{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T21:27:07Z","timestamp":1793222827848,"version":"4.5.0"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,4,21]],"date-time":"2023-04-21T00:00:00Z","timestamp":1682035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p>The chronic metabolic disease named type 2 diabetes (T2D) accounts for over 90% of diabetes mellitus. An increasing number of evidences have revealed that hypoxia has a significantly suppressive effect on cell-mediated immunity, as well as the utilization of glucose in diabetics. Therefore, we aimed to screen and identify hypoxia-immune-related hub genes in T2D through bioinformatic analysis. The Gene Expression Omnibus (GEO) database was used to get T2D gene expression profile data in the peripheral blood samples (GSE184050), and hypoxia-related genes were acquired from Molecular Signatures Database (MSigDB). Differentially expressed mRNAs (DEGs) and lncRNAs (DELs) between T2D and normal samples were identified by DeSeq2 package. The clusterProfiler package was used to perform enrichment analyses for the overlapped genes of DEGs and hypoxia-related genes. Further, Hypoxia-related hub genes were discovered using two machine learning algorithms. Next, the compositional patterns of immune and stromal cells in T2D and healthy groups were estimated by using xCell algorithm. Moreover, we used the weighted correlation network analysis (WGCNA) to examine the connection between genes and immune cells to screen immune-related genes. Gene Set Enrichment Analysis (GSEA) was used to investigate the functions of the hypoxia-immune-related hub genes. Finally, two peripheral blood cohorts of T2D (GSE184050 and GSE95849) as well as the quantitative real-time PCR (qRT-PCR) experiments for clicinal peripheral blood samples with T2D were used for verification analyses of hub genes. And meanwhile, a lncRNA-TF-mRNA network was constructed. Following the differentially expressed analysis, 38 out of 3822 DEGs were screened as hypoxia-related DEGs, and 493 DELs were found. These hypoxia-related DEGs were mainly enriched in the GO terms of pyruvate metabolic process, cytoplasmic vesicle lumen and monosaccharide binding, and the KEGG pathways of glycolysis\/gluconeogenesis, pentose phosphate pathway and biosynthesis of nucleotide sugars. Moreover, 7 out of hypoxia-related DEGs were identified as hub genes. There were six differentially expressed immune cell types between T2D and healthy samples, which were further used as the clinical traits for WGCNA to identify <jats:italic>AMPD3<\/jats:italic> and <jats:italic>IER3<\/jats:italic> as the hypoxia-immune-related hub genes. The results of the KEGG pathways of genes in high-expression groups of <jats:italic>AMPD3<\/jats:italic> and <jats:italic>IER3<\/jats:italic> were mainly concentrated in glycosaminoglycan degradation and vasopressin-regulated water reabsorption, while the low-expression groups of <jats:italic>AMPD3<\/jats:italic> and <jats:italic>IER3<\/jats:italic> were mainly associated with RNA degradation and nucleotide excision repair. Finally, when compared to normal samples, both the <jats:italic>AMPD3<\/jats:italic> and <jats:italic>IER3<\/jats:italic> were highly expressed in the T2D groups in the GSE184050 and GSE95849 datasets. The result of lncRNA-TF-mRNA regulatory network showed that lncRNAs such as BACH1-IT1 and SNHG15 might induce the expression of the corresponding TFs such as TFAM and THAP12 and upregulate the expression of <jats:italic>AMPD3<\/jats:italic>. This study identified <jats:italic>AMPD3<\/jats:italic> and <jats:italic>IER3<\/jats:italic> as hypoxia-immune-related hub genes and potential regulatory mechanism for T2D, which provided a new perspective for elucidating the upstream molecular regulatory mechanism of diabetes mellitus.<\/jats:p>","DOI":"10.3389\/fgene.2023.1154839","type":"journal-article","created":{"date-parts":[[2023,4,21]],"date-time":"2023-04-21T04:45:57Z","timestamp":1682052357000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Identification and analysis of hub genes of hypoxia-immunity in type 2 diabetes mellitus"],"prefix":"10.3389","volume":"14","author":[{"given":"Jing","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ni","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofeng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shenglin","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyou","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,4,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1308","DOI":"10.3109\/10715762.2015.1067697","article-title":"The novel NADPH oxidase 4 inhibitor GLX351322 counteracts glucose intolerance in high-fat diet-treated C57BL\/6 mice","volume":"49","author":"Anvari","year":"2015","journal-title":"Free Radic. Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1186\/s13059-017-1349-1","article-title":"xCell: digitally portraying the tissue cellular heterogeneity landscape","volume":"18","author":"Aran","year":"2017","journal-title":"Genome Biol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1038\/nm1185","article-title":"IKK-beta links inflammation to obesity-induced insulin resistance","volume":"11","author":"Arkan","year":"2005","journal-title":"Nat. Med."},{"key":"B4","doi-asserted-by":"publisher","first-page":"690","DOI":"10.1161\/01.res.0000012922.40318.05","article-title":"Identification of IEX-1 as a biomechanically controlled nuclear factor-kappaB target gene that inhibits cardiomyocyte hypertrophy","volume":"90","author":"De Keulenaer","year":"2002","journal-title":"Circ. Res."},{"key":"B5","doi-asserted-by":"publisher","first-page":"2087","DOI":"10.1091\/mbc.e09-12-1003","article-title":"The NADPH oxidase subunit NOX4 is a new target gene of the hypoxia-inducible factor-1","volume":"21","author":"Diebold","year":"2010","journal-title":"Mol. Biol. Cell"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1017","DOI":"10.2337\/dc08-1776","article-title":"Obstructive sleep apnea among obese patients with type 2 diabetes","volume":"32","author":"Foster","year":"2009","journal-title":"Diabetes Care"},{"key":"B7","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1097\/shk.0000000000000740","article-title":"Hyperoxia induces inflammation and cytotoxicity in human adult cardiac myocytes","volume":"47","author":"Hafner","year":"2017","journal-title":"Shock"},{"key":"B8","doi-asserted-by":"publisher","first-page":"2525","DOI":"10.2337\/db08-1261","article-title":"Interleukin-10 prevents diet-induced insulin resistance by attenuating macrophage and cytokine response in skeletal muscle","volume":"58","author":"Hong","year":"2009","journal-title":"Diabetes"},{"key":"B9","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1038\/nm.4245","article-title":"Dissociation of muscle insulin sensitivity from exercise endurance in mice by HDAC3 depletion","volume":"23","author":"Hong","year":"2017","journal-title":"Nat. Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/j.yjmcc.2021.01.002","article-title":"Xanthine oxidoreductase-mediated injury is amplified by upregulated AMP deaminase in type 2 diabetic rat hearts under the condition of pressure overload","volume":"154","author":"Igaki","year":"2021","journal-title":"J. Mol. Cell Cardiol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.tem.2014.12.001","article-title":"Lymphocyte roles in metabolic dysfunction: Of men and mice","volume":"26","author":"Ip","year":"2015","journal-title":"Trends Endocrinol. Metab."},{"key":"B12","first-page":"806","article-title":"Low expression of long non-coding RNA LET inhibits carcinogenesis of cervical cancer","volume":"8","author":"Jiang","year":"2015","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1186\/1471-2105-9-559","article-title":"Wgcna: an R package for weighted correlation network analysis","volume":"9","author":"Langfelder","year":"2008","journal-title":"BMC Bioinforma."},{"key":"B14","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1016\/j.schres.2019.05.011","article-title":"Differential gene expression analysis in blood of first episode psychosis patients","volume":"209","author":"Leirer","year":"2019","journal-title":"Schizophr. Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1016\/j.clinbiochem.2009.09.022","article-title":"Expression of HIF-1 alpha, VEGF and EPO in peripheral blood from patients with two cardiac abnormalities associated with hypoxia","volume":"43","author":"Lemus-Varela","year":"2010","journal-title":"Clin. Biochem."},{"key":"B16","doi-asserted-by":"publisher","first-page":"368","DOI":"10.18632\/aging.203813","article-title":"LINC02362 attenuates hepatocellular carcinoma progression through the miR-516b-5p\/SOSC2 axis","volume":"14","author":"Li","year":"","journal-title":"Aging (Albany NY)"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1605064","DOI":"10.3389\/ijph.2022.1605064","article-title":"System dynamic model simulates the growth trend of diabetes mellitus in Chinese population: Implications for future urban public Health governance","volume":"67","author":"Li","year":"","journal-title":"Int. J. Public Health"},{"key":"B18","doi-asserted-by":"publisher","first-page":"4693471","DOI":"10.1155\/2016\/4693471","article-title":"Long noncoding RNA-LET suppresses tumor growth and EMT in lung adenocarcinoma","volume":"2016","author":"Liu","year":"2016","journal-title":"Biomed. Res. Int."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1187","DOI":"10.1038\/sj.ijo.0802407","article-title":"Effects of hypoxia on the expression of proangiogenic factors in differentiated 3T3-F442A adipocytes","volume":"27","author":"Lolm\u00e8de","year":"2003","journal-title":"Int. J. Obes. Relat. Metab. Disord."},{"key":"B20","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1172\/jci29881","article-title":"Obesity induces a phenotypic switch in adipose tissue macrophage polarization","volume":"117","author":"Lumeng","year":"2007","journal-title":"J. Clin. Invest."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1844","DOI":"10.1128\/mcb.24.5.1844-1854.2004","article-title":"The NAD(P)H oxidase homolog Nox4 modulates insulin-stimulated generation of H2O2 and plays an integral role in insulin signal transduction","volume":"24","author":"Mahadev","year":"2004","journal-title":"Mol. Cell Biol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"154864","DOI":"10.1016\/j.metabol.2021.154864","article-title":"AMP deamination is sufficient to replicate an atrophy-like metabolic phenotype in skeletal muscle","volume":"123","author":"Miller","year":"2021","journal-title":"Metabolism"},{"key":"B24","doi-asserted-by":"publisher","first-page":"918","DOI":"10.1016\/s0140-6736(20)31761-x","article-title":"NCD Countdown 2030: Pathways to achieving sustainable development goal target 3.4","volume":"396","year":"2020","journal-title":"Lancet"},{"key":"B25","doi-asserted-by":"publisher","first-page":"13147","DOI":"10.1038\/srep13147","article-title":"CD73 and AMPD3 deficiency enhance metabolic performance via erythrocyte ATP that decreases hemoglobin oxygen affinity","volume":"5","author":"O'Brien","year":"2015","journal-title":"Sci. Rep."},{"key":"B26","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1016\/j.ymben.2023.02.002","article-title":"(13)C-Metabolic flux analysis of 3T3-L1 adipocytes illuminates its core metabolism under hypoxia","volume":"76","author":"Oates","year":"2023","journal-title":"Metab. Eng."},{"key":"B27","doi-asserted-by":"publisher","first-page":"e15608","DOI":"10.14814\/phy2.15608","article-title":"Downregulation of extramitochondrial BCKDH and its uncoupling from AMP deaminase in type 2 diabetic OLETF rat hearts","volume":"11","author":"Ogawa","year":"2023","journal-title":"Physiol. Rep."},{"key":"B28","doi-asserted-by":"publisher","first-page":"216","DOI":"10.3390\/biomedicines9020216","article-title":"Mitochondrial oxidative stress and \"Mito-Inflammation\": Actors in the diseases","volume":"9","author":"Patergnani","year":"2021","journal-title":"Biomedicines"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1070918","DOI":"10.3389\/fpubh.2022.1070918","article-title":"Disparities of obesity and non-communicable disease burden between the Tibetan Plateau and developed megacities in China","volume":"10","author":"Peng","year":"2022","journal-title":"Front. Public Health"},{"key":"B30","doi-asserted-by":"publisher","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"Limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"B31","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1186\/s12859-018-2451-4","article-title":"SVM-RFE: Selection and visualization of the most relevant features through non-linear kernels","volume":"19","author":"Sanz","year":"2018","journal-title":"BMC Bioinforma."},{"key":"B32","doi-asserted-by":"publisher","first-page":"e7250","DOI":"10.1371\/journal.pone.0007250","article-title":"12\/15-lipoxygenase is required for the early onset of high fat diet-induced adipose tissue inflammation and insulin resistance in mice","volume":"4","author":"Sears","year":"2009","journal-title":"PLoS One"},{"key":"B33","doi-asserted-by":"publisher","first-page":"15304","DOI":"10.1074\/jbc.M600054200","article-title":"Distinct domains for anti- and pro-apoptotic activities of IEX-1","volume":"281","author":"Shen","year":"2006","journal-title":"J. Biol. Chem."},{"key":"B34","doi-asserted-by":"publisher","first-page":"954","DOI":"10.2337\/dc18-2004","article-title":"Risk of incident obstructive sleep apnea among patients with type 2 diabetes","volume":"42","author":"Subramanian","year":"2019","journal-title":"Diabetes Care"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12974-021-02372-z","article-title":"SNHG15 is a negative regulator of inflammation by mediating TRAF2 ubiquitination in stroke-induced immunosuppression","volume":"19","author":"Sun","year":"2022","journal-title":"J. Neuroinflammation"},{"key":"B36","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1007\/s12032-015-0673-0","article-title":"Long noncoding RNA-LET, which is repressed by EZH2, inhibits cell proliferation and induces apoptosis of nasopharyngeal carcinoma cell","volume":"32","author":"Sun","year":"2015","journal-title":"Med. Oncol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"81","DOI":"10.17925\/ee.2015.11.02.81","article-title":"Obstructive sleep apnoea and vascular disease in patients with type 2 diabetes","volume":"11","author":"Tahrani","year":"2015","journal-title":"Eur. Endocrinol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1177\/1479164117714397","article-title":"Obstructive sleep apnoea in diabetes: Does it matter?","volume":"14","author":"Tahrani","year":"2017","journal-title":"Diab Vasc. Dis. Res."},{"key":"B39","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/j.yjmcc.2018.05.003","article-title":"Translational regulation by miR-301b upregulates AMP deaminase in diabetic hearts","volume":"119","author":"Tatekoshi","year":"2018","journal-title":"J. Mol. Cell Cardiol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"e0123932","DOI":"10.1371\/journal.pone.0123932","article-title":"Neuroprotective effect of neuroserpin in oxygen-glucose deprivation- and reoxygenation-treated rat astrocytes in vitro","volume":"10","author":"Wang","year":"2015","journal-title":"PLoS One"},{"key":"B41","doi-asserted-by":"publisher","first-page":"1376","DOI":"10.1113\/expphysiol.2013.072454","article-title":"Impairment of pancreatic \u03b2-cell function by chronic intermittent hypoxia","volume":"98","author":"Wang","year":"2013","journal-title":"Exp. Physiol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1139\/bcb-2016-0167","article-title":"Chronic intermittent hypoxia disturbs insulin secretion and causes pancreatic injury via the MAPK signaling pathway","volume":"95","author":"Wang","year":"2017","journal-title":"Biochem. Cell Biol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"100141","DOI":"10.1016\/j.xinn.2021.100141","article-title":"clusterProfiler 4.0: A universal enrichment tool for interpreting omics data","volume":"2","author":"Wu","year":"2021","journal-title":"Innov. (Camb)"},{"key":"B44","doi-asserted-by":"publisher","first-page":"1083","DOI":"10.1016\/j.molcel.2013.01.010","article-title":"Repression of the long noncoding RNA-LET by histone deacetylase 3 contributes to hypoxia-mediated metastasis","volume":"49","author":"Yang","year":"2013","journal-title":"Mol. Cell"},{"key":"B45","doi-asserted-by":"publisher","first-page":"5720","DOI":"10.1038\/s41467-019-13700-6","article-title":"TRIB3 supports breast cancer stemness by suppressing FOXO1 degradation and enhancing SOX2 transcription","volume":"10","author":"Yu","year":"2019","journal-title":"Nat. Commun."},{"key":"B46","doi-asserted-by":"publisher","first-page":"1314","DOI":"10.3389\/fonc.2019.01314","article-title":"An immune-related signature predicts survival in patients with lung adenocarcinoma","volume":"9","author":"Zhang","year":"2019","journal-title":"Front. Oncol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"6845","DOI":"10.1038\/sj.onc.1206707","article-title":"Development of T-cell lymphomas in Emu-IEX-1 mice","volume":"22","author":"Zhang","year":"2003","journal-title":"Oncogene"},{"key":"B48","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1038\/ni.1831","article-title":"Thioredoxin-interacting protein links oxidative stress to inflammasome activation","volume":"11","author":"Zhou","year":"2010","journal-title":"Nat. Immunol."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2023.1154839\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,22]],"date-time":"2023-05-22T08:08:32Z","timestamp":1684742912000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2023.1154839\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,21]]},"references-count":48,"alternative-id":["10.3389\/fgene.2023.1154839"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2023.1154839","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,21]]},"article-number":"1154839"}}