基于胰岛素抵抗小鼠模型研究消渴方及其等效成分群的作用机制  

Exploration on bioactive equivalent combinatorial components of Xiaoke formula and its mechanism based on insulin resistance mice

作　　者：张建 马文娟[2,3] 董琳捷 龙江兰 张瑜 鄢丹[2] ZHANG Jian;MA Wen-juan;DONG Lin-jie;LONG Jiang-lan;ZHANG Yu;YAN Dan(School of Pharmacy,Chengdu University of Traditional Chinese Medicine,Chengdu 611137,China;Beijing Institute of Clinical Pharmacy,Beijing Friendship Hospital,Capital Medical University,Beijing 100050,China;School of Traditional Chinese Materia Medica,Shenyang Pharmaceutical University,Benxi 110016,China)

机构地区：[1]成都中医药大学药学院,四川成都611137 [2]首都医科大学附属北京友谊医院北京市临床药学研究所,北京100050 [3]沈阳药科大学中药学院,辽宁本溪110016

出　　处：《药学学报》2024年第6期1698-1705,共8页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金重点项目(82130112);青年北京学者项目(2022-051);国家中医药管理局高水平中医药重点学科建设项目(zyyzdxk-2023003).

摘　　要：消渴方(Xiaoke formula,XKF)是治疗消渴症的经典名方,具有改善胰岛素抵抗(insulin resistance,IR)作用,但其等效成分群(bioactive equivalent combinatorial components,BECC)目前尚不清楚。本研究基于团队前期研究基础,以小檗碱、黄芪甲苷、绿原酸作为消渴方BECC组成候选成分,探讨其药效和生物机制。采用高脂饮食诱导IR小鼠模型,检测消渴方及消渴方BECC给药后小鼠血糖、胰岛素敏感性、血脂代谢、免疫炎症因子等指标,采用病理切片染色检测组织病理改变,利用网络药理学预测消渴方及其BECC潜在作用靶点与信号通路,并用Western blot对网络药理学结果进行验证。动物福利和实验过程均遵循北京迈德康纳生物技术有限公司实验动物伦理委员会的规定(MDKN-2023-019)。结果显示,由小檗碱、黄芪甲苷、绿原酸按消渴方原方配比组成的消渴方BECC,在改善IR小鼠的血糖、胰岛素敏感性、组织病理损伤、血脂紊乱、免疫炎症等方面与消渴方作用相当;网络药理学和Western blot结果表明,消渴方及其BECC可能是通过促进肝脏磷脂酰肌醇3-激酶活化(PI3K)、蛋白激酶B(AKT)磷酸化,抑制肝脏糖异生关键限速酶葡萄糖-6-磷酸酶(G6PC)、磷酸烯醇式丙酮酸羧激酶1(PCK1)表达,最终实现改善IR。综上,小檗碱、黄芪甲苷、绿原酸可作为消渴方改善IR的潜在等效成分群,其通过调节脂质代谢、免疫炎症,促进IR小鼠肝脏PI3K/AKT通路信号传递,进而抑制肝脏糖异生途径,调节葡萄糖稳态改善IR。Xiaoke formula(XKF)is a classic formula for the treatment of insulin resistance(IR),but there is still unclear on bioactive equivalent combinatorial components(BECC)of XKF.In this study,based on the previous research of our team,three components,berberine,astragaloside IV and chlorogenic acid,were selected as the BECC of XKF,and their efficacy and mechanism were investigated.A high-fat diet-induced IR mouse model was used to detect blood glucose,insulin sensitivity,lipid metabolism,immune&inflammatory factors,etc.,and staining of pathology sections was used to detect histopathological changes.Network pharmacology was used to predict the potential targets and signaling pathways of XKF and its BECC,and the results of the network were verified by Western blot.The animal welfare and experimental procedures followed the regulations of the Laboratory Animal Ethics Committee of Beijing MDKN Biotech Company(MDKN-2023-019).The results showed that BECC,which was composed of berberine,astragaloside IV and chlorogenic acid in the ratio of the original formula of XKF,was comparable to XKF in improving the glycemia,insulin sensitivity,histopathological damage,dyslipidemia,and immuno-inflammation in IR mice.The results of network pharmacology and Western blot suggested that the BECC of XKF and XKF might alleviate IR by promoting the activation of hepatic phosphatidylinositol 3-kinase(PI3K),phosphorylation of protein kinase B(AKT),and inhibiting the expression of glucose-6-phosphate phosphatase(G6PC)and phosphoenolpyruvate carboxykinase 1(PCK1),the key limiting enzymes of hepatic gluconeogenesis.The above results suggest that berberine,astragaloside IV and chlorogenic acid can be used as the potential BECC of XKF to improve IR,and can regulate lipid metabolism,immuno-inflammation,and promote hepatic PI3K/AKT signaling to inhibit hepatic gluconeogenesis,regulate glucose homeostasis,and improve IR in mice.

关 键 词：消渴方 等效成分群 胰岛素抵抗 PI3K/AKT信号通路 糖异生 

分 类 号：R928[医药卫生—药学]