Evaluation of the insulin-releasing and glucose-lowering effects of GPR120 activation in pancreatic β-cells.

Abstract

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. 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. 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. 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.