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Department of Endocrinology, The Second Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510120, People’s Republic of China

(Requests for offprints should be addressed to H Cheng; Email: hcheng_4374{at}yahoo.com)

Free fatty acids (FFAs) exert divergent effects on ß-cells. Acute exposure to FFAs stimulates insulin secretion, whereas chronic exposure impairs ß-cell function and induces apoptosis. The G protein-coupled receptor 40 (GPR40) is preferentially expressed in ß-cells and is activated by a wide range of FFAs. In this study, we used small interfering RNA technology and apoptosis assay in mouse ß-cell NIT-1 to address the role of GPR40 in ß-cell lipoapoptosis and function. Results showed that palmitate induced ß-cell apoptosis, which was not mediated through GPR40, whereas oleate protected NIT-1 cells from palmitate-induced lipoapoptosis, which was mediated at least in part through GPR40. Moreover, by detecting the activation of the phosphatidylinositol 3-kinase and MAP kinase (MAPK) pathways, we found that oleate promoted the activation of extracellular signal-regulated protein kinase–MAPK pathway mainly via GPR40, increased the expression of early growth response gene-1, leading to the anti-lipoapoptotic effect on NIT-1 cells. It was suggested that GPR40 might be implicated in the control of ß-cell mass plasticity and GPR40 probably provide a link between obesity and type 2 diabetes.