沙格列汀通过抑制 SDF-1 降解促进 2 型糖尿病大鼠胰岛β细胞增殖

目的 探讨二肽基肽酶Ⅳ(DPP-4)抑制剂沙格列汀促进糖尿病大鼠胰岛β细胞增殖的相关机制。方法 将 SD 大鼠随机分为对照 （NC） 组 （n=10）、 糖尿病(DM)组 （n=10） 和沙格列汀治疗(DM-S)组 （n=10）。DM-S 组给予沙格列汀 1 mg/ （kg·d）灌胃 12 周。高糖钳夹法测胰岛功能， 免疫荧光双染观察胰腺组织中α细胞、 β细胞及 DPP-4、 基质细胞生成因子（SDF） -1 的表达， PCNA 免疫染色观察胰岛β细胞增殖， Western Blot 法检测丝氨酸苏氨酸蛋白激酶 (Akt)、 p-Akt、 β-catenin 及 free-β-catenin 的表达， Real Time-PCR 法检测基因 c-myc 及 cyclinD1 的表达。结果 与NC 组相比， DM 组大鼠血糖明显升高， 胰岛分泌功能明显受损， 胰岛β细胞明显减少。与 DM 组相比， 沙格列汀明显抑制 DPP-4 表达， 减少 SDF-1 降解， 增加胰岛β细胞增殖， 改善胰岛功能及病理学损害。结论 DPP-4 抑制剂沙格列汀能够明显改善胰岛功能， 其机制与抑制胰腺组织 DPP-4 表达， 减少 SDF-1 降解， 促进胰岛β细胞增殖有关。

The protective effects of saxagliptin on β-cell proliferation by inhibiting the degradation of SDF-1 in type 2 diabetes rats#br#

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 expressionlevels 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.