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 mu;M), S 21403, like classical sulphonylurea, induced insulin release in the absence of glucose. In contrast, at therapeutic (0.1-1.0 μM) 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 first-phase response. 4 The effect of S 21403 was strongly modulated by physiological factors. Thus, 0.1 μM 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 μM 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 β-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. © 2005 Nature Publishing Group All rights reserved.