Metabolomic signatures of dietary carbohydrates and differential association with type 2 diabetes

Xiaowen Wang; Pengfei Xia; Fenglei Wang; Zhiyuan Wu; Yang Hu; A. Heather Eliassen; Oana A. Zeleznik; Shilpa N. Bhupathiraju; Seyed Mohammad Mousavi; Ross L. Prentice; Lesley F. Tinker; Cheng Zheng; Simin Liu; Ying Huang; Sandi L. Navarro; Mary C. Playdon; Steven C. Moore; Linda Snetselaar; Fred K. Tabung; JoAnn E. Manson; Lihong Qi; Daniel Raftery; Walter C. Willett; Johanna W. Lampe; Marian L. Neuhouser; Qi Sun

doi:10.1038/s44360-025-00023-8

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Metabolomic signatures of dietary carbohydrates and differential association with type 2 diabetes

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Metabolomic signatures of dietary carbohydrates and differential association with type 2 diabetes

Xiaowen Wang, Pengfei Xia, Fenglei Wang, Zhiyuan Wu, Yang Hu, A. Heather Eliassen, Oana A. Zeleznik, Shilpa N. Bhupathiraju, Seyed Mohammad Mousavi, Ross L. Prentice, …

Nature Health, Vol.1(1), pp.145-157

01/2026

DOI: 10.1038/s44360-025-00023-8

PMCID: PMC13290266

PMID: 42344277

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Abstract

Metabolomic indices summarizing diet-related metabolic responses are instrumental for examining and replicating diet–disease associations. Here we aim to identify metabolomic signatures characterizing the amounts and types of dietary carbohydrate and assess their associations with type 2 diabetes (T2D) risk. Nutritional metabolomics indices were developed using data from 1,196 healthy participants in the Lifestyle Validation Study with 7-day diet records (7DDRs). Elastic net regression within cross-validation was used to derive metabolomic indices of total carbohydrates and primary food sources. Replication was conducted using feeding menu data among 153 women from the Nutrition and Physical Activity Assessment Study. Associations with incident T2D were examined using multivariable Cox regression in 11,454 participants from the Nurses’ Health Study, Nurses’ Health Study II and Health Professionals Follow-up Study. Metabolites positively associated with total carbohydrates and added sugars mainly included glycerolipids (diacylglycerols and triglycerides), whereas glycerophospholipids (phosphatidylethanolamines and phosphatidylcholines) were inversely associated. Whole grains were linked to betaine, 3-indolepropionic acid (IPA) and hippuric acid; vegetables and legumes to IPA, N -acetylornithine and pipecolic acid; and fruits to proline-betaine and IPA. Identified metabolomic signatures showed significant correlations with a 7-day diet record-assessed diet in the Lifestyle Validation Study (Pearson r 0.33–0.65). In the Nutrition and Physical Activity Assessment Study, the metabolomic index of total carbohydrates was also significantly correlated with intake ( r = 0.40). Signatures for total carbohydrates, added sugars, refined grains and potatoes were associated with higher T2D risk (HR per s.d. (95% confidence interval): 1.07 (1.02–1.12), 1.09 (1.03–1.14), 1.12 (1.07–1.18) and 1.36 (1.29–1.43)), whereas whole grain, vegetable, fruit and legume signatures were inversely associated (HR per s.d. (95% confidence interval): 0.73 (0.70–0.77), 0.95 (0.90–0.99), 0.88 (0.83–0.92) and 0.93 (0.88–0.97)). The metabolomic signatures of carbohydrate sources were differentially associated with T2D risk, highlighting the utility of blood metabolomics to objectively capture dietary carbohydrates and support dietary guidelines emphasizing fruits, vegetables and whole grains for diabetes prevention. Metabolite signatures were identified for subtypes of dietary carbohydrate, including added sugar, whole grain and refined grain, and showed different associations with type 2 diabetes, providing an objective measure of dietary risk.

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Details

Title: Subtitle: Metabolomic signatures of dietary carbohydrates and differential association with type 2 diabetes
Creators: Xiaowen Wang - Harvard University
Pengfei Xia - Harvard University
Fenglei Wang - Harvard University
Zhiyuan Wu - Harvard University
Yang Hu - Harvard University
A. Heather Eliassen - Harvard University
Oana A. Zeleznik - Brigham and Women's Hospital
Shilpa N. Bhupathiraju - Harvard University
Seyed Mohammad Mousavi - Harvard University
Ross L. Prentice - Fred Hutch Cancer Center
Lesley F. Tinker - Fred Hutch Cancer Center
Cheng Zheng - University of Nebraska Medical Center
Simin Liu - University of California, Irvine
Ying Huang - Fred Hutch Cancer Center
Sandi L. Navarro - Fred Hutch Cancer Center
Mary C. Playdon - University of Utah
Steven C. Moore - National Cancer Institute
Linda Snetselaar - University of Iowa
Fred K. Tabung - The Ohio State University
JoAnn E. Manson - Brigham and Women's Hospital
Lihong Qi - University of California, Davis
Daniel Raftery - University of Washington
Walter C. Willett - Harvard University
Johanna W. Lampe - University of Washington
Marian L. Neuhouser - Fred Hutch Cancer Center
Qi Sun - Harvard University
Resource Type: Journal article
Publication Details: Nature Health, Vol.1(1), pp.145-157
DOI: 10.1038/s44360-025-00023-8
PMID: 42344277
PMCID: PMC13290266
NLM abbreviation: Nat Health
ISSN: 3005-0693
eISSN: 3005-0693
Publisher: Nature Publishing Group UK
Number of pages: 13
Grant note: NNF24SA0092022 / Novo Nordisk Fonden (Novo Nordisk Foundation) (https://doi.org/10.13039/501100009708) 75N92021D00001, 75N92021D00002, 75N92021D00003, 75N92021D00004, 75N92021D00005 / U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) (https://doi.org/10.13039/100000050) National Institutes of Health (grant No. UM1 CA186107, U01 CA176726, U01 CA167552, P01 CA87969, R01 HL034594, R01 HL035464, R01 HL60712, R01 DK120870, R01 DK126698, R01 DK119268, U2C DK129670, DK119268, R01 ES022981, R01 ES036206, R21 AG070375, P30 DK035816, P30 CA015704, R01 CA119171)
Language: English
Date published: 01/2026
Academic Unit: Epidemiology; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
Record Identifier: 9985121598102771

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