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

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


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.

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Aminopyridines / pharmacology*
  • Aminopyridines / therapeutic use
  • Animals
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Experimental / drug therapy
  • Diabetes Mellitus, Experimental / metabolism
  • Enzyme Activation / drug effects
  • Enzyme Activators / pharmacology*
  • Enzyme Activators / therapeutic use
  • Female
  • Glucose / metabolism*
  • Hypoglycemic Agents / pharmacology*
  • Hypoglycemic Agents / therapeutic use
  • Indoles / pharmacology*
  • Indoles / therapeutic use
  • Liver / drug effects
  • Liver / metabolism
  • Macaca fascicularis
  • Male
  • Mice, Inbred C57BL
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism


  • Aminopyridines
  • Blood Glucose
  • Enzyme Activators
  • Hypoglycemic Agents
  • Indoles
  • PF-249
  • AMP-Activated Protein Kinases
  • Glucose