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Diabetes Obes Metab. 2018 Apr;20(4):930-942. doi: 10.1111/dom.13180. Epub 2018 Jan 10.

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

Author information

1
Department of Diabetes, Faculty of Life Sciences and Medicine, King's College London, London, UK.
2
Blizard Institute, Barts and The London School of Medicine and Dentistry, London, UK.
3
Canceromics Laboratory, Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, Instituto de Biomedicina de Málaga (IBIMA), Universidad de Málaga, Malaga, Spain.
4
Unidad de Gestión Clínica Intercentros de Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Malaga, Spain.
5
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Malaga, Spain.

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

PMID:
29205751
DOI:
10.1111/dom.13180
[Indexed for MEDLINE]

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