title: GPR39 receptors and actions of trace metals on pancreatic beta cell function and glucose homoeostasis.
abstract: OBJECTIVE
  G-protein-coupled receptor 39 (GPR39) has been implicated in glucose homoeostasis, appetite control and gastrointestinal tract function.
  
  
  METHODS
  This study used clonal BRIN-BD11 cells and mouse pancreatic islets to assess the insulin-releasing actions of trace metals believed to act via GPR39, and the second messenger pathways involved in mediating their effects. Micromolar concentrations of Zn(2+), Cu(2+), Ni(2+) and Co(2+) were examined under normoglycaemic and hyperglycaemic conditions. Mechanistic studies investigated changes of intracellular Ca(2+), cAMP generation and assessment of cytotoxicity by LDH release. Cellular localisation of GPR39 was determined by double immunohistochemical staining.
  
  
  RESULTS
  All trace metals (7.8-500 µmol/l) stimulated insulin release with Cu(2+) being the most potent in isolated islets, with an EC50 value of 87 μmol/l. Zn(2+) was the most selective with an EC50 value of 125 μmol/l. Enhancement of insulin secretion was also observed with Ni(2+) (179 μmol/l) and Co(2+) (190 μmol/l). These insulin-releasing effects were confirmed using clonal BRIN-BD11 cells which exhibited enhanced intracellular Ca(2+) (p < 0.05-p < 0.001) and cAMP generation (p < 0.05-p < 0.001) in response to trace metals. Oral administration of Zn(2+), Ni(2+) and Cu(2+) (50 µmol/kg together with 18 mmol/kg glucose) decreased the glycaemic excursion (p < 0.05-p < 0.01) and augmented insulin secretion (p < 0.05-p < 0.01) in NIH Swiss mice.
  
  
  CONCLUSIONS
  This study has demonstrated the presence of GPR39 and the insulinotropic actions of trace metals on BRIN-BD11 cells and pancreatic beta cells, together with their antihyperglycaemic actions in vivo. These data suggest that development of agonists capable of specifically activating GPR39 may be a useful new therapeutic approach for diabetes management.
authors.affiliation: Biomedical Sciences Research Institute, SAAD Centre for Pharmacy and Diabetes, University of Ulster, Cromore Road, Coleraine, BT52 1SA, Northern Ireland, UK.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Moran
authors.affiliation: Biomedical Sciences Research Institute, SAAD Centre for Pharmacy and Diabetes, University of Ulster, Cromore Road, Coleraine, BT52 1SA, Northern Ireland, UK.
authors.forename: Yasser H A
authors.initials: YH
authors.lastname: Abdel-Wahab
authors.affiliation: Biomedical Sciences Research Institute, SAAD Centre for Pharmacy and Diabetes, University of Ulster, Cromore Road, Coleraine, BT52 1SA, Northern Ireland, UK.
authors.forename: Srividya
authors.initials: S
authors.lastname: Vasu
authors.affiliation: Biomedical Sciences Research Institute, SAAD Centre for Pharmacy and Diabetes, University of Ulster, Cromore Road, Coleraine, BT52 1SA, Northern Ireland, UK.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Flatt
authors.affiliation: Biomedical Sciences Research Institute, SAAD Centre for Pharmacy and Diabetes, University of Ulster, Cromore Road, Coleraine, BT52 1SA, Northern Ireland, UK. am.mckillop@ulster.ac.uk.
authors.forename: Aine M
authors.initials: AM
authors.lastname: McKillop
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D018149:Glucose Intolerance / Q000097:blood; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics; D006943:Hyperglycemia / Q000097:blood; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D051379:Mice; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000502:physiology*; D014131:Trace Elements / Q000494:pharmacology*
chemical_list: C512928:GPR39 protein, mouse; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; D014131:Trace Elements; D000242:Cyclic AMP; D005947:Glucose; D002118:Calcium
keywords: G-protein-coupled receptor 39; Glucose tolerance; Insulin secretion; Pancreatic beta cells; Trace metals