Per- and polyfluoroalkyl substance plasma concentrations and metabolomic markers of type 2 diabetes in the Diabetes Prevention Program trial

Susanna D. Mitro, Population Health Sciences Program, Harvard University, Boston, MA, USA.
Jinxi Liu, Department of Epidemiology and Biostatistics, Biostatistics Center and Milken Institute School of Public Health, George Washington University, Rockville, MD, USA.
Lindsay M. Jaacks, Department of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Abby F. Fleisch, Pediatric Endocrinology and Diabetes, Maine Medical Center and Center for Outcomes Research and Evaluation, Maine Medical Center Research Institute, Portland, ME, USA.
Paige L. Williams, Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, USA; Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
William C. Knowler, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ, USA.
Blandine Laferrère, New York Obesity Research Center, Division of Endocrinology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
Wei Perng, Department of Epidemiology, Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center, Colorado School of Public Health, University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA.
George A. Bray, Pennington Biomedical Research Center/Louisiana State University, Baton Rouge, LA, USA.
Amisha Wallia, Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Marie-France Hivert, Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA; Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA.
Emily Oken, Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA.
Tamarra M. James-Todd, Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA; Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard T.H. Chan School of Public Health and Division of Women's Health, Department of Medicine, Connors Center for Women's Health and Gender Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Marinella Temprosa, Department of Epidemiology and Biostatistics, Biostatistics Center and Milken Institute School of Public Health, George Washington University, Rockville, MD, USA. Electronic address: dppmail@bsc.gwu.edu.

Abstract

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 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 perfluorooctanesulfonic acid (PFOS), total perfluorooctanoic acid (PFOA), and Sb-PFOA [branched isomers of PFOA]) and 77 metabolites. We used log-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 of either total PFOA or n-PFOA was 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: PFAS concentrations are associated with metabolites linked to type 2 diabetes (particularly amino acid, glycerolipid and glycerophospholipid pathways). Further prospective research is needed to test whether these metabolites mediate associations of PFAS and type 2 diabetes.