Abstract Body: Background: The effects of reducing dietary carbohydrate intake and glycemic index (GI) levels on temporal changes in blood metabolomic profiles and their impact on improving glucose tolerance remain unclear.
Aim: We examined temporal changes in circulating metabolites induced by lowering dietary carbohydrate content and GI levels and aimed to identify specific metabolites associated with improved glucose tolerance and insulin sensitivity.
Methods: We analyzed data from 162 adults in the OmniCarb trial, a crossover feeding study of diets varying in carbohydrate amount and GI levels. Each diet was consumed for 5 weeks, with at least a 2-week washout period. Global metabolomics was repeatedly performed to calculate temporal changes. Oral glucose tolerance tests (OGTTs) were conducted for all participants; 12-hour meal tests were performed in a subsample (n=59). To validate and explore long-term associations in an independent study (n=670), we analyzed 6-month changes in metabolites in response to weight-loss diets varying in macronutrient composition among participants in the POUNDS Lost trial.
Results: At baseline, 189 of 906 analyzed metabolites showed suggestive associations (crude p <0.05) for the area under the curve of glucose during the OGTT, and 51 metabolites remained significant after correcting for multiple testing (P-FDR <0.05). We found that 170 metabolites (19%) after overnight fasting were significantly modified by lowering carbohydrate amount and GI. In addition, at 30 minutes post-meal (after breakfast), 101 metabolites changed significantly, indicating that the low-carbohydrate, low-GI diet altered postprandial metabolite responses. Particularly, changes in gut microbiota-related metabolites, including 3-hydroxybutyrate, 3-aminoisobutyrate, kynurenate, N-acetylglycine, and hippurate, were associated with improved 12-hour postprandial glucose responses following the low-carbohydrate, low-GI diet. In the POUNDS Lost trial, 6-month increases in 3-hydroxybutyrate, 3-aminoisobutyrate, and N-acetylglycine were associated with greater reductions in fasting glucose and insulin resistance at 6 months. These initial (6-month) metabolite changes were associated with 2-year improvements in glucose metabolism and insulin sensitivity.
Conclusions: Dietary interventions focusing on carbohydrate amount and GI altered circulating metabolites, including gut microbiota-related metabolites, which were linked to improved glucose tolerance and insulin sensitivity.