the secretory machinery in single voltage-clamped mouse beta-cells. Two binding sites were identified: a high-affinity repaglinide (KD = 3.6 nmol/l) site having lower affinity for glibenclamide (14.4 nmol/l) and one high-affinity glibenclamide (25 nmol/l) site having lower affinity for repaglinide (550 nmol/l). In contrast to glibenclamide, repaglinide (in concentrations as high as 5 micromol/l) lacked the ability to enhance exocytosis in voltage-clamped beta-cells. Repaglinide was more potent than glibenclamide in stimulating insulin release from perifused mouse islets (EC50 29 vs. 80 nmol/l). The greater potency of repaglinide in vitro was paralleled by similar actions in vivo. The ED50 values for the hypoglycemic action were determined to be 10.4 and 15.6 microg/kg after intravenous and oral administration, respectively. The corresponding values for glibenclamide were 70.3 microg/kg (intravenous) and 203.2 microg/kg (oral). Further, repaglinide (1 mg/kg p.o.) was effective (P < 0.001) as an insulin-releasing agent in a rat model (low-dose streptozotocin) of type 2 diabetes. These observations suggest that the insulinotropic actions of repaglinide and glibenclamide in vitro and in vivo are secondary to their binding to the high-affinity repaglinide site and that the insulinotropic action of repaglinide involves both distinct and common cellular mechanisms.

Small-molecule agonists for the glucagon-like peptide 1 receptor

“…Mouse islet isolation and assay were performed as previously described (46). In brief, the islets were isolated from adult CD1 wild-type mice or CD1 GLP-1 receptor knockout mice by collagenase digestion and kept in tissue culture overnight in 5 ml of RPMI medium 1640 supplemented with 10% newborn calf serum.…”

The importance of early insulin secretion and its impact on glycaemic regulation

“…In contrast to glibenclamide, repaglinide has been shown in vitro to have an insulin secretagogue action that is more completely dependent on the presence of glucose. 22,23 Thus, repaglinide enhances glucose-mediated insulin release, another property suited to its employment in prandial glucose regulation. Of greatest importance however, is the ®nding that repaglinide, but not glibenclamide, accelerates early insulin release, clearly establishing the potential for prandial regulation with repaglinide.…”

Review of prandial glucose regulation with repaglinide: a solution to the problem of hypoglycaemia in the treatment of Type 2 diabetes?

“…51,52 This ®nding implies that stimulated insulin secretion will not be curtailed during periods of hypoglycaemia. It also raises concerns about whether sulphonylureas have exocytotic actions in secretory cells of the endocrine system other than pancreatic beta-cells.…”

“…However, in contrast to the sulphonylureas, repaglinide does not stimulate insulin release independently of its effects on beta-cell potassium channels, and does not inhibit insulin biosynthesis. 51,52,64,65 Another pharmacological difference of potential clinical importance between repaglinide and the sulphonylureas is that repaglinide augments insulin release from pancreatic islets in vitro only in the presence of glucose. 51,66 Thus, repaglinide enhances glucosemediated insulin release, and hence may be less likely to cause hypoglycaemia.…”