Institute of Comparative Medicine, Yangzhou, 225009, Jiangsu Province, China.
College of Veterinary Medicine, Yangzhou, 225009, Jiangsu Province, China.
Mol Nutr Food Res. 2018 Dec;62(23):e1800709. doi: 10.1002/mnfr.201800709. Epub 2018 Oct 17.
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.
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 and S6K1 but decreases S6 and insulin receptor substrate 1 (IRS-1) 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.
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.
姜提取物中的生物活性成分是其具有降血糖作用的原因，但其作用机制尚不完全清楚。姜烯酮 A（Gin A）已被确定为 p70 S6（S6K1）的抑制剂，S6K1 在胰岛素抵抗的发病机制中起着关键作用。本研究旨在评估 Gin A 是否可以通过抑制 S6K1 活性来使胰岛素受体敏感。
Western blot 分析显示，Gin A 在鼠 3T3-L1 脂肪细胞和大鼠 L6 肌管中诱导磷脂酰肌醇-3 激酶（PI3K）反馈激活，这表现为 AKT 和 S6K1 的增加以及 S6 和胰岛素受体底物 1（IRS-1）的磷酸化减少。Western blot 和免疫沉淀分析显示，Gin A 增加了 L6 肌管中的胰岛素受体酪氨酸磷酸化和 3T3-L1 脂肪细胞中 IRS-1 与 PI3K 的结合。共聚焦显微镜显示，Gin A 增强了胰岛素诱导的 L6 细胞中葡萄糖转运蛋白 4（GLUT4）向细胞膜的易位。2-NBDG（2-N-（硝基苯-2-氧代-1,3-二唑-4-基）氨基-2-脱氧葡萄糖）荧光测定显示，Gin A 增强了 3T3-L1 脂肪细胞和 L6 肌管中胰岛素刺激的葡萄糖摄取。
Gin A 通过抑制 S6K1 活性克服胰岛素抵抗并增加葡萄糖摄取。Gin A 或其他植物来源的 S6K1 抑制剂可开发为新型抗糖尿病药物。
