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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #429939
Research Project: Enhancing Childhood Health and Lifestyle Behaviors

Location: Children's Nutrition Research Center

Title: Circulating metabolomics, genetics and lifestyle factors in relation to future risk of type 2 diabetes

Author
item LI, JUN - Brigham & Women'S Hospital
item HU, JIE - Brigham & Women'S Hospital
item YUN, HUAN - Harvard School Of Public Health
item MEI, ZHENDONG - Brigham & Women'S Hospital
item WANG, XINGYAN - Harvard School Of Public Health
item LUO, KAI - Albert Einstein College Of Medicine
item GUASCH-FERRÉ, MARTA - Harvard School Of Public Health
item HAN, XIKUN - Harvard School Of Public Health
item TRUONG, BUU - Harvard School Of Public Health
item MERINO, JORDI - University Of Copenhagen
item JIA, CHENGYONG - Albert Einstein College Of Medicine
item RUIZ-CANELA, MIGUEL - University Of Navarra
item REBHOLZ, CASEY - Johns Hopkins School Of Public Health
item MOON, EUN - University Of Texas Health Science Center
item ALKIS, TARYN - University Of Texas Health Science Center
item LIU, GUNING - University Of Texas Health Science Center
item YAO, JIE - Harbor-Ucla Medical Center
item ZHANG, XIYUAN - University Of Massachusetts, Lowell
item PORNEALA, BIANCA - Brandeis University
item SALAS-SALVADÓ, JORDI - Instituto De Salud Carlos Iii
item WANG, THOMAS - University Of Michigan
item DUPUIS, JOSÉE - Boston University School Of Public Health
item SELVIN, ELIZABETH - Johns Hopkins School Of Public Health
item GUO, XIUQING - Harbor-Ucla Medical Center
item BHUPATHIRAJU, SHILPA - Brigham & Women'S Hospital
item BRODY, JENNIFER - University Of Washington
item LIU, YONGMEI - Duke University Medical Center
item WOOD, ALEXIS - Children'S Nutrition Research Center (CNRC)
item NORTH, KARI - University Of North Carolina
item JUNG, SU - University Of California (UCLA)
item LIU, CHING - Boston University School Of Public Health
item SOTOODEHNIA, NONA - University Of Washington
item LIU, SIMIN - University Of California Irvine
item TINKER, LESLEY - Fred Hutchinson Cancer Research Center
item ELIASSEN, A - Harvard School Of Public Health
item MANSON, JOANN - Brigham & Women'S Hospital
item FLOREZ, JOSE - Massachusetts General Hospital
item GERSZTEN, ROBERT - Broad Institute Of Mit/harvard
item CLISH, CLARY - Broad Institute Of Mit/harvard
item LIANG, LIMING - Harvard School Of Public Health
item LEMAITRE, ROZENN - University Of Washington
item TUCKER, KATHERINE - University Of Massachusetts, Lowell
item RICH, STEPHEN - University Of Virginia
item ROTTER, JEROME - Harbor-Ucla Medical Center
item MARTÍNEZ-GONZÁLEZ, MIGUEL - Harvard School Of Public Health
item REXRODE, KATHRYN - Brigham & Women'S Hospital
item MEIGS, JAMES - Broad Institute Of Mit/harvard
item BOERWINKLE, ERIC - University Of Texas Health Science Center
item KAPLAN, ROBERT - Albert Einstein College Of Medicine
item HU, FRANK - Harvard School Of Public Health
item YU, BING - University Of Texas Health Science Center
item QI, QIBIN - Albert Einstein College Of Medicine

Submitted to: Nature Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/6/2025
Publication Date: 1/14/2026
Citation: Li, J., Hu, J., Yun, H., Mei, Z., Wang, X., Luo, K., Guasch-Ferré, M., Han, X., Truong, B., Merino, J., Jia, C., Ruiz-Canela, M., Rebholz, C.M., Moon, E.H., Alkis, T., Liu, G., Yao, J., Zhang, X., Porneala, B.C., Salas-Salvadó, J., Wang, T.J., Dupuis, J., Selvin, E., Guo, X., Bhupathiraju, S., Brody, J.A., Liu, Y., Wood, A.C., North, K.E., Jung, S.Y., Liu, C.T., Sotoodehnia, N., Liu, S., Tinker, L.F., Eliassen, A.H., Manson, J.E., Florez, J.C., Gerszten, R.E., Clish, C.B., Liang, L., Lemaitre, R.N., Tucker, K.L., Rich, S.S., Rotter, J.I., Martínez-González, M.A., Rexrode, K.M., Meigs, J.B., Boerwinkle, E., Kaplan, R.C., Hu, F.B., Yu, B., Qi, Q. 2026. Circulating metabolomics, genetics and lifestyle factors in relation to future risk of type 2 diabetes. Nature Medicine. https://doi.org/10.1038/s41591-025-04105-8.
DOI: https://doi.org/10.1038/s41591-025-04105-8

Interpretive Summary: Type 2 diabetes develops through complex interactions between genes, environment, and metabolism, but the specific metabolites involved are not fully known. In this large study of over 23,000 adults followed for up to 26 years, researchers analyzed 469 circulating metabolites and found 235 that predicted future diabetes risk, including 67 not previously reported. These metabolites were linked to biological pathways involved in insulin resistance, lipid metabolism, liver function, and fat storage, and many were influenced by both genetic factors and modifiable lifestyle factors such as physical activity, diet, and obesity. Some metabolites acted as mediators, explaining how lifestyle behaviors influence diabetes risk. A combined "metabolite signature" of 44 molecules significantly improved the ability to predict who would develop diabetes, identifying individuals with up to fivefold differences in risk. These findings deepen our understanding of how metabolic changes contribute to diabetes development and could help scientists, clinicians, and public health professionals design more precise prevention strategies tailored to metabolic profiles.

Technical Abstract: 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, ectopic fat deposition, energy/lipid regulation and liver function. Lifestyle factors—particularly physical activity, obesity and diet—explained greater variations in T2D-associated versus non-associated metabolites, with specific metabolites revealed as potential mediators. Finally, a 44-metabolite signature improved T2D risk prediction beyond conventional factors. These findings provide a foundation for understanding T2D mechanisms and may inform precision prevention targeting specific metabolic pathways.