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 ²⁺ ] _i, 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 ²⁺ ] _i in human islets and islets from both GPR55 ^+/+ and GPR55 ^-/- mice. LH-21 also increased insulin secretion and [Ca ²⁺ ] _i 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.
(© 2017 John Wiley & Sons Ltd.)