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

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.