{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T22:24:27Z","timestamp":1783981467795,"version":"3.55.0"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"7","license":[{"start":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T00:00:00Z","timestamp":1773792000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T00:00:00Z","timestamp":1773792000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100007289","name":"Nanjing Medical University","doi-asserted-by":"publisher","award":["Award NMUR20230003"],"award-info":[{"award-number":["Award NMUR20230003"]}],"id":[{"id":"10.13039\/501100007289","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007270","name":"University of Michigan","doi-asserted-by":"publisher","award":["Precision Health Scholarship (X. Y.)"],"award-info":[{"award-number":["Precision Health Scholarship (X. Y.)"]}],"id":[{"id":"10.13039\/100007270","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018537","name":"National Science and Technology Major Project","doi-asserted-by":"publisher","award":["2025ZD0550702"],"award-info":[{"award-number":["2025ZD0550702"]}],"id":[{"id":"10.13039\/501100018537","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002341","name":"Research Council of Finland","doi-asserted-by":"publisher","award":["Grant no. 321428 (M. L.)"],"award-info":[{"award-number":["Grant no. 321428 (M. L.)"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000041","name":"American Diabetes Association","doi-asserted-by":"publisher","award":["Postdoctoral Fellowship (1-19-PDF-061"],"award-info":[{"award-number":["Postdoctoral Fellowship (1-19-PDF-061"]}],"id":[{"id":"10.13039\/100000041","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000041","name":"American Diabetes Association","doi-asserted-by":"publisher","award":["X. Y.)"],"award-info":[{"award-number":["X. Y.)"]}],"id":[{"id":"10.13039\/100000041","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Jiangsu Professorship"},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82574183(X. Y.)"],"award-info":[{"award-number":["82574183(X. Y.)"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000098","name":"Clinical Center","doi-asserted-by":"publisher","award":["R01 DK119380"],"award-info":[{"award-number":["R01 DK119380"]}],"id":[{"id":"10.13039\/100000098","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000098","name":"Clinical Center","doi-asserted-by":"publisher","award":["R35 GM138121"],"award-info":[{"award-number":["R35 GM138121"]}],"id":[{"id":"10.13039\/100000098","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000098","name":"Clinical Center","doi-asserted-by":"publisher","award":["U01 DK062370"],"award-info":[{"award-number":["U01 DK062370"]}],"id":[{"id":"10.13039\/100000098","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Sigrid Juselius Foundation"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Diabetologia"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims\/hypothesis<\/jats:title>\n                    <jats:p>A recent study has suggested eight clusters of genetic variants associated with type 2 diabetes. We aimed to characterise metabolite associations for these eight clusters.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We constructed type 2 diabetes overall and cluster-partitioned polygenic risk scores (PRSs) in 10,015 Finnish men with 979 named plasma metabolites measured in Metabolon HD4 mass spectrometry platform. We evaluated metabolite\u2013PRS associations using linear regression. We also performed a mediation analysis to examine whether metabolites statistically accounted for part of the association between genetic risk and incident type 2 diabetes that developed in a mean of 13.6 years\u2019 follow-up.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We identified 337 metabolites significantly associated with type 2 diabetes genetic risk, including 242 exclusive to cluster-partitioned PRSs. Of the significant metabolites, 26 exhibited significantly heterogeneous associations across clusters. We identified significant enrichment for 33 metabolic pathways among the cluster-associated metabolites. Notably, metabolites for the two pancreatic beta cell-related clusters exhibited enrichment in distinct pathways: the beta cell + proinsulin (PI) cluster in fructose, mannose and galactose metabolism; and the beta cell \u2212 PI cluster in branched-chain amino acid metabolism. Mediation analysis suggested that &gt;50% of the associated metabolites showed patterns statistically consistent with a mediating role in the associations between PRSs and incident type 2 diabetes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>This study underscores the value of type 2 diabetes clustering and highlights metabolic heterogeneity across clusters. The findings have the potential to guide personalised interventions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Data availability<\/jats:title>\n                    <jats:p>The datasets generated during and\/or analysed in the current study are available in dbGaP (accession ID: phs000743.v4.p1 and phs004033.v1.p1).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-026-06710-9","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T12:25:22Z","timestamp":1773836722000},"page":"1869-1881","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Plasma metabolite association profiles for type 2 diabetes genetic clusters in Finnish men"],"prefix":"10.1007","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-9892-7637","authenticated-orcid":false,"given":"Ruyi","family":"Peng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1786-0740","authenticated-orcid":false,"given":"Lei","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6396-8578","authenticated-orcid":false,"given":"Xiaomeng","family":"Chu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3449-0286","authenticated-orcid":false,"given":"Zhijie","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2463-3123","authenticated-orcid":false,"given":"Qi","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0225-842X","authenticated-orcid":false,"given":"Lilian Fernandes","family":"Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5930-041X","authenticated-orcid":false,"given":"Xiaolong","family":"Ji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6185-3173","authenticated-orcid":false,"given":"Xinxian","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2127-8377","authenticated-orcid":false,"given":"Yuxi","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6126-0701","authenticated-orcid":false,"given":"Jack","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4164-2871","authenticated-orcid":false,"given":"Brady","family":"Ryan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3177-6608","authenticated-orcid":false,"given":"Debraj","family":"Bose","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2991-6392","authenticated-orcid":false,"given":"Heather M.","family":"Stringham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4829-8283","authenticated-orcid":false,"given":"Jean","family":"Morrison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8990-2737","authenticated-orcid":false,"given":"Xiaoquan","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4886-5084","authenticated-orcid":false,"given":"Laura J.","family":"Scott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9189-5003","authenticated-orcid":false,"given":"Charles F.","family":"Burant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9739-0249","authenticated-orcid":false,"given":"Eric","family":"Fauman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6375-3622","authenticated-orcid":false,"given":"Tao","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6442-7754","authenticated-orcid":false,"given":"Michael","family":"Boehnke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3394-7749","authenticated-orcid":false,"given":"Markku","family":"Laakso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6454-2384","authenticated-orcid":false,"given":"Xianyong","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,18]]},"reference":[{"issue":"11","key":"6710_CR1","doi-asserted-by":"publisher","first-page":"1758","DOI":"10.1007\/s00125-022-05769-4","volume":"65","author":"AJ Deutsch","year":"2022","unstructured":"Deutsch AJ, Ahlqvist E, Udler MS (2022) Phenotypic and genetic classification of diabetes. Diabetologia 65(11):1758\u20131769. https:\/\/doi.org\/10.1007\/s00125-022-05769-4","journal-title":"Diabetologia"},{"issue":"1","key":"6710_CR2","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1038\/s43856-023-00360-3","volume":"3","author":"S Misra","year":"2023","unstructured":"Misra S, Wagner R, Ozkan B et al (2023) Precision subclassification of type 2 diabetes: a systematic review. Commun Med (Lond) 3(1):138. https:\/\/doi.org\/10.1038\/s43856-023-00360-3","journal-title":"Commun Med (Lond)"},{"issue":"8003","key":"6710_CR3","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1038\/s41586-024-07019-6","volume":"627","author":"K Suzuki","year":"2024","unstructured":"Suzuki K, Hatzikotoulas K, Southam L et al (2024) Genetic drivers of heterogeneity in type 2 diabetes pathophysiology. Nature 627(8003):347\u2013357. https:\/\/doi.org\/10.1038\/s41586-024-07019-6","journal-title":"Nature"},{"key":"6710_CR4","doi-asserted-by":"publisher","unstructured":"Mandla R, Lorenz K, Yin X et al (2024) Multi-omics characterization of type 2 diabetes associated genetic variation. medRxiv[Preprint]. https:\/\/doi.org\/10.1101\/2024.07.15.24310282","DOI":"10.1101\/2024.07.15.24310282"},{"issue":"3","key":"6710_CR5","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1007\/s00125-022-05848-6","volume":"66","author":"H Kim","year":"2023","unstructured":"Kim H, Westerman KE, Smith K et al (2023) High-throughput genetic clustering of type 2 diabetes loci reveals heterogeneous mechanistic pathways of metabolic disease. Diabetologia 66(3):495\u2013507. https:\/\/doi.org\/10.1007\/s00125-022-05848-6","journal-title":"Diabetologia"},{"issue":"4","key":"6710_CR6","doi-asserted-by":"publisher","first-page":"1065","DOI":"10.1038\/s41591-024-02865-3","volume":"30","author":"K Smith","year":"2024","unstructured":"Smith K, Deutsch AJ, McGrail C et al (2024) Multi-ancestry polygenic mechanisms of type 2 diabetes. Nat Med 30(4):1065\u20131074. https:\/\/doi.org\/10.1038\/s41591-024-02865-3","journal-title":"Nat Med"},{"issue":"9","key":"6710_CR7","doi-asserted-by":"publisher","first-page":"e1002654","DOI":"10.1371\/journal.pmed.1002654","volume":"15","author":"MS Udler","year":"2018","unstructured":"Udler MS, Kim J, von Grotthuss M et al (2018) Type 2 diabetes genetic loci informed by multi-trait associations point to disease mechanisms and subtypes: a soft clustering analysis. PLoS Med 15(9):e1002654. https:\/\/doi.org\/10.1371\/journal.pmed.1002654","journal-title":"PLoS Med"},{"issue":"1","key":"6710_CR8","doi-asserted-by":"publisher","first-page":"2124","DOI":"10.1038\/s41467-025-56695-z","volume":"16","author":"DP Loesch","year":"2025","unstructured":"Loesch DP, Garg M, Matelska D et al (2025) Identification of plasma proteomic markers underlying polygenic risk of type 2 diabetes and related comorbidities. Nat Commun 16(1):2124. https:\/\/doi.org\/10.1038\/s41467-025-56695-z","journal-title":"Nat Commun"},{"issue":"3","key":"6710_CR9","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1194\/jlr.O072629","volume":"58","author":"M Laakso","year":"2017","unstructured":"Laakso M, Kuusisto J, Stancakova A et al (2017) The Metabolic Syndrome in Men study: a resource for studies of metabolic and cardiovascular diseases. J Lipid Res 58(3):481\u2013493. https:\/\/doi.org\/10.1194\/jlr.O072629","journal-title":"J Lipid Res"},{"issue":"1","key":"6710_CR10","doi-asserted-by":"publisher","first-page":"1644","DOI":"10.1038\/s41467-022-29143-5","volume":"13","author":"X Yin","year":"2022","unstructured":"Yin X, Chan LS, Bose D et al (2022) Genome-wide association studies of metabolites in Finnish men identify disease-relevant loci. Nat Commun 13(1):1644. https:\/\/doi.org\/10.1038\/s41467-022-29143-5","journal-title":"Nat Commun"},{"issue":"7809","key":"6710_CR11","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","volume":"581","author":"KJ Karczewski","year":"2020","unstructured":"Karczewski KJ, Francioli LC, Tiao G et al (2020) The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581(7809):434\u2013443. https:\/\/doi.org\/10.1038\/s41586-020-2308-7","journal-title":"Nature"},{"issue":"11","key":"6710_CR12","doi-asserted-by":"publisher","first-page":"1476","DOI":"10.1038\/s42255-021-00478-5","volume":"3","author":"SC Ritchie","year":"2021","unstructured":"Ritchie SC, Lambert SA, Arnold M et al (2021) Integrative analysis of the plasma proteome and polygenic risk of cardiometabolic diseases. Nat Metab 3(11):1476\u20131483. https:\/\/doi.org\/10.1038\/s42255-021-00478-5","journal-title":"Nat Metab"},{"issue":"4","key":"6710_CR13","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1023\/a:1026595011371","volume":"1","author":"DP MacKinnon","year":"2000","unstructured":"MacKinnon DP, Krull JL, Lockwood CM (2000) Equivalence of the mediation, confounding and suppression effect. Prev Sci 1(4):173\u2013181. https:\/\/doi.org\/10.1023\/a:1026595011371","journal-title":"Prev Sci"},{"issue":"5","key":"6710_CR14","doi-asserted-by":"publisher","first-page":"1","DOI":"10.18637\/jss.v059.i05","volume":"59","author":"D Tingley","year":"2014","unstructured":"Tingley D, Yamamoto T, Hirose K, Keele L, Imai K (2014) mediation: R package for causal mediation analysis. J Stat Softw 59(5):1\u201338. https:\/\/doi.org\/10.18637\/jss.v059.i05","journal-title":"J Stat Softw"},{"issue":"Database issue","key":"6710_CR15","doi-asserted-by":"publisher","first-page":"D668","DOI":"10.1093\/nar\/gkj067","volume":"34","author":"DS Wishart","year":"2006","unstructured":"Wishart DS, Knox C, Guo AC et al (2006) DrugBank: a comprehensive resource for in silico drug discovery and exploration. Nucleic Acids Res 34(Database issue):D668-672. https:\/\/doi.org\/10.1093\/nar\/gkj067","journal-title":"Nucleic Acids Res"},{"issue":"W1","key":"6710_CR16","doi-asserted-by":"publisher","first-page":"W199","DOI":"10.1093\/nar\/gkz401","volume":"47","author":"Y Liao","year":"2019","unstructured":"Liao Y, Wang J, Jaehnig EJ, Shi Z, Zhang B (2019) WebGestalt 2019: gene set analysis toolkit with revamped UIs and APIs. Nucleic Acids Res 47(W1):W199\u2013W205. https:\/\/doi.org\/10.1093\/nar\/gkz401","journal-title":"Nucleic Acids Res"},{"issue":"1","key":"6710_CR17","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1186\/s12920-020-00768-z","volume":"13","author":"X Ma","year":"2020","unstructured":"Ma X, Wang P, Xu G, Yu F, Ma Y (2020) Integrative genomics analysis of various omics data and networks identify risk genes and variants vulnerable to childhood-onset asthma. BMC Med Genomics 13(1):123. https:\/\/doi.org\/10.1186\/s12920-020-00768-z","journal-title":"BMC Med Genomics"},{"issue":"1","key":"6710_CR18","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1186\/s13073-024-01308-5","volume":"16","author":"AP Doumatey","year":"2024","unstructured":"Doumatey AP, Shriner D, Zhou J et al (2024) Untargeted metabolomic profiling reveals molecular signatures associated with type 2 diabetes in Nigerians. Genome Med 16(1):38. https:\/\/doi.org\/10.1186\/s13073-024-01308-5","journal-title":"Genome Med"},{"issue":"2","key":"6710_CR19","doi-asserted-by":"publisher","first-page":"639","DOI":"10.2337\/db12-0495","volume":"62","author":"A Floegel","year":"2013","unstructured":"Floegel A, Stefan N, Yu Z et al (2013) Identification of serum metabolites associated with risk of type 2 diabetes using a targeted metabolomic approach. Diabetes 62(2):639\u2013648. https:\/\/doi.org\/10.2337\/db12-0495","journal-title":"Diabetes"},{"issue":"12","key":"6710_CR20","doi-asserted-by":"publisher","first-page":"2617","DOI":"10.2337\/dc18-0840","volume":"41","author":"C Razquin","year":"2018","unstructured":"Razquin C, Toledo E, Clish CB et al (2018) Plasma lipidomic profiling and risk of type 2 diabetes in the PREDIMED trial. Diabetes Care 41(12):2617\u20132624. https:\/\/doi.org\/10.2337\/dc18-0840","journal-title":"Diabetes Care"},{"issue":"12","key":"6710_CR21","doi-asserted-by":"publisher","first-page":"2804","DOI":"10.1007\/s00125-024-06282-6","volume":"67","author":"S Sharma","year":"2024","unstructured":"Sharma S, Dong Q, Haid M et al (2024) Role of human plasma metabolites in prediabetes and type 2 diabetes from the IMI-DIRECT study. Diabetologia 67(12):2804\u20132818. https:\/\/doi.org\/10.1007\/s00125-024-06282-6","journal-title":"Diabetologia"},{"issue":"2","key":"6710_CR22","doi-asserted-by":"publisher","first-page":"184","DOI":"10.2337\/db21-0490","volume":"71","author":"NA Yousri","year":"2022","unstructured":"Yousri NA, Suhre K, Yassin E et al (2022) Metabolic and metabo-clinical signatures of type 2 diabetes, obesity, retinopathy, and dyslipidemia. Diabetes 71(2):184\u2013205. https:\/\/doi.org\/10.2337\/db21-0490","journal-title":"Diabetes"},{"issue":"11","key":"6710_CR23","doi-asserted-by":"publisher","first-page":"2683","DOI":"10.2337\/db20-1281","volume":"70","author":"RC Slieker","year":"2021","unstructured":"Slieker RC, Donnelly LA, Fitipaldi H et al (2021) Distinct molecular signatures of clinical clusters in people with type 2 diabetes: an IMI-RHAPSODY study. Diabetes 70(11):2683\u20132693. https:\/\/doi.org\/10.2337\/db20-1281","journal-title":"Diabetes"},{"issue":"4","key":"6710_CR24","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1016\/j.clinthera.2014.12.018","volume":"37","author":"T Heise","year":"2015","unstructured":"Heise T, Mattheus M, Woerle HJ, Broedl UC, Macha S (2015) Assessing pharmacokinetic interactions between the sodium glucose cotransporter 2 inhibitor empagliflozin and hydrochlorothiazide or torasemide in patients with type 2 diabetes mellitus: a randomized, open-label, crossover study. Clin Ther 37(4):793\u2013803. https:\/\/doi.org\/10.1016\/j.clinthera.2014.12.018","journal-title":"Clin Ther"},{"issue":"3","key":"6710_CR25","doi-asserted-by":"publisher","first-page":"314","DOI":"10.2165\/00003495-198836030-00004","volume":"36","author":"PA Todd","year":"1988","unstructured":"Todd PA, Ward A (1988) Gemfibrozil. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in dyslipidaemia. Drugs 36(3):314\u2013339. https:\/\/doi.org\/10.2165\/00003495-198836030-00004","journal-title":"Drugs"},{"issue":"5","key":"6710_CR26","doi-asserted-by":"publisher","first-page":"982","DOI":"10.1038\/s41591-022-01790-7","volume":"28","author":"ATN Nair","year":"2022","unstructured":"Nair ATN, Wesolowska-Andersen A, Brorsson C et al (2022) Heterogeneity in phenotype, disease progression and drug response in type 2 diabetes. Nat Med 28(5):982\u2013988. https:\/\/doi.org\/10.1038\/s41591-022-01790-7","journal-title":"Nat Med"},{"issue":"1","key":"6710_CR27","doi-asserted-by":"publisher","first-page":"100477","DOI":"10.1016\/j.xcrm.2021.100477","volume":"3","author":"A Wesolowska-Andersen","year":"2022","unstructured":"Wesolowska-Andersen A, Brorsson CA, Bizzotto R et al (2022) Four groups of type 2 diabetes contribute to the etiological and clinical heterogeneity in newly diagnosed individuals: an IMI DIRECT study. Cell Rep Med 3(1):100477. https:\/\/doi.org\/10.1016\/j.xcrm.2021.100477","journal-title":"Cell Rep Med"},{"issue":"5","key":"6710_CR28","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1016\/S2213-8587(18)30051-2","volume":"6","author":"E Ahlqvist","year":"2018","unstructured":"Ahlqvist E, Storm P, Karajamaki A et al (2018) Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables. Lancet Diabetes Endocrinol 6(5):361\u2013369. https:\/\/doi.org\/10.1016\/S2213-8587(18)30051-2","journal-title":"Lancet Diabetes Endocrinol"},{"issue":"1","key":"6710_CR29","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1038\/s41591-024-03317-8","volume":"31","author":"S Hodgson","year":"2024","unstructured":"Hodgson S, Williamson A, Bigossi M et al (2024) Genetic basis of early onset and progression of type 2 diabetes in South Asians. Nat Med 31(1):323\u2013331. https:\/\/doi.org\/10.1038\/s41591-024-03317-8","journal-title":"Nat Med"},{"issue":"2","key":"6710_CR30","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/S2213-8587(23)00329-7","volume":"12","author":"M Schon","year":"2024","unstructured":"Schon M, Prystupa K, Mori T et al (2024) Analysis of type 2 diabetes heterogeneity with a tree-like representation: insights from the prospective German Diabetes Study and the LURIC cohort. Lancet Diabetes Endocrinol 12(2):119\u2013131. https:\/\/doi.org\/10.1016\/S2213-8587(23)00329-7","journal-title":"Lancet Diabetes Endocrinol"},{"issue":"1","key":"6710_CR31","doi-asserted-by":"publisher","first-page":"7121","DOI":"10.1038\/s41467-022-34754-z","volume":"13","author":"SB Zaghlool","year":"2022","unstructured":"Zaghlool SB, Halama A, Stephan N et al (2022) Metabolic and proteomic signatures of type 2 diabetes subtypes in an Arab population. Nat Commun 13(1):7121. https:\/\/doi.org\/10.1038\/s41467-022-34754-z","journal-title":"Nat Commun"},{"issue":"5","key":"6710_CR32","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1007\/s00203-022-02884-z","volume":"204","author":"M Salman","year":"2022","unstructured":"Salman M, Tariq A, Mustafa G, Javed MR, Naheed S, Qamar SA (2022) Cyclo(L-Leucyl-L-Prolyl) from Lactobacillus coryniformis BCH-4 inhibits the proliferation of Aspergillus flavus: an in vitro to in silico approach. Arch Microbiol 204(5):267. https:\/\/doi.org\/10.1007\/s00203-022-02884-z","journal-title":"Arch Microbiol"},{"issue":"20","key":"6710_CR33","doi-asserted-by":"publisher","first-page":"7756","DOI":"10.1039\/c9nj00645a","volume":"43","author":"M Lozano-Gonz\u00e1lez","year":"2019","unstructured":"Lozano-Gonz\u00e1lez M, Ovalle-Magallanes B, Rangel-Grimaldo M et al (2019) Antidiabetic in vitro and in vivo evaluation of cyclodipeptides isolated from Pseudomonas fluorescens IB-MR-66e. New J Chem 43(20):7756\u20137762. https:\/\/doi.org\/10.1039\/c9nj00645a","journal-title":"New J Chem"},{"issue":"1","key":"6710_CR34","doi-asserted-by":"publisher","first-page":"9","DOI":"10.2337\/db14-1516","volume":"64","author":"N Rabbani","year":"2015","unstructured":"Rabbani N, Thornalley PJ (2015) Hidden complexities in the measurement of fructosyl-lysine and advanced glycation end products for risk prediction of vascular complications of diabetes. Diabetes 64(1):9\u201311. https:\/\/doi.org\/10.2337\/db14-1516","journal-title":"Diabetes"},{"issue":"4","key":"6710_CR35","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1038\/nm.2307","volume":"17","author":"TJ Wang","year":"2011","unstructured":"Wang TJ, Larson MG, Vasan RS et al (2011) Metabolite profiles and the risk of developing diabetes. Nat Med 17(4):448\u2013453. https:\/\/doi.org\/10.1038\/nm.2307","journal-title":"Nat Med"},{"issue":"29","key":"6710_CR36","doi-asserted-by":"publisher","first-page":"24795","DOI":"10.1074\/jbc.M112.344259","volume":"287","author":"J Yang","year":"2012","unstructured":"Yang J, Dolinger M, Ritaccio G et al (2012) Leucine stimulates insulin secretion via down-regulation of surface expression of adrenergic alpha2A receptor through the mTOR (mammalian target of rapamycin) pathway: implication in new-onset diabetes in renal transplantation. J Biol Chem 287(29):24795\u201324806. https:\/\/doi.org\/10.1074\/jbc.M112.344259","journal-title":"J Biol Chem"},{"issue":"9","key":"6710_CR37","doi-asserted-by":"publisher","first-page":"1594","DOI":"10.1002\/oby.21926","volume":"25","author":"W Perng","year":"2017","unstructured":"Perng W, Hector EC, Song PXK et al (2017) Metabolomic determinants of metabolic risk in Mexican adolescents. Obesity (Silver Spring) 25(9):1594\u20131602. https:\/\/doi.org\/10.1002\/oby.21926","journal-title":"Obesity (Silver Spring)"},{"issue":"12","key":"6710_CR38","doi-asserted-by":"publisher","first-page":"984","DOI":"10.3390\/genes10120984","volume":"10","author":"S Payankaulam","year":"2019","unstructured":"Payankaulam S, Raicu AM, Arnosti DN (2019) Transcriptional regulation of INSR, the insulin receptor gene. Genes (Basel) 10(12):984. https:\/\/doi.org\/10.3390\/genes10120984","journal-title":"Genes (Basel)"},{"issue":"11","key":"6710_CR39","doi-asserted-by":"publisher","first-page":"866","DOI":"10.1038\/nrd3893","volume":"12","author":"RJ Harvey","year":"2013","unstructured":"Harvey RJ, Yee BK (2013) Glycine transporters as novel therapeutic targets in schizophrenia, alcohol dependence and pain. Nat Rev Drug Discov 12(11):866\u2013885. https:\/\/doi.org\/10.1038\/nrd3893","journal-title":"Nat Rev Drug Discov"},{"key":"6710_CR40","doi-asserted-by":"publisher","first-page":"884549","DOI":"10.3389\/fendo.2022.884549","volume":"13","author":"X Pan","year":"2022","unstructured":"Pan X, Tao S, Tong N (2022) Potential therapeutic targeting neurotransmitter receptors in diabetes. Front Endocrinol (Lausanne) 13:884549. https:\/\/doi.org\/10.3389\/fendo.2022.884549","journal-title":"Front Endocrinol (Lausanne)"},{"issue":"3","key":"6710_CR41","doi-asserted-by":"publisher","first-page":"384","DOI":"10.3390\/metabo13030384","volume":"13","author":"A Al-Sayyar","year":"2023","unstructured":"Al-Sayyar A, Hammad MM, Williams MR, Al-Onaizi M, Abubaker J, Alzaid F (2023) Neurotransmitters in type 2 diabetes and the control of systemic and central energy balance. Metabolites 13(3):384. https:\/\/doi.org\/10.3390\/metabo13030384","journal-title":"Metabolites"}],"container-title":["Diabetologia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00125-026-06710-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00125-026-06710-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00125-026-06710-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T14:41:32Z","timestamp":1780584092000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00125-026-06710-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,18]]},"references-count":41,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2026,7]]}},"alternative-id":["6710"],"URL":"https:\/\/doi.org\/10.1007\/s00125-026-06710-9","relation":{},"ISSN":["0012-186X","1432-0428"],"issn-type":[{"value":"0012-186X","type":"print"},{"value":"1432-0428","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,18]]},"assertion":[{"value":"9 August 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 January 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 March 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"We thank all the METSIM participants for their contribution to this research.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"The datasets generated during and\/or analysed in the current study are available in dbGaP (accession ID: phs000743.v4.p1 and phs004033.v1.p1).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"This work was supported by the National Institutes of Health (NIH) under awards U01 DK062370 (MB), R35 GM138121 (XQW), R01 DK119380 (XQW), the American Diabetes Association Postdoctoral Fellowship (1-19-PDF-061, XY), the University of Michigan Precision Health Scholarship (XY), the Academy of Finland (grant no. 321428, ML), the Sigrid Juselius Foundation (ML), National Natural Science Foundation of China (82574183, XY), Noncommunicable Chronic Diseases-National Science and Technology Major Project (2025ZD0550702, XY), Jiangsu Professorship (XY) and Nanjing Medical University (NMUR20230003, XY).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"EF is an employee and stockholder of Pfizer. The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"XY, MB and ML conceived and designed the study. XY, MB, ML, LFS, JL, BR, DB, HMS, JM, XW, LJS, CFB and EF contributed to the acquisition of data. RP, LL, XC, ZX, QF, XJ, XH, YL and TY analysed or interpreted the data. RP and LL drafted the manuscript. XY, MB, ML, XC, ZX, QF, LFS, XJ, XH, YL, JL, BR, DB, HMS, JM, XW, LJS, CFB, EF and TY critically revised the manuscript for important intellectual content. All authors approved the final version to be published. XY, MB and ML 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","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}