沙格列汀对脂肪肝合并糖尿病大鼠的治疗作用

摘要

目的：观察沙格列汀对脂肪肝合并糖尿病大鼠模型干预疗效，探讨其改善脂肪肝的可能机制。方法利用高糖高脂饮食加小剂量链脲佐菌素（STZ）建立非酒精性脂肪肝（NAFLD）合并2型糖尿病（T2DM）大鼠模型。实验动物分为3组，分别是正常对照组、模型对照组及沙格列汀干预组，干预组给予沙格列汀溶液（10 mg/kg/d）灌胃8周，对照组给予同体积生理盐水灌胃。实验结束后检测各组大鼠空腹血糖、胰岛素、血脂、肝功能、肝指数、肝组织氧化应激指标及病理改变，透射电镜检测肝细胞超微结构，免疫组化及Western blot检测凋亡蛋白Bcl-2、Bax在肝组织的表达。结果与模型组比，干预组血糖、胰岛素、HOMA-IR、肝功能、肝质量、肝指数均显著降低（P<0.01)，体质量、血脂略有降低，但差异不显著（P>0.05），SOD显著升高（P<0.01），MDA显著降低（P<0.05）；与正常组比，干预组谷草转氨酶无显著差异（P>0.05）。HE及油红染色结果显示：与模型组比，干预组肝细胞内脂肪滴减少。电镜结果显示：模型组细胞浆内见大量脂肪滴，粗面内质网水肿，离散，线粒体数目减少，结构紊乱，肿胀。干预组细胞浆内脂肪滴减少，内质网围绕核膜排列整齐，线粒体结构较清晰。免疫组化法、Western blot检测结果显示：与正常组比，模型组Bax表达增多，Bcl-2表达减少；与模型组比，干预组Bax表达减少，Bcl-2表达增多。结论沙格列汀对高糖高脂饮食联合小剂量链脲佐菌素诱导的脂肪肝合并糖尿病大鼠有较好的治疗作用。其可能通过有效降糖，缓和胰岛素抵抗及降低氧化应激反应、保护细胞器结构、增加抗凋亡蛋白基因表达等发挥对非酒精性脂肪性肝病的治疗作用。%Objective To observe the therapeutic effect of saxagliptin in a rat model of nonalcoholic fatty liver and type 2 diabetes and investigate the possible mechanism. Methods Rats models of nonalcoholic fatty liver and type 2 diabetes established by feeding on a high glucose and fat diet and streptozotocin injection were treated with saxagliptin (daily dose of 10 mg/kg) gavage for 8 weeks, using saline as the control. After the treatment, fasting blood glucose, serum insulin, blood lipids, liver function, liver oxidative indices, and hepatic pathologies were evaluated in all the rats, and the expressions of Bcl-2 and Bax in the liver tissue were detected with immunohistochemistry and Western blotting. Results Compared with the model group, saxagliptin intervention significantly reduced blood glucose and HOMA-IR, improved the liver function and SOD activity (P<0.01), lowered the liver weight, liver index (P<0.01) and MDA level (P<0.05), and slightly lowered the body weight and blood lipids (P>0.05); AST level was similar between the normal control group and saxagliptin intervention group (P>0.05). HE and oil red staining showed obvious hepatic pathologies in the model group, and saxagliptin intervention significantly reduced lipid droplets in the hepatocytes and improved the structural damage of the liver. Hepatic Bax expression significantly increased and Bcl-2 expression decreased in the model group, and these changes were reversed by saxagliptin. Conclusion Saxagliptin shows good therapeutic effect in rat models of nonalcoholic fatty liver and type 2 diabetes possibly by controlling blood glucose, lowering insulin resistance, alleviating hepatic oxidative stress and hepatocyte damage, and regulating the expression of apoptosis-related proteins.