LH-21 and abnormal cannabidiol improve β-cell function in isolated human and mouse islets through GPR55-dependent and -independent signalling.

AIMS

To examine the effects of Abn-CBD (GPR55 agonist) and LH-21 (CB1 antagonist) on human and mouse islet function, and to determine signalling via GPR55 using islets from GPR55 mice.

MATERIALS AND METHODS

Islets isolated from human organ donors and mice were incubated in the absence or presence of Abn-CBD or LH-21, and insulin secretion, [Ca ] cAMP apoptosis, β-cell proliferation and CREB and AKT phosphorylation were examined using standard techniques.

RESULTS

Abn-CBD potentiated glucose-stimulated insulin secretion and elevated [Ca ] in human islets and islets from both GPR55 and GPR55 mice. LH-21 also increased insulin secretion and [Ca ] in human islets and GPR55 mouse islets, but concentrations of LH-21 up to 0.1 μM were ineffective in islets from GPR55 mice. Neither ligand affected basal insulin secretion or islet cAMP levels. Abn-CBD and LH-21 reduced cytokine-induced apoptosis in human islets and GPR55 mouse islets, and these effects were suppressed after GPR55 deletion. They also increased β-cell proliferation: the effects of Abn-CBD were preserved in islets from GPR55 mice, while those of LH-21 were abolished. Abn-CBD and LH-21 increased AKT phosphorylation in mouse and human islets.

CONCLUSIONS

This study showed that Abn-CBD and LH-21 improve human and mouse islet β-cell function and viability. Use of islets from GPR55 mice suggests that designation of Abn-CBD and LH-21 as a GPR55 agonist and a CB1 antagonist, should be revised.