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Saxagliptin Induces ?-Cell Proliferation through Increasing Stromal Cell-Derived Factor-1? In Vivo and In Vitro.


ABSTRACT: Dipeptidyl peptidase-4 inhibitors, such as saxagliptin, have been reported to have beneficial effects on ?-cell function, but the specific underlying mechanism remains unclear. Stromal cell-derived factor-1? (SDF-1?), a chemokine produced in multiple organs, has been considered as a crucial regulator in promoting ?-cell survival. Here, we speculate that SDF-1? might mediate the effect of saxagliptin on improving ?-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 ?-cell to ?-cell areas ratio were observed. Saxagliptin significantly induced ?-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-1? levels in the saxagliptin-treated diabetic rats, subsequently the key WNT-signaling regulators, ?-catenin, and AKT were activated. However, the effect of saxagliptin inducing ?-cell proliferation was attenuated when we silenced the SDF-1? receptor (CXCR4) with RNAi in INS cell lines. Collectively, our data indicate that SDF-1? mediates the protective effect of saxagliptin on ?-cell proliferation, suggesting that DPP-4 inhibitors have the potential role on delaying ?-cell failure and SDF-1? could be a therapeutic target of ?-cell regeneration.

SUBMITTER: Li CJ 

PROVIDER: S-EPMC5711777 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Saxagliptin Induces β-Cell Proliferation through Increasing Stromal Cell-Derived Factor-1α <i>In Vivo</i> and <i>In Vitro</i>.

Li Chun-Jun CJ   Sun Bei B   Fang Qian-Hua QH   Ding Min M   Xing Yun-Zhi YZ   Chen Li-Ming LM   Yu De-Min DM  

Frontiers in endocrinology 20171127


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  ...[more]

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