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

J Clin Endocrinol Metab. 2010 Nov;95(11):5028-36. doi: 10.1210/jc.2010-1041. Epub 2010 Aug 25.


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 a generalized enhancement of β-cell function and through fasting restricted changes in glucose turnover.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Benzeneacetamides / pharmacology*
  • Blood Glucose / drug effects*
  • Blood Glucose / metabolism
  • C-Peptide / blood
  • Cross-Over Studies
  • Diabetes Mellitus, Type 2 / metabolism*
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Glucokinase / metabolism*
  • Glucose Tolerance Test
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Insulin / blood
  • Insulin-Secreting Cells / drug effects


  • Benzeneacetamides
  • Blood Glucose
  • C-Peptide
  • Hypoglycemic Agents
  • Insulin
  • piragliatin
  • Glucokinase