Identifying the Ratio of Circulating Cinnamoylglycine to Isoleucine as a Biomarker Linking Diet Quality, Microbial Metabolism, and Type 2 Diabetes Risk in the Coronary Artery Risk Development in Young Adults (CARDIA) Cohorts

Background: Unhealthy diet and microbiota dysbiosis are known risk factors of type 2 diabetes (T2D), but the value of microbial metabolites as indicators of diet quality and T2D risk has rarely been explored. Objectives: In this prospective study, we examined the correlations of dietary intake and circulating microbial metabolism-associated metabolites with T2D parameters in adults enrolled in the Coronary Artery Risk Development in Young Adults study. Methods: A cohort of 2296 nondiabetic participants was examined on their diet quality, plasma metabolome, fasting glucose, and insulin in year 7 of the coronary artery risk development in young adults study, and the occurrence of incident T2D afterward. Dietary intake was assessed by an interviewer-administered diet history. Diet quality was characterized by the Healthy Eating Index 2020 score. Spearman correlation analysis assessed the associations of plasma metabolites with healthy eating index, fasting glucose, insulin, and homeostatic model assessment indexes. Subsequent propensity matching of 131 incident T2D cases with controls yielded a paired dataset for logistic and multivariate regression analyses, resulting in the predictive markers that were further validated by Cox proportional hazard models on 3 random cohorts selected from the full cohort. Results: Among 611 circulating plasma metabolites, 41 were classified as microbial metabolites or their dietary precursors. Cinnamoylglycine, a metabolite produced jointly by microbial phenylalanine fermentation and hepatic glycine conjugation, was positively correlated with diet quality and inversely associated with incident T2D risk [odds ratio (OR): 0.66; 95% confidence interval (CI): 0.49, 0.87]. Isoleucine was inversely correlated with diet quality and positively associated with T2D risk (OR: 1.98; 95% CI: 1.36, 2.87). This contrast between cinnamoylglycine and isoleucine provided a cinnamoylglycine/isoleucine ratio as a predictive indicator of diet quality and incident T2D risk (OR: 0.61; 95% CI: 0.46, 0.82), which was validated from the 3 randomly selected samples (hazard ratio: 0.75; 95% CI: 0.59, 0.96; P = 0.02). Conclusions: The cinnamoylglycine/isoleucine ratio may be an effective indicator linking diet quality, microbial metabolism, and T2D risk.