{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T02:23:15Z","timestamp":1792894995631,"version":"4.5.0"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,9,6]],"date-time":"2023-09-06T00:00:00Z","timestamp":1693958400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Aims\/hypothesis<\/jats:title><jats:p>Appearance of multiple islet cell autoantibodies in early life is indicative of future progression to overt type 1 diabetes, however, at varying rates. Here, we aimed to study whether distinct metabolic patterns could be identified in rapid progressors (RP, disease manifestation within 18 months after the initial seroconversion to autoantibody positivity) <jats:italic>vs.<\/jats:italic> slow progressors (SP, disease manifestation at 60 months or later from the appearance of the first autoantibody).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Longitudinal samples were collected from RP (n=25) and SP (n=41) groups at the ages of 3, 6, 12, 18, 24, or \u2265 36 months. We performed a comprehensive metabolomics study, analyzing both polar metabolites and lipids. The sample series included a total of 239 samples for lipidomics and 213 for polar metabolites.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We observed that metabolites mediated by gut microbiome, such as those involved in tryptophan metabolism, were the main discriminators between RP and SP. The study identified specific circulating molecules and pathways, including amino acid (threonine), sugar derivatives (hexose), and quinic acid that may define rapid <jats:italic>vs<\/jats:italic>. slow progression to type 1 diabetes. However, the circulating lipidome did not appear to play a major role in differentiating between RP and SP.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion\/interpretation<\/jats:title><jats:p>Our study suggests that a distinct metabolic profile is linked with the type 1 diabetes progression. The identification of specific metabolites and pathways that differentiate RP from SP may have implications for early intervention strategies to delay the development of type 1 diabetes.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2023.1211015","type":"journal-article","created":{"date-parts":[[2023,9,6]],"date-time":"2023-09-06T17:29:38Z","timestamp":1694021378000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":16,"title":["Circulating metabolic signatures of rapid and slow progression to type 1 diabetes in islet autoantibody-positive children"],"prefix":"10.3389","volume":"14","author":[{"given":"Santosh","family":"Lamichhane","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Partho","family":"Sen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex M.","family":"Dickens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matilda","family":"Kr\u00e5kstr\u00f6m","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorma","family":"Ilonen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Lempainen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heikki","family":"Hy\u00f6ty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riitta","family":"Lahesmaa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riitta","family":"Veijola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorma","family":"Toppari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuulia","family":"Hy\u00f6tyl\u00e4inen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikael","family":"Knip","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matej","family":"Ore\u0161i\u010d","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,9,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"17016","DOI":"10.1038\/nrdp.2017.16","article-title":"Type 1 diabetes mellitus","volume":"3","author":"Katsarou","year":"2017","journal-title":"Nat Rev Dis Primers"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.54.suppl_2.S125","article-title":"Environmental triggers and determinants of type 1 diabetes","author":"Knip","year":"2005","journal-title":"Diabetes"},{"key":"B3","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1007\/s11892-018-1113-2","article-title":"The environmental determinants of diabetes in the young (TEDDY) study: 2018 update","volume":"18","author":"Rewers","year":"2018","journal-title":"Curr Diabetes Rep"},{"key":"B4","doi-asserted-by":"publisher","first-page":"293","DOI":"10.3390\/ijms21082937","article-title":"Endocrine disrupting chemicals and type 1 diabetes","volume":"21","author":"Predieri","year":"2020","journal-title":"Int J Mol Sci 21"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2013.6285","article-title":"Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children","volume":"309","author":"Ziegler","year":"2013","journal-title":"JAMA"},{"key":"B6","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1007\/s13340-019-00414-9","article-title":"Islet autoantibodies in disease prediction and pathogenesis","volume":"11","author":"Jia","year":"2020","journal-title":"Diabetol Int"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.2337\/dc20-1836","article-title":"Islet autoimmunity and HLA markers of presymptomatic and clinical type 1 diabetes: joint analyses of prospective cohort studies in Finland, Germany, Sweden, and the U.S","volume":"44","author":"Anand","year":"2021","journal-title":"Diabetes Care"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-013-2896-y","article-title":"Characteristics of rapid vs slow progression to type 1 diabetes in multiple islet autoantibody-positive children","volume":"56","author":"Achenbach","year":"2013","journal-title":"Diabetologia"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.2337\/dc10-2088","article-title":"Age of islet autoantibody appearance and mean levels of insulin, but not GAD or IA-2 autoantibodies, predict age of diagnosis of type 1 diabetes: diabetes autoimmunity study in the young","volume":"34","author":"Steck","year":"2011","journal-title":"Diabetes Care"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.2337\/dc14-2426","article-title":"Predictors of progression from the appearance of islet autoantibodies to early childhood diabetes: The environmental determinants of diabetes in the young (TEDDY)","volume":"38","author":"Steck","year":"2015","journal-title":"Diabetes Care"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-019-04980-0","article-title":"Circulating metabolites in progression to islet autoimmunity and type 1 diabetes","volume":"62","author":"Lamichhane","year":"2019","journal-title":"Diabetologia"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20081800","article-title":"Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes","volume":"205","author":"Oresic","year":"2008","journal-title":"J Exp Med"},{"key":"B13","doi-asserted-by":"publisher","first-page":"10635","DOI":"10.1038\/s41598-018-28907-8","article-title":"Dynamics of plasma lipidome in progression to islet autoimmunity andtype 1 diabetes - type 1 diabetes prediction and prevention Study (DIPP)","volume":"8","author":"Lamichhane","year":"2018","journal-title":"Sci Rep"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-020-05107-6","article-title":"Metabolic alterations in immune cells associate with progression to type 1 diabetes","volume":"63","author":"Sen","year":"2020","journal-title":"Diabetologia"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1007\/s001250051616","article-title":"Juvenile Diabetes Research Foundation Centre for the Prevention of Type, Feasibility of genetic and immunological prediction of type I diabetes in a population-based birth cohort","volume":"44","author":"Kupila","year":"2001","journal-title":"Diabetologia"},{"key":"B16","doi-asserted-by":"publisher","first-page":"795","DOI":"10.2337\/diacare.19.8.795","article-title":"Rapid HLA-DQB1 genotyping for four alleles in the assessment of risk for IDDM in the Finnish population. The Childhood Diabetes in Finland (DiMe) Study Group","volume":"19","author":"Ilonen","year":"1996","journal-title":"Diabetes Care"},{"key":"B17","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1111\/pedi.12327","article-title":"Genetic susceptibility to type 1 diabetes in childhood - estimation of HLA class II associated disease risk and class II effect in various phases of islet autoimmunity","author":"Ilonen","year":"2016","journal-title":"Pediatr Diabetes"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.2337\/db08-1305","article-title":"Predictive characteristics of diabetes-associated autoantibodies among children with HLA-conferred disease susceptibility in the general population","volume":"58","author":"Siljander","year":"2009","journal-title":"Diabetes"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(74)90140-8","article-title":"Islet-cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies","volume":"2","author":"Bottazzo","year":"1974","journal-title":"Lancet"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1007\/s001250051067","article-title":"Autoantibodies associated with Type I diabetes mellitus persist after diagnosis in children","volume":"41","author":"Savola","year":"1998","journal-title":"Diabetologia"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2249.2001.01506.x","article-title":"Pregnancy induces nonimmunoglobulin insulin-binding activity in both maternal and cord blood serum","volume":"124","author":"Ronkainen","year":"2001","journal-title":"Clin Exp Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1007\/s001250050925","article-title":"IA-2 antibodies\u2013a sensitive marker of IDDM with clinical onset in childhood and adolescence. Childhood Diabetes in Finland Study Group","volume":"41","author":"Savola","year":"1998","journal-title":"Diabetologia"},{"key":"B23","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/S0021-9258(18)64849-5","article-title":"A simple method for the isolation and purification of total lipids from animal tissues","volume":"226","author":"Folch","year":"1957","journal-title":"J Biol Chem"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-61737-985-7_15","article-title":"Liquid chromatography-mass spectrometry (LC-MS)-based lipidomics for studies of body fluids and tissues","volume":"708","author":"Nygren","year":"2011","journal-title":"Methods Mol Biol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-018-0064-z","article-title":"A computational framework to integrate high-throughput '-omics' datasets for the identification of potential mechanistic links","volume":"13","author":"Pedersen","year":"2018","journal-title":"Nat Protoc"},{"key":"B26","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1186\/1471-2105-11-395","article-title":"MZmine 2: modular framework for processing, visualizing, and analyzing mass spectrometry-based molecular profile data","volume":"11","author":"Pluskal","year":"2010","journal-title":"BMC Bioinform"},{"key":"B27","doi-asserted-by":"publisher","first-page":"W388","DOI":"10.1093\/nar\/gkab382","article-title":"MetaboAnalyst 5.0: narrowing the gap between raw spectra and functional insights","volume":"49","author":"Pang","year":"2021","journal-title":"Nucleic Acids Res"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0183228","article-title":"Metabolite patterns predicting sex and age in participants of the Karlsruhe Metabolomics and Nutrition (KarMeN) study","volume":"12","author":"Rist","year":"2017","journal-title":"PloS One"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0620-2","article-title":"The human gut microbiome in early-onset type 1 diabetes from the TEDDY study","volume":"562","author":"Vatanen","year":"2018","journal-title":"Nature"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.04.007","article-title":"Variation in microbiome LPS immunogenicity contributes to autoimmunity in humans","volume":"165","author":"Vatanen","year":"2016","journal-title":"Cell"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2015.218","article-title":"The role of the intestinal microbiota in type 1 diabetes mellitus","volume":"12","author":"Knip","year":"2016","journal-title":"Nat Rev Endocrinol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1002\/dmrr.3043","article-title":"Gut microbiome in type 1 diabetes: A comprehensive review","volume":"34","author":"Zheng","year":"2018","journal-title":"Diabetes Metab Res Rev"},{"key":"B33","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1111\/pedi.12524","article-title":"Metabolomics reveals new metabolic perturbations in children with type 1 diabetes","volume":"19","author":"Galderisi","year":"2018","journal-title":"Pediatr Diabetes"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1002\/elps.201300062","article-title":"Plasma and urine metabolic fingerprinting of type 1 diabetic children","volume":"34","author":"Balderas","year":"2013","journal-title":"Electrophoresis"},{"key":"B35","doi-asserted-by":"publisher","first-page":"12689","DOI":"10.1038\/srep12689","article-title":"Adaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indoles","volume":"5","author":"Hubbard","year":"2015","journal-title":"Sci Rep"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2018.01.011","article-title":"Microbiota-derived indole metabolites promote human and murine intestinal homeostasis through regulation of interleukin-10 receptor","volume":"188","author":"Alexeev","year":"2018","journal-title":"Am J Pathol"},{"key":"B37","doi-asserted-by":"publisher","first-page":"3294","DOI":"10.1038\/s41467-018-05470-4","article-title":"Microbial tryptophan catabolites in health and disease","volume":"9","author":"Roager","year":"2018","journal-title":"Nat Commun"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1002\/mnfr.201100542","article-title":"Relevance of protein fermentation to gut health","volume":"56","author":"Windey","year":"2012","journal-title":"Mol Nutr Food Res"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1375.058","article-title":"Why diabetes incidence increases\u2013a unifying theory","volume":"1079","author":"Ludvigsson","year":"2006","journal-title":"Ann N Y Acad Sci"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1111\/pedi.13251","article-title":"Increasing plasma glucose before the development of type 1 diabetes-the TRIGR study","volume":"22","author":"Ludvigsson","year":"2021","journal-title":"Pediatr Diabetes"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-015-3621-9","article-title":"OGTT and random plasma glucose in the prediction of type 1 diabetes and time to diagnosis","volume":"58","author":"Helminen","year":"2015","journal-title":"Diabetologia"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-017-4258-7","article-title":"Characterisation of rapid progressors to type 1 diabetes among children with HLA-conferred disease susceptibility","volume":"60","author":"P\u00f6ll\u00e4nen","year":"2017","journal-title":"Diabetologia"},{"key":"B43","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1186\/s13059-021-02262-w","article-title":"Integrative analyses of TEDDY omics data reveal lipid metabolism abnorMalities, increased intracellular ROS and heightened inflammation prior to autoimmunity for type 1 diabetes","volume":"22","author":"Balzano-Nogueira","year":"2021","journal-title":"Genome Biol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.2337\/dc21-0737","article-title":"Circulating free fatty acid and phospholipid signature predicts early rapid kidney function decline in patients with type 1 diabetes","volume":"44","author":"Afshinnia","year":"2021","journal-title":"Diabetes Care"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-018-4614-2","article-title":"Abnormal islet sphingolipid metabolism in type 1 diabetes","volume":"61","author":"Holm","year":"2018","journal-title":"Diabetologia"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1900\/RDS.2012.9.236","article-title":"Metabolomics in the studies of islet autoimmunity and type 1 diabetes","volume":"9","author":"Oresic","year":"2012","journal-title":"Rev Diabetes Stud"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2023.1211015\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,6]],"date-time":"2023-09-06T17:29:41Z","timestamp":1694021381000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2023.1211015\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,6]]},"references-count":46,"alternative-id":["10.3389\/fendo.2023.1211015"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2023.1211015","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,6]]},"article-number":"1211015"}}