Relationship between per-fluoroalkyl and polyfluoroalkyl substance exposure and insulin resistance in nondiabetic adults: Evidence from NHANES 2003–2018

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BACKGROUND: Studies have linked per- and polyfluoroalkyl substances (PFAS) to chronic metabolic diseases. However, the relationship between PFAS exposure and insulin resistance (IR), a key pathophysiological basis of these metabolic diseases, in nondiabetic individuals have yet to be determined. METHODS: This study analyzed data from 3909 participants (aged ≥20) from the NHANES 2003-2018 to investigate the associations between serum levels of seven PFAS and and IR indicators, including including HOMA-IR, HOMA-β, fasting insulin, QUICKI, and TyG index. Linear and logistic regression models were used, along with a restricted cubic spline to assess dose-response. Weighted quantile sum (WQS) regression and quantile g-computation (qgcomp) models were used to assess the association between mixed PFAS exposure and IR. RESULTS: Linear regression revealed that elevated exposure to PFOS [β (95 % CI): 0.04 (0.02, 0.06)], PFOA [0.04 (0.01, 0.06)], and Me_PFOSA_AcOH [0.04 (0.02, 0.06)] was associated with a higher TyG index in adults. Notably, Me_PFOSA_AcOH was negatively associated with IR when assessed by HOMA-IR >2.6 [OR (95 % CI): 0.88 (0.79, 0.98)], although this was not supported by linear regression findings. When IR was defined by a TyG index >8.6, exposure to the highest quartiles of PFOS, PFOA, and Me_PFOSA_AcOH was associated with an increased risk of IR by 63 %, 42 %, and 85 %, respectively [1.63 (1.21, 2.20); 1.42 (1.06, 1.92); 1.85 (1.37, 2.50)]. PFOS, PFOA, and Me_PFOSA_AcOH demonstrated a nonlinear dose-response relationship with IR risk. The WQS and qgcomp models revealed significant positive correlations with the TyG index. CONCLUSION: Mixed PFAS exposure in US nondiabetic adults was positively associated with IR, as indicated by the TyG index, particularly for PFOS, PFOA, and Me_PFOSA_AcOH. Further research is needed to establish causality, and reinforcing environmental risk mitigation strategies to reduce PFAS exposure is recommended.

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