Startseite Activation of GPR119 by fatty acid agonists augments insulin release from clonal β-cells and isolated pancreatic islets and improves glucose tolerance in mice
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Activation of GPR119 by fatty acid agonists augments insulin release from clonal β-cells and isolated pancreatic islets and improves glucose tolerance in mice

  • Brian M. Moran , Yasser H.A. Abdel-Wahab , Peter R. Flatt und Aine M. McKillop EMAIL logo
Veröffentlicht/Copyright: 6. Dezember 2013

Abstract

G-protein coupled receptor 119 (GPR119) is emerging as a potential target for the treatment of type 2 diabetes with beneficial effects on glucose homeostasis. This study assessed the insulin-secreting properties of various GPR119 agonists and the distribution of GPR119 in pancreatic islets. Endogenous ligands [oleoylethanolamide (OEA), palmitoylethanolamine (PEA)] and chemically synthetic analogues (AS-1269574, PSN-375963) were investigated in clonal BRIN-BD11 cells and mouse pancreatic islets. Secondary messenger assays such as intracellular Ca2+ and cAMP in response to agonists at normoglycaemic and hyperglycaemic conditions were assessed. Cytotoxicity was assessed by LDH release. AS-1269574 was the most potent and selective agonist tested in isolated islets, with an EC50 value of 9.7×10-7 mol/l, enhancing insulin release maximally by 63.2%. Stimulation was also observed with GPR119 ligands; OEA (3.0×10-6 mol/l; 37.5%), PSN-375963 (2.4×10-6 mol/l; 28.7%) and PEA (1.2×10-6 mol/l; 22.2%). Results were corroborated by studies using BRIN-BD11 cells, which revealed augmentation of intracellular Ca2+ and cAMP. Both OEA and AS-1269574 enhanced insulin release and improved glucose tolerance in vivo in NIH Swiss mice. These results demonstrate the cellular localisation of GPR119 on islet cells (β and pancreatic polypeptide cells), its activation of the β-cell stimulus-secretion coupling pathway and glucose lowering effects in vivo.


Corresponding author: Aine M. McKillop, Biomedical Sciences Research Institute, SAAD Centre for Pharmacy & Diabetes, University of Ulster, Cromore Road, Coleraine, BT52 1SA, Northern Ireland, UK, e-mail:

Acknowledgments

These studies were supported by the Department of Education and Learning, Northern Ireland.

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Received: 2013-9-13
Accepted: 2013-12-2
Published Online: 2013-12-6
Published in Print: 2014-4-1

©2014 by Walter de Gruyter Berlin/Boston

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