Glucose-stimulated insulin secretion (GSIS) is essential for the control of metabolic fuel homeostasis and its impairment is a key element in the failure of beta-cells in type 2 diabetes. Trans-caryophyllene (TC), an important constituent of the essential oil of several species of plants, has been reported to activate the type 2 cannabinoid receptor (CB2R). The effects of TC on GSIS are still unknown. Our results demonstrate that administration of TC in MIN6 cells promotes GSIS in a dose dependent manner. However, inhibition of CB2R by a specific inhibitor or specific RNA interference abolished the effects of TC on GSIS, which suggests that the effects of TC on GSIS are dependent on activation of CB2R. Further study demonstrated that treatment with TC leads to the activation of small G protein Arf6 as well as Rac1 and Cdc42. Importantly, Arf6 silencing abolished the effects of TC on GSIS, which suggests that Arf6 participates in mediating the effects of TC on GSIS. We conclude from these data that TC has a novel role in regulating GSIS in pancreatic beta-cells. 0 2014 Elsevier Inc. All rights reserved.