{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T04:59:37Z","timestamp":1785473977925,"version":"3.56.0"},"reference-count":50,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:00:00Z","timestamp":1782432000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:00:00Z","timestamp":1782432000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100021856","name":"Ministero dell'Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["PNRR PE_00000019 HEAL ITALIA"],"award-info":[{"award-number":["PNRR PE_00000019 HEAL ITALIA"]}],"id":[{"id":"10.13039\/501100021856","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021856","name":"Ministero dell'Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["PRIN 2017KAM2R5"],"award-info":[{"award-number":["PRIN 2017KAM2R5"]}],"id":[{"id":"10.13039\/501100021856","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021856","name":"Ministero dell'Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["PRIN 2022NS7PRM"],"award-info":[{"award-number":["PRIN 2022NS7PRM"]}],"id":[{"id":"10.13039\/501100021856","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Universit\u00e0 degli Studi di Roma La Sapienza"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Diabetologia"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims\/hypothesis<\/jats:title>\n                    <jats:p>The heterogeneity of autoimmune diabetes may be associated with variable metabolic alterations. Our aim was to investigate differences in the metabolomic and lipidomic profile of autoimmune diseases and to identify pathways linked to beta cell damage. To this end, we compared latent autoimmune diabetes in adults (LADA) and type 1 diabetes, also comparing them with rheumatoid arthritis (RA), a related autoimmune condition, and healthy control participants.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Metabolomic and lipidomic analyses were performed for 136 individuals (49 with LADA, 44 with type 1 diabetes, 29 with RA and 14 control participants). Omics of pancreatic islets from healthy donors were also evaluated after in vitro treatment with proinflammatory cytokines.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      LADA and type 1 diabetes differed from RA in terms of lipidomics and metabolomics. Phosphatidylethanolamines, ceramides, lysophosphatidylcholine and several metabolites at the entry sites of the tricarboxylic acid cycle were higher in type 1 diabetes compared with LADA. In pancreatic islets treated with proinflammatory cytokines, tryptophan concentration was reduced by 80%, indicating the activation of tryptophan metabolism in response to the inflammatory stimulus. In people with autoimmune disorders, kynurenine\/tryptophan ratio (Kyn\/Trp), a marker of tryptophan pathway activation, was higher than in the control group (Kyn\/Trp ratio in control group, median [25th\u201375th percentile]: 0.014 [0.012\u20130.019]), with a progressive decline from RA (0.027 [0.022\u20130.032]) to LADA (0.021 [0.018\u20130.024]) and then to type 1 diabetes (0.018 [0.014\u20130.022]), ANCOVA\n                      <jats:italic>p<\/jats:italic>\n                      &lt;0.0001. In LADA, Kyn\/Trp was directly associated with fasting C-peptide levels in the multivariate regression model accounting for confounders (\n                      <jats:italic>p<\/jats:italic>\n                      =0.038).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>Metabolomic and lipidomic profiles differ between LADA and type 1 diabetes and vs RA, providing new insights into the heterogeneity of autoimmune diabetes. Our results confirm the involvement of tryptophan metabolism in autoimmune disorders, suggesting that the impaired activation of this pathway of immune tolerance in LADA is less pronounced than in type 1 diabetes, consistent with its milder degree of beta cell loss.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-026-06777-4","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T11:02:29Z","timestamp":1782471749000},"page":"2607-2619","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metabolomic profile differs between LADA and type 1 diabetes identifying tryptophan metabolism as a pathway involved in the heterogeneity of autoimmune diabetes"],"prefix":"10.1007","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3844-9463","authenticated-orcid":false,"given":"Ernesto","family":"Maddaloni","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1285-4946","authenticated-orcid":false,"given":"Samantha","family":"Pezzica","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8740-0549","authenticated-orcid":false,"given":"Rocco","family":"Amendolara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3251-4412","authenticated-orcid":false,"given":"Silvia","family":"Sabatini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5392-0909","authenticated-orcid":false,"given":"Gabriele","family":"Mocciaro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4374-8564","authenticated-orcid":false,"given":"Guido","family":"Sebastiani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3905-0139","authenticated-orcid":false,"given":"Luca","family":"D\u2019Onofrio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2540-1110","authenticated-orcid":false,"given":"Fabrizia","family":"Carli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6451-9053","authenticated-orcid":false,"given":"Marta","family":"Tesi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2478-8782","authenticated-orcid":false,"given":"Mara","family":"Suleiman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8537-1510","authenticated-orcid":false,"given":"Luca","family":"Navarini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6251-3069","authenticated-orcid":false,"given":"Laura","family":"Nigi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7703-8216","authenticated-orcid":false,"given":"Caterina","family":"Formichi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9744-5628","authenticated-orcid":false,"given":"Marta","family":"Vomero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9736-4475","authenticated-orcid":false,"given":"Marco","family":"Minerba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4907-0635","authenticated-orcid":false,"given":"Piero","family":"Marchetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4947-7478","authenticated-orcid":false,"given":"Francesco","family":"Dotta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1490-6041","authenticated-orcid":false,"given":"Raffaella","family":"Buzzetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2594-1651","authenticated-orcid":false,"given":"Amalia","family":"Gastaldelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,26]]},"reference":[{"key":"6777_CR1","doi-asserted-by":"publisher","first-page":"17016","DOI":"10.1038\/nrdp.2017.16","volume":"3","author":"A Katsarou","year":"2017","unstructured":"Katsarou A, Gudbjornsdottir S, Rawshani A et al (2017) Type 1 diabetes mellitus. Nat Rev Dis Primers 3:17016. https:\/\/doi.org\/10.1038\/nrdp.2017.16","journal-title":"Nat Rev Dis Primers"},{"issue":"7","key":"6777_CR2","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1002\/dmrr.877","volume":"24","author":"RD Leslie","year":"2008","unstructured":"Leslie RD, Kolb H, Schloot NC et al (2008) Diabetes classification: grey zones, sound and smoke: action LADA 1. Diabetes Metab Res Rev 24(7):511\u2013519. https:\/\/doi.org\/10.1002\/dmrr.877","journal-title":"Diabetes Metab Res Rev"},{"issue":"11","key":"6777_CR3","doi-asserted-by":"publisher","first-page":"674","DOI":"10.1038\/nrendo.2017.99","volume":"13","author":"R Buzzetti","year":"2017","unstructured":"Buzzetti R, Zampetti S, Maddaloni E (2017) Adult-onset autoimmune diabetes: current knowledge and implications for management. Nat Rev Endocrinol 13(11):674\u2013686. https:\/\/doi.org\/10.1038\/nrendo.2017.99","journal-title":"Nat Rev Endocrinol"},{"key":"6777_CR4","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.maturitas.2020.04.014","volume":"137","author":"E Maddaloni","year":"2020","unstructured":"Maddaloni E, Moretti C, Mignogna C, Buzzetti R (2020) Adult-onset autoimmune diabetes in 2020: an update. Maturitas 137:37\u201344. https:\/\/doi.org\/10.1016\/j.maturitas.2020.04.014","journal-title":"Maturitas"},{"issue":"Suppl 1","key":"6777_CR5","doi-asserted-by":"publisher","first-page":"S20","DOI":"10.2337\/dc24-S002","volume":"47","author":"American Diabetes Association Professional Practice C","year":"2024","unstructured":"American Diabetes Association Professional Practice C (2024) 2. Diagnosis and classification of diabetes: standards of care in diabetes-2024. Diabetes Care 47(Suppl 1):S20\u2013S42. https:\/\/doi.org\/10.2337\/dc24-S002","journal-title":"Diabetes Care"},{"key":"6777_CR6","unstructured":"World Health Organization\u00a0(2019) Classification of diabetes mellitus. Available from: https:\/\/www.who.int\/publications\/i\/item\/classification-of-diabetes-mellitus"},{"issue":"3","key":"6777_CR7","doi-asserted-by":"publisher","first-page":"718","DOI":"10.2337\/db14-0509","volume":"64","author":"KM Sas","year":"2015","unstructured":"Sas KM, Karnovsky A, Michailidis G, Pennathur S (2015) Metabolomics and diabetes: analytical and computational approaches. Diabetes 64(3):718\u2013732. https:\/\/doi.org\/10.2337\/db14-0509","journal-title":"Diabetes"},{"issue":"7","key":"6777_CR8","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1038\/nrm.2016.25","volume":"17","author":"CH Johnson","year":"2016","unstructured":"Johnson CH, Ivanisevic J, Siuzdak G (2016) Metabolomics: beyond biomarkers and towards mechanisms. Nat Rev Mol Cell Biol 17(7):451\u2013459. https:\/\/doi.org\/10.1038\/nrm.2016.25","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"11","key":"6777_CR9","doi-asserted-by":"publisher","first-page":"2206","DOI":"10.1007\/s00125-005-1960-7","volume":"48","author":"S Fourlanos","year":"2005","unstructured":"Fourlanos S, Dotta F, Greenbaum CJ et al (2005) Latent autoimmune diabetes in adults (LADA) should be less latent. Diabetologia 48(11):2206\u20132212. https:\/\/doi.org\/10.1007\/s00125-005-1960-7","journal-title":"Diabetologia"},{"key":"6777_CR10","doi-asserted-by":"publisher","first-page":"1335839","DOI":"10.3389\/fgene.2024.1335839","volume":"15","author":"W Xie","year":"2024","unstructured":"Xie W, Jiang H, Chen Y et al (2024) Relationship between type 1 diabetes and autoimmune diseases in european populations: a two-sample Mendelian randomization study. Front Genet 15:1335839. https:\/\/doi.org\/10.3389\/fgene.2024.1335839","journal-title":"Front Genet"},{"issue":"9","key":"6777_CR11","doi-asserted-by":"publisher","first-page":"604","DOI":"10.7326\/0003-4819-150-9-200905050-00006","volume":"150","author":"AS Levey","year":"2009","unstructured":"Levey AS, Stevens LA, Schmid CH et al (2009) A new equation to estimate glomerular filtration rate. Ann Intern Med 150(9):604\u2013612. https:\/\/doi.org\/10.7326\/0003-4819-150-9-200905050-00006","journal-title":"Ann Intern Med"},{"issue":"4","key":"6777_CR12","doi-asserted-by":"publisher","first-page":"e3798","DOI":"10.1002\/dmrr.3798","volume":"40","author":"G Della Pepa","year":"2024","unstructured":"Della Pepa G, Carli F, Sabatini S et al (2024) Clusters of adipose tissue dysfunction in adults with type 2 diabetes identify those with worse lipidomic profile despite similar glycaemic control. Diabetes Metab Res Rev 40(4):e3798. https:\/\/doi.org\/10.1002\/dmrr.3798","journal-title":"Diabetes Metab Res Rev"},{"key":"6777_CR13","first-page":"1","volume-title":"Gut microbiome, microbial metabolites and cardiometabolic risk","author":"S Fenizia","year":"2023","unstructured":"Fenizia S, Scoditti E, Gastaldelli A (2023) Methods to study metabolomics. In: Federici M, Menghini R (eds) Gut microbiome, microbial metabolites and cardiometabolic risk. Springer International Publishing, Cham, pp 1\u201341"},{"key":"6777_CR14","doi-asserted-by":"publisher","first-page":"2565","DOI":"10.3389\/fimmu.2019.02565","volume":"10","author":"FJH Sorgdrager","year":"2019","unstructured":"Sorgdrager FJH, Naude PJW, Kema IP, Nollen EA, Deyn PP (2019) Tryptophan metabolism in inflammaging: from biomarker to therapeutic target. Front Immunol 10:2565. https:\/\/doi.org\/10.3389\/fimmu.2019.02565","journal-title":"Front Immunol"},{"issue":"9","key":"6777_CR15","doi-asserted-by":"publisher","first-page":"108466","DOI":"10.1016\/j.celrep.2020.108466","volume":"33","author":"L Marselli","year":"2020","unstructured":"Marselli L, Piron A, Suleiman M et al (2020) Persistent or transient human beta cell dysfunction induced by metabolic stress: specific signatures and shared gene expression with type 2 diabetes. Cell Rep 33(9):108466. https:\/\/doi.org\/10.1016\/j.celrep.2020.108466","journal-title":"Cell Rep"},{"issue":"1","key":"6777_CR16","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","volume":"57","author":"Y Benjamini","year":"1995","unstructured":"Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B (Methodol) 57(1):289\u2013300. https:\/\/doi.org\/10.1111\/j.2517-6161.1995.tb02031.x","journal-title":"J R Stat Soc Ser B (Methodol)"},{"issue":"10","key":"6777_CR17","doi-asserted-by":"publisher","first-page":"1912","DOI":"10.1111\/dom.14785","volume":"24","author":"E Maddaloni","year":"2022","unstructured":"Maddaloni E, Bolli GB, Frier BM et al (2022) C-peptide determination in the diagnosis of type of diabetes and its management: a clinical perspective. Diabetes Obes Metab 24(10):1912\u20131926. https:\/\/doi.org\/10.1111\/dom.14785","journal-title":"Diabetes Obes Metab"},{"issue":"5","key":"6777_CR18","doi-asserted-by":"publisher","first-page":"980","DOI":"10.1016\/j.bbadis.2015.02.001","volume":"1852","author":"JJ Liu","year":"2015","unstructured":"Liu JJ, Raynal S, Bailbe D et al (2015) Expression of the kynurenine pathway enzymes in the pancreatic islet cells. Activation by cytokines and glucolipotoxicity. Biochim Biophys Acta 1852(5):980\u2013991. https:\/\/doi.org\/10.1016\/j.bbadis.2015.02.001","journal-title":"Biochim Biophys Acta"},{"issue":"9","key":"6777_CR19","doi-asserted-by":"publisher","first-page":"1858","DOI":"10.2337\/db17-1281","volume":"67","author":"F Anquetil","year":"2018","unstructured":"Anquetil F, Mondanelli G, Gonzalez N et al (2018) Loss of IDO1 expression from human pancreatic beta-cells precedes their destruction during the development of type 1 diabetes. Diabetes 67(9):1858\u20131866. https:\/\/doi.org\/10.2337\/db17-1281","journal-title":"Diabetes"},{"issue":"3","key":"6777_CR20","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1038\/sj.gene.6364045","volume":"5","author":"JL Newton","year":"2004","unstructured":"Newton JL, Harney SM, Wordsworth BP, Brown MA (2004) A review of the MHC genetics of rheumatoid arthritis. Genes Immun 5(3):151\u2013157. https:\/\/doi.org\/10.1038\/sj.gene.6364045","journal-title":"Genes Immun"},{"issue":"7","key":"6777_CR21","doi-asserted-by":"publisher","first-page":"1702","DOI":"10.1002\/art.37964","volume":"65","author":"R Strollo","year":"2013","unstructured":"Strollo R, Ponchel F, Malmstrom V et al (2013) Autoantibodies to posttranslationally modified type II collagen as potential biomarkers for rheumatoid arthritis. Arthritis Rheum 65(7):1702\u20131712. https:\/\/doi.org\/10.1002\/art.37964","journal-title":"Arthritis Rheum"},{"issue":"3","key":"6777_CR22","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1007\/s00125-012-2780-1","volume":"56","author":"R Strollo","year":"2013","unstructured":"Strollo R, Rizzo P, Spoletini M et al (2013) HLA-dependent autoantibodies against post-translationally modified collagen type II in type 1 diabetes mellitus. Diabetologia 56(3):563\u2013572. https:\/\/doi.org\/10.1007\/s00125-012-2780-1","journal-title":"Diabetologia"},{"issue":"11","key":"6777_CR23","doi-asserted-by":"publisher","first-page":"2740","DOI":"10.2337\/db10-1652","volume":"60","author":"M Pflueger","year":"2011","unstructured":"Pflueger M, Seppanen-Laakso T, Suortti T et al (2011) Age- and islet autoimmunity-associated differences in amino acid and lipid metabolites in children at risk for type 1 diabetes. Diabetes 60(11):2740\u20132747. https:\/\/doi.org\/10.2337\/db10-1652","journal-title":"Diabetes"},{"issue":"1","key":"6777_CR24","doi-asserted-by":"publisher","first-page":"10635","DOI":"10.1038\/s41598-018-28907-8","volume":"8","author":"S Lamichhane","year":"2018","unstructured":"Lamichhane S, Ahonen L, Dyrlund TS et al (2018) Dynamics of plasma lipidome in progression to islet autoimmunity and type 1 diabetes - type 1 Diabetes Prediction and Prevention Study (DIPP). Sci Rep 8(1):10635. https:\/\/doi.org\/10.1038\/s41598-018-28907-8","journal-title":"Sci Rep"},{"issue":"9","key":"6777_CR25","doi-asserted-by":"publisher","first-page":"3268","DOI":"10.2337\/db13-0159","volume":"62","author":"M Oresic","year":"2013","unstructured":"Oresic M, Gopalacharyulu P, Mykkanen J et al (2013) Cord serum lipidome in prediction of islet autoimmunity and type 1 diabetes. Diabetes 62(9):3268\u20133274. https:\/\/doi.org\/10.2337\/db13-0159","journal-title":"Diabetes"},{"issue":"11","key":"6777_CR26","doi-asserted-by":"publisher","first-page":"3951","DOI":"10.2337\/db13-0215","volume":"62","author":"D La Torre","year":"2013","unstructured":"La Torre D, Seppanen-Laakso T, Larsson HE et al (2013) Decreased cord-blood phospholipids in young age-at-onset type 1 diabetes. Diabetes 62(11):3951\u20133956. https:\/\/doi.org\/10.2337\/db13-0215","journal-title":"Diabetes"},{"issue":"1","key":"6777_CR27","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1038\/s41572-022-00390-6","volume":"8","author":"R Buzzetti","year":"2022","unstructured":"Buzzetti R, Maddaloni E, Gaglia J, Leslie RD, Wong FS, Boehm BO (2022) Adult-onset autoimmune diabetes. Nat Rev Dis Primers 8(1):63. https:\/\/doi.org\/10.1038\/s41572-022-00390-6","journal-title":"Nat Rev Dis Primers"},{"issue":"4","key":"6777_CR28","doi-asserted-by":"publisher","first-page":"806","DOI":"10.2337\/db16-0779","volume":"66","author":"M Al-Majdoub","year":"2017","unstructured":"Al-Majdoub M, Ali A, Storm P, Rosengren AH, Groop L, Spegel P (2017) Metabolite profiling of LADA challenges the view of a metabolically distinct subtype. Diabetes 66(4):806\u2013814. https:\/\/doi.org\/10.2337\/db16-0779","journal-title":"Diabetes"},{"issue":"3","key":"6777_CR29","doi-asserted-by":"publisher","first-page":"416","DOI":"10.2337\/dc08-1775","volume":"32","author":"J Guy","year":"2009","unstructured":"Guy J, Ogden L, Wadwa RP et al (2009) Lipid and lipoprotein profiles in youth with and without type 1 diabetes: the SEARCH for Diabetes in Youth case-control study. Diabetes Care 32(3):416\u2013420. https:\/\/doi.org\/10.2337\/dc08-1775","journal-title":"Diabetes Care"},{"issue":"6","key":"6777_CR30","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1016\/j.tem.2020.01.015","volume":"31","author":"B Verges","year":"2020","unstructured":"Verges B (2020) Dyslipidemia in type 1 diabetes: AMaskedDanger. Trends Endocrinol Metab 31(6):422\u2013434. https:\/\/doi.org\/10.1016\/j.tem.2020.01.015","journal-title":"Trends Endocrinol Metab"},{"issue":"9","key":"6777_CR31","doi-asserted-by":"publisher","first-page":"2217","DOI":"10.2337\/diabetes.53.9.2217","volume":"53","author":"H Gylling","year":"2004","unstructured":"Gylling H, Tuominen JA, Koivisto VA, Miettinen TA (2004) Cholesterol metabolism in type 1 diabetes. Diabetes 53(9):2217\u20132222. https:\/\/doi.org\/10.2337\/diabetes.53.9.2217","journal-title":"Diabetes"},{"issue":"12","key":"6777_CR32","doi-asserted-by":"publisher","first-page":"948","DOI":"10.1016\/j.clinbiochem.2010.04.075","volume":"43","author":"CM Sorensen","year":"2010","unstructured":"Sorensen CM, Ding J, Zhang Q et al (2010) Perturbations in the lipid profile of individuals with newly diagnosed type 1 diabetes mellitus: lipidomics analysis of a Diabetes Antibody Standardization Program sample subset. Clin Biochem 43(12):948\u2013956. https:\/\/doi.org\/10.1016\/j.clinbiochem.2010.04.075","journal-title":"Clin Biochem"},{"issue":"10","key":"6777_CR33","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1007\/s11306-020-01730-x","volume":"16","author":"A AnderssonSvard","year":"2020","unstructured":"Andersson Svard A, Kaur S, Trost K et al (2020) Characterization of plasma lipidomics in adolescent subjects with increased risk for type 1 diabetes in the DiPiS cohort. Metabolomics 16(10):109. https:\/\/doi.org\/10.1007\/s11306-020-01730-x","journal-title":"Metabolomics"},{"issue":"6","key":"6777_CR34","doi-asserted-by":"publisher","first-page":"1110","DOI":"10.1038\/s12276-023-01018-9","volume":"55","author":"M Lee","year":"2023","unstructured":"Lee M, Lee SY, Bae YS (2023) Functional roles of sphingolipids in immunity and their implication in disease. Exp Mol Med 55(6):1110\u20131130. https:\/\/doi.org\/10.1038\/s12276-023-01018-9","journal-title":"Exp Mol Med"},{"issue":"2","key":"6777_CR35","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/s0006-2952(02)01179-6","volume":"64","author":"JH Kabarowski","year":"2002","unstructured":"Kabarowski JH, Xu Y, Witte ON (2002) Lysophosphatidylcholine as a ligand for immunoregulation. Biochem Pharmacol 64(2):161\u2013167. https:\/\/doi.org\/10.1016\/s0006-2952(02)01179-6","journal-title":"Biochem Pharmacol"},{"issue":"1","key":"6777_CR36","doi-asserted-by":"publisher","first-page":"282","DOI":"10.2337\/db20-0696","volume":"70","author":"Q Li","year":"2021","unstructured":"Li Q, Liu X, Yang J et al (2021) Plasma metabolome and circulating vitamins stratified onset age of an initial islet autoantibody and progression to type 1 diabetes: the TEDDY Study. Diabetes 70(1):282\u2013292. https:\/\/doi.org\/10.2337\/db20-0696","journal-title":"Diabetes"},{"issue":"9","key":"6777_CR37","doi-asserted-by":"publisher","first-page":"372","DOI":"10.3390\/metabo10090372","volume":"10","author":"KJ Harber","year":"2020","unstructured":"Harber KJ, de Goede KE, Verberk SGS et al (2020) Succinate is an inflammation-induced immunoregulatory metabolite in macrophages. Metabolites 10(9):372. https:\/\/doi.org\/10.3390\/metabo10090372","journal-title":"Metabolites"},{"issue":"11","key":"6777_CR38","doi-asserted-by":"publisher","first-page":"1588","DOI":"10.1038\/s41588-019-0524-6","volume":"51","author":"M Ramos-Rodriguez","year":"2019","unstructured":"Ramos-Rodriguez M, Raurell-Vila H, Colli ML et al (2019) The impact of proinflammatory cytokines on the beta-cell regulatory landscape provides insights into the genetics of type 1 diabetes. Nat Genet 51(11):1588\u20131595. https:\/\/doi.org\/10.1038\/s41588-019-0524-6","journal-title":"Nat Genet"},{"key":"6777_CR39","doi-asserted-by":"publisher","first-page":"1257159","DOI":"10.3389\/fimmu.2023.1257159","volume":"14","author":"AA Mangoni","year":"2023","unstructured":"Mangoni AA, Zinellu A (2023) A systematic review and meta-analysis of the kynurenine pathway of tryptophan metabolism in rheumatic diseases. Front Immunol 14:1257159. https:\/\/doi.org\/10.3389\/fimmu.2023.1257159","journal-title":"Front Immunol"},{"issue":"10","key":"6777_CR40","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1038\/nri1457","volume":"4","author":"AL Mellor","year":"2004","unstructured":"Mellor AL, Munn DH (2004) IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol 4(10):762\u2013774. https:\/\/doi.org\/10.1038\/nri1457","journal-title":"Nat Rev Immunol"},{"issue":"18","key":"6777_CR41","doi-asserted-by":"publisher","first-page":"9879","DOI":"10.3390\/ijms22189879","volume":"22","author":"A Krupa","year":"2021","unstructured":"Krupa A, Kowalska I (2021) The kynurenine pathway-new linkage between innate and adaptive immunity in autoimmune endocrinopathies. Int J Mol Sci 22(18):9879. https:\/\/doi.org\/10.3390\/ijms22189879","journal-title":"Int J Mol Sci"},{"issue":"8","key":"6777_CR42","doi-asserted-by":"publisher","first-page":"e71044","DOI":"10.1371\/journal.pone.0071044","volume":"8","author":"MS Poormasjedi-Meibod","year":"2013","unstructured":"Poormasjedi-Meibod MS, Jalili RB, Hosseini-Tabatabaei A, Hartwell R, Ghahary A (2013) Immuno-regulatory function of indoleamine 2,3 dioxygenase through modulation of innate immune responses. PloS one 8(8):e71044. https:\/\/doi.org\/10.1371\/journal.pone.0071044","journal-title":"PloS one"},{"issue":"9","key":"6777_CR43","doi-asserted-by":"publisher","first-page":"1964","DOI":"10.1002\/jcp.25301","volume":"231","author":"Y Zhang","year":"2016","unstructured":"Zhang Y, Jalili RB, Kilani RT et al (2016) IDO-expressing fibroblasts protect islet beta cells from immunological attack and reverse hyperglycemia in non-obese diabetic mice. J Cell Physiol 231(9):1964\u20131973. https:\/\/doi.org\/10.1002\/jcp.25301","journal-title":"J Cell Physiol"},{"issue":"10","key":"6777_CR44","doi-asserted-by":"publisher","first-page":"2082","DOI":"10.1111\/jcmm.12360","volume":"18","author":"MT Pallotta","year":"2014","unstructured":"Pallotta MT, Orabona C, Bianchi R et al (2014) Forced IDO1 expression in dendritic cells restores immunoregulatory signalling in autoimmune diabetes. J Cell Mol Med 18(10):2082\u20132091. https:\/\/doi.org\/10.1111\/jcmm.12360","journal-title":"J Cell Mol Med"},{"issue":"10","key":"6777_CR45","doi-asserted-by":"publisher","first-page":"6303","DOI":"10.4049\/jimmunol.0901577","volume":"183","author":"F Fallarino","year":"2009","unstructured":"Fallarino F, Volpi C, Zelante T et al (2009) IDO mediates TLR9-driven protection from experimental autoimmune diabetes. J Immunol 183(10):6303\u20136312. https:\/\/doi.org\/10.4049\/jimmunol.0901577","journal-title":"J Immunol"},{"issue":"6","key":"6777_CR46","doi-asserted-by":"publisher","first-page":"e96244","DOI":"10.1172\/jci.insight.96244","volume":"3","author":"C Orabona","year":"2018","unstructured":"Orabona C, Mondanelli G, Pallotta MT et al (2018) Deficiency of immunoregulatory indoleamine 2,3-dioxygenase 1in juvenile diabetes. JCI insight 3(6):e96244. https:\/\/doi.org\/10.1172\/jci.insight.96244","journal-title":"JCI insight"},{"issue":"12","key":"6777_CR47","doi-asserted-by":"publisher","first-page":"1137","DOI":"10.1016\/j.molmed.2024.07.009","volume":"30","author":"S Sarkar","year":"2024","unstructured":"Sarkar S, Zheng X, Clair GC et al (2024) Exploring new frontiers in type 1 diabetes through advanced mass-spectrometry-based molecular measurements. Trends Mol Med 30(12):1137\u20131151. https:\/\/doi.org\/10.1016\/j.molmed.2024.07.009","journal-title":"Trends Mol Med"},{"issue":"1","key":"6777_CR48","doi-asserted-by":"publisher","first-page":"250","DOI":"10.2337\/diabetes.53.1.250","volume":"53","author":"JP Palmer","year":"2004","unstructured":"Palmer JP, Fleming GA, Greenbaum CJ et al (2004) C-peptide is the appropriate outcome measure for type 1 diabetes clinical trials to preserve beta-cell function: report of an ADA workshop, 21\u201322 October 2001. Diabetes 53(1):250\u2013264. https:\/\/doi.org\/10.2337\/diabetes.53.1.250","journal-title":"Diabetes"},{"key":"6777_CR49","doi-asserted-by":"publisher","first-page":"104589","DOI":"10.1016\/j.ebiom.2023.104589","volume":"91","author":"J Yan","year":"2023","unstructured":"Yan J, Kothur K, Mohammad S et al (2023) CSF neopterin, quinolinic acid and kynurenine\/tryptophan ratio are biomarkers of active neuroinflammation. EBioMedicine 91:104589. https:\/\/doi.org\/10.1016\/j.ebiom.2023.104589","journal-title":"EBioMedicine"},{"issue":"5","key":"6777_CR50","doi-asserted-by":"publisher","first-page":"978","DOI":"10.2337\/dc22-0885","volume":"46","author":"S Abdelgani","year":"2023","unstructured":"Abdelgani S, Khattab A, Adams J et al (2023) Distinct mechanisms responsible for the increase in glucose production and ketone formation caused by empagliflozin in T2DM patients. Diabetes Care 46(5):978\u2013984. https:\/\/doi.org\/10.2337\/dc22-0885","journal-title":"Diabetes Care"}],"container-title":["Diabetologia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00125-026-06777-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00125-026-06777-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00125-026-06777-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T04:29:55Z","timestamp":1785472195000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00125-026-06777-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,26]]},"references-count":50,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["6777"],"URL":"https:\/\/doi.org\/10.1007\/s00125-026-06777-4","relation":{},"ISSN":["0012-186X","1432-0428"],"issn-type":[{"value":"0012-186X","type":"print"},{"value":"1432-0428","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,26]]},"assertion":[{"value":"20 February 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 April 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 June 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"We are grateful to all the participants who volunteered for these studies. We also thank S. Fenizia, D. Ciociaro and E. Spagnolo (Institute of Clinical Physiology, CNR) for their technical support. Some of the data presented in this study were included in the PhD thesis of S. Pezzica (\n                      \n                      ).","order":1,"name":"Ethics","label":"Acknowledgements","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"Supplementary material reports tables with lipids and metabolites measured for each group of subjects. Other data will be available for 5 years from the guarantors of the work upon reasonable request. Data will be shared for scientific research purposes only, subject to ethical approval and to the subscription of a data sharing agreement according to the institutional data sharing policy. Requests should be sent to the corresponding author(s), who will evaluate the appropriateness of the request.","order":2,"name":"Ethics","label":"Data availability","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"Open access funding provided by Universit\u00e0 degli Studi di Roma La Sapienza within the CRUI-CARE Agreement. Funding was provided by the Italian Ministry of University and Research (PRIN 2017: protocol no. 2017KAM2R5) to PM, FD, RB and AG; EM has been supported by European Union-Next Generation EU, Mission 4, Component 1, CUP B53D23021820001, Italian Ministry of University and Research, PRIN project no. 2022NS7PRM; MS has been supported by the European Union\u2014Next Generation EU, through the Italian Ministry of University and Research under PNRR\u2014M4C2-1.3, Project PE_00000019 HEAL ITALIA.","order":3,"name":"Ethics","label":"Funding","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"EM reports consulting fees, payment or honoraria for lectures, presentations or advisory boards from Abbott, Astra Zeneca, Eli Lilly, MSD, MTD, Novo Nordisk, PikDare; RB reports research grants from Astra Zeneca and speaker\/consultancy fees from Eli Lilly, Sanofi, Abbott, Vertex, Novo Nordisk, Boehringer Ingelheim, Astra Zeneca, Mundipharma and Guidotti. AG reports consultancy\/advisory boards fee for Boehringer Ingelheim, Eli Lilly and Company, Merck Sharp & Dohme, Novo Nordisk, Pfizer, Regeneron Pharmaceuticals; and received lecture fees from Boehringer Ingelheim, Eli Lilly and Company, Merck Sharp & Dohme, Madrigal, Novo Nordisk. The other authors report no conflicts of interests related to this manuscript.","order":4,"name":"Ethics","label":"Authors\u2019 relationships and activities","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"EM interpreted data, wrote the first draft of the manuscript and contributed to study design and ideation; SP carried out metabolomic profiling, data interpretation and contributed to manuscript writing; RA contributed to enrolment of patients, sample collection and processing; SS contributed to data analysis and interpretation; GM and FC contributed to lipidomic profiling and data interpretation; GS contributed to enrolment of patients, sample collection and processing; LDO undertook enrolment of patients and contributed to study design; MT and MS contributed to in vitro experiments on beta cells; LNa, LNi, CF, MV and MM contributed to enrolment of patients, sample collection and processing; PM and FD contributed to study design and to data interpretation; RB contributed to study ideation and study design, interpretation of results and critically reviewed the manuscript; AG contributed to study ideation and study design, metabolomic\/lipidomic profiling and interpretation of results, and critically reviewed the manuscript. All authors reviewed the final version of the manuscript and agreed to manuscript submission and publication. EM, SP, RB and AG are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.","order":5,"name":"Ethics","label":"Contribution statement","group":{"name":"EthicsHeading","label":"Ethics"}}]}}