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

Diabetes Obes Metab. 2017 Dec 5. doi: 10.1111/dom.13180.
[Epub ahead of print]

Abstract

PM 2 site 207AIMS:

CB1 and GPR55 are GPCRs expressed by islet β-cells. Pharmacological compounds have been used to investigate their function, but off-target effects of ligands have been reported. This study examined the effects of Abn-CBD (GPR55 agonist) and LH-21 (CB1 antagonist) on human and mouse islet function, and islets from GPR55-/- mice were used to determine signalling via GPR55.

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 by 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 following 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 demonstrated 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 GPR55 agonist and CB1 antagonist, should be revised.

KEYWORDS:

cannabinoids; insulin secretion; islets; proliferation; β-cell function

PMID: 29205751

 

DOI: 10.1111/dom.13180
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