title: Evaluation of the insulin releasing and antihyperglycaemic activities of GPR55 lipid agonists using clonal beta-cells, isolated pancreatic islets and mice.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Insulin secretion and changes in intracellular Ca(2) (+) 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.
  
  
  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 [Ca(2) (+) ]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
  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.
authors.affiliation: Biomedical Sciences Research Institute, SAAD Centre for Pharmacy & Diabetes, University of Ulster, Cromore Road, Coleraine, BT52 1SA, Northern Ireland.
authors.forename: A M
authors.initials: AM
authors.lastname: McKillop
authors.forename: B M
authors.initials: BM
authors.lastname: Moran
authors.forename: Y H A
authors.initials: YH
authors.lastname: Abdel-Wahab
authors.forename: P R
authors.initials: PR
authors.lastname: Flatt
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002185:Cannabidiol / Q000031:analogs & derivatives / Q000494:pharmacology; D002460:Cell Line; D002999:Clone Cells; D000242:Cyclic AMP / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004983:Ethanolamines / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000633:toxicity; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D009829:Oleic Acids / Q000494:pharmacology; D010169:Palmitic Acids / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D043882:Receptors, Cannabinoid / Q000187:drug effects* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D012118:Resorcinols / Q000494:pharmacology; D013997:Time Factors
chemical_list: C479832:4-(3-3,4-p-menthadien-(1,8)-yl)olivetol; D001786:Blood Glucose; D004983:Ethanolamines; C526692:GPR55 protein, mouse; C568825:GPR55 protein, rat; D007004:Hypoglycemic Agents; D007328:Insulin; D009829:Oleic Acids; C440229:Oleylethanolamide; D010169:Palmitic Acids; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D043562:Receptors, G-Protein-Coupled; D012118:Resorcinols; D002185:Cannabidiol; C568537:O-1602 compound; C103505:AM 251; D000242:Cyclic AMP; D002118:Calcium
keywords: BRIN-BD11 cells; GPR55; glucose tolerance; insulin secretion; isolated islets; lipid agonists