A novel protein tyrosine phosphatase 1 B inhibitor-geranylated flavonoid from mulberry leaves ameliorates insulin resistance

Mulberry leaf is a common vegetable with a variety of beneficial effects, such as hypoglycemic activity. However, the underlying mechanism of its hypoglycemic effect have not been fully revealed. In this study, two flavonoid derivatives were isolated from mulberry leaves, a new geranylated flavonoid compound (1) and its structural analogue (2). The structure of 1 and 2 were elucidated using spectroscopic analysis. To study the potential hypoglycemic properties of these compounds, their regulatory effects on protein tyrosine phosphatase 1B (PTP1B) were investigated. Compared with oleanolic acid, compounds 1 and 2 showed significant inhibitory activities (IC50 = 4.53 ± 0.31 and 10.53 ± 1.76 μM) against PTP1B, the positive control (IC50 = 7.94 ± 0.76 µM). Molecular docking predicted the binding sites of 1 to PTP1B. In insulin-resistance HepG2 cell, 1 promoted glucose consumption in a dose-dependent manner. Furthermore, western blot and PCR analyses indicated that 1 might regulate glucose consumption through the PTP1B/IRS/PI3K/AKT pathway. In conclusion, geranylated flavonoids in mulberry leaves inhibite PTP1B and increase the glucose consumption in insulin-resistant cells. These findings provide an important basis for the use of mulberry leaf flavonoids as dietary supplement to regulate glucose metabolism.