Piragliatin (RO4389620), a Novel Glucokinase Activator, Lowers Plasma Glucose Both in the Postabsorptive State and after a Glucose Challenge in Patients with Type 2 Diabetes Mellitus: A Mechanistic Study

Context: Glucokinase plays a key role in glucose homeostasis. Glucokinase activators can lower glucose levels in both animal and human type 2 diabetes, but their mechanism of action has never been explored in humans. Objective: The objective of the study was to investigate the effects of the glucokinase activator piragliatin (RO4389620) on beta-cell function and glucose fluxes in both fasting and fed (oral glucose tolerance test) states in patients with type 2 diabetes. Design: This was a phase Ib randomized, double-blind, placebo-controlled crossover trial of two(25 and 100 mg) doses of piragliatin. Setting: This study was conducted at a clinical research center. Patients: Patients included 15 volunteer ambulatory patients with mild type 2 diabetes. Interventions: Interventions included three 10-h (-300' to +300') studies, with an interval of at least 14 d. Administration of a single dose of placebo or piragliatin 25 mg or piragliatin 100 mg at -120'. Oral glucose tolerance test (at 0') with dual (iv and oral routes) tracer dilution technique was conducted. Main Outcome Measures: The primary measure was plasma glucose concentration. The secondary measure was model assessed beta-cell function and tracer-determined glucose fluxes. Results: Piragliatin caused a dose-dependent reduction of glucose levels in both fasting and fed states (P < 0.01). In the fasting state, piragliatin caused a dose-dependent increase in beta-cell function, a fall in endogenous glucose output, and a rise in glucose use (all P < 0.01). In the fed state, the primary effects of piragliatin were on beta cell function (P < 0.01). Conclusions: The glucokinase activator piragliatin has an acute glucose-lowering action in patients with mild type 2 diabetes, mainly mediated through a generalized enhancement of beta-cell function and through fasting restricted changes in glucose turnover. (J Clin Endocrinol Metab 95: 5028-5036, 2010)