2320-P: Per- and Polyfluoroalkyl Substances Exposure, Blood Metabolome, and Risk of Incident Type 2 Diabetes in Hispanic Community Health Study/Study of Latinos (HCHS/SOL)

Introduction and Objective: Per- and polyfluoroalkyl substances (PFAS) are ubiquitous environmental endocrine disruptors, but their relationship with incident type 2 diabetes (T2D) remains unclear. We aimed to investigate whether PFAS exposure increases T2D risk and the role of circulating metabolites. Methods: We examined prospective associations of eight PFAS with incident T2D among 7,960 T2D-free adults at baseline (1,316 incident cases over 6+ years of follow-up) from HCHS/SOL. We further characterized metabolomic signatures (756 metabolites included) of PFAS and evaluated their mediating roles in PFAS-T2D associations. Results: Perfluorooctanoic acid (PFOA), perfluoroheptanoic acid (PFHpA), perfluorobutane sulfonic acid (PFBS) were positively associated with T2D risk (Fig.a) and were associated with 103, 107 and 53 metabolites (FDR<0.05), respectively. These metabolites were mainly phospholipids and amino acids and showed concordant associations with both PFAS and T2D (Fig.b). Mediation analyses identified shared and PFAS-specific metabolic pathways, with insulin resistance-related metabolites (e.g., lactocyl amino acids) mediated associations for three PFAS with T2D, whereas primary bile acids and sex steroid precursors specifically linked PFHpA to T2D (Fig.c). Conclusion: Some PFAS may contribute to increased T2D risk, potentially through shared and PFAS-specific metabolic pathways. Disclosure K. Luo: None. G. Liu: None. P. Wu: None. C. Jia: None. M.E. Turyk: None. B. Yu: None. R. Kaplan: None. Q. Qi: None. Funding The HCHS/SOL is a collaborative study supported by contracts from the NHLBI to the University of North Carolina (HHSN268201300001I/N01-HC-65233), University of Miami (HHSN268201300004I/N01-HC-65234), Albert Einstein College of Medicine (HHSN268201300002I/N01-HC-65235), University of Illinois at Chicago (HHSN268201300003I/N01-HC-65236 Northwestern University) and San Diego State University (HHSN268201300005I/N01-HC-65237).