吐根碱通过GLP-1R促进大鼠胰岛组织胰岛素分泌作用的研究  

Effects of emetine on insulin secretion in rat islets through GLP-1R

作　　者：薛欢 路志红 王彬 余思婷 张茜 胡斌 曾庆轩 章毅 XUE Huan;LU Zhi-hong;WANG Bin;YU Si-ting;ZHANG Xi;HU Bin;ZENG Qing-xuan;ZHANG Yi(Dept of Pharmacology,Ministry of Education,Shanxi Medical University,Taiyuan 030001,China;School of Pharmacy,Ministry of Education,Shanxi Medical University,Taiyuan 030001,China;Medicinal Basic Research Innovation Center of Chronic Kidney Disease,Ministry of Education,Shanxi Medical University,Taiyuan 030001,China)

机构地区：[1]山西医科大学基础医学院药理学教研室,山西太原030001 [2]山西医科大学药学院,山西太原030001 [3]山西医科大学教育部医药基础研究创新中心,山西太原030001

出　　处：《中国药理学通报》2024年第7期1267-1272,共6页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金资助项目(No 81973378,82073909);中央引导地方科技发展资金项目(No YDZJSX2022A059);山西省专利转化专项计划(No 202304016);山西省“四个一批”科技兴医创新计划项目(No 2023XM022);山西省青年科学研究项目(No 202103021223219)。

摘　　要：目的探讨吐根碱通过胰高血糖素样肽-1受体(glucagon-like peptide-1 receptor,GLP-1R)促进离体大鼠胰岛组织胰岛素分泌作用。方法分离大鼠胰岛组织进行胰岛素分泌实验,根据实验设计使用不同浓度的吐根碱(2、10、50μmol·L^(-1))、不同浓度葡萄糖(2.8、11.1、16.7 mmol·L^(-1))以及特异性GLP-1R拮抗剂Exendin(9-39)孵育胰岛组织。酶联放射免疫的检测方法测定每组上清液胰岛素分泌量。使用SYBYL-X2.0软件将小分子化合物与GLP-1R(PDB代码:5NX2)进行对接。结果胰岛素分泌实验结果显示在高糖(11.1 mmol·L^(-1))条件下,胰岛素分泌量在吐根碱作用下明显升高,且具有剂量依赖性。低糖(2.8 mmol·L^(-1))条件下,胰岛素分泌量在吐根碱干预下没有明显变化,但在高糖(11.1、16.7 mmol·L^(-1))条件下,胰岛素分泌量在吐根碱作用下明显升高,具有类似GLP-1R激动剂葡萄糖浓度依赖性促胰岛素分泌特点。吐根碱与GLP-1R对接打分是Total Score=6.82,C Score=5,表明吐根碱与GLP-1R有良好的亲和力。当GLP-1R被Exendin(9-39)阻断后,吐根碱促胰岛素分泌作用明显降低。结论吐根碱通过激活GLP-1R发挥促离体大鼠胰岛组织胰岛素分泌作用。Aim To study the effect of emetine on insulin secretion through glucagon-like peptide-1 receptor(GLP-1R).Methods Isolating rat islets were used to carry out insulin secretion experiment.Islets were incubated with different concentrations of emetine(2,10,50μmol·L^(-1)),different concentrations of glucose solution(2.8,11.1,16.7 mmol·L^(-1))or specific GLP-1R antagonist Exendin(9-39).The amount of insulin secretion in the supernatant of each group was determined by an enzyme-linked radioimmunoassay.Small molecule compounds were docked to GLP-1R(PDB code:5NX2)using SYBYL-X2.0 software.Results Emetine could promote insulin secretion in high glucose(11.1mmol·L^(-1))in a dose-dependent manner.In low glucose(2.8 mmol·L^(-1)),insulin secretion did not change after intervention of emetine.But in high glucose(11.1,16.7 mmol·L^(-1)),insulin secretion significantly increased under the treatment of emetine in a glucose-dependent manner.The docking score of emetine and GLP-1R was Total Score=6.82,C Score=5,indicating that emetine had a good binding affinity with GLP-1R.Using Exendin(9-39)to block GLP-1R,the insulinotropic effect of emetine was reduced.Conclusion Emetine could promote insulin secretion,which is related to the activation of GLP-1R.

关 键 词：胰高血糖素样肽-1受体 分子对接 2型糖尿病 吐根碱 胰岛素分泌 小分子化合物 

分 类 号：R-332[医药卫生] R284.1R322.57R347.8R587.1R977.15