Abstract: Objective To investigate the mechanism of a dipeptidyl-peptidase-4 (DPP-4) inhibitor, saxagliptin, promoting the regeneration of islet beta cells in diabetic rats.  Methods The male SD rats were randomly divided into three groups including control group (NC, n=10), diabetes group (DM, n=10) and diabetes treated with saxagliptin group (DM-S, n=10). DM-S group was treated with saxagliptin 1 mg/(kg·d) for twelve weeks. The pancreatic β cell function was analysed by hyperglycemic clamps. Immunohistochemistry with anti-PCNA was performed to observe the proliferation rate of pancreatic β cells. Immunofluorescence double staining with anti-insulin, anti-glucagon, anti-DPP-4 and anti-SDF-1 were performed to observe the expression of insulin, glucagon, DPP-4 and SDF-1 in pancreatic tissue. Western blot assay was performed to test the expression of Akt, p-Akt, β-catenin and free-β-catenin protein, and RT-PCR was performed to test the expression  levels of c-myc and cyclinD1 mRNA in pancreatic tissue. Results Compared with NC group, there were significantly increased blood glucose, decreased islet function and β cell mass in DM group. Compared with DM rats, saxagliptin treatment significantly inhibited the expression of DPP-4, decreased the degradation of SDF-1, stimulated the proliferation of β cells, and ultimately improved the islet function and histopathological changes of pancreas. Conclusion DPP-4 inhibitor saxagliptin can significantly improve islet function, which involved in the inhibition of the expression of DPP- 4, the decreased degradation of SDF-1 and the stimulation of the proliferation of β cells.

Key words: dipeptidyl-peptidase Ⅳ inhibitors, diabetes mellitus, type 2, cell proliferation, islet beta cell, stromal cell derived factor