Unique iridoids and lignans in Patrinia villosa improve insulin resistance of HepG2 cells

• Six unreported iridoids (1, 4, 7, 10, 11 - 12 ) and iridoid glycosides were isolated from P. villosa . • Two lignans ( 13, 15 ) could improve IR by increasing glucose uptake in IR- HepG-2 cells. • Two lignans ( 13, 15 ) activating the PI-3K/AKT, inhibiting the gluconeogenic pathway and activating the glycogen synthesis pathway to improve IR. Six unreported iridoids and iridoid glycosides: patrirscabioin P ( 1 ), patrirscabioin Q ( 4 ), 7- O - cis - p -coumaroylpatrinoside ( 7 ), patrinoside J ( 10 ), patrinoside K ( 11 ), and patrinoside I ( 12 ) together with 14 known compounds ( 2 - 3, 4 - 5, 8 - 9, 13 - 20 ) were isolated from Patrinia villosa . The hypoglycemic activity showed that compounds 3, 5, 13 , and 15 increased glucose uptakes in insulin-resistant (IR) HepG2 cells at 12.5, 25 and 50 μM. Compound 8 also increased glucose uptake of IR-HepG2 cells at 25 and 50 μM, but there was no significant activity at 12.5 μM. Besides, Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and western blot results showed that compounds 13 and 15 promoted the mRNA transcription of phosphatidylinositol 3 kinase (PI3K), protein kinase B (AKT) and glycogen synthase kinase 3β (GSK3β), and inhibited the mRNA transcription of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), promoted the expression of PI3K, p-AKT, glucose transporter type 4 (GLUT4), and p-GSK3β proteins, inhibited the expression of PEPCK and G6Pase proteins. Thus, compounds 13 and 15 improved IR by activating the PI3K/AKT signaling pathway, inhibiting the gluconeogenic pathway, and activating glycogen synthesis.