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 AMPK-dependent. When muscle glycogen levels were 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.
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Research Article|
May 29 2014
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
Yu-Chiang Lai;
Yu-Chiang Lai
*Université catholique de Louvain and de Duve Institute, Avenue Hippocrate 75, bte B1.74.02, B-1200 Brussels, Belgium
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Samanta Kviklyte;
Samanta Kviklyte
*Université catholique de Louvain and de Duve Institute, Avenue Hippocrate 75, bte B1.74.02, B-1200 Brussels, Belgium
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Didier Vertommen;
Didier Vertommen
*Université catholique de Louvain and de Duve Institute, Avenue Hippocrate 75, bte B1.74.02, B-1200 Brussels, Belgium
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Louise Lantier;
Louise Lantier
†INSERM U1016, Institut Cochin, Paris, France
‡CNRS UMR8104, Paris, France
§Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France
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Marc Foretz;
Marc Foretz
†INSERM U1016, Institut Cochin, Paris, France
‡CNRS UMR8104, Paris, France
§Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France
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Benoît Viollet;
Benoît Viollet
†INSERM U1016, Institut Cochin, Paris, France
‡CNRS UMR8104, Paris, France
§Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France
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Stefan Hallén;
Stefan Hallén
1
∥AstraZeneca Research and Development, SE-431 83 Mölndal, Sweden
1Correspondence may be addressed to either of these authors, who made an equal contribution to this work (email [email protected] or [email protected]).
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Mark H. Rider
Mark H. Rider
1
*Université catholique de Louvain and de Duve Institute, Avenue Hippocrate 75, bte B1.74.02, B-1200 Brussels, Belgium
1Correspondence may be addressed to either of these authors, who made an equal contribution to this work (email [email protected] or [email protected]).
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Publisher: Portland Press Ltd
Received:
December 23 2013
Revision Received:
March 18 2014
Accepted:
March 25 2014
Accepted Manuscript online:
March 25 2014
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2014 Biochemical Society
2014
Biochem J (2014) 460 (3): 363–375.
Article history
Received:
December 23 2013
Revision Received:
March 18 2014
Accepted:
March 25 2014
Accepted Manuscript online:
March 25 2014
Citation
Yu-Chiang Lai, Samanta Kviklyte, Didier Vertommen, Louise Lantier, Marc Foretz, Benoît Viollet, Stefan Hallén, Mark H. Rider; 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. Biochem J 15 June 2014; 460 (3): 363–375. doi: https://doi.org/10.1042/BJ20131673
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