The role of small molecule GPR119 agonist, AS1535907, in glucose-stimulated insulin secretion and pancreatic β-cell function

Aim: AS1535907, a small molecule agonist of GPR119, was assessed for its glucose-stimulated insulin secretory activity and pancreatic beta-cell function in type 2 diabetes. Methods: Both in vitro and in vivo tests were conducted using NIT-1 and HEK293 cell lines, male normal and db/db mice and isolated perfused rat pancreas preparations. Results: AS1535907 had an EC(50) value of 1.5 mu M for human GPR119 transfected in HEK293 cells. AS1535907 enhanced insulin secretion in NIT-1 cells and in the perfused rat pancreas. A transient increase in the human insulin promoter activity was also observed in NIT-1 cells. First-phase insulin secretion was particularly more evident in the AS1535907-treated perfused rat pancreas than that in the nateglinide or glibenclamide-treated group. Oral glucose tolerance improved following a single dose of AS1535907 in normal and db/db mice. Subsequently, 2 weeks of multiple dosing significantly increased plasma insulin levels and decreased blood glucose levels in db/db mice. After 3 weeks of treatment in db/db mice, the numbers of insulin and proliferation cell nuclear antigen-positive cells and the islet area were significantly higher than those in the vehicle-treated mice. As compared with the vehicle, gene expression analysis revealed that AS1535907 significantly upregulated transcription factors (Nkx 2.2, Nkx 6.1, NeuroD and activin A), responsible for beta-cell regulation and prohormone-converting enzyme 1 responsible for insulin biosynthesis. Conclusion: These results suggest that AS1535907 can potentially regulate first-phase insulin secretion and exert a protective effect on pancreatic beta-cell function via regulation of transcription factors.