{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T03:02:35Z","timestamp":1783566155769,"version":"3.55.0"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,24]],"date-time":"2022-11-24T00:00:00Z","timestamp":1669248000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","award":["3381\/2013"],"award-info":[{"award-number":["3381\/2013"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Considering the potential role of miRNAs as biomarkers and their interaction with both nuclear and mitochondrial genes, we investigated the miRNA expression profile in type 1 diabetes (T1DM) patients, including the pathways in which they are involved considering both nuclear and mitochondrial functions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We analyzed samples of T1DM patients and control individuals (normal glucose tolerance) by high throughput miRNA sequencing (miRNome). Next, five miRNAs \u2013 <jats:italic>hsa-miR-26b-5p<\/jats:italic>, <jats:italic>hsa-let-7i-5p<\/jats:italic>, <jats:italic>hsa-miR-143-3p<\/jats:italic>, <jats:italic>hsa-miR-501-3p<\/jats:italic> and <jats:italic>hsa-miR-100-5p \u2013<\/jats:italic> were validated by RT-qPCR. The identification of target genes was extracted from miRTarBase and mitoXplorer database. We also performed receiver operating characteristic (ROC) curves and miRNAs that had an AUC &amp;gt; 0.85 were considered potential biomarkers.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Overall, 41 miRNAs were differentially expressed in T1DM patients compared to control. <jats:italic>Hsa-miR-21-5p<\/jats:italic> had the highest number of predicted target genes and was associated with several pathways, including insulin signaling and apoptosis. 34.1% (14\/41) of the differentially expressed miRNAs also targeted mitochondrial genes, and 80.5% (33\/41) of them targeted nuclear genes involved in the mitochondrial metabolism. All five validated miRNAs were upregulated in T1DM. Among them, <jats:italic>hsa-miR-26b-5p<\/jats:italic> showed AUC&amp;gt;0.85, being suggested as potential biomarker to T1DM.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our results demonstrated 41 DE miRNAs that had a great accuracy in discriminating T1DM and control group. Furthermore, we demonstrate the influence of these miRNAs on numerous metabolic pathways, including mitochondrial metabolism. <jats:italic>Hsa-miR-26b-5p<\/jats:italic> and <jats:italic>hsa-miR-21-5p<\/jats:italic> were highlighted in our results, possibly acting on nuclear and mitochondrial dysfunction and, subsequently, T1DM dysregulation.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2022.1033809","type":"journal-article","created":{"date-parts":[[2022,11,24]],"date-time":"2022-11-24T06:12:20Z","timestamp":1669270340000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Global miRNA expression reveals novel nuclear and mitochondrial interactions in Type 1 diabetes mellitus"],"prefix":"10.3389","volume":"13","author":[{"given":"Rafaella Sousa","family":"Ferraz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas Cau\u00ea Bezerra","family":"Santos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca Lais","family":"da-Silva-Cruz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cintia Helena","family":"Braga-da-Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leandro","family":"Magalh\u00e3es","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur","family":"Ribeiro-dos-Santos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Vidal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana","family":"Vinasco-Sandoval","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"La\u00eds","family":"Reis-das-Merc\u00eas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camille","family":"Sena-dos-Santos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adenilson Le\u00e3o","family":"Pereira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilian Souza D\u2019Albuquerque","family":"Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franciane T. Cunha de","family":"Melo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Carolina C. Braga de","family":"Souza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Val\u00e9ria S. Galv\u00e3o","family":"Leal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priscila B. Barbosa de","family":"Figueiredo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo\u00e3o F. Abrah\u00e3o","family":"Neto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorena Vilhena de","family":"Moraes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela Nascimento de","family":"Lemos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nat\u00e9rcia Neves Marques de","family":"Queiroz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karem Mil\u00e9o","family":"Fel\u00edcio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna C.","family":"Cavalcante","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c2ndrea","family":"Ribeiro-dos-Santos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo\u00e3o Soares","family":"Fel\u00edcio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dsx.2018.10.008","article-title":"Type 1 and 2 diabetes mellitus: A review on current treatment approach and gene therapy as potential intervention","volume":"13","author":"Tan","year":"2019","journal-title":"Diabetes Metab Syndrome: Clin Res Rev"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.2147\/PHMT.S364454","article-title":"Health-related quality-of-Life and associated factors among children and adolescents with type 1 diabetes mellitus: A cross-sectional study","volume":"13","author":"Bekele","year":"2022","journal-title":"PHMT"},{"key":"B3","unstructured":"IDF diabetes atlas 9th edition 20192019"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21010036","article-title":"Epigenetic regulation in etiology of type 1 diabetes mellitus","volume":"21","author":"Cerna","year":"2019","journal-title":"Int J Mol Sci"},{"key":"B5","doi-asserted-by":"publisher","first-page":"13","DOI":"10.4239\/wjd.v11.i1.13","article-title":"Current understandings of the pathogenesis of type 1 diabetes: Genetics to environment","volume":"11","author":"Giwa","year":"2020","journal-title":"World J Diabetes"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1530\/EC-17-0248","article-title":"MicroRNA expression profiles and type 1 diabetes mellitus: systematic review and bioinformatic analysis","volume":"6","author":"Assmann","year":"2017","journal-title":"Endocrine Connections"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2013.86","article-title":"Circulating microRNAs as novel biomarkers for diabetes mellitus","volume":"9","author":"Guay","year":"2013","journal-title":"Nat Rev Endocrinol"},{"key":"B8","first-page":"98","article-title":"Biomarkers for type 1 diabetes","volume":"1","author":"Purohit","year":"2008","journal-title":"Int J Clin Exp Med"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2018.00402","article-title":"Overview of MicroRNA biogenesis, mechanisms of actions, and circulation","volume":"9","author":"O\u2019Brien","year":"2018","journal-title":"Front Endocrinol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/jcla.21928","article-title":"The association between circulating levels of miRNA-181a and pancreatic beta cells dysfunction via SMAD7 in type 1 diabetic children and adolescents","volume":"30","author":"Nabih","year":"2016","journal-title":"J Clin Lab Anal"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2017-01417","article-title":"Two novel MicroRNA biomarkers related to \u03b2-cell damage and their potential values for early diagnosis of type 1 diabetes","volume":"103","author":"Liu","year":"2018","journal-title":"J Clin Endocrinol Metab"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/nature03076","article-title":"A pancreatic islet-specific microRNA regulates insulin secretion","volume":"432","author":"Poy","year":"2004","journal-title":"Nature"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-015-3683-8","article-title":"The ia-2\u03b2 intronic miRNA, miR-153, is a negative regulator of insulin and dopamine secretion through its effect on the Cacna1c gene in mice","volume":"58","author":"Xu","year":"2015","journal-title":"Diabetologia"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellimm.2009.10.012","article-title":"microRNA-342, microRNA-191 and microRNA-510 are differentially expressed in T regulatory cells of type 1 diabetic patients","volume":"260","author":"Hezova","year":"2010","journal-title":"Cell Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2019.06.009","article-title":"The role of T cell miRNAs for regulatory T cell induction in islet autoimmunity","volume":"27","author":"Scherm","year":"2019","journal-title":"Mol Metab"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1096\/fj.15-273649","article-title":"Multiple microRNAs within the 14q32 cluster target the mRNAs of major type 1 diabetes autoantigens IA-2, IA-2\u03b2, and GAD65","volume":"29","author":"Abuhatzira","year":"2015","journal-title":"FASEB J"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2014\/960362","article-title":"Effects of downregulation of MicroRNA-181a on H2O2-induced H9c2 cell apoptosis via the mitochondrial apoptotic pathway","volume":"2014","author":"Wang","year":"2014","journal-title":"Oxid Med Cell Longevity"},{"key":"B18","doi-asserted-by":"publisher","first-page":"97","DOI":"10.2337\/diaclin.33.2.97","article-title":"Standards of medical care in diabetes\u20132015 abridged for primary care providers","volume":"33","year":"2015","journal-title":"Clin Diabetes"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu170","article-title":"Trimmomatic: a flexible trimmer for illumina sequence data","volume":"30","author":"Bolger","year":"2014","journal-title":"Bioinformatics"},{"key":"B20","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu638","article-title":"HTSeq\u2013a Python framework to work with high-throughput sequencing data","volume":"31","author":"Anders","year":"2015","journal-title":"Bioinformatics"},{"key":"B22","doi-asserted-by":"publisher","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":"B23","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq1107","article-title":"miRTarBase: a database curates experimentally validated microRNA\u2013target interactions","volume":"39","author":"Hsu","year":"2011","journal-title":"Nucleic Acids Res"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1039\/C5MB00663E","article-title":"ReactomePA: An R\/Bioconductor package for reactome pathway analysis and visualization","volume":"12","author":"Yu","year":"2016","journal-title":"Mol Biosyst"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: an r package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"OMICS: A J Integr Biol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: A software environment for integrated models of biomolecular interaction networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz1128","article-title":"mitoXplorer, a visual data mining platform to systematically analyze and visualize mitochondrial expression dynamics and mutations","volume":"48","author":"Yim","year":"2020","journal-title":"Nucleic Acids Res"},{"key":"B28","unstructured":"Vienna, AustriaR Foundation for Statistical ComputingR: A language and environment for statistical computing2018"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.mce.2019.03.008","article-title":"Post-transcriptional markers associated with clinical complications in type 1 and type 2 diabetes mellitus","volume":"490","author":"Massaro","year":"2019","journal-title":"Mol Cell Endocrinol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1042\/BSR20203481","article-title":"Mitochondria-related core genes and TF-miRNA-hub mrDEGs network in breast cancer","volume":"41","author":"Yan","year":"2021","journal-title":"Biosci Rep"},{"key":"B31","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.bone.2013.10.001","article-title":"Collagen advanced glycation inhibits its discoidin domain receptor 2 (DDR2)-mediated induction of lysyl oxidase in osteoblasts","volume":"58","author":"Khosravi","year":"2014","journal-title":"Bone"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2021.174081","article-title":"Endogenous asymmetric dimethylarginine accumulation precipitates the cardiac and mitochondrial dysfunctions in type 1 diabetic rats","volume":"902","author":"Xiong","year":"2021","journal-title":"Eur J Pharmacol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.17305\/bjbms.2017.1961","article-title":"Apoptosis of pancreatic \u03b2-cells in type 1 diabetes","volume":"17","author":"Tomita","year":"2017","journal-title":"Bosn J Basic Med Sci"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.016675","article-title":"Insulin is a stronger inducer of insulin resistance than hyperglycemia in mice with type 1 diabetes mellitus (T1DM)","volume":"284","author":"Liu","year":"2009","journal-title":"J Biol Chem"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21051838","article-title":"Mitochondrial epigenetics: Non-coding RNAs as a novel layer of complexity","volume":"21","author":"Cavalcante","year":"2020","journal-title":"IJMS"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.mito.2013.05.001","article-title":"Lipidomic characterization of streptozotocin-induced heart mitochondrial dysfunction","volume":"13","author":"Ferreira","year":"2013","journal-title":"Mitochondrion"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2006.1458","article-title":"Impact of mitochondrial ROS production in the pathogenesis of diabetes mellitus and its complications","volume":"9","author":"Nishikawa","year":"2007","journal-title":"Antioxidants Redox Signaling"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.18926\/AMO\/54413","article-title":"Mitochondrial dynamics and mitochondrial dysfunction in diabetes","volume":"70","author":"Wada","year":"2016","journal-title":"Acta Medica Okayama"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.2337\/dc11-1833","article-title":"The association between IGF-I and insulin resistance","volume":"35","author":"Friedrich","year":"2012","journal-title":"Diabetes Care"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13443","article-title":"The antagonistic pleiotropy of insulin-like growth factor 1","volume":"20","author":"Zhang","year":"2021","journal-title":"Aging Cell"},{"key":"B41","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1016\/j.cyto.2012.03.019","article-title":"Insulin-like growth factor-1 cytokines cross-talk in type 1 diabetes mellitus: Relationship to microvascular complications and bone mineral density","volume":"59","author":"AboElAsrar","year":"2012","journal-title":"Cytokine"},{"key":"B42","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s12276-018-0186-y","article-title":"Differential effects of type 1 diabetes mellitus and subsequent osteoblastic \u03b2-catenin activation on trabecular and cortical bone in a mouse model","volume":"50","author":"Chen","year":"2018","journal-title":"Exp Mol Med"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.630248","article-title":"A balanced act: The effects of GH\u2013GHR\u2013IGF1 axis on mitochondrial function","volume":"9","author":"Hu","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1172\/JCI146415","article-title":"Insulin and IGF-1 receptors regulate complex I\u2013dependent mitochondrial bioenergetics and supercomplexes via FoxOs in muscle","volume":"131","author":"Bhardwaj","year":"2021","journal-title":"J Clin Invest"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2021.101910","article-title":"The lncRNA Malat1 regulates microvascular function after myocardial infarction in mice via miR-26b-5p\/Mfn1 axis-mediated mitochondrial dynamics","volume":"41","author":"Chen","year":"2021","journal-title":"Redox Biol"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2022.1033809\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,24]],"date-time":"2022-11-24T06:12:30Z","timestamp":1669270350000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2022.1033809\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,24]]},"references-count":45,"alternative-id":["10.3389\/fendo.2022.1033809"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2022.1033809","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,24]]},"article-number":"1033809"}}