Metabolomic Profiles of Plant and Animal Protein and Type 2 Diabetes: Four Prospective US Cohort Studies.

Objective: This study aimed to characterize plasma metabolomic signatures reflecting the metabolic pathways of plant and animal protein intake, and examine their association with the risk of type 2 diabetes (T2D). Methods: In three cohorts, plasma metabolites were profiled from 11,742 participants from the Nurses' Health Study (NHS; mean age 56.8 y), NHSII (mean age 44.6 y), and Health Professional's Follow-Up Study (mean age 63.3 y) using liquid chromatography mass spectrometry. Protein intakes (% kcal) were derived from two repeated food frequency questionnaires closest to the blood draw. Elastic net regressions identified metabolomic signatures of plant and animal protein intake and their ratio. Metabolomic signatures were replicated in the Women's Health Initiative (WHI; n = 2,092) cohort. Multivariable-adjusted Cox regression models evaluated associations between signatures and T2D. Results: Signatures for plant protein, animal protein, and their ratio comprised 63, 50, 40 metabolites. Seventeen metabolites overlapped between the three signatures, including creatine, C34:5 phosphatidylcholine plasmalogens, C18:0 sphingomyelin, and N-acetylornithine. Higher plant protein signature scores were associated with lower T2D risk [HR per 1SD = 0.91 (0.83, 1.00); p = 0.049], while higher animal protein signature scores were associated with higher risk [HR per 1SD = 1.13 (1.03, 1.23); p = 0.008], with consistent replication. Conclusions: Plant and animal protein intake have distinct plasma metabolomic signatures. The biological footprint of plant protein exposure is favorably associated with T2D, whereas that of animal protein is adverse. Findings from these prospective cohort studies support that increased plant protein intake may provide benefits for T2D prevention.