A small-molecule benzimidazole derivative that potently activates AMPK to increase glucose transport in skeletal muscle: Comparison with effects of contraction and other AMPK activators

Research output: Contribution to journalArticlepeer-review

Authors

  • Samanta Kviklyte
  • Didier Vertommen
  • Louise Lantier
  • Marc Foretz
  • Benoît Viollet
  • Stefan Hallén
  • Mark H. Rider

Colleges, School and Institutes

External organisations

  • Duve Institute
  • Institut Cochin
  • CNRS-CEA
  • Paris Descartes University
  • AstraZeneca

Abstract

AMPK(AMP-activated protein kinase) is an attractive therapeutic drug target for treating metabolic disorders. We studied the effects of an AMPK activator developed by Merck (ex229 from patent application WO2010036613), comparing chemical activation with contraction in intact incubated skeletal muscles. We also compared effects of ex229 with those of the Abbott A769662 compound and AICAR (5-amino-4- imidazolecarboxamide riboside). In rat epitrochlearis muscle, ex229 dose-dependently increased AMPK activity of α1-, α2-, β1- and β2-containing complexes with significant increases in AMPK activity seen at a concentration of 50 μM. At a concentration of 100 μM, AMPK activation was similar to that observed after contraction and importantly led to an ∼2- fold increase in glucose uptake. In AMPK α1-/α2- catalytic subunit double-knockout myotubes incubated with ex229, the increases in glucose uptake and ACC (acetyl-CoA carboxylase) phosphorylation seen in control cells were completely abolished, suggesting that the effects of the compound were AMPKdependent. Whenmuscle glycogen levelswere reduced by∼50% after starvation, ex229-induced AMPK activation and glucose uptake were amplified in a wortmannin-independent manner. In L6 myotubes incubated with ex229, fatty acid oxidation was increased. Furthermore, in mouse EDL (extensor digitorum longus) and soleus muscles, ex229 increased both AMPK activity and glucose uptake at least 2-fold. In summary, ex229 efficiently activated skeletal muscle AMPK and elicited metabolic effects in muscle appropriate for treating Type 2 diabetes by stimulating glucose uptake and increasing fatty acid oxidation.

Details

Original languageEnglish
Pages (from-to)363-375
Number of pages13
JournalBiochemical Journal
Volume460
Issue number3
Early online date29 May 2014
Publication statusPublished - 15 Jun 2014

Keywords

  • Acetyl-CoA carboxylase (ACC), AMP-activated protein kinase activator (AMPK activator), Fatty acid oxidation, Glycogen, Protein synthesis