title: Evaluation of the insulin-releasing and glucose-lowering effects of GPR120 activation in pancreatic β-cells.
abstract: OBJECTIVE
  To assess the potency and selectivity of various GPR120 agonists and to determine the cellular localization of GPR120 in clonal β-cells and pancreatic islets.
  
  
  METHODS
  Insulin secretion and alterations in intracellular Ca(2+) and cAMP response to glucose and GPR120 agonists, including endogenous agonists α-linolenic acid (ALA), docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and a synthetic analogue (GW-9508), were examined using clonal pancreatic BRIN-BD11 cells, mouse pancreatic islets and in vivo studies using NIH Swiss mice. Cytotoxicity was assessed by lactate dehydrogenase release. Cellular localization of GPR120 was explored by double-staining immunohistochemistry.
  
  
  RESULTS
  The most potent and selective GPR120 agonist tested was ALA (half maximum effective concentration 1.2 × 10(-8) mol/l) with a maximum stimulation of insulin secretion of 53% at 10(-4) mol/l (p < 0.001) in BRIN-BD11 cells. Stimulation of insulin secretion was also observed with GW-9508 (6.4 × 10(-8) mol/l; 47%), EPA (7.9 × 10(-8) mol/l; 36%) and DHA (1.0 × 10(-7) mol/l; 50%). Results were corroborated by islet studies, with no evidence of cytotoxic effects. Dose-dependent insulin secretion by GPR120 agonists was glucose-sensitive and accompanied by significant elevations of intracellular Ca(2+) and cAMP. Immunocytochemistry showed GPR120 expression on BRIN-BD11 cells and was confined to islet β-cells with no distribution on α-cells. Administration of GPR120 agonists (0.1 µmol/kg body weight) in glucose tolerance studies significantly reduced plasma glucose and augmented insulin release in mice.
  
  
  CONCLUSIONS
  These results indicate that GPR120 is expressed on pancreatic β-cells and that agonists at this receptor are potent insulin secretagogues with therapeutic potential for type 2 diabetes.
authors.affiliation: Biomedical Sciences Research Institute, SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, UK.
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
authors.forename: A M
authors.initials: AM
authors.lastname: McKillop
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D004281:Docosahexaenoic Acids / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015118:Eicosapentaenoic Acid / Q000378:metabolism; D005260:Female; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D017962:alpha-Linolenic Acid / Q000378:metabolism
chemical_list: D001786:Blood Glucose; C498007:FFAR4 protein, mouse; D007004:Hypoglycemic Agents; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; D017962:alpha-Linolenic Acid; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid; D000242:Cyclic AMP
keywords: GPR120; insulin secretion; lipid agonists; type 2 diabetes; β-cells