桑枝总生物碱与二甲双胍联合应用改善2型糖尿病KKAy小鼠糖代谢的作用及机制研究  

Effects and mechanism of Morus alba L.(Sangzhi)alkaloids combined with metformin on glucose metabolism in diabetic KKAy mice

作　　者：陈蕾蕾 雷丽冉 曹慧 刘泉 李彩娜 雷蕾 环奕 刘玉玲 申竹芳 刘率男 CHEN Lei-lei;LEI Li-ran;CAO Hui;LIU Quan;LI Cai-na;LEI Lei;HUAN Yi;LIU Yu-ling;SHEN Zhu-fang;LIU Shuai-nan(State Key Laboratory of Bioactive Substance and Function of Natural Medicines,Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China;Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China;Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations,Beijing 100050,China;Beijing Key Laboratory of Polymorphic Drugs,Beijing 100050,China)

机构地区：[1]中国医学科学院、北京协和医学院药物研究所,天然药物活性物质与功能国家重点实验室,北京100050 [2]中国医学科学院糖尿病研究中心,北京100050 [3]药物传输技术与新型制剂北京市重点实验室,北京100050 [4]晶型药物研究北京市重点实验室,北京100050

出　　处：《药学学报》2023年第12期3619-3627,共9页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(81973379);中国医学科学院创新工程项目(2021-I2M-1-026,2022-I2M-2-002);北京市自然科学基金资助项目(7202137);北京高校卓越青年科学家计划项目(BJJWZYJH01201910023028)

摘　　要：本文考察了桑枝总生物碱(SZ-A)与临床一线用药二甲双胍(Met)联合应用对2型糖尿病KKAy小鼠糖代谢的影响并初步探讨其潜在机制。采用自发性2型糖尿病KKAy小鼠,根据其糖脂代谢相关指标分为模型对照组、桑枝总生物碱组(SZ-A,100mg·kg^(-1))、二甲双胍组(Met,100mg·kg^(-1))及SZ-A与Met联合给药组(100mg·kg^(-1) SZ-A+100mg·kg^(-1) Met),每组10只,每天灌胃1次,连续7周,动态监测小鼠的摄食量、饮水量、体重和血糖等生化指标,并分别在给药2、5和6周后进行口服葡萄糖耐量、胰岛素耐量及丙酮酸钠耐量实验。实验经中国医学科学院药物研究所实验动物管理和使用委员会的审查批准(批准号:00004332)。给药结束后组织取材,对肝脏进行称重、肝脏指数计算、脂质含量测定及病理分析,并采用Western blot检测KKAy小鼠肝脏、肌肉、脂肪组织中糖代谢及胰岛素信号通路相关因子的蛋白表达水平。结果表明,SZ-A和Met联合给药可明显降低KKAy小鼠的摄食量、饮水量、空腹血糖、随机血糖、糖化血红蛋白水平,还可显著改善小鼠的葡萄糖耐受性、增强胰岛素敏感性及抑制体内糖异生过程,且作用优于SZ-A或Met单药组。PI3K/PDK1/Akt/GLUT信号通路与胰岛素敏感性及葡萄糖摄取密切相关,与单药组相比,SZ-A和Met联合给药组KKAy小鼠肝脏、肌肉及脂肪组织中的PI3K/PDK1/Akt/GLUT信号通路相关因子显著上调。另外,SZ-A与Met联合给药也可改善肝脏脂质堆积,降低血转氨酶水平。综上,SZ-A和Met联合应用可激活外周组织胰岛素依赖的糖摄取通路,促进KKAy小鼠外周组织的糖摄取和利用,与单药组相比,联合给药对于随病程发展的血糖升高具有更好的控制作用。该研究可为糖尿病临床治疗药物的合理联用提供数据支持,为SZ-A的IV期临床再评价提供实验研究依据。To investigate the effects and mechanism of the combination of Morus alba L.(Sangzhi)alkaloids(SZ-A)and metformin(Met)on glucose metabolism in type 2 diabetic mice,KKAy mice were divided into four groups according to the glucose and lipid indexes:control group(control),Morus alba L.(Sangzhi)alkaloids group(SZ-A,100mg·kg^(-1)),metformin group(Met,100 mg·kg^(-1))and combined administration group(combination,Comb,100 mg·kg^(-1) SZ-A+100 mg·kg^(-1) Met).All groups were administered by gavage once daily for 7 weeks accompanied with monitoring food intake,water intake,body weight as well as glycemia.Additionally,oral glucose tolerance test(OGTT),insulin tolerance test(ITT)and oral sodium pyruvate tolerance test(OPTT)were performed at week 2,week 5,week 6,respectively.The experiments were approved by the Institutional Animal Care and Use Committee of the Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College(00004332).We determined the weight and lipid content of liver,and then performed the histopathological analysis after sacrificed.Furthermore,Western blot assay was used to detect the protein levels of key molecules of PI3K/PDK1/Akt/GLUT signaling pathway in liver,muscle and adipose tissue.Compared to the SZ-A or Met monotherapy group,SZ-A+Met significantly improved the glucose metabolism disorder,which was showed in reduced food intake,water intake,the level of fasting blood glucose,postprandial blood glucose and glycosylated hemoglobin Alc(HbAlc)of KKAy mice,as well as improved glucose tolerance,enhanced insulin sensitivity and inhibited gluconeogenesis.In addition,SZ-A+Met obviously up-regulated the protein expression levels in PI3K/PDKI/Akt/GLUT signaling pathway in liver,muscle and adipose tissue of KKAy mice.Moreover,the liver lipid accumulation and blood aminotransferase level of KKAy mice in the combined administration group were significantly reduced.Therefore,we concluded that the combination of SZ-A and Met improved glucose metabolism and inhibited the occurren

关 键 词：桑枝总生物碱 二甲双胍 联合用药 2型糖尿病 胰岛素信号通路 

分 类 号：R966[医药卫生—药理学]