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Cell Metab. 2017 May 2;25(5):1147-1159.e10. doi: 10.1016/j.cmet.2017.04.010.

Activation of Skeletal Muscle AMPK Promotes Glucose Disposal and Glucose Lowering in Non-human Primates and Mice.

Author information

1
Cardiovascular, Metabolic, and Endocrine Diseases Research Unit, Pfizer Inc., Cambridge, MA 02139, USA.
2
Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen 1017, Denmark.
3
Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., Groton, CT 06340, USA.
4
Worldwide Medicinal Chemistry, Pfizer Worldwide Research & Development, Pfizer Inc., Groton, CT 06340, USA.
5
Drug Safety Research and Development, Pfizer Inc., Groton, CT 06340, USA.
6
Computational Sciences, Pfizer Inc., Cambridge, MA 02139, USA.
7
Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., Cambridge, MA 02139, USA.
8
Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., San Diego, CA 92121, USA.
9
INSERM, U1016, Institut Cochin, Paris 75014, France; CNRS, UMR8104, Paris 75016, France; Université Paris Descartes, Sorbonne Paris Cité, Paris 75006, France.
10
Cardiovascular, Metabolic, and Endocrine Diseases Medicinal Chemistry, Pfizer Inc., Cambridge, MA 02139, USA.
11
Cardiovascular, Metabolic, and Endocrine Diseases Research Unit, Pfizer Inc., Cambridge, MA 02139, USA. Electronic address: russell.miller@pfizer.com.

Abstract

The AMP-activated protein kinase (AMPK) is a potential therapeutic target for metabolic diseases based on its reported actions in the liver and skeletal muscle. We evaluated two distinct direct activators of AMPK: a non-selective activator of all AMPK complexes, PF-739, and an activator selective for AMPK β1-containing complexes, PF-249. In cells and animals, both compounds were effective at activating AMPK in hepatocytes, but only PF-739 was capable of activating AMPK in skeletal muscle. In diabetic mice, PF-739, but not PF-249, caused a rapid lowering of plasma glucose levels that was diminished in the absence of skeletal muscle, but not liver, AMPK heterotrimers and was the result of an increase in systemic glucose disposal with no impact on hepatic glucose production. Studies of PF-739 in cynomolgus monkeys confirmed translation of the glucose lowering and established activation of AMPK in skeletal muscle as a potential therapeutic approach to treat diabetic patients.

KEYWORDS:

AMPK; diabetes; glucose uptake; pharmacology

PMID:
28467931
DOI:
10.1016/j.cmet.2017.04.010
[Indexed for MEDLINE]
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