Regulation of GLUT4 activity in myotubes by 3-O-methyl-d-glucose

Biochim Biophys Acta Biomembr. 2017 Oct;1859(10):1900-1910. doi: 10.1016/j.bbamem.2017.06.013. Epub 2017 Jun 23.


The rate of glucose influx to skeletal muscles is determined primarily by the number of functional units of glucose transporter-4 (GLUT4) in the myotube plasma membrane. The abundance of GLUT4 in the plasma membrane is tightly regulated by insulin or contractile activity, which employ distinct pathways to translocate GLUT4-rich vesicles from intracellular compartments. Various studies have indicated that GLUT4 intrinsic activity is also regulated by conformational changes and/or interactions with membrane components and intracellular proteins in the vicinity of the plasma membrane. Here we show that the non-metabolizable glucose analog 3-O-methyl-d-glucose (MeGlc) augmented the rate of hexose transport into myotubes by increasing GLUT4 intrinsic activity without altering the content of the transporter in the plasma membrane. This effect was not a consequence of ATP depletion or hyperosmolar stress and did not involve Akt/PKB or AMPK signal transduction pathways. MeGlc reduced the inhibitory potency (increased Ki) of indinavir, a selective inhibitor of GLUT4, in a dose-dependent manner. Kinetic analyses indicate that MeGlc induced changes in GLUT4 or GLUT4 complexes within the plasma membrane, which enhanced the hexose transport activity and reduced the potency of indinavir inhibition. Finally, we present a simple kinetic analysis for screening and discovering low molecular weight compounds that augment GLUT4 activity.

Keywords: Glucose transport; Glucose transporter type-4 (GLUT4); HIV-protease inhibitor; Intrinsic activity; Kinetics; Skeletal muscle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-O-Methylglucose / pharmacology*
  • Adenosine Triphosphate / metabolism
  • Animals
  • Biological Transport / drug effects
  • Biological Transport / physiology
  • Cell Line
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Glucose / metabolism
  • Glucose Transporter Type 4 / metabolism*
  • Insulin / metabolism
  • Kinetics
  • Mitogen-Activated Protein Kinases / metabolism
  • Muscle Contraction / drug effects
  • Muscle Contraction / physiology
  • Muscle Fibers, Skeletal / drug effects
  • Muscle Fibers, Skeletal / metabolism*
  • Muscle Proteins / metabolism
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Signal Transduction / drug effects
  • Signal Transduction / physiology


  • Glucose Transporter Type 4
  • Insulin
  • Muscle Proteins
  • Slc2a4 protein, rat
  • 3-O-Methylglucose
  • Adenosine Triphosphate
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases
  • Glucose