Characterization of the action of S 21403 (mitiglinide) on insulin secretion and biosynthesis in normal and diabetic β‐cells

Abstract

1 S 21403 (mitiglinide) is a new drug for type 2 diabetes mellitus (T2DM). Its action on insulin release and biosynthesis was investigated in several experimental systems utilizing pancreas from normal and T2DM animals. 2 At high concentrations (10 mM), S 21403, like classical sulphonylurea, induced insulin release in the absence of glucose. In contrast, at therapeutic (0.1-1.0 mM) concentrations, S 21403 amplified insulin secretion glucose dose-dependently and with similar magnitude in normal and diabetic GK rat islets. 3 In perfused GK rat pancreas, S 21403 induced normal kinetics of insulin secretion including firstphase response. 4 The effect of S 21403 was strongly modulated by physiological factors. Thus, 0.1 mM adrenaline inhibited S 21403-induced insulin release. There was marked synergism between S 21403 and arginine in GK rat islets, combination of the two normalizing insulin secretion. 5 In primary islet cultures from normal rats or prediabetic Psammomys obesus, prolonged exposure to S 21403 did not induce further depletion of insulin stores under normal or 'glucotoxic' conditions. 6 Proinsulin biosynthesis was not affected by 2-h exposure of rat or prediabetic P. obesus islets to 1 mM S 21403. Yet, 24-h exposure of rat islets to S 21403 resulted in 30% increase in proinsulin biosynthesis at 8.3 mM glucose. 7 Amplification by S 21403 of glucose-induced insulin secretion in diabetic GK b-cells with restoration of first-phase response, a strong synergistic interaction with arginine and marked inhibition by adrenaline, make it a prime candidate for successful oral antidiabetic agent.

Pharmacogenomic analysis of ATP-sensitive potassium channels coexpressing the common type 2 diabetes risk variants E23K and S1369A

“…The concentration range over which we observed significant differences in sulfonylurea/glinide potencies are similar to the plasma concentrations observed in clinical practice for type 2 diabetes [33][34][35][36][37][38]. It has been suggested that sulfonylureas administered at higher doses are the therapy of choice for patients with neonatal diabetes caused by the most pronounced activating mutations in KCNJ11 and ABCC8 genes [39].…”

Postprandial hyperglycemia and endothelial function in type 2 diabetes: focus on mitiglinide

“…Mitiglinide, an insulinotropic sulfonylurea (SU) receptor ligand, is a benzylsuccinic acid derivative developed in Japan. It is an insulin secretagogue that acts on pancreatic β-cells, and unlike other SU agents, it has rapid action and short action time [ 73 - 77 ]. Its preprandial administration controls postprandial hyperglycemia and improves overall glycemic control [ 78 ].…”