Stimulation of glucose uptake by theasinensins through the AMP-activated protein kinase pathway in rat skeletal muscle cells

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Graphical abstractTheasinensins A and B promote GLUT4 translocation to plasma membrane in L6 myotubes through CaMKK/AMPK signaling pathway.Theasinensins, dimeric catechins, have been reported to possess anti-hyperglycemic activity, but the underlying mechanism for this activity remains unknown. In this study, the effect of theasinensins A and B on glucose uptake into rat skeletal muscle cells (L6 myotubes) was investigated. A glucose uptake study using 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose (2-NBDG) indicated that both theasinensins A and B stimulated glucose uptake in a concentration-dependent manner and translocation of glucose transporter 4 (GLUT4) to the plasma membrane. In addition, inhibition studies measuring 2-NBDG uptake in L6 cells revealed that compound C (AMP-activated protein kinase inhibitor) suppressed theasinensin-stimulated glucose uptake, whereas genistein (insulin receptor tyrosine kinase inhibitor) and wortmannin (phosphatidylinositol 3-kinase inhibitor) were inactive. Subsequent experiments on GLUT4-related signaling pathways in L6 cells demonstrated that theasinensins promoted the phosphorylation of AMPK, but not that of Akt, and that the theasinensin-promoted glucose uptake was blocked in the presence of a CaMKK inhibitor. The promotion of AMPK phosphorylation by theasinensins was not blocked in LKB1-knockdown cells. Consequently, it was concluded that theasinensins A and B did in fact promote GLUT4 translocation to the plasma membrane in L6 myotubes through the CaMKK/AMPK signaling pathway, but not through the PI3K/Akt pathway.

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