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

• Published in: British journal of pharmacology Vol. 170; no. 5; pp. 978 - 990
• Main Authors: McKillop, A M, Moran, B M, Abdel‐Wahab, Y H A, Flatt, P R
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.11.2013; Blackwell publishing Ltd
• Subjects: Animals; Blood Glucose - drug effects; Blood Glucose - metabolism; BRIN‐BD11 cells; Calcium - metabolism; Cannabidiol - analogs & derivatives; Cannabidiol - pharmacology; Cell Line; Clone Cells; Cyclic AMP - metabolism; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - physiopathology; Dose-Response Relationship, Drug; Ethanolamines - pharmacology; glucose tolerance; GPR55; Hypoglycemic Agents - pharmacology; Hypoglycemic Agents - toxicity; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Islets of Langerhans - drug effects; Islets of Langerhans - metabolism; isolated islets; lipid agonists; Mice; Oleic Acids - pharmacology; Palmitic Acids - pharmacology; Piperidines - pharmacology; Pyrazoles - pharmacology; Rats; Receptors, Cannabinoid - drug effects; Receptors, Cannabinoid - metabolism; Receptors, G-Protein-Coupled - agonists; Receptors, G-Protein-Coupled - metabolism; Research Papers; Resorcinols - pharmacology; Time Factors; isolated islets; BRIN-BD11 cells; insulin secretion; glucose tolerance; GPR55; lipid agonists
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.12356

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 cannabidiol (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 localization 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−1 (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. Conclusion 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 agonizing the GPR55 receptor may have therapeutic potential in the treatment of type 2 diabetes.