Depsidone and xanthones from Garcinia xanthochymus with hypoglycemic activity and the mechanism of promoting glucose uptake in L6 myotubes.

Garcinia xanthochymus is a widely used folk medicine in southwestern China. Previous studies indicated it possesses potential anti-diabetic activities both in vitro (Fu et al., 2014; Nguyen et al., 2017) and in vivo (Shivanand et al., 2017). To discover bioactive ingredients from it and unveil their mechanism of action against diabetes, the present study was designed to isolate constituents from extract of G. xanthochymus, determine their structures, screen their activities and investigate mechanism of action of the active substances. Twenty compounds including a new depsidone named garciniadepsidone A (20) and 19 known xanthones were obtained. All of them were screened to discover the active compounds with anti-diabetic activities. Finally, three xanthones including 12b-hydroxy-des-d-garcigerrin (5), 1,2,5,6-tretrahydroxy-4-(1,1-dimethyl-2-propenyl)-7-(3-methyl-2-butenyl) xanthone (13) and 1,5,6-trihydroxy-7,8-di(3-methyl-2-butenyl)-6',6'-dimethylpyrano (2',3':3,4) xanthone (18) were found to be able to significantly stimulate the glucose uptake in the skeleton muscle cells. The effects of the three compounds were comparable to those of insulin and metformin. Based on molecular mechanistic study, it was found that both of compound 5 and 13 promoted glucose uptake by activating phosphatidylinositol-3 kinase (PI3K)/the serine/threonine kinase protein kinase B (PKB/Akt) signaling pathway and AMP-activated protein kinase (AMPK) signaling pathway, resulting in the translocation of GLUT4 in L6 myotubes without affecting the expression of GLUT4. Compound 5 and 13 have great potential to be developed as promising leads to target diabetes.