biostudies-literatureLi JNovo Nordisk Fonden (Novo Nordisk Foundation)U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases)U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)American Heart Association (American Heart Association, Inc.)660-670https://www.ebi.ac.uk/biostudies/studies/S-EPMC12920144biostudies-literatureUnknown32(2)The human metabolome reflects complex metabolic states affected by genetic and environmental factors. However, metabolites associated with type 2 diabetes (T2D) risk and their determinants remain insufficiently characterized. Here we integrated blood metabolomic, genomic and lifestyle data from up to 23,634 initially T2D-free participants from ten cohorts. Of 469 metabolites examined, 235 were associated with incident T2D during up to 26 years of follow-up, including 67 associations not previously reported across bile acid, lipid, carnitine, urea cycle and arginine/proline, glycine and histidine pathways. Further genetic analyses linked these metabolites to signaling pathways and clinical traits central to T2D pathophysiology, including insulin resistance, glucose/insulin response, ectopicNature medicineCirculating metabolites, genetics and lifestyle factors in relation to future risk of type 2 diabetes.PMC12920144R01AG085320R01HL060712U01DK140761R01DK119268; R01DK126698; U01DK140761; R01DK120870R01HL136266R00DK122128R01HL15317823POST1020455R01DK081572NNF24OC0095435R01DK134672K24HL152440R01HL060712; R01HL170904Gerszten REDupuis JFlorez JCRotter JIGuo XMerino JBoerwinkle ERich SSAlkis TTruong BWang TJRebholz CMBhupathiraju SNLiang LWang XYao JLi JManson JEHu FBWood ACSalas-Salvado JRexrode KMPorneala BCLiu CTHu JBrody JAMartinez-Gonzalez MAKaplan RCYun HJia CMei ZMeigs JBHan XClish CBLiu STucker KLSotoodehnia NQi QLiu YJung SYSelvin ELemaitre RNGuasch-Ferre MTinker LFRuiz-Canela MEliassen AHLuo KYu BZhang XMoon EHLiu GNorth KEfalseCirculating metabolites, genetics and lifestyle factors in relation to future risk of type 2 diabetes.The human metabolome reflects complex metabolic states affected by genetic and environmental factors. However, metabolites associated with type 2 diabetes (T2D) risk and their determinants remain insufficiently characterized. Here we integrated blood metabolomic, genomic and lifestyle data from up to 23,634 initially T2D-free participants from ten cohorts. Of 469 metabolites examined, 235 were associated with incident T2D during up to 26 years of follow-up, including 67 associations not previously reported across bile acid, lipid, carnitine, urea cycle and arginine/proline, glycine and histidine pathways. Further genetic analyses linked these metabolites to signaling pathways and clinical traits central to T2D pathophysiology, including insulin resistance, glucose/insulin response, ectopic2026-01-01T00:00:00Z2026 Feb2026-07-16T12:59:48.81Z2026-07-09T10:57:03.675ZS-EPMC129201444153538610.1038/s41591-025-04105-8