Quercetin-3-O--L-arabinopyranosyl-(12)--D-glucopyranoside Isolated from Eucommia ulmoides Leaf Relieves Insulin Resistance in HepG2 Cells via the IRS-1/PI3K/Akt/GSK-3 Pathway

For nearly 2000 years, Eucommia ulmoides Oliver (EUO) has been utilized in traditional Chinese medi-cine (TCM) throughout China. Flavonoids present in bark and leaves of EUO are responsible for their an-tioxidant, anti-inflammatory, antitumor, anti-osteoporosis, hypoglycemic, hypolipidemic, antibacterial, and antiviral properties, but the main bioactive compound has not been established yet. In this study, we isolated and identified quercetin glycoside (QAG) from EUO leaves (EUOL) and preliminarily explored its molecular mechanism in improving insulin resistance (IR). The results showed that QAG increased uptake of glucose as well as glycogen production in the palmitic acid (PA)-induced HepG2 cells in a dose-dependent way. Further, we observed that QAG increases glucose transporters 2 and 4 (GLUT2 and GLUT4) expression and sup-presses the phosphorylation of insulin receptor substrate (IRS)-1 at serine(612), thus promoting the expression of phosphatidylinositol-3-kinase (PI3K) at tyrosine458 and tyrosine(199,) as well as protein kinase B (Akt) and glycogen synthase kinase (GSK)-3 beta at serine(473) and serine(9), respectively. The influence posed by QAG on the improvement of uptake of glucose was significantly inhibited by LY294002, a PI3K inhibitor. In addition, the molecular docking result showed that QAG could bind to insulin receptors. In summary, our data established that QAG improved IR as demonstrated by the increased uptake of glucose and glycogen production through a signaling pathway called IRS-1/PI3K/Akt/GSK-3 beta.