[1]张 普a,张 俊b,李雪锋b.AMPK/IR/IRS1通路介导影响糖尿病小鼠心肌胰岛素抵抗机制的实验研究[J].现代检验医学杂志,2025,40(02):119.[doi:10.3969/j.issn.1671-7414.2025.02.022]
　ZHANG Pua,ZHANG Junb,LI Xuefengb.Experimental Study of AMPK/ IR /IRS1 Pathway Mediating the Mechanism of Myocardial Insulin Resistance in Diabetic Mice[J].Journal of Modern Laboratory Medicine,2025,40(02):119.[doi:10.3969/j.issn.1671-7414.2025.02.022]
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AMPK/IR/IRS1通路介导影响糖尿病小鼠心肌胰岛素抵抗机制的实验研究()
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《现代检验医学杂志》[ISSN:/CN:]

卷:
第40卷
期数:
2025年02期
页码:
119
栏目:
论著
出版日期:
2025-03-15

文章信息/Info

Title:
Experimental Study of AMPK/ IR /IRS1 Pathway Mediating the Mechanism of Myocardial Insulin Resistance in Diabetic Mice
文章编号:
1671-7414（2025）02-119-05
作者:
张 普a; 张 俊b; 李雪锋b
［太和医院（湖北医药学院附属医院） a．心血管疾病诊疗中心；b．内分泌风湿免疫科，湖北十堰 442000］
Author(s):
ZHANG Pua; ZHANG Junb; LI Xuefengb
［a.Cardiovascular Disease Diagnosis and Treatment Center； b.Department of Endocrinology, Rheumatology and Immunology，Taihe Hospital （Affiliated Hospital of Hubei University of Medicine），Hubei Shiyan 442000，China］
关键词:
糖尿病; 心肌; AMP 依赖的蛋白激酶/ 胰岛素受体/ 胰岛素受体底物通路; 胰岛素抵抗; 氧化应激
分类号:
R-332
DOI:
10.3969/j.issn.1671-7414.2025.02.022
文献标志码:
A
摘要:
目的 探究AMP 依赖的蛋白激酶（AMPK）/ 胰岛素受体（IR）/ 胰岛素受体底物（IRS1）通路在糖尿病小鼠心肌胰岛素抵抗中的作用及可能机制。方法 将30 只C57BL/6J 小鼠根据实验设计随机分为对照组、糖尿病组及AMPK激活组，每组10 只。使用小鼠动态血糖检测仪检测小鼠空腹血糖（FBG）；糖化血红蛋白（HbA1c）试剂盒检测小鼠HbA1c 水平；胰岛素检测试剂盒检测小鼠空腹胰岛素（FINS）；超声心动图检测小鼠心率（HR）、左心室收缩末期内径(LVIDd)、左心室舒张末期内径（LVIDs）、射血分数（EF）及左室短轴缩短率（LVFS）。Masson 染色检测小鼠心肌胶原沉积水平。ELISA 试剂盒检测小鼠总胆固醇（TC）、三酰甘油（TG）、低密度脂蛋白- 胆固醇（LDL-C）、谷胱甘肽（GSH）、丙二醛（MDA）及活性氧（ROS）水平。蛋白质免疫印迹（WB）检测心肌组织中AMPK，IR，IRS1 蛋白水平。RT-qPCR 检测心肌组织中AMPK，IR，IRS1 的mRNA 水平。结果 与对照组相比，糖尿病组小鼠FBG，HbA1c，FINS，TC，TG，LDL-C 水平增加（t=14.94 ～ 63.46），心功能指标HR，EF 及LVFS 减少（t=56.62，199.00，42.50），LVIDd 增加（t=176.80），差异具有统计学意义（均P<0.05）；LVIDs 变化差异无统计学意义（t=3.46，P>0.05）；小鼠心肌间质小血管周围胶原沉积增加；血清GSH 水平减少（t=5.75），ROS 与MDA 水平增加（t=22.60，15.18），心肌组织中AMPK，IR，IRS1 蛋白（t=7.00，4.33，3.66）及mRNA（t=2.61，5.17，6.79）表达水平减少，差异具有统计学意义（均P<0.05）。与糖尿病组相比，AMPK 激活组小鼠FBG，HbA1c，FINS，TC，TG，LDL-C 水平减少（t=9.14 ～ 56.34），心功能指标HR，EF 及LVFS 增加（t=135.90，152.00，41.99），LVIDd 减少（t=203.20），差异具有统计学意义（均P<0.05）；LVIDs 变化差异无统计学意义（t=1.58，P>0.05）；血管周围胶原沉积减少；血清GSH 水平增加（t=19.60），ROS 与MDA 水平减少（t=32.90，23.44），心肌组织AMPK，IR，IRS1 蛋白（t=15.14，29.44，17.15）及mRNA（t=11.52，9.67，8.49）表达水平增加，差异具有统计学意义（均P<0.05）。结论 激活AMPK可改善糖尿病小鼠心功能结构，降低血糖血脂水平并下调氧化应激水平，作用机制可能与AMPK/ IR /IRSs 通路介导的胰岛素抵抗相关。
Abstract:
Objective To explore the role and possible mechanism of adenosine monophosphate (AMP)-dependent protein kinase（AMPK）/insulin receptor (IR)/ insulin receptor substrate(IRS1) pathway in myocardial insulin resistance in diabetic mice. Methods Thirty C57BL/6J mice were randomly divided into control group, diabetes group and AMPK-activated group according to the experimental design, with 10 mice in each group. Fasting blood glucose (FBG) was detected by a dynamic blood glucose detector detected . Glycosylated hemoglobin kit (HbA1c) was used to detect the level of HbA1c in mice. Fasting insulin (FINS) was detected by insulin detection kit in mice. Heart rate (HR)，left ventricular end-systolic diameter(LVIDd), left ventricular end-diastolic diameter (LVIDs), ejection fraction(EF) and left ventricular fractional shortening (LVFS) were measured by echocardiography. Masson staining was used to detect myocardial collagen deposition in mice. The levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), glutathione (GSH), malondialdehyde (MDA) and reactive oxygen species (ROS) were detected by ELISA kit. The protein levels of AMPK, IR and IRS1 in myocardial tissue were detected by Western blotting(WB). RT-qPCR detected the mRNA levels of AMPK, IR and IRS1 in myocardial tissue. Results Compared with the control group, the levels of FBG，HbA1c，FINS，TC，TG and LDL-C in diabetic group were increased （t=14.94 ～ 63.46）, the cardiac function indexes HR，EF and LVFS decreased（t=56.62, 199.00, 42.50），LVIDd increased (t=176.80), and the differences were statistically significan（t all P<0.05），and there was no significant difference in LVIDs (t=3.46, P>0.05). The collagen deposition around small blood vessels in myocardial interstitial was increased, and the serum GSH level was decreased(t=5.75), ROS and MDA levels increased (t= 22.60, 15.18), the expression levels of AMPK, IR, IRS1 protein (t=7.00, 4.33, 3.66) and mRNA (t=2.61, 5.17, 6.79) in myocardial tissue decreased，and the differences were statistically significant（all P<0.05）. Compared with diabetic group, the levels of FBG，HbA1c，FINS，TC，TG and LDL-C in AMPK activated group were decreased （t=9.14 ～ 56.34）, the cardiac function indexes HR，EF and LVFS increased（t=135.90, 152.00, 41.99）, LVIDd decreased (t=203.20), and the differences were statistically significant（all P<0.05），and there was no significant difference in LVIDs (t=1.58, P>0.05). Perivascular collagen deposition decreased and serum GSH level increased(t=19.60), ROS and MDA levels decreased (t=32.90, 23.44), the expression levels of AMPK, IR, IRS1 protein (t=15.14, 29.44, 17.15) and mRNA (t=11.52, 9.67, 8.49) in myocardial tissue increased, and the differences were statistically significan（t all P<0.05）. Conclusion Activation of AMPK can improve the cardiac function structure, reduce blood glucose and lipid levels and reduce oxidative stress levels in diabetic mice. The mechanism of action may be related to insulin resistance mediated by AMPK/ IR/IRS1 pathway.

参考文献/References:

[1] ZHENG Yan, LEY S H, HU F B. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications[J].Nature Reviews Endocrinology, 2018, 14(2): 88-98.
[2] CHO N H, SHAW J E, KARURANGA S, et al. IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045 [J]. Diabetes Research and Clinical Practice, 2018, 138: 271-281.
[3] NEWMAN J D, VANI A K, ALEMAN J O, et al. The changing landscape of diabetes therapy for cardiovascular risk reduction: JACC state-of-theart review[J]. Journal of the American College of Cardiology, 2018, 72(15): 1856-1869.
[4] KUSUNOSE K, IMAI T, TANAKA A,et al. Effects of canagliflozin on NT-proBNP stratified by left ventricular diastolic function in patients with type 2 diabetes and chronic heart failure: a sub analysis of the CANDLE trial[J]. Cardiovascular Diabetology, 2021,20(1):186.
[5] PFEIFER M, TOWNSEND R R, DAVIES M J, et al. Effects of canagliflozin, a Sodium glucose cotransporter 2 inhibitor, on blood pressure and markers of arterial stiffness in patients with type 2 diabetes mellitus: a post hoc analysis[J]. Cardiovascular Diabetology, 2017, 16(1): 29.
[6] CHEN Meixiang, HUANG Nanqu, LIU Ju, et al. AMPK: a bridge between diabetes mellitus and Alzheimer’s disease [J]. Behavioural Brain Research, 2021, 400: 113043.
[7] POSNER B I. Insulin signalling: the inside story [J].Canadian Journal of diabetes, 2017, 41(1): 108-113.
[8] YARIBEYGI H, FARROKHI F R, BUTLER A E, et al. Insulin resistance: review of the underlying molecular mechanisms[J].Journal of Cellular Physiology, 2019, 234(6): 8152-8161.
[9] SU Jingqian, TANG Lu, LUO Yingsheng, et al. Research progress on drugs for diabetes based on insulin receptor/insulin receptor substrate [J].Biochemical Pharmacology,2023,217:115830.
[10] DARENSKAYA M A, KOLESNIKOVA L I , KOLESNIKOV S I. Oxidative stress: pathogenetic role in diabetes mellitus and its complications and therapeutic approaches to correction[J]. Bulletin of Experimental Biology and Medicine, 2021, 171(2): 179-189.
[11] 沈伟兴, 汤佳瑾, 傅鹏.2 型糖尿病肾病患者外周血micorRNA-155 水平与肾小球滤过率的相关性研究[J]. 现代检验医学杂志,2022,37(1):12-16, 37. SHEN Weixing, TANG Jiajin, FU Peng. Correlation between microRNA-155 level in peripheral blood and glomerular filtration rate in patients with type 2 diabetic nephropathy [J]. Journal of Modern Laboratory Medicine, 2022, 37(1): 12-16, 37.
[12] SUN Yaoxiang, TAO Qing, WU Xueqin, et al. The utility of exosomes in diagnosis and therapy of diabetes mellitus and associated complications [J]. Frontiers in Endocrinology(Lausanne),2021,12:756581.
[13] KENNY H C, ABEL E D. Heart failure in type 2 diabetes mellitus[J]. Circulation Research, 2019, 124(1): 121-141.
[14] ENTEZARI M, HASHEMI D, TAHERIAZAM A, et al. AMPK signaling in diabetes mellitus, insulin resistance and diabetic complications: a pre-clinical and clinical investigation [J]. Biomedicine & Pharmacotherapy,2022,146:112563.
[15] LI Sai,HUANG Qin,ZHANG Liwen,et al. Effect of CAPE-pNO2 against type 2 diabetes mellitus via the AMPK/GLUT4/ GSK3β/PPARα pathway in HFD/STZ-induced diabetic mice [J]. European Journal of Pharmacology,2019,853:1-10.
[16] WANG Chunyan, ZHU Lijie, YUAN Wenlin, et al. Diabetes aggravates myocardial ischaemia reperfusion injury via activating Nox2-related programmed cell death in an AMPK-dependent manner[J]. Journal of Cellular and Molecular Medicine, 2020, 24(12): 6670-6679.

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备注/Memo

备注/Memo:
基金项目：湖北省卫生健康委员会科研项目（WJ2020231）。
作者简介：张普（1987-），男，本科，主治医师，研究方向：血管疾病与代谢性疾病，E-mail：yingyingwang980809@163.com。
更新日期/Last Update: 2025-03-15