Picrotoxane-type sesquiterpenoids from Dendrobium improve insulin resistance and increase glucose-stimulated insulin secretion

[Display omitted] •Rare 10, 11-γ-lactone ring picrotoxane-type sesquiterpenoid was isolated from D. wardianum.•The hypoglycemic activity of picrotoxane-type sesquiterpenoids was done for the first time.•The lactone ring at C-15 to C-3 is necessary in picrotoxane-type sesquiterpenoids for hypoglycemic activity. Twelve picrotoxane-type sesquiterpenoids were isolated from Dendrobium wardianum, of which dendrowardins K-N (1–4) are new compounds and dendrowardins O and P (9, 10) are new natural products. Notably, the structure of dendrowardin K contains the rarely observed 10,11-γ-lactone ring. The structural configurations of these compounds were determined through comprehensive 1D and 2D nuclear magnetic resonance (NMR), single-crystal X-ray diffraction, and other spectroscopic analyses. Additionally, the hypoglycaemic activities of the picrotoxane-type sesquiterpenes and their analogues were systematically evaluated by determining the antidiabetic activities of these compounds and six others (13–18) obtained from genus Dendrobium. Twelve compounds (1, 2, 4–6, 8, 12, 13 ∼ 15, 17, and 18) significantly improved insulin resistance. Further experiments revealed that compound 6 improved insulin resistance by increasing GLUT-4 expression, the possible mechanism is related to AKT-related pathways, and the effects of treatment with 50 μM compound 6 were comparable to those of the positive control drug metformin. Compounds 4–6 and 13–15, 17 displayed great increases in the secretion of insulin from β-TC-6 cells. On the basis of these findings, the structure–activity relationships (SARs) of picrotoxane-type sesquiterpenoids were discussed for the first time.