葡萄糖上调胰腺β细胞CFTR表达而升高胰岛素水平在2型糖尿病中的作用  

Elevated insulin level in pancreatic isletβcells by glucose via up-regula⁃tion of CFTR contributes to pathogenesis of type 2 diabetes mellitus

作　　者：赵心怡 吴勇[1] 黄文庆 张雪莲[3] 郭景慧 ZHAO Xin-yi;WU Yong;HUANG Wen-qing;ZHANG Xue-lian;GUO Jing-hui(Department of Physiology,School of Medicine,Jinan University,Guangzhou 510632,China;Department of Transfu-sion Medicine,Shenzhen Hospital,Southern Medical University,Shenzhen 518000,China;Department of Endocrinology,Beijing Tongren Hospital,Capital Medical University,Beijing 100005,China)

机构地区：[1]暨南大学基础医学与公共卫生学院生理系,广东广州510632 [2]南方医科大学深圳医院输血科,广东深圳518000 [3]北京同仁医院内分泌科,北京100005

出　　处：《中国病理生理杂志》2021年第11期1942-1948,共7页Chinese Journal of Pathophysiology

基　　金：国家自然科学基金资助项目(No.81901441);深圳市科技计划基础研究项目(No.JCYJ20180306174210850)。

摘　　要：目的:探究长期高葡糖糖水平对胰腺β细胞囊性纤维化跨膜传导调节因子(CFTR)表达水平的影响,及其是否介导2型糖尿病发病初期胰岛素水平异常。方法:(1)体外实验分别将大鼠胰腺β细胞系RINm5F和原代分离的C57BL/6小鼠胰岛暴露于含有0、10、20和30 mmol/L葡萄糖的RPMI-1640培养液中处理24 h或48 h,通过RT-qPCR和Western blot技术检测不同浓度的葡萄糖对CFTR mRNA和蛋白表达水平的影响,利用酶联免疫吸附实验(ELISA)检测不同浓度的葡萄糖处理24 h后胰岛素的本底释放水平。(2)临床样本来自北京同仁医院共计278例,其中包括未患有糖尿病病例132人及患有2型糖尿病病例146人,检测这些样本的空腹血糖及CFTR含量。结果:(1)10、20和30 mmol/L的葡萄糖可以显著上调胰腺β细胞CFTR的mRNA水平(P<0.05),且5、15、20和30 mmol/L的葡萄糖显著性升高CFTR的蛋白水平(P<0.05或P<0.01);30 mmol/L的葡萄糖显著升高小鼠原代胰岛细胞CFTR的mRNA水平(P<0.01);20和30 mmol/L的葡萄糖处理胰腺β细胞24 h后,胰腺β细胞表现出显著性升高的胰岛素本底释放(P<0.05)。(2)在临床样本中,空腹血糖与血浆内CFTR蛋白水平之间存在显著正相关关系(r=0.314,P<0.01)。结论:葡萄糖可以上调胰腺β细胞中CFTR的表达进而升高其胰岛素的本底释放,这可能与2型糖尿病的发病机制有关。AIM:To investigate the effect of long-term high glucose level on the expression of cystic fibrosis transmembrane conductance regulator(CFTR)in pancreaticβcells,and whether it mediates abnormal insulin level in the early stage of type 2 diabetes mellitus(T2DM).METHODS:(1)In the in vitro experiments,0,10,20 and 30 mmol/L glucose was administered to rat pancreaticβcell line RINm5F and primarily isolated C57BL/6 mouse pancreatic islets for 24 h or 48 h.The effects of different concentrations of glucose on the mRNA and protein expression levels of CFTR were detected by RT-qPCR and Western blot.Enzyme-linked immunosorbent assay(ELISA)was used to detect the basal secre-tion of insulin after glucose pretreatment at different concentrations for 24 h.(2)A total of 278 clinical samples were col-lected from Beijing Tongren Hospital,including 132 patients without diabetes and 146 patients with T2DM.The fasting blood glucose and CFTR levels of these samples were detected.RESULTS:(1)Glucose at 10,20 and 30 mmol/L signifi-cantly increased the mRNA level of CFTR(P<0.05),and glucose at 5,15,20 and 30 mmol/L significantly increased the protein level of CFTR(P<0.05 or P<0.01)in pancreaticβcell line.Glucose at 30 mmol/L significantly increased the mRNA level of CFTR in primarily isolated mouse pancreatic islets(P<0.01).Pancreaticβcells treated with 20 and 30 mmol/L glucose for 24 h showed significantly higher basal insulin level(P<0.05).(2)In clinical samples,there was a significant positive correlation between fasting blood glucose and plasma CFTR protein level(r=0.314,P<0.01).CON⁃CLUSION:Glucose up-regulates the level of CFTR in pancreaticβcells and thus increasing the basal insulin level,which may contribute to the pathogenesis of T2DM.

关 键 词：葡萄糖 囊性纤维化跨膜传导调节因子 胰腺Β细胞 胰岛素 2型糖尿病 

分 类 号：R587.1[医药卫生—内分泌] R363.2[医药卫生—内科学]