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

Abstract

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, [Ca²⁺ ]_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 [Ca²⁺ ]_i in human islets and islets from both GPR55^+/+ and GPR55^-/- mice. LH-21 also increased insulin secretion and [Ca²⁺ ]_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.

Keywords: cannabinoids; insulin secretion; islets; proliferation; β-cell function.