iNOS/IRS1/AKT/GSK-3β信号通路在慢性间歇低氧致胰岛素抵抗中的作用  

Role of the iNOS/IRS1/AKT/GSK-3βsignaling pathway in chronic intermittent hypoxia-induced insulin resistance

作　　者：靳美娜 周雪利 李海波 白炜 贾楚璇 高立 任丽珏[2] 陈青宇[3] 王瑞[4] 李华 魏翠英[1] Jin Meina;Zhou Xueli;Li Haibo;Bai Wei;Jia Chuxuan;Gao Li;Ren Lijue;Chen Qingyu;Wang Rui;Li Hua;Wei Cuiying(Dept of Geriatrics,The First Affiliated Hospital of Baotou Medical College,Baotou 014000;Dept of Endocrinology,The First Affiliated Hospital of Baotou Medical College,Baotou 014000;Dept of Stomatology,The First Affiliated Hospital of Baotou Medical College,Baotou 014000;Animal Research Laboratory,Baotou Medical College,Baotou 014000;People′s Hospital of Gushang County,Baotou,Inner Mongolia Autonomous Region,Baotou 014200)

机构地区：[1]包头医学院第一附属医院老年医学科,包头014000 [2]包头医学院第一附属医院内分泌科,包头014000 [3]包头医学院第一附属医院口腔科,包头014000 [4]包头医学院动物研究室,包头014000 [5]包头市固阳县人民医院,包头014200

出　　处：《安徽医科大学学报》2025年第2期210-217,共8页Acta Universitatis Medicinalis Anhui

基　　金：国家自然科学基金(编号:81660020);内蒙古自治区自然科学基金(编号:2023MS08044);内蒙古自治区科技计划项目(编号:2021GG0219)。

摘　　要：目的对照观察慢性间歇低氧-复氧条件下大鼠肝脏病理改变和诱导型一氧化氮合酶(iNOS)、磷酸化胰岛素受体底物1丝氨酸307(p-IRS1ser 307)、磷酸化蛋白激酶B丝氨酸473(p-AKTser 473)、糖原合成酶激酶-3β(GSK-3β)、糖原合酶(GS)蛋白的表达水平,探讨iNOS/IRS1/AKT/GSK-3β信号通路在慢性间歇低氧所致胰岛素抵抗中的作用。方法将40只SD大鼠随机分为对照组(NC组)和实验组(CIH组),每组20只。NC组置于常氧环境12周,CIH组先予间歇低氧8周,随后恢复常氧饲养至第12周。两组均于基线、第8周、第12周分别测定空腹血糖(FBG)、空腹胰岛素(FINS)水平,并取肝脏组织进行病理检测和iNOS、p-IRS1ser 307、p-AKTser 473、GSK3β、GS水平测定,比较组间差异。结果基线时,两组肝脏病理及各项观察指标间差异无统计学意义;8周时,与NC组比较,CIH组肝脏病理出现肝血窦和肝细胞索排列紊乱、肝细胞水肿、细胞核变小、淋巴细胞浸润增多并可见少量脂肪空泡,FBG、FINS、胰岛素抵抗指数(HOMA-IR)、iNOS mRNA、p-IRS1ser 307蛋白、GSK-3β蛋白水平升高,p-AKTser 473蛋白、GS蛋白水平降低,差异均有统计学意义(均P<0.05);12周时,与NC组比较,CIH组未见淋巴细胞浸润,脂肪空泡增多,其它已发生的病理损伤无改善,p-AKTser 473蛋白水平升高,p-IRS1ser 307蛋白与GS蛋白水平降低,差异均有统计学意义(均P<0.05)。Pearson相关分析显示:8周时CIH组HOMA-IR与iNOS mRNA、p-IRS1ser 307蛋白、GSK-3β蛋白水平正相关(r=0.874,0.817,0.872;均P<0.05),与p-AKTser473蛋白、GS蛋白水平呈负相关(r=-0.886,-0.879;均P<0.05)。结论慢性间歇低氧可以导致肝脏病理损害,即使复氧干预也不能逆转,并可能通过上调iNOS mRNA的表达,调控IRS1/AKT/GSK-3β信号通路,从而介导胰岛素抵抗的发生。Objective To pathological changes and inducible nitric oxide synthase(iNOS),phosphorylated insulin receptor substrate 1 serine 307(p-IRS1ser 307),phosphorylated protein kinase B serine 473(p-AKTser 473),glycogen synthase kinase-3β(GSK-3β),and gluconeogenic synthase(GS)proteins were observed in the liver of rats under the condition of chronic intermittent hypoxia-replicated oxygen in control.And to explore the role of iNOS/IRS1/AKT/GSK-3βsignaling pathway in chronic intermittent hypoxia-induced insulin resistance.Methods Forty SD rats were randomly divided into a control group(NC group)and an experimental group(CIH group),with 20 rats in each group.The NC group was placed in a normoxic environment for 12 weeks,while the CIH group was first subjected to intermittent hypoxia for 8 weeks,and then resumed normoxic rearing until the 12th week.Fasting blood glucose(FBG)and fasting insulin(FINS)were measured at baseline,week 8 and week 12,and liver tissues were taken for pathology and measurement of iNOS,p-IRS1ser 307,p-AKTser 473,GSK3βand GS levels,to compare the differences between groups.Results At baseline,there was no significant difference in liver pathology between the two groups,and the observed indexes were not statistically significant(P>0.05);at 8 weeks,compared with the NC group,liver pathology in the CIH group showed significant disorganization of hepatic blood sinusoids and hepatocyte cords,obvious hepatocyte edema,smaller nuclei,increased lymphocyte infiltration,and a small number of fat vacuoles,significantly higher levels of FBG,FINS,insulin resistance index(HOMA-IR),iNOS mRNA,p-IRS1ser 307 protein,GSK-3βprotein levels,and decreased p-AKTser 473 protein and GS protein levels,all of which were statistically significant(all P<0.05).IRS1ser 307 protein,GSK-3βprotein levels were increased,p-AKTser 473 protein and GS protein levels were decreased,and the differences were statistically significant(all P<0.05);at 12 weeks,no lymphocyte infiltration was seen in the CIH group compared with that of the NC gr

关 键 词：慢性间歇低氧-复氧 胰岛素抵抗 诱导型一氧化氮合酶 IRS1/AKT/GSK-3β信号通路 SD大鼠 肝脏 

分 类 号：R587.1[医药卫生—内分泌]