炎症细胞因子在肝硬化患者糖代谢紊乱中的作用

吴云冲; 杨颜颜; 李川; 吴小欢; 林世德

doi:10.12449/JCH240926

炎症细胞因子在肝硬化患者糖代谢紊乱中的作用

DOI: 10.12449/JCH240926

遵义医科大学附属医院感染科，贵州遵义 563000

基金项目:

国家自然科学基金 (81860114)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：吴云冲负责对研究思路的设计、论文的撰写；吴云冲、杨颜颜、李川、吴小欢负责查阅相关文献；林世德负责指导修改论文及最后定稿。

详细信息

通信作者:
林世德， linshide6@zmc.edu.cn （ORCID： 0000-0001-8803-4069）

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- 被引次数: 0
出版历程
- 收稿日期: 2023-12-13
- 录用日期: 2024-02-22
- 出版日期: 2024-09-25

Role of inflammatory cytokines in disorder of glucose metabolism in patients with liver cirrhosis

Department of Infectious Diseases，Affiliated Hospital of Zunyi Medical University，Zunyi，Guizhou 563000，China

Research funding:

National Natural Science Foundation of China (81860114)

More Information

Corresponding author: LIN Shide， linshide6@zmc.edu.cn （ORCID： 0000-0001-8803-4069）

摘要

摘要: 近年来对肝硬化发生、发展过程中白细胞介素-1β、白细胞介素-6、白细胞介素-10、白细胞介素-17、肿瘤坏死因子-α、干扰素-γ、C反应蛋白等常见的炎症细胞因子的作用及机制有了更深入的了解，对炎症细胞因子与糖代谢紊乱及胰岛功能受损的相关性研究也取得了较大的进展。本文综述了肝硬化患者炎症细胞因子及其在糖代谢紊乱、胰岛功能受损中的作用，为阐明肝源性糖尿病的发生机制及其临床管理提供理论依据。
- 肝硬化 /
- 胰岛素抵抗 /
- 炎症 /
- 细胞因子类
Abstract: In recent years， there has been a deeper understanding of the role and mechanisms of common inflammatory cytokines in the development and progression of liver cirrhosis， such as interleukin-1β， interleukin-6， interleukin-10， interleukin-17， tumor necrosis factor-α， interferon-γ， and C-reactive protein， and significant achievements have also been made in the research on the association of these inflammatory cytokines with disorder of glucose metabolism and pancreatic islet dysfunction. This article reviews the role of inflammatory cytokines in patients with liver cirrhosis and their impact on disorder of glucose metabolism and pancreatic islet dysfunction， in order to provide a theoretical basis for clarifying the pathogenesis of hepatogenous diabetes and performing the clinical management of the disease.
- Liver Cirrhosis /
- Insulin Resistance /
- Inflammation /
- Cytokines

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参考文献(60)

[1]	HAN HS, KANG G, KIM JS, et al. Regulation of glucose metabolism from a liver-centric perspective[J]. Exp Mol Med, 2016, 48( 3): e218. DOI: 10.1038/emm.2015.122.
[2]	RODEN M, BERNROIDER E. Hepatic glucose metabolism in humans: Its role in health and disease[J]. Best Pract Res Clin Endocrinol Metab, 2003, 17( 3): 365- 383. DOI: 10.1016/s1521-690x(03)00031-9.
[3]	ADEVA-ANDANY MM, PÉREZ-FELPETE N, FERNÁNDEZ-FERNÁNDEZ C, et al. Liver glucose metabolism in humans[J]. Biosci Rep, 2016, 36( 6): e00416. DOI: 10.1042/BSR20160385.
[4]	RADWAN HA, HAMED EH, SALEH OM. Significance of serum adiponectin and insulin resistance levels in diagnosis of Egyptian patients with chronic liver disease and HCC[J]. Asian Pac J Cancer Prev, 2019, 20( 6): 1833- 1839. DOI: 10.31557/APJCP.2019.20.6.1833.
[5]	GARCÍA-COMPEÁN D, GONZÁLEZ-GONZÁLEZ JA, LAVALLE-GONZÁLEZ FJ, et al. Hepatogenous diabetes: Is it a neglected condition in chronic liver disease?[J]. World J Gastroenterol, 2016, 22( 10): 2869- 2874. DOI: 10.3748/wjg.v22.i10.2869.
[6]	REHMAN K, AKASH MS. Mechanisms of inflammatory responses and development of insulin resistance: How are they interlinked?[J]. J Biomed Sci, 2016, 23( 1): 87. DOI: 10.1186/s12929-016-0303-y.
[7]	PEIRÓ T, PATEL DF, AKTHAR S, et al. Neutrophils drive alveolar macrophage IL-1β release during respiratory viral infection[J]. Thorax, 2018, 73( 6): 546- 556. DOI: 10.1136/thoraxjnl-2017-210010.
[8]	XIAO WS, LE YY, ZENG SL, et al. Role of pyroptosis in liver diseases[J]. J Clin Hepatol, 2020, 36( 12): 2847- 2850. DOI: 10.3969/j.issn.1001-5256.2020.12.044. 肖伟松, 乐滢玉, 曾胜澜, 等. 细胞焦亡在肝脏疾病中的作用[J]. 临床肝胆病杂志, 2020, 36( 12): 2847- 2850. DOI: 10.3969/j.issn.1001-5256.2020.12.044.
[9]	WANG Y, CUI L, YANG GF, et al. Hepatitis B e antigen inhibits NF-κB activity by interrupting K63-linked ubiquitination of NEMO[J]. J Virol, 2019, 93( 2): e00667- e00618. DOI: 10.1128/JVI.00667-18.
[10]	DONG DJ, LU HB, WU W, et al. Correlation between the expression levels of NLRP3 and IL-1β mRNA and the pathogenesis of alcoholic cirrhosis and its mechanism[J]. Chin Hepatol, 2019, 24( 3): 265- 267. DOI: 10.14000/j.cnki.issn.1008-1704.2019.03.017. 董德嘉, 卢海波, 吴伟, 等. NLRP3、IL-1β mRNA表达水平与酒精性肝硬化发病相关性及作用机制分析[J]. 肝脏, 2019, 24( 3): 265- 267. DOI: 10.14000/j.cnki.issn.1008-1704.2019.03.017.
[11]	BÖNI-SCHNETZLER M, THORNE J, PARNAUD G, et al. Increased interleukin(IL)-1beta messenger ribonucleic acid expression in beta-cells of individuals with type 2 diabetes and regulation of IL-1beta in human islets by glucose and autostimulation[J]. J Clin Endocrinol Metab, 2008, 93( 10): 4065- 4074. DOI: 10.1210/jc.2008-0396.
[12]	WU WT, SYED F, SIMPSON E, et al. The impact of pro-inflammatory cytokines on alternative splicing patterns in human islets[J]. Diabetes, 2021, 71( 1): 116- 127. DOI: 10.2337/db20-0847.
[13]	CHEN HM, JIN GJ. Downregulation of Salusin-β protects renal tubular epithelial cells against high glucose-induced inflammation, oxidative stress, apoptosis and lipid accumulation via suppressing miR-155-5p[J]. Bioengineered, 2021, 12( 1): 6155- 6165. DOI: 10.1080/21655979.2021.1972900.
[14]	SHA WX, HU F, BU SZ. Mitochondrial dysfunction and pancreatic islet β-cell failure(Review)[J]. Exp Ther Med, 2020, 20( 6): 266. DOI: 10.3892/etm.2020.9396.
[15]	BENSELLAM M, CHAN JY, LEE KL, et al. Phlda3 regulates beta cell survival during stress[J]. Sci Rep, 2019, 9( 1): 12827. DOI: 10.1038/s41598-019-49289-5.
[16]	RUSCITTI P, MASEDU F, ALVARO S, et al. Anti-interleukin-1 treatment in patients with rheumatoid arthritis and type 2 diabetes(TRACK): A multicentre, open-label, randomised controlled trial[J]. PLoS Med, 2019, 16( 9): e1002901. DOI: 10.1371/journal.pmed.1002901.
[17]	KAUR S, BANSAL Y, KUMAR R, et al. A panoramic review of IL-6: Structure, pathophysiological roles and inhibitors[J]. Bioorg Med Chem, 2020, 28( 5): 115327. DOI: 10.1016/j.bmc.2020.115327.
[18]	LI YX, REN YL, FU HJ, et al. Hepatitis B virus middle protein enhances IL-6 production via p38 MAPK/NF-κB pathways in an ER stress-dependent manner[J]. PLoS One, 2016, 11( 7): e0159089. DOI: 10.1371/journal.pone.0159089.
[19]	CHEN Z, LI YX, FU HJ, et al. Hepatitis B virus core antigen stimulates IL-6 expression via p38, ERK and NF-κB pathways in hepatocytes[J]. Cell Physiol Biochem, 2017, 41( 1): 91- 100. DOI: 10.1159/000455954.
[20]	YI HY, ZHANG Y, YANG XF, et al. Hepatitis B core antigen impairs the polarization while promoting the production of inflammatory cytokines of M2 macrophages via the TLR2 pathway[J]. Front Immunol, 2020, 11: 535. DOI: 10.3389/fimmu.2020.00535.
[21]	COSTA D, SIMBRUNNER B, JACHS M, et al. Systemic inflammation increases across distinct stages of advanced chronic liver disease and correlates with decompensation and mortality[J]. J Hepatol, 2021, 74( 4): 819- 828. DOI: 10.1016/j.jhep.2020.10.004.
[22]	AWAZAWA M, UEKI K, INABE K, et al. Adiponectin enhances insulin sensitivity by increasing hepatic IRS-2 expression via a macrophage-derived IL-6-dependent pathway[J]. Cell Metab, 2011, 13( 4): 401- 412. DOI: 10.1016/j.cmet.2011.02.010.
[23]	MOHAMAD HE, ASKER ME, KESHAWY MM, et al. Infliximab ameliorates tumor necrosis factor-alpha exacerbated renal insulin resistance induced in rats by regulating insulin signaling pathway[J]. Eur J Pharmacol, 2020, 872: 172959. DOI: 10.1016/j.ejphar.2020.172959.
[24]	WANG XQ, ZHAO DN, CUI YJ, et al. Proinflammatory macrophages impair skeletal muscle differentiation in obesity through secretion of tumor necrosis factor-α via sustained activation of p38 mitogen-activated protein kinase[J]. J Cell Physiol, 2019, 234( 3): 2566- 2580. DOI: 10.1002/jcp.27012.
[25]	FANG PH, ZHANG L, YU M, et al. Activiated galanin receptor 2 attenuates insulin resistance in skeletal muscle of obese mice[J]. Peptides, 2018, 99: 92- 98. DOI: 10.1016/j.peptides.2017.11.018.
[26]	ISAC L, SONG JQ. Interleukin 10 promotor gene polymorphism in the pathogenesis of psoriasis[J]. Acta Dermatovenerol Alp Pannonica Adriat, 2019, 28( 3): 119- 123.
[27]	CLÀRIA J, STAUBER RE, COENRAAD MJ, et al. Systemic inflammation in decompensated cirrhosis: Characterization and role in acute-on-chronic liver failure[J]. Hepatology, 2016, 64( 4): 1249- 1264. DOI: 10.1002/hep.28740.
[28]	LI C, XING SJ, DUAN XZ, et al. The changes of frequencies of regulatory T cells in peripheral blood and serum levels of IL-1β, IL-6 and IL-10 in patients with HBV-related liver cirrhosis[J]. J Clin Hepatol, 2012, 15( 3): 244- 246. DOI: 10.3969/j.issn.1672-5069.2012.03.023. 李晨, 邢少军, 段学章, 等. 乙型肝炎肝硬化患者外周血调节性T细胞频率及血清IL-1β、IL-6和IL-10水平的变化[J]. 实用肝脏病杂志, 2012, 15( 3): 244- 246. DOI: 10.3969/j.issn.1672-5069.2012.03.023.
[29]	GE DH. Changes and significance of Th1 and Th2 cytokines in peripheral blood of patients with chronic hepatitis B, liver cirrhosis and liver cancer[J]. Chin J Public Health Eng, 2022, 21( 1): 160- 162. DOI: 10.19937/j.issn.1671-4199.2022.01.057. 葛大赫. 慢性乙型肝炎及肝硬化、肝癌患者外周血Th1、Th2类细胞因子表达变化及意义[J]. 中国卫生工程学, 2022, 21( 1): 160- 162. DOI: 10.19937/j.issn.1671-4199.2022.01.057.
[30]	KUMAR R, NG S, ENGWERDA C. The role of IL-10 in malaria: A double edged sword[J]. Front Immunol, 2019, 10: 229. DOI: 10.3389/fimmu.2019.00229.
[31]	HOLDER KA, GRANT MD. Human cytomegalovirus IL-10 augments NK cell cytotoxicity[J]. J Leukoc Biol, 2019, 106( 2): 447- 454. DOI: 10.1002/JLB.2AB0418-158RR.
[32]	GOTOH K, INOUE M, MASAKI T, et al. A novel anti-inflammatory role for spleen-derived interleukin-10 in obesity-induced inflammation in white adipose tissue and liver[J]. Diabetes, 2012, 61( 8): 1994- 2003. DOI: 10.2337/db11-1688.
[33]	BEPPU LY, MOOLI RGR, QU XY, et al. Tregs facilitate obesity and insulin resistance via a Blimp-1/IL-10 axis[J]. JCI Insight, 2021, 6( 3): e140644. DOI: 10.1172/jci.insight.140644.
[34]	ZHANG HB, YAN X, YANG C, et al. Intrahepatic T helper 17 cells recruited by hepatitis B virus X antigen-activated hepatic stellate cells exacerbate the progression of chronic hepatitis B virus infection[J]. J Viral Hepat, 2020, 27( 11): 1138- 1149. DOI: 10.1111/jvh.13352.
[35]	ZHAO CJ, ZHANG J, YANG Y, et al. Correlation analysis of Th17 and related cytokines with liver stiffness measurement, liver function and adiponectin levels in alcoholic cirrhosis patients[J]. Prog Mod Biomed, 2020, 20( 22): 4303- 4306. DOI: 10.13241/j.cnki.pmb.2020.22.022. 赵春娟, 张静, 杨艳, 等. Th17及相关细胞因子与酒精性肝硬化患者肝脏硬度值、肝功能及脂联素水平的相关性分析[J]. 现代生物医学进展, 2020, 20( 22): 4303- 4306. DOI: 10.13241/j.cnki.pmb.2020.22.022.
[36]	CHEHIMI M, VIDAL H, ELJAAFARI A. Pathogenic role of IL-17-producing immune cells in obesity, and related inflammatory diseases[J]. J Clin Med, 2017, 6( 7): 68. DOI: 10.3390/jcm6070068.
[37]	ABDEL-MONEIM A, BAKERY HH, ALLAM G. The potential pathogenic role of IL-17/Th17 cells in both type 1 and type 2 diabetes mellitus[J]. Biomed Pharmacother, 2018, 101: 287- 292. DOI: 10.1016/j.biopha.2018.02.103.
[38]	DUAN W, DING YC, YU XF, et al. Metformin mitigates autoimmune insulitis by inhibiting Th1 and Th17 responses while promoting Treg production[J]. Am J Transl Res, 2019, 11( 4): 2393- 2402.
[39]	WAJANT H, PFIZENMAIER K, SCHEURICH P. Tumor necrosis factor signaling[J]. Cell Death Differ, 2003, 10( 1): 45- 65. DOI: 10.1038/sj.cdd.4401189.
[40]	BARATHAN M, RIAZALHOSSEINI B, IYADORAI T, et al. Comparative expression of pro-inflammatory and apoptotic biosignatures in chronic HBV-infected patients with and without liver cirrhosis[J]. Microb Pathog, 2021, 161( Pt A): 105231. DOI: 10.1016/j.micpath.2021.105231.
[41]	JALAN R, FERNANDEZ J, WIEST R, et al. Bacterial infections in cirrhosis: A position statement based on the EASL Special Conference 2013[J]. J Hepatol, 2014, 60( 6): 1310- 1324. DOI: 10.1016/j.jhep.2014.01.024.
[42]	VOMHOF-DEKREY EE, PICKLO MJ SR. The Nrf2-antioxidant response element pathway: A target for regulating energy metabolism[J]. J Nutr Biochem, 2012, 23( 10): 1201- 1206. DOI: 10.1016/j.jnutbio.2012.03.005.
[43]	BOUTARI C, TZIOMALOS K, ATHYROS VG. The adipokines in the pathogenesis and treatment of nonalcoholic fatty liver disease[J]. Hippokratia, 2016, 20( 4): 259- 263.
[44]	ZHOU C, GAO F, ZHANG JY, et al. The role of tumor necrosis factor α invertase in insulin resistance and its related mechanism[J]. Res Integr Tradit Chin West Med, 2019, 11( 5): 270- 272, 275. DOI: 10.3969/j.issn.1674-4616.2019.05.016. 周聪, 高峰, 张皎月, 等. 肿瘤坏死因子α转化酶在胰岛素抵抗中的作用及有关机制[J]. 中西医结合研究, 2019, 11( 5): 270- 272, 275. DOI: 10.3969/j.issn.1674-4616.2019.05.016.
[45]	BOGAN JS. Regulation of glucose transporter translocation in health and diabetes[J]. Annu Rev Biochem, 2012, 81: 507- 532. DOI: 10.1146/annurev-biochem-060109-094246.
[46]	SCHEITHAUER TPM, RAMPANELLI E, NIEUWDORP M, et al. Gut microbiota as a trigger for metabolic inflammation in obesity and type 2 diabetes[J]. Front immunol, 2020, 11: 571731. DOI: 10.3389/fimmu.2020.571731.
[47]	YANG LY, WU PW, YANG YN. Cytokine mediated β cell injury mechanism in type 2 diabetes[J]. Foreign Med Sci: Endocrinol, 2005, 25( 1): 13- 15 DOI: CNKI:SUN:GNFM.0.2005-01-005. 杨立勇, 吴佩文, 杨永年. 细胞因子介导的2型糖尿病β细胞损伤机制[J]. 国外医学: 内分泌学分册, 2005, 25( 1): 13- 15. DOI: 10.3760/cma.j.issn.1673-4157.2005.01.005.
[48]	LEFRANÇAIS E, ORTIZ-MUÑOZ G, CAUDRILLIER A, et al. The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors[J]. Nature, 2017, 544( 7648): 105- 109. DOI: 10.1038/nature21706.
[49]	NOOR MT, MANORIA P. Immune dysfunction in cirrhosis[J]. J Clin Transl Hepatol, 2017, 5( 1): 50- 58. DOI: 10.14218/JCTH.2016.00056.
[50]	ŠESTAN M, MARINOVIĆ S, KAVAZOVIĆ I, et al. Virus-induced interferon-γ causes insulin resistance in skeletal muscle and derails glycemic control in obesity[J]. Immunity, 2018, 49( 1): 164- 177. e 6. DOI: 10.1016/j.immuni.2018.05.005.
[51]	ZHOU HY, PENG XY, HU J, et al. DsbA-L deficiency in T cells promotes diet-induced thermogenesis through suppressing IFN-γ production[J]. Nat Commun, 2021, 12( 1): 326. DOI: 10.1038/s41467-020-20665-4.
[52]	EIZIRIK DL, PASQUALI L, CNOP M. Pancreatic β-cells in type 1 and type 2 diabetes mellitus: Different pathways to failure[J]. Nat Rev Endocrinol, 2020, 16( 7): 349- 362. DOI: 10.1038/s41574-020-0355-7.
[53]	BAE HR, SHIN SK, HAN Y, et al. D-allulose ameliorates dysregulated macrophage function and mitochondrial NADH homeostasis, mitigating obesity-induced insulin resistance[J]. Nutrients, 2023, 15( 19): 4218. DOI: 10.3390/nu15194218.
[54]	SLAATS J, OEVER J TEN, van de VEERDONK FL, et al. IL-1β/IL-6/CRP and IL-18/ferritin: Distinct inflammatory programs in infections[J]. PLoS Pathog, 2016, 12( 12): e1005973. DOI: 10.1371/journal.ppat.1005973.
[55]	CHUNG W, PROMRAT K, WANDS J. Clinical implications, diagnosis, and management of diabetes in patients with chronic liver diseases[J]. World J Hepatol, 2020, 12( 9): 533- 557. DOI: 10.4254/wjh.v12.i9.533.
[56]	WANG LQ, LI YJ, XUE SJ, et al. The effect of entecavir combined with Fuzhenghuayu capsule in the treatment of decompensated cirrhosis patients with HBV infection and its influence on serum inflammatory factors[J]. Chin J Difficult Complicat Cases, 2020, 19( 10): 985- 989. DOI: 10.3969/j.issn.1671-6450.2020.10.004. 王柳青, 李雅静, 薛素娟, 等. 恩替卡韦联合扶正化瘀胶囊治疗HBV感染失代偿期肝硬化患者的疗效及对血清炎性因子的影响[J]. 疑难病杂志, 2020, 19( 10): 985- 989. DOI: 10.3969/j.issn.1671-6450.2020.10.004.
[57]	ELKRIEF L, RAUTOU PE, SARIN S, et al. Diabetes mellitus in patients with cirrhosis: Clinical implications and management[J]. Liver Int, 2016, 36( 7): 936- 948. DOI: 10.1111/liv.13115.
[58]	ALFADUL H, SABICO S, AL-DAGHRI NM. The role of interleukin-1β in type 2 diabetes mellitus: A systematic review and meta-analysis[J]. Front Endocrinol, 2022, 13: 901616. DOI: 10.3389/fendo.2022.901616.
[59]	BIAN F, YANG XY, XU G, et al. CRP-induced NLRP3 inflammasome activation increases LDL transcytosis across endothelial cells[J]. Front Pharmacol, 2019, 10: 40. DOI: 10.3389/fphar.2019.00040.
[60]	YANG ML, QIU S, HE YR, et al. Genetic ablation of C-reactive protein gene confers resistance to obesity and insulin resistance in rats[J]. Diabetologia, 2021, 64( 5): 1169- 1183. DOI: 10.1007/s00125-021-05384-9.