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  

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

作　　者：邢云芝 李春君[1] 丁敏[1] 于倩[1] 于德民[1] 

机构地区：[1]天津医科大学代谢病医院,卫生部激素与发育重点实验室,300070

出　　处：《天津医药》2015年第11期1221-1225,I0002,I0003,共7页Tianjin Medical Journal

摘　　要：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cyclin D1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。Objective To investigate the mechanism of a dipeptidyl-peptidase-4 （DPP-4） inhibitor, saxagliptin, pro-moting 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 pancreaticβcell function was analysed by hyperglycemic clamps. Immunohistochemistry with anti-PCNA was performed to observe the proliferation rate of pancreaticβcells. 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 in？creased blood glucose, decreased islet function andβcell 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 ofβcells, and ultimately improved the islet function and histopathological changes of pancreas. Conclusion DPP-4 inhibitor saxa-gliptin 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 ofβcells.

关 键 词：二肽基肽酶Ⅳ抑制剂 糖尿病 2型 细胞增殖 胰岛Β细胞 基质细胞生成因子 

分 类 号：R587.1[医药卫生—内分泌]