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.
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.
Bonadonna
Riccardo C
RC
Division of Endocrinology and Metabolism, Department of Medicine, University of Verona School of Medicine, Verona, Italy. riccardo.bonadonna@tiscali.it
Heise
Tim
T
Arbet-Engels
Christophe
C
Kapitza
Christoph
C
Avogaro
Angelo
A
Grimsby
Joe
J
Zhi
Jay
J
Grippo
Joseph F
JF
Balena
Raffaella
R
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
D044482:Benzeneacetamides; D001786:Blood Glucose; D002096:C-Peptide; D007004:Hypoglycemic Agents; D007328:Insulin; C553963:piragliatin; D005941:Glucokinase