慢性间歇性低压低氧对糖尿病小鼠糖代谢关键酶基因表达和启动子区甲基化的影响  

Effects of chronic intermittent hypobaric hypoxia on expression and promoter region methylation of key enzyme genes related to glucose metabolism in diabetic mice

作　　者：隋春红 何岩涛 徐亚维[4] 纪朋艳 常影 张东芳 赵东海 金连海[2] 王程 SUI Chunhong;HE Yantao;XU Yawei;JI Pengyan;CHANG Ying;ZHANG Dongfang;ZHAO Donghai;JIN Lianhai;WANG Cheng(School of Pharmacy,Jilin Medical University,Jilin,Jilin 132013,China;School of Clinical Medicine,Jilin Medical University,Jilin,Jilin 132013,China;School of Basic Medical Sciences,Jilin Medical University,Jilin,Jilin 132013,China;Institute of Biological Engineering,Jilin Agricultural Science and Technology University,Jilin,Jilin 132019,China)

机构地区：[1]吉林医药学院药学院,吉林吉林132013 [2]吉林医药学院临床医学院,吉林吉林132013 [3]吉林医药学院基础医学院,吉林吉林132013 [4]吉林农业科技学院生物工程学院,吉林吉林132019

出　　处：《环境与职业医学》2024年第8期911-918,共8页Journal of Environmental and Occupational Medicine

基　　金：吉林省教育厅科学技术研究规划项目(JJKH20230541KJ)。

摘　　要：[背景]慢性间歇性低压低氧(CIHH)能有效改善2型糖尿病(T2DM)。其过程是否与糖代谢关键酶基因启动子区域DNA甲基化这一表观遗传学调控机制有关尚待明确。[目的]研究CIHH对T2DM小鼠糖代谢关键酶基因表达和启动子区甲基化的影响,探讨CIHH调节糖代谢的可能机制。[方法]40只C57BL/6J雄性小鼠随机分为常压常氧对照(NN/CON)组、慢性间歇性低压低氧干预对照(CIHH/CON)组、常压常氧糖尿病模型(NN/DM)组、慢性间歇性低压低氧干预糖尿病模型(CIHH/DM)组。高脂高糖饲料喂养NN/DM组和CIHH/DM组小鼠7周后,连续5 d按每天40 mg·kg^(-1)(以体重计)剂量腹腔注射50 mmol·L^(-1)链脲佐菌素(STZ)建立T2DM小鼠模型。CIHH/DM组和CIHH/CON组小鼠每天按模拟5000 m海拔低压低氧干预6 h,NN/DM组和NN/CON组小鼠一直处于常压常氧环境中,连续4周,期间检测血糖变化。CIHH干预实验后评估小鼠葡萄糖耐受性和胰岛素敏感性,测定小鼠肝中糖酵解关键酶葡萄糖激酶(GK)、丙酮酸激酶(PK)和糖异生关键酶磷酸烯醇式丙酮酸羧激酶(PEPCK)、葡萄糖-6-磷酸酶(G6P)的酶活力、基因mRNA相对表达水平和启动子区域DNA甲基化水平。[结果]与NN/DM组相比,CIHH/DM组小鼠在CIHH干预第25天后血糖降低(P<0.05)。NN/DM组和CIHH/DM组小鼠均呈现糖尿病性耐量曲线,但CIHH/DM组曲线下面积(AUC)低于NN/DM组(P<0.05)。与NN/DM组相比,CIHH/DM组小鼠血清胰岛素含量和胰岛素抵抗指数(HOMA-IRI)降低(P<0.05),肝GK和PK酶活力升高且基因mRNA表达上调(P<0.05),PEPCK和G6P酶活力下降且基因m RNA表达下调(P<0.05)。各组小鼠肝GK、PK、PEPCK和G6P基因启动子区域DNA平均甲基化水平的差异无统计学意义,且与mRNA表达的关联性也无统计学意义。[结论]CIHH干预可降低T2DM小鼠血糖,改善葡萄糖耐受性和缓解胰岛素抵抗,协调调控糖代谢关键酶活力及其基因m RNA表达,但上述现象与这些糖代谢关键酶基�[Background]Chronic intermittent hypobaric hypoxia(CIHH)can effectively alleviate type 2 diabetes mellitus(T2DM).In this process,the underlying mechanism in its association with the epigenetic regulation of DNA methylation in the promoter regions of glucose metabolism key enzyme genes remains unclear yet.[Objective]To investigate the effects of CIHH on expression and promoter region methylation of key enzyme genes related to glucose metabolism in diabetes mice,and to explore the underlying mechanism by which CIHH regulates glucose metabolism.[Methods]Forty C57BL/6J male mice were divided randomly into a normobaric normoxic control(NN/CON)group,a chronic intermittent hypobaric hypoxia intervention control(CIHH/CON)group,a normobaric normoxic diabetic model(NN/DM)group,and a chronic intermittent hypobaric hypoxia intervention diabetic model(CIHH/DM)group.The mice in the NN/DM and the CIHH/DM groups were fed for 7 weeks with high-fat and high-sugar diet.Subsequently,these mice were intraperitoneally injected consecutively with 50 mmol·L^(-1)streptozotocin(STZ)for 5 d at a dose of 40 mg·kg^(-1)(body weight)per day to create T2DM model mice.The mice in the CIHH/DM and the CIHH/CON groups were intervened by simulating hypobaric hypoxia at 5000 m altitude for 6 h per day,while the mice in the NN/DM and the NN/CON groups were always placed in a normobaric normoxic environment.All mice were continuously treated for 4 weeks,and blood glucose were monitored during this period.After the CIHH intervention experiment,the glucose tolerance and insulin sensitivity of mice were evaluated.A set of indicators involved in key glycolytic enzymes glucokinase(GK)and pyruvate kinase(PK),as well as key gluconeogenic enzymes phosphoenolpyruvate carboxyl kinase(PEPCK)and glucose-6-phosphatase(G6P)were measured in the liver of mice,including enzyme activity,relative mRNA expression level,and DNA methylation level in the gene promoter regions.[Results]Compared with the mice in the NN/DM group,the blood glucose levels of the mice in the CIH

关 键 词：慢性间歇性低压低氧干预 糖尿病 葡萄糖代谢 关键酶 DNA甲基化 

分 类 号：R11[医药卫生—公共卫生与预防医学]