Journal of Shandong University (Health Sciences) ›› 2020, Vol. 58 ›› Issue (3): 99-106.doi: 10.6040/j.issn.1671-7554.0.2019.1396

Previous Articles     Next Articles

A mechanism study on the association of type 2 diabetes and high-density lipoprotein

TANG Bo1,2, SHAO Jing3, CUI Jing4, SUN Jianping1,4   

  1. 1.Nutrition and Food Hygiene, School of Public Health, Qingdao University, Qingdao 266021, Shandong, China;
    2. Department of Otolaryngology, Peoples Hospital of Pingyi County, Linyi 273300, Shandong, China;
    3. Family Planning Service Center for Maternal and Child Health in Licang District, Qingdao 266041, Shandong, China;
    4. Qingdao Municipal Center for Disease Control and Prevention, Qingdao Institute of Preventive Medicine, Qingdao 266033, Shandong, China
  • Online:2020-03-10 Published:2022-09-27

PDF (PC)

22

Abstract: Objective To explore the molecular mechanism of type 2 diabetes(T2DM)and high-density lipoprotein(HDL)by bioinformatics. Methods Genes of T2DM and HDL were obtained from GEO database and Comparative Toxicogenomics Database(CTD)to screen the same differentially expressed genes(DEGs). Gene function enrichment analysis of gene ontology(GO)and KEGG pathway in DEGs were analyzed with DAVID online software. Protein-protein interaction(PPI)network about DEGs was analyzed with String online software and MCODE of Cytoscape. 山 东 大 学 学 报 (医 学 版)58卷3期 -唐博,等.2型糖尿病发病与高密度脂蛋白关系的机制研究 \=- Results There were 13 DEGs associated with T2DM and HDL, which played a role in cholesterol metabolic process. The DEGs were involved in HIF-1 signaling pathway, Toll-like receptor signaling pathway and cGMP-PKG signaling pathway. All 13 DEGs were involved in the PPI network, which had 27 edges, with average protein node degree of 4.15 and local clustering coefficient of 0.74. The PPI network had a significant difference (P<0.001). The PPI network associated with T2DM and HDL was composed of 6 node proteins, including LEPR, MAPK3, AKT1, NOS3, APOE and SCARB1. Conclusion The pathogenesis of T2DM involves abnormal HDL through cholesterol metabolic process, HIF-1 signaling pathway, Toll-like receptor signaling pathway and cGMP-PKG signaling pathway. Further studies are needed to clarify the possible causal association between lipid and T2DM.

Key words: Type 2 diabetes mellitus, High-density lipoprotein, Gene ontology analysis, KEGG analysis, Protein-protein interaction network

CLC Number: 

  • R587.1
[1] Saeedi P, Petersohn I, Salpea P, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9(th)edition [J]. Diabetes Res Clin Pract, 2019, 157: 107843. doi: 10.1016/j.diabres.2019.107843.
[2] Dominguez-Cruz MG, de Lourdes MM, Totomoch-Serra A, et al. Maya gene variants related to the risk of type 2 diabetes in a family-based association study [J]. Gene, 2020, 730: 144259. doi: 10.1016/j.gene.2019.144259.
[3] Almgren P, Lehtovirta M, Isomaa B, et al. Heritability and familiality of type 2 diabetes and related quantitative traits in the Botnia Study [J]. Diabetologia, 2011, 54(11): 2811-2819.
[4] Merino J, Udler M S, Leong A, et al. A Decade of Genetic and Metabolomic Contributions to Type 2 Diabetes Risk Prediction [J]. Curr Diab Rep, 2017,17(12): 135.
[5] 莫志伟, 欧志君, 区景松. 高密度脂蛋白的水平与功能[J]. 生理科学进展, 2018,49(4): 247-252. MO Zhiwei, OU Zhijun, OU Jingsong. High Density Lipoprotein: Levels and Functions [J]. Progress in Physiological Sciences, 2018, 49(4): 247-252.
[6] Hermans MP, Valensi P. Elevated triglycerides and low high-density lipoprotein cholesterol level as marker of very high risk in type 2 diabetes [J]. Curr Opin Endocrinol Diabetes Obes, 2018, 25(2): 118-129.
[7] Jain P, Vig S, Datta M, et al. Systems biology approach reveals genome to phenome correlation in type 2 diabetes [J]. PLoS One, 2013, 8(1): e53522.
[8] Frederiksen CM, Hojlund K, Hansen L, et al. Transcriptional profiling of myotubes from patients with type 2 diabetes: no evidence for a primary defect in oxidative phosphorylation genes [J]. Diabetologia, 2008, 51(11): 2068-2077.
[9] Dalmas E, Venteclef N, Caer C, et al. T cell-derived IL-22 amplifies IL-1beta-driven inflammation in human adipose tissue: relevance to obesity and type 2 diabetes [J]. Diabetes, 2014, 63(6): 1966-1977.
[10] van Tienen F H, van der Kallen C J, Lindsey P J, et al. Preadipocytes of type 2 diabetes subjects display an intrinsic gene expression profile of decreased differentiation capacity [J]. Int J Obes(Lond), 2011, 35(9): 1154-1164.
[11] Haemmerle M, Keller T, Egger G, et al. Enhanced lymph vessel density, remodeling, and inflammation are reflected by gene expression signatures in dermal lymphatic endothelial cells in type 2 diabetes [J]. Diabetes, 2013, 62(7): 2509-2529.
[12] Karolina DS, Armugam A, Tavintharan S, et al. MicroRNA 144 impairs insulin signaling by inhibiting the expression of insulin receptor substrate 1 in type 2 diabetes mellitus [J]. PLoS One, 2011, 6(8): e22839.
[13] Grayson BL, Wang L, Aune TM. Peripheral blood gene expression profiles in metabolic syndrome, coronary artery disease and type 2 diabetes [J]. Genes Immun, 2011, 12(5): 341-351.
[14] Kaizer EC, Glaser CL, Chaussabel D, et al. Gene expression in peripheral blood mononuclear cells from children with diabetes [J]. J Clin Endocrinol Metab, 2007, 92(9): 3705-3711.
[15] Kanatsuna N, Taneera J, Vaziri-Sani F, et al. Autoimmunity against INS-IGF2 protein expressed in human pancreatic islets [J]. J Biol Chem, 2013, 288(40): 29013-29023.
[16] Taneera J, Fadista J, Ahlqvist E, et al. Expression profiling of cell cycle genes in human pancreatic islets with and without type 2 diabetes [J]. Mol Cell Endocrinol, 2013, 375(1-2): 35-42.
[17] Taneera J, Lang S, Sharma A, et al. A systems genetics approach identifies genes and pathways for type 2 diabetes in human islets [J]. Cell Metab, 2012, 16(1): 122-134.
[18] Dominguez V, Raimondi C, Somanath S, et al. Class II phosphoinositide 3-kinase regulates exocytosis of insulin granules in pancreatic beta cells [J]. J Biol Chem, 2011, 286(6): 4216-4225.
[19] Andreou E, Papandreou D, Hajigeorgiou P, et al. Type 2 diabetes and its correlates in a first nationwide study among Cypriot adults [J]. Prim Care Diabetes, 2017, 11(2): 112-118.
[20] Chen L, Chen XW, Huang X, et al. Regulation of glucose and lipid metabolism in health and disease [J]. Sci China Life Sci, 2019, 62(11): 1420-1458.
[21] Ding J, Reynolds LM, Zeller T, et al. Alterations of a Cellular Cholesterol Metabolism Network Are a Molecular Feature of Obesity-Related Type 2 Diabetes and Cardiovascular Disease [J]. Diabetes, 2015, 64(10): 3464-3474.
[22] Dullaart R, Pagano S, Perton FG, et al. Antibodies Against the C-Terminus of ApoA-1 Are Inversely Associated with Cholesterol Efflux Capacity and HDL Metabolism in Subjects with and without Type 2 Diabetes Mellitus [J]. Int J Mol Sci, 2019, 20(3). pii: E732. doi: 10.3390/ijms20030732.
[23] Leanca CC, Nunes VS, Nakandakare ER, et al. Does plasma HDL-C concentration interact with whole-body cholesterol metabolism? [J]. Nutr Metab Cardiovasc Dis, 2013, 23(4): 279-284.
[24] Montemurro C, Nomoto H, Pei L, et al. IAPP toxicity activates HIF1alpha/PFKFB3 signaling delaying beta-cell loss at the expense of beta-cell function [J]. Nat Commun, 2019, 10(1): 2679.
[25] Lin Y, Shen J, Li D, et al. MiR-34a contributes to diabetes-related cochlear hair cell apoptosis via SIRT1/HIF-1alpha signaling [J]. Gen Comp Endocrinol, 2017, 246: 63-70.
[26] Li L, Pan Z, Yang X. Key genes and co-expression network analysis in the livers of type 2 diabetes patients [J]. J Diabetes Investig, 2019, 10(4): 951-962.
[27] Nishiyama Y, Goda N, Kanai M, et al. HIF-1alpha induction suppresses excessive lipid accumulation in alcoholic fatty liver in mice [J]. J Hepatol, 2012, 56(2): 441-447.
[28] Arias-Loste M T, Fabrega E, Lopez-Hoyos M, et al. The Crosstalk between Hypoxia and Innate Immunity in the Development of Obesity-Related Nonalcoholic Fatty Liver Disease [J]. Biomed Res Int, 2015, 2015: 319745.
[29] Walter KM, Schonenberger MJ, Trotzmuller M, et al. Hif-2alpha promotes degradation of mammalian peroxisomes by selective autophagy [J]. Cell Metab, 2014, 20(5): 882-897.
[30] Taha IM, Abdu AA, Abd EGE. Expression of toll-like receptor 4 and its connection with type 2 diabetes mellitus [J]. Cell Mol Biol(Noisy-le-grand), 2018, 64(13): 15-20.
[31] Westwell-Roper C, Nackiewicz D, Dan M, et al. Toll-like receptors and NLRP3 as central regulators of pancreatic islet inflammation in type 2 diabetes[J]. Immunol Cell Biol, 2014, 92(4):314-323.
[32] Ji Y, Sun S, Shrestha N, et al. Toll-like receptors TLR2 and TLR4 block the replication of pancreatic beta cells in diet-induced obesity[J]. Nat Immunol, 2019, 20(6):677-686.
[33] Yamada H, Umemoto T, Kawano M, et al. High-density lipoprotein and apolipoprotein A-I inhibit palmitate-induced translocation of toll-like receptor 4 into lipid rafts and inflammatory cytokines in 3T3-L1 adipocytes[J]. Biochem Biophys Res Commun, 2017, 484(2):403-408.
[34] Schuchardt M, Prufer N, Tu Y, et al. Dysfunctional high-density lipoprotein activates toll-like receptors via serum amyloid A in vascular smooth muscle cells[J]. Sci Rep, 2019, 9(1):3421.
[35] Reyna S M, Ghosh S, Tantiwong P, et al. Elevated toll-like receptor 4 expression and signaling in muscle from insulin-resistant subjects[J]. Diabetes, 2008, 57(10):2595-2602.
[36] Zhang X, Hiam D, Hong YH, et al. Nitric oxide is required for the insulin sensitizing effects of contraction in mouse skeletal muscle[J]. J Physiol, 2017, 595(24):7427-7439.
[37] Hopf AE, Andresen C, Kotter S, et al. Diabetes-Induced Cardiomyocyte Passive Stiffening Is Caused by Impaired Insulin-Dependent Titin Modification and Can Be Modulated by Neuregulin-1[J]. Circ Res, 2018, 123(3):342-355.
[38] Kuo KK, Wu BN, Liu CP, et al. Xanthine-based KMUP-1 improves HDL via PPARgamma/SR-B1, LDL via LDLRs, and HSL via PKA/PKG for hepatic fat loss[J]. J Lipid Res, 2015, 56(11):2070-2084.
[1] LYU Li, JIANG Lu, CHEN Shihong, ZHUANG Xianghua, SONG Yuwen, WANG Dianhui, AN Wenjuan, LI Qian, PAN Zhe. Related factors of osteoporosis in 210 postmenopausal women with type 2 diabetes mellitus [J]. Journal of Shandong University (Health Sciences), 2021, 59(7): 19-25.
[2] Fengjie ZHENG,Yuwen SONG,Aili SUN,Zhe PAN,Dianhui WANG,Nengjun LOU,Li LYU,Xianghua ZHUANG,Shihong CHEN. Correlation between diabetic peripheral neuropathy and sarcopenia [J]. Journal of Shandong University (Health Sciences), 2021, 59(6): 38-44.
[3] Ping LIU,Yuwen SONG,Ping WANG,Guangwei TIAN,Fengjie ZHENG,Li LYU,Jiaojiao DU,Jing ZHANG,Xianghua ZHUANG,Shihong CHEN. Correlation between vitamin D deficiency and depression in patients with type 2 diabetes mellitus [J]. Journal of Shandong University (Health Sciences), 2021, 59(6): 51-56,102.
[4] JIN Haiyan, ZHANG Yan, MA Xiaoli, HAN Yu, ZHAO Huichen, LIU Yuantao, ZHANG Yuchao. Expressions of miR-122 and miR-33a in patients with type 2 diabetes complicated with coronary artery disease [J]. Journal of Shandong University (Health Sciences), 2020, 58(3): 94-98.
[5] LI Mingzhuo, SUN Xiubin, WANG Chunxia, YANG Yang, LIU Xinhui, LIU Yanxun, XUE Fuzhong, YUAN Zhongshang. Association between longitudinal changes of HDL-C and coronary heart disease in a population with normal serum lipids: a retrospective cohort study [J]. Journal of Shandong University (Health Sciences), 2019, 57(8): 110-116.
[6] TIAN Zhongyan, LI Yuqian, LIU Xiaotian, SHI Yuanyuan, ZHANG Haiqing, ZHANG Xia, QIAN Xinling, YIN Lei, ZHAO Jingzhi, WANG Chongjian. Relationship between PSMD6 gene rs831571 locus polymorphism and the susceptibility of T2DM: a case-control study [J]. Journal of Shandong University (Health Sciences), 2018, 56(7): 51-56.
[7] CHEN Pan, JIANG Chunxia, LEI Yi. Correlation between peripheral Syntaxin 8 expression and chronic inflammation and glucose-lipid metabolism in type 2 diabetes mellitus patients [J]. Journal of Shandong University (Health Sciences), 2018, 56(12): 26-32.
[8] LI Shuai, WANG Yalin, SUN Zhongwen, ZHU Meijia. Expression changes and mechanism of Nod-like receptor protein 3 inflammasome in the cerebral microvascular endothelial cells in type 2 diabetes mellitus [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2017, 55(3): 6-11.
[9] PENG Li, QIANG Ye, ZHAO Huichen, CHEN Shihong, YAO Weidong, LIU Yuantao. Clinical studies on type 2 diabetic patients treated with sitagliptin [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2016, 54(8): 60-63.
[10] LIN Dong, GUAN Qingbo. Association of serum testosterone level and non-alcoholic fatty liver disease in male patients with T2DM [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2016, 54(7): 33-37.
[11] Muhadasi TUERXUNYIMING, Patamu MOHEMAITI, Tuolanguli MAIMAITIKUERBAN. Association of CDKAL1 rs10946398 C/A polymorphism with type 2 diabetes [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2016, 54(2): 75-85.
[12] YU Ning, GAO Yanyan, XIAN Yuxin, NIU Jiapeng, LI Li, WANG Jing, CAO Caixia. Effect of exenatide on serum chemerin level and liver fat contents in type 2 diabetes mellitus combined with non-alcoholic fatty liver disease patients [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2016, 54(11): 51-55.
[13] LIU Yanxun, LIU Jia, ZHANG Tao, WANG Lu, XUE Fuzhong, WANG Ping. Type 2 diabetes mellitus associated with thyroid nodules: a longitudinal health check-up cohort study [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2015, 53(8): 83-86.
[14] PEI Leilei, SUN Zhonghua, LI Zhe, ZHAO Wenping. Effects of sitagliptin combined with high-dose insulin on type 2 diabetes mellitus [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2015, 53(2): 39-42.
[15] HU Fangzhi, ZHANG Zhengjun, GENG Houfa, LIANG Qiuhua, SUN Lin. Relationship between microalbuminuria and brain damage in patients with type 2 diabetes mellitus [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2015, 53(2): 43-47.
Viewed
Full text


Abstract

Cited
  Shared   
  Discussed   
No Suggested Reading articles found!
Copyright 2018 © Editorial office of Journal of Shandong University (Health Sciences)
Supported by Beijing Magtech Co.Ltd