Identification of the mechanism of action of a glucokinase activator from oral glucose tolerance test data in type 2 diabetic patients based on an integrated glucose-insulin model

J Clin Pharmacol. 2012 Dec;52(12):1861-71. doi: 10.1177/0091270011422231. Epub 2011 Dec 15.


A mechanistic drug-disease model was developed on the basis of a previously published integrated glucose-insulin model by Jauslin et al. A glucokinase activator was used as a test compound to evaluate the model's ability to identify a drug's mechanism of action and estimate its effects on glucose and insulin profiles following oral glucose tolerance tests. A kinetic-pharmacodynamic approach was chosen to describe the drug's pharmacodynamic effects in a dose-response-time model. Four possible mechanisms of action of antidiabetic drugs were evaluated, and the corresponding affected model parameters were identified: insulin secretion, glucose production, insulin effect on glucose elimination, and insulin-independent glucose elimination. Inclusion of drug effects in the model at these sites of action was first tested one-by-one and then in combination. The results demonstrate the ability of this model to identify the dual mechanism of action of a glucokinase activator and describe and predict its effects: Estimating a stimulating drug effect on insulin secretion and an inhibiting effect on glucose output resulted in a significantly better model fit than any other combination of effect sites. The model may be used for dose finding in early clinical drug development and for gaining more insight into a drug candidate's mechanism of action.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Cross-Over Studies
  • Diabetes Mellitus, Type 2 / metabolism*
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Female
  • Glucokinase / metabolism*
  • Glucose / metabolism*
  • Glucose Tolerance Test
  • Humans
  • Insulin / metabolism*
  • Male
  • Middle Aged
  • Models, Biological*


  • Insulin
  • Glucokinase
  • Glucose