Metabolomic Signatures of Dietary Carbohydrates and Differential Association with Type 2 Diabetes

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