Saxagliptin Induces β-Cell Proliferation through Increasing Stromal Cell-Derived Factor-1α In Vivo and In Vitro

Frontiers in Endocrinology

Min Ding¹  Bei Sun¹  Li-Ming Chen¹  Qian-Hua Fang²  Yun-Zhi Xing²  Chun-Jun Li²  De-Min Yu² 

[1] Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China;;Key Laboratory of Hormones and Development (Ministry of Health), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Metabolic Diseases Hospital &

关键词: DPP-4 inhibitor;    β-cell;    type 2 diabetes;    stromal cell-derived factor-1;    cell proliferation;   

DOI  :  10.3389/fendo.2017.00326

来源: DOAJ

【 摘 要 】

Dipeptidyl peptidase-4 inhibitors, such as saxagliptin, have been reported to have beneficial effects on β-cell function, but the specific underlying mechanism remains unclear. Stromal cell-derived factor-1α (SDF-1α), a chemokine produced in multiple organs, has been considered as a crucial regulator in promoting β-cell survival. Here, we speculate that SDF-1α might mediate the effect of saxagliptin on improving β-cell function. After 12-week saxagliptin treatment in high-fat diet/streptozotocin-induced diabetic rats, significant improvement in pancreas insulin secretion capacity evaluated by hyperglycemia clamp and increased β-cell to α-cell areas ratio were observed. Saxagliptin significantly induced β-cell proliferation and upregulated the expression of proliferation-related factors including c-myc and cyclind D1 determined with western blotting from the isolated islets. The expression/activity of DPP-4 was significantly reduced and paralleled with the restoration of SDF-1α levels in the saxagliptin-treated diabetic rats, subsequently the key WNT-signaling regulators, β-catenin, and AKT were activated. However, the effect of saxagliptin inducing β-cell proliferation was attenuated when we silenced the SDF-1α receptor (CXCR4) with RNAi in INS cell lines. Collectively, our data indicate that SDF-1α mediates the protective effect of saxagliptin on β-cell proliferation, suggesting that DPP-4 inhibitors have the potential role on delaying β-cell failure and SDF-1α could be a therapeutic target of β-cell regeneration.

【 授权许可】

Unknown