LH-21 and Abn-CBD 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, [Ca2+](i,) cAMP(,) apoptosis, beta-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 mu M 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 beta-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 beta-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.