title: 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.
abstract: BACKGROUND
  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.
  
  
  METHODS
  This was a phase Ib randomized, double-blind, placebo-controlled crossover trial of two (25 and 100 mg) doses of piragliatin.
  
  
  METHODS
  This study was conducted at a clinical research center.
  
  
  METHODS
  Patients included 15 volunteer ambulatory patients with mild type 2 diabetes.
  
  
  METHODS
  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.
  
  
  METHODS
  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 a generalized enhancement of β-cell function and through fasting restricted changes in glucose turnover.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of Verona School of Medicine, Verona, Italy. riccardo.bonadonna@tiscali.it
authors.forename: Riccardo C
authors.initials: RC
authors.lastname: Bonadonna
authors.forename: Tim
authors.initials: T
authors.lastname: Heise
authors.forename: Christophe
authors.initials: C
authors.lastname: Arbet-Engels
authors.forename: Christoph
authors.initials: C
authors.lastname: Kapitza
authors.forename: Angelo
authors.initials: A
authors.lastname: Avogaro
authors.forename: Joe
authors.initials: J
authors.lastname: Grimsby
authors.forename: Jay
authors.initials: J
authors.lastname: Zhi
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Grippo
authors.forename: Raffaella
authors.initials: R
authors.lastname: Balena
mesh_terms: D000704:Analysis of Variance; D044482:Benzeneacetamides / Q000494:pharmacology*; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D002096:C-Peptide / Q000097:blood; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005941:Glucokinase / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000187:drug effects
chemical_list: D044482:Benzeneacetamides; D001786:Blood Glucose; D002096:C-Peptide; D007004:Hypoglycemic Agents; D007328:Insulin; C553963:piragliatin; D005941:Glucokinase