Metabolites and proteins may mediate the relationship between diet quality and insulin sensitivity in young adult cohort

Purpose: Poor diet quality is a known risk factor for type 2 diabetes and related outcomes, including declines in insulin sensitivity. Biological changes that occur in response to diet may explain this relationship. Methods: = 77, 52% female, 57% Hispanic). High dimensional mediation analyses (HIMA) were performed to identity potential metabolite, protein, and miRNA mediators of the relationship between the Healthy Eating Index-2015 (HEI) and insulin sensitivity (Matsuda Index) over a four year follow up period. Features identified by HIMA and significant after correction for multiple comparisons (q < 0.05) were assessed using causal mediation analyses. The indirect effects and proportion mediated by each feature were calculated independently. Results: Each point increase in HEI was associated with a 0.051 (95% CI:0.004, 0.098) point increase in Matsuda Index. Four potential mediators were identified using HIMA: three metabolites (5Z,8Z,11Z-eicosatrienoic acid, pipecolic acid, and biotin), and one protein (F9). Each of these features exhibited a positive indirect effect and independently mediated between 35 and 43% of the total effect. No miRNAs were selected as potential mediators. Conclusion: These findings suggest that specific metabolites and proteins may mediate the association between diet and diabetes-related outcomes such as declines in insulin sensitivity, likely through pathways related to inflammation. F9, biotin, pipecolic acid, and 5Z,8Z,11Z-eicosatrienoic acid may be potential targets for monitoring efforts for diet adherence or disease prevention. Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-026-01918-3.