Evaluation of the insulin releasing and antihyperglycaemic activities of GPR55 lipid agonists using clonal beta-cells, isolated pancreatic islets and mice.

BACKGROUND AND PURPOSE: G-protein coupled receptor (GPR)55 is a novel lipid sensing receptor activated by both cannabinoid endogenous ligands (endocannabinoids) and other non-cannabinoid lipid transmitters. This study assessed the effects of various GPR55 agonists on glucose homeostasis.EXPERIMENTAL APPROACH: Insulin secretion and changes in intracellular Ca2+ and cAMP in response to glucose and a range of GPR55 agonists (endogenous ligands (OEA, PEA), chemically synthetic CBD analogues (Abn-CBD, 0-1602), an analogue of rimonabant (AM-251) and antagonist (CBD)) were investigated in clonal BRIN-BD11 cells and mouse pancreatic islets. Cytotoxicity was assessed by LDH release, cellular localisation by double-staining immunohistochemistry and in vivo effects assessed in mice.KEY RESULTS: The most potent and selective GPR55 agonist was the synthetic CBD analogue, Abn-CBD (pEC50 10.33), maximum stimulation of 67% at 10-4 mol/l (p