Per- and polyfluoroalkyl substances and type 2 diabetes risk: Evidence from metabolomics and triglyceride-glucose index-related pathways.

Per- and polyfluoroalkyl substances (PFAS), including emerging alternatives, have been implicated in type 2 diabetes (T2D), but epidemiological evidence remains inconsistent and the underlying mechanisms are unclear. We aimed to investigate the associations of individual and mixed PFAS exposure with T2D risk and to explore the roles of triglyceride-glucose (TyG)-related indices and metabolomic alterations. A total of 1647 participants (749 participants with T2D and 898 controls) were included. Multivariable logistic regression and weighted quantile sum (WQS) regression were used to evaluate the associations of single PFAS and mixed PFAS with T2D risk, respectively. Mediation analyses were conducted for TyG-related indices, and untargeted metabolomics and sequential mediation analyses were further performed in a nested case-control subset. Most individual PFAS were positively associated with T2D risk. Mixed-exposure analyses consistently showed that PFAS mixture was associated with increased T2D risk, with 6:2 FTS, PFNS, and PFPeS identified as the main contributors. Mediation analyses indicated that TyG-related indices (TyG, TyG-BMI, TyG-WC, and TyG-WHtR) were significantly associated with both PFAS mixture and T2D. Metabolomic analyses identified 35 shared metabolites associated with both PFAS mixture and T2D, mainly enriched in lipid-related pathways. Sequential mediation analyses further suggested that palmitic acid, stearic acid, and glutamine, together with TyG, might be involved in the pathways in the association between PFAS exposure and T2D risk. PFAS exposure was associated with T2D, with TyG-related indices and metabolites potentially involved in this association.