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<jats:p>The aim of this study was to identify shared and distinct metabolite profiles prospectively associated with nephropathy, retinopathy and neuropathy at 15\u00a0years\u2019 follow-up among 1947 participants in the Diabetes Prevention Program Outcomes Study, the long-term follow-up of the Diabetes Prevention Program (DPP).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We applied bootstrapped LASSO to 353 annotated metabolites to identify metabolites associated with one or more complication. For these metabolite hits, we tested for an interaction with DPP treatment arm, and ran multivariable models for the pooled sample or within treatment group as appropriate.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      At follow-up, 572 participants had one or more complication (\n                      <jats:italic>n<\/jats:italic>\n                      =277 nephropathy,\n                      <jats:italic>n<\/jats:italic>\n                      =194 retinopathy,\n                      <jats:italic>n<\/jats:italic>\n                      =212 neuropathy). Of 105 metabolites that predicted any complication, 74 predicted one, 27 predicted two, and four predicted all three. In a pooled analysis of 69 metabolites without treatment arm interactions, histidine predicted lower odds of nephropathy (OR 0.75; 95% CI 0.69, 0.88), and serine predicted lower odds of nephropathy (OR 0.69; 95% CI 0.58, 0.82) and neuropathy (OR 0.68; 95% CI 0.56, 0.84). Of 36 metabolites that interacted with treatment arm, higher\n                      <jats:italic>N<\/jats:italic>\n                      -carbamoyl-\u03b2-alanine predicted greater odds of nephropathy (OR 1.99; 95% CI 1.38, 2.99) and C22:0-sphingomyelin predicted lower odds of neuropathy (OR 0.54; 95% CI 0.37, 0.77) in the metformin arm. In the lifestyle intervention arm, quinolinic acid predicted greater odds of neuropathy (OR 1.64; 95% CI 1.24, 2.19). These estimates accounted for sex, race, baseline age, BMI and smoking, and time elapsed during follow-up. Further adjustment for HbA\n                      <jats:sub>1c<\/jats:sub>\n                      during follow-up, incident diabetes and eGFR did not change the results.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>The existence of distinct metabolite profiles associated with single microvascular complications highlights the importance of characterising pathophysiological mechanisms specific to each complication, in addition to studying shared mechanisms across multiple complications.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-025-06571-8","type":"journal-article","created":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T14:57:43Z","timestamp":1760194663000},"page":"103-113","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Shared and distinct metabolomics profiles associated with microvascular complications in the Diabetes Prevention Program Outcomes Study"],"prefix":"10.1007","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8552-6850","authenticated-orcid":false,"given":"Wei","family":"Perng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiyu","family":"Shu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"Nathan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose A.","family":"Luchsinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert E.","family":"Gerszten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roeland J. 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A complete list of centres, investigators and staff is provided in the\n                      \n                      .","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"In accordance with the NIH Public Access Policy, we continue to provide all manuscripts to PubMed Central including this manuscript. DPP\/DPPOS have provided the protocols and lifestyle and medication intervention manuals to the public through its public website (\n                      \n                      ). The DPPOS abides by the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) data sharing policy and implementation guidance as required by the NIH\/NIDDK (\n                      \n                      ).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"The research reported in this publication was supported by the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) of the NIH under award numbers U01 DK048489, U01 DK048339, U01 DK048377, U01 DK048349, U01 DK048381, U01 DK048468, U01 DK048434, U01 DK048485, U01 DK048375, U01 DK048514, U01 DK048437, U01 DK048413, U01 DK048411, U01 DK048406, U01 DK048380, U01 DK048397, U01 DK048412, U01 DK048404, U01 DK048387, U01 DK048407, U01 DK048443, and U01 DK048400, in part by the National Institute on Aging of the NIH under award number 5\u00a0U19 AG078558, and by supplemental funding by the National Cancer Institute. These grants provided funding during the DPP and the DPPOS to the clinical centres and the coordinating centre for the design and conduct of the study, and collection, management, analysis and interpretation of the data. Funding was also provided by the National Institute of Child Health and Human Development, the National Institute on Aging, the National Eye Institute, the National Heart Lung and Blood Institute, the National Cancer Institute, the Office of Research on Women\u2019s Health, the National Institute on Minority Health and Health Disparities, the Centers for Disease Control and Prevention, and the ADA. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The Southwestern American Indian Centers were supported directly by the NIDDK, including its Intramural Research Program, and by the Indian Health Service. The General Clinical Research Center Program, National Center for Research Resources, and the Department of Veterans Affairs supported data collection at many of the clinical centres. Merck KGaA provided medication for the DPPOS. The DPP\/DPPOS have also received donated materials, equipment or medicines for concomitant conditions from Bristol-Myers Squibb, Parke-Davis, LifeScan Inc., Health O Meter, Hoechst Marion Roussel Inc., Merck-Medco Managed Care Inc., Merck and Co., Nike Sports Marketing, Slim Fast Foods Co., Quaker Oats Co., McKesson BioServices Corp. and Matthews Media Group Inc. The Henry M. Jackson Foundation provided support services under subcontract with the coordinating centre. The sponsor of this study was represented on the steering committee and played a part in study design, how the study was performed and the decision to publish. All authors in the writing group had access to all data. The opinions expressed are those of the study group and do not necessarily reflect the views of the funding agencies.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"RJWM was an employee of the Joslin Diabetes Center at the time the research was conducted, and has received research support from, and is now an employee of Novo Nordisk. WP received an honorarium from George Washington University for otherwise unfunded effort in leading this work. The remaining authors declare that there are no 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":"WP, SS, MT, DD, DMN, JAL, REG, RJWM, WCK and SEK made substantial contributions to the conception or design of the work, as well as the interpretation of data. WP, SS and MT led the analysis approach, and SS implemented the analysis. WP drafted the article and incorporated co-author feedback. SS, DMN, JAL, REG, RJWM, SEK, WCK, DD and MT reviewed the article critically for important intellectual content. All authors gave final approval of the version to be published. WP is the guarantor of this work.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}