Geniposide acutely stimulates insulin secretion in pancreatic β-cells by regulating GLP-1 receptor/cAMP signaling and ion channels

• Geniposide regulates insulin secretion through GLP-1R and cAMP signaling pathway.
• Geniposide inhibits Kv channels by acting on the downstream of cAMP.
• Kv channels mediate geniposide-regulated insulin secretion.

Geniposide, an iridoid glycoside, has antidiabetic effects. The present study aimed to evaluate whether geniposide has direct effects on insulin secretion from rat pancreatic islets. The results demonstrated that geniposide potentiated insulin secretion via activating the glucagon-like-1 receptor (GLP-1R) as well as the adenylyl cyclase (AC)/cAMP signaling pathway. Inhibition of protein kinase A (PKA) suppressed the insulinotropic effect of geniposide. Geniposide also inhibited voltage-dependent potassium (Kv) channels, and this effect could be attenuated by inhibition of GLP-1R or PKA. Current-clamp recording showed that geniposide prolonged action potential duration. These results collectively imply that inhibition of Kv channels is linked to geniposide-potentiated insulin secretion by acting downstream of the GLP-1R/cAMP/PKA signaling pathway. Moreover, activation of Ca2+ channels by geniposide was observed, indicating that the Ca2+ channel is also an important player in the geniposide effects. Together, these findings provide new insight into the mechanism underlying geniposide-regulated insulin secretion.