High fatty acid reduces insulin secretion in pancreatic β-cells and miR-139-5p is increased in dia-betic pancreatic tissues and induces islet β-cell apoptosis.However,to date,there is no study exploring whether or not miR-139-5p is involved in high fatty acid-induced insulin secretion.In the present study,INS-1 cells were exposed to different concentrations (0.1,0.2,and 0.4 mM) of palmi-tate for different time periods (12,24,and 48 h).The expression levels of miR-139-5p and neuronal pentraxin 1 (NPTX1) were evaluated by real-time PCR and western blot analysis.The regulation of NPTX1 by miR-139-5p was examined by luciferase assay.Cell transfection was conducted using Lipo8000 or Lipofectamine RNAiMAX.Potassium or glucose-stimulated insulin secretion levels were used to verify the function of miR-139-5p or NPTX1 in insulin secretion.Insulin secretion levels were detected by radioimmunoassay.We found that miR-139-5p was increased in INS-1 cells stimulated with palmitate.In addition,miR-139-5p was also elevated in islets of high-fat diet-fed mice and db/db mice compared to those in islets of normal diet-fed mice and wild-type mice.Knockdown of miR-139-5p could reverse high fatty acid-induced insulin secretion defects in INS-1 cells.Furthermore,we demonstrated that NPTX1 is a target of miR-139-5p.miR-139-5p mediated palmitate-induced insulin secretion defects by targeting NPTX1.Moreover,palmitate treatment declined the expression of NPTX1 and the NPTX1 expression was also decreased in islets of high-fat diet-fed mice and db/db mice.Impaired NPTX1 expression is involved in fatty acid-induced insulin secretion defects.Collectively,our results illustrate that the induction of β-cell insulin secre-tion defects by fatty acids is mediated,at least in part,by miR-139-5p via downregulation of NPTX1 expression.