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

Aims: To assess the potency and selectivity of various GPR120 agonists and to determine the cellular localization of GPR120 in clonal fl-cells and pancreatic islets. Methods: Insulin secretion and alterations in intracellular Ca2+ and cAMP response to glucose and GPR120 agonists, including endogenous agonists a-linolenic acid (ALA), docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and a synthetic analogue (GIN-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 x 10' mo1/1) with a maximum stimulation of insulin secretion of 534 at 10' mo1/1 (p <0.001) in BRIN-BD11 cells. Stimulation of insulin secretion was also observed with GIN-9508 (6.4 x 10-3 mol/1; 47%), EPA (7.9 x 10-e mol; 3604) and DHA (1.0 x 10-1 mol; 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 Ca2+ and cAMP. lmmunocytochemistry showed GPR120 expression on BRIN-BD11 cells and was confined to islet fl-cells with no distribution on a-cells. Administration of GPR120 agonists (0.1 pmolfkg 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 fl-cells and that agon s s at his receptor are potent insulin secretagogues with therapeutic potential for type 2 diabetes.