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 β ‐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 µM 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 β ‐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 β ‐cell function via regulation of transcription factors.