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

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 AKT S473 and S6K1 T389 but decreases S6 S235/236 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.