利拉鲁肽对2型糖尿病大鼠胰岛β细胞凋亡的调控机制

摘要

目的 探讨利拉鲁肽对2型糖尿病大鼠胰岛β细胞凋亡的调控机制.方法 将60只SPF级SD雄性大鼠随机分为正常对照组、模型组、阳性对照组 (二甲双胍, 140 mg·kg-1·d-1) 、利拉鲁肽低剂量组 (0. 12 mg·kg-1·d-1) 和利拉鲁肽高剂量组 (6. 30 mg·kg-1·d-1) , 每组12只.除正常对照组外, 其余各组均采用高脂、高糖饲养, 同时联合腹腔注射链脲佐菌素 (STZ, 30 mg/kg) , 建立大鼠2型糖尿病模型.成功建模7 d后, 利拉鲁肽高、低剂量组皮下注射利拉鲁肽;阳性对照组灌胃给予二甲双胍 (140 mg·kg-1·d-1) ;正常对照组和模型组均灌胃给予等量的生理盐水 (10 ml·kg-1·d-1) , 1次/d.治疗8 w后, 检测各组空腹血糖浓度、胰岛素和抵抗素水平, 免疫组化法检测各组胰岛β细胞Bcl-2和Bax蛋白表达水平, Western印迹测定各组胰岛β细胞Caspase-3蛋白的表达水平.结果 与正常对照组比较, 模型组空腹血糖浓度、胰岛素和抵抗素水平、Bax蛋白和Caspases-3蛋白的表达水平显著升高 (P<0. 05) , Bcl-2表达水平明显降低 (P<0. 05) ;与模型组比较, 利拉鲁肽组和阳性对照组空腹血糖浓度、胰岛素和抵抗素水平、Bax蛋白和Caspases-3蛋白表达水平显著降低 (P<0. 05) , Bcl-2蛋白表达水平显著升高 (P<0. 05) .结论 利拉鲁肽能显著改善2型糖尿病大鼠胰岛素抵抗、抑制胰岛β细胞凋亡, 其机制可能与提高Bcl-2表达, 下调Bax表达, 进而降低Caspase-3的活性有关.%Objective To investigate the apoptosis mechanism of liraglutide against islet beta cells in type 2 diabetes mellitusrats.Methods 60 SPF-grade SD male rats were randomly divided into five groups with 12 rats in each group, including the normalcontrol, model, positive control (metformin, 140 mg·kg-1·d-1) , liraglutide low-dose (0.12 mg·kg-1·d-1) and liraglutide high-dose (6.30 mg·kg-1·d-1) groups. The type 2 diabetes mellitus rats model was constructed by feeding of high fat and high sugar dietsand injecting with streptozotocin (STZ, 30 mg/kg) . After 7 days of successful modeling, the high and low doses of liraglutide weresubcutaneously injected to the rats, respectively. Metformin (140 mg·kg-1·d-1) was feed by gavage for the positive control group, and saline (10 ml·kg-1·d-1) was feed by gavage for the normal control group and model group. Treated for 8 weeks, the fastingblood glucose, insulin and resistin levels were measured. Furthermore, the expression levels of Bcl-2 and Bax proteins were detected byimmunohistochemistry and the expression level of caspase-3 protein was detected by Western blot.Results Compared with the normalcontrol group, the fasting blood glucose concentration, insulin and resistin levels, and the expression level of Bax and Caspases-3 pro-teins in model group significantly increased (P<0.05) . However, the expression level of Bcl-2 protein obviously decreased (P<0.05) .Moreover, the fasting blood glucose concentration, insulin and resistin levels, the expression levels of Bax and Caspases-3 protein in li-raglutide group and positive control group were significantly lower (P<0.05) than those in the model group. But the expression level ofBcl-2 protein in liraglutide group and positive control group was obviously higher (P<0.05) than that in the model group.ConclusionsLiraglutide can efficiently improve the insulin resistance and inhibit the islet beta cell apoptosis in type 2 diabetes mellitus rats. Themechanism might be related to increasing of Bcl-2 expression, decreasing Bax expression and Caspase-3 protein activity.