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.
Junhong Chen  1  2 ,  Jing Sun  1  2 ,  Richard A Prinz  3 ,  Yi Li  4 ,  Xiulong Xu  1  2  5  6
Affiliations
  • 1. Institute of Comparative Medicine, Yangzhou, 225009, Jiangsu Province, China.
  • 2. College of Veterinary Medicine, Yangzhou, 225009, Jiangsu Province, China.
  • 3. Department of Surgery, NorthShore University Health System, Evanston, IL, USA.
  • 4. Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.
  • 5. Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou University, Yangzhou, 225009, Jiangsu Province, China.
  • 6. Department of Cell and Molecular Medicine, Rush University Medical Center, Chicago, IL, 60612, USA.
PMID: 30296358 DOI: 10.1002/mnfr.201800709
Abstract

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.
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