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However, these markers only cover a small subset of molecular biomarkers linked to the disease. In this study, we aimed to profile a more comprehensive set of molecular biomarkers and explore their temporal association with incident diabetes.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>We performed a targeted analysis of 54 proteins and 171 metabolites and lipoprotein particles measured in three sequential samples spanning up to 11 years of follow-up in 324 individuals with incident diabetes and 359 individuals without diabetes in the Danish Blood Donor Study (DBDS) matched for sex and birth year distribution. We used linear mixed-effects models to identify temporal changes before a diabetes diagnosis, either for any incident diabetes diagnosis or for type 1 and type 2 diabetes mellitus diagnoses specifically. We further performed linear and non-linear feature selection, adding 28 polygenic risk scores to the biomarker pool. We tested the time-to-event prediction gain of the biomarkers with the highest variable importance, compared with selected clinical covariates and plasma glucose.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>We identified two proteins and 16 metabolites and lipoprotein particles whose levels changed temporally before diabetes diagnosis and for which the estimated marginal means were significant after FDR adjustment. Sixteen of these have not previously been described. Additionally, 75 biomarkers were consistently higher or lower in the years before a diabetes diagnosis. We identified a single temporal biomarker for type 1 diabetes, IL-17A\/F, a cytokine that is associated with multiple other autoimmune diseases. Inclusion of 12 biomarkers improved the 10-year prediction of a diabetes diagnosis (i.e. the area under the receiver operating curve increased from 0.79 to 0.84), compared with clinical information and plasma glucose alone.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions\/interpretation<\/jats:title>\n                <jats:p>Systemic molecular changes manifest in plasma several years before a diabetes diagnosis. A particular subset of biomarkers shows distinct, time-dependent patterns, offering potential as predictive markers for diabetes onset. Notably, these biomarkers show shared and distinct patterns between type 1 diabetes and type 2 diabetes. After independent replication, our findings may be used to develop new clinical prediction models.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Graphical Abstract<\/jats:title>\n                \n              <\/jats:sec>","DOI":"10.1007\/s00125-024-06231-3","type":"journal-article","created":{"date-parts":[[2024,7,30]],"date-time":"2024-07-30T14:02:48Z","timestamp":1722348168000},"page":"2289-2303","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Longitudinal metabolite and protein trajectories prior to diabetes mellitus diagnosis in Danish blood donors: a nested case\u2013control study"],"prefix":"10.1007","volume":"67","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7447-6560","authenticated-orcid":false,"given":"Agnete T.","family":"Lundgaard","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0128-8432","authenticated-orcid":false,"given":"David","family":"Westergaard","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6841-4056","authenticated-orcid":false,"given":"Timo","family":"R\u00f6der","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5814-6844","authenticated-orcid":false,"given":"Kristoffer S.","family":"Burgdorf","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1679-5103","authenticated-orcid":false,"given":"Margit H.","family":"Larsen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6151-369X","authenticated-orcid":false,"given":"Michael","family":"Schwinn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4391-4956","authenticated-orcid":false,"given":"Lise W.","family":"Th\u00f8rner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5002-9077","authenticated-orcid":false,"given":"Erik","family":"S\u00f8rensen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"DBDS Genomic Consortium","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4406-9643","authenticated-orcid":false,"given":"Kaspar R.","family":"Nielsen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4436-6798","authenticated-orcid":false,"given":"Henrik","family":"Hjalgrim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6551-6647","authenticated-orcid":false,"given":"Christian","family":"Erikstrup","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9953-9521","authenticated-orcid":false,"given":"Bertram D.","family":"Kjerulff","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9439-3906","authenticated-orcid":false,"given":"Lotte","family":"Hindhede","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6703-7762","authenticated-orcid":false,"given":"Thomas F.","family":"Hansen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4973-8543","authenticated-orcid":false,"given":"Mette","family":"Nyegaard","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8314-8497","authenticated-orcid":false,"given":"Ewan","family":"Birney","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hreinn","family":"Stefansson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"K\u00e1ri","family":"Stef\u00e1nsson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2312-5976","authenticated-orcid":false,"given":"Ole B. 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Requests should be directed to the corresponding author. Approval is contingent on adherence to Danish law and may be subject to restrictions.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"Open access funding provided by Copenhagen University. ATL, DW, TR, KB and SB were supported by the Novo Nordisk Foundation (grants NNF14CC0001 and NNF17OC0027594). BDK was supported by the Novo Nordisk Foundation Challenge Programme (grant NNF17OC0027864). LHM acknowledges support from the Novo Nordisk Foundation (grants NNF17OC0027812 and NNF17OC0027594). DV has received research grants from Bayer A\/S, Sanofi A\/S, Novo Nordisk A\/S, and Boehringer Ingelheim; all fees were given to the Steno Diabetes Center Copenhagen. PR reports receipt of honoraria to Steno Diabetes Center Copenhagen for education and consultancy from Abbott, AstraZeneca, Bayer A\/S, Boehringer Ingelheim, Lexicon Inc, Novartis and Novo Nordisk A\/S.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"DV holds shares in Novo Nordisk A\/S and is employed at Novo Nordisk A\/S (current affiliation). SB holds shares in Intomics A\/S, Hoba Therapeutics Aps, Novo Nordisk A\/S and Lundbeck A\/S, and managing board memberships in Proscion A\/S and Intomics A\/S. The remaining authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"ATL, DV, DW, HU, KB, LHM and SB conceived and designed the study. ATL, BDK, the DBDS Genomic Consortium, LH, LHM, MHL and TR carried out the analysis. ATL, DV, KB, TR and SB drafted the manuscript. SB is responsible for the integrity of the work as a whole. All authors acquired and interpreted the data, critically revised the paper, and had final responsibility for the decision to submit for publication.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}