Gingerenone A Sensitizes the Insulin Receptor and Increases Glucose Uptake by Inhibiting the Activity of p70 S6 Kinase

Mol Nutr Food Res. 2018 Dec;62(23):e1800709. doi: 10.1002/mnfr.201800709. Epub 2018 Oct 17.


Scope: The bioactive constituents in ginger extract are responsible for anti-hyperglycemic effects and the underlying mechanisms are incompletely understood. Gingerenone A (Gin A) has been identified as an inhibitor of p70 S6 (S6K1), a kinase that plays a critical role in the pathogenesis of insulin resistance. This study aims to evaluate if Gin A can sensitize the insulin receptor by inhibiting S6K1 activity.

Methods and results: Western blot analysis reveals that Gin A induces phosphatidylinositide-3 kinase (PI3K) feedback activation in murine 3T3-L1 adipocytes and rat L6 myotubes, as evidenced by increased AKTS473 and S6K1T389 but decreases S6S235/236 and insulin receptor substrate 1 (IRS-1)S1101 phosphorylation. Western blot and immunoprecipitation analysis reveal that Gin A increases insulin receptor tyrosine phosphorylation in L6 myotubes and IRS-1 binding to the PI3K in 3T3-L1 adipocytes. Confocal microscopy reveals that Gin A enhances insulin-induced translocation of glucose transporter 4 (GLUT4) into the cell membrane in L6 cells. 2-NBDG (2-N-(Nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose) Fluorescent assay reveals that Gin A enhances insulin-stimulated glucose uptake in 3T3-L1 adipocytes and L6 myotubes.

Conclusions: Gin A overcomes insulin resistance and increases glucose uptake by inhibiting S6K1 activity. Gin A or other plant-derived S6K1 inhibitors could be developed as novel antidiabetic agents.

Keywords: gingerenone A; glucose uptake; insulin receptors; insulin resistance; p70 S6 kinase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Animals
  • Diarylheptanoids / pharmacology*
  • Feedback, Physiological / drug effects
  • Glucose / metabolism*
  • Glucose Transporter Type 4 / metabolism
  • Hypoglycemic Agents / pharmacology
  • Insulin / pharmacology
  • Insulin Receptor Substrate Proteins / metabolism
  • Insulin Resistance
  • Mice
  • Muscle Fibers, Skeletal / drug effects
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Transport / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Receptor, Insulin / metabolism
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism*


  • Diarylheptanoids
  • Glucose Transporter Type 4
  • Hypoglycemic Agents
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, mouse
  • Slc2a4 protein, mouse
  • gingerenone A
  • Phosphatidylinositol 3-Kinases
  • Receptor, Insulin
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases, 70-kDa
  • Glucose