PFOS Is Detected in Human Pancreas and Dysregulates Glucose-Stimulated Insulin Secretion across Model Systems

Perfluoroalkyl acids (PFAAs) are a class of fluorinated chemicals that have been linked to increased type-2 diabetes risk, but whether this is caused by direct effects of PFAAs on the endocrine pancreas remains unclear. We measured concentrations of three legacy PFAAs (PFOS, PFOA, PFHxS) in plasma and pancreas from 88 human organ donors. PFOS was detected in 99% of human pancreas samples, whereas PFHxS was detected in 70% and PFOA in only 16% of pancreas samples. We also validated in a mouse model that PFOS distributes in pancreas at concentrations 2x higher than PFOA. Next, we exposed immortalized INS-1 cells, primary human donor islets, and primary mouse islets to DMSO (vehicle) or PFOS (1, 10, or 100 μM) either acutely during a glucose-stimulated insulin secretion (GSIS) assay or for 48 h (prolonged) before measuring GSIS Prolonged high-dose PFOS exposure suppressed GSIS in INS-1 832/3 cells and mouse islets, whereas acute high-dose PFOS exposure stimulated GSIS in mouse islets and in a subset of human donor islets. Acute hypersecretion of insulin in PFOS-exposed mouse islets was partially mitigated by a co-administration of a GLP-1 receptor antagonist. Lastly, we exposed mice to DMSO or 10 mg/kg PFOS with or without a glucose bolus and showed that acute PFOS exposure increased plasma insulin levels in vivo, but only when PFOS exposure was concurrent with glucose. Our findings support emerging evidence that PFOS causes β-cell dysfunction and emphasize the importance of model selection when assessing toxicological effects of PFAAs on islet function.