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Background: Per- and polyfluoroalkyl substances (PFAS) are widely used chemicals, some of which have been linked to type 2 diabetes. We tested whether PFAS concentrations were cross-sectionally associated with metabolites previously shown to predict incident type 2 diabetes at baseline using the Diabetes Prevention Program (DPP), a trial of individuals at high risk of type 2 diabetes.
Methods: We evaluated 691 participants enrolled in the DPP with baseline measures of 10 PFAS (including total perfluorooctanoic sulfate (PFOS), total perfluorooctanoic acid (PFOA), and Sb-PFOA [branched isomers of PFOA]) and 77 metabolites. We used log₂-transformed PFAS concentrations as exposures and standardized metabolite concentrations as outcomes in linear regression models adjusted for age, sex, race/ethnicity, use of anti-hyperlipidemic or triglyceride lowering medication, income, years of education, marital status, smoking, and family history of diabetes, with Benjamini-Hochberg linear step-up false discovery rate correction.
Results: Sb-PFOA was associated with the largest number of tested metabolites (29 of 77). Each doubling in Sb-PFOA was associated with higher leucine (β=0.07 [95%CI: 0.02, 0.11] SD) and lower glycine (-0.08 [95%CI:-0.03, -0.13] SD). Each doubling in total PFOA and n-PFOA were both associated with -0.13 [95%CI:-0.04, -0.22] SD lower glycine. PFOA and Sb-PFOA were positively associated with multiple triacylglycerols and diacylglycerols, and total PFOS, total PFOA, and Sb-PFOA were positively associated with phosphatidylethanolamines.
Conclusions: These cross-sectional results suggest that PFAS may increase risk of type 2 diabetes through alterations in amino acid, glycerolipid and glycerophospholipid metabolism pathways, but further prospective research is needed to elucidate mechanisms.