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

Abstract

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.

SDF‐1 inhibits the dedifferentiation of islet β cells in hyperglycaemia by up‐regulating FoxO1 via binding to CXCR4

“…DPP‐IV can cleave and inactivate SDF‐1, which can then no longer activate CXCR4. In our previous research group studies, we found that compared with non‐diabetic mice, the expression of DPP‐IV in the islets of diabetic mice was enhanced 13 . Therefore, with a diabetic condition, SDF‐1 was abundantly expressed in pancreatic tissues, but the number of islets β cells undergoing dedifferentiation was not reduced.…”

“…SDF‐1 is associated with the mediation of islet β cells function. For example, our previous study found that the DPP‐IV inhibitor Saxagliptin improved the function of islet β cells through regulating SDF‐1 expression 13 . Another study also revealed the important role of SDF‐1 in β cells survival after islet transplantation 14 .…”

“…For example, our previous study found that the DPP‐IV inhibitor Saxagliptin improved the function of islet β cells through regulating SDF‐1 expression. 13 Another study also revealed the important role of SDF‐1 in β cells survival after islet transplantation. 14 Furthermore, during the terminal differentiation stage of mature β cells, SDF‐1 has been proven to prevent apoptosis and necrosis through activating PI3K/AKT and WNT/β‐catenin pathways.…”

Effect of Saxagliptin on Endothelial Function in Patients with Type 2 Diabetes: A Prospective Multicenter Study

“…The reason for this discrepancy between clinical observations and experimental studies is due to the methodological differences in SDF-1α assays. In addition, experimental studies have shown that a DPP-4 inhibitor significantly increased SDF-1α levels in a murine model of type 1 diabetes 34,35 . Further studies in which the relationship between effects of DPP-4 inhibitors on SDF-1α levels is evaluated in a murine model of type 2 diabetes may reveal the reason for this discrepancy.…”

Type 2 Diabetes Mellitus non-surgical remission: A possible mission

“…We matched the cases and control for BMI and adjusted all factors against BMI in cox regression analysis. This could be explained by activation of hematopoietic stem cells in response to DPP4 inhibitors which control inflammatory and immune response pathogenesis of T2DM [13], in association with β-cell regeneration [14].…”