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 β-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 β-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 β-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 β-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 ageneralized enhancement of β-cell function and through fasting restricted changesin glucose turnover.
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