Mckillop, Aine, Moran, BM, Abdel-Wahab, Yasser and Flatt, Peter (2013) Evaluation of the insulin releasing and antihyperglycaemic activities of GPR55 lipid agonists using clonal beta-cells, isolated pancreatic islets and mice. British Journal of Pharmacology, 170 (5). pp. 978-990. [Journal article]
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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<0.001) in BRIN-BD11 cells. AM-251 (pEC50 7.0), OEA (pEC50 7.0), 0-1602 (pEC50 7.3) and PEA (pEC50 6.0) stimulated insulin secretion. Results were corroborated by islet studies, with no cytotoxic effects. Concentration-dependent insulin secretion by GPR55 agonists was glucose-sensitive and accompanied by elevations of [Ca2+ ]i (p<0.01-p<0.001) and cAMP (p<0.05-p<0.01). GPR55 agonists exhibited insulinotropic and glucose lowering activity in vivo. GPR55 was expressed on BRIN-BD11 cells and confined to islet beta cells with no distribution on alpha cells.CONCLUSIONS AND IMPLICATIONS: These results demonstrate GPR55 is distributed in pancreatic beta cells and is a strong activator of insulin secretion, with glucose-lowering effects in vivo. Development of agents agonising the GPR55 receptor may have therapeutic potential in the treatment of type 2 diabetes.
|Item Type:||Journal article|
|Faculties and Schools:||Faculty of Life and Health Sciences > School of Biomedical Sciences|
Faculty of Life and Health Sciences
|Research Institutes and Groups:||Biomedical Sciences Research Institute|
Biomedical Sciences Research Institute > Diabetes
|Deposited By:||Dr Nigel Irwin|
|Deposited On:||17 Sep 2013 11:34|
|Last Modified:||01 Nov 2013 12:24|
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