SAT-640 - PFAS Exposure and Diabetes: β-Cell Mitochondrial Complex II and ATP as Mechanistic Links

The prevalence of diabetes mellitus is rapidly increasing, yet the drivers of this trend are not fully understood. Environmental exposure to the “forever chemicals” per- and polyfluoroalkyl substances (PFAS) has emerged as a potential contributing factor. PFAS comprise approximately 7,000 synthetic chemicals, with perfluorooctanesulfonic acid (PFOS) being one of the most predominant and representative compounds, and PFOS is commonly present in drinking water sources. The Centers for Disease Control and Prevention report that PFOS is detectable in the blood of virtually all Americans, and epidemiological studies link higher PFOS levels with increased diabetes risk. However, it remains unclear whether PFOS can directly cause diabetes and, if so, through which mechanisms in pancreatic β-cells. We tested the hypothesis that PFOS exposure impairs β-cell mitochondrial complex II, leading to decreased ATP levels and subsequent failure of glucose-stimulated insulin secretion (GSIS), and that the mitochondria-targeted antioxidant MitoQ would preserve mitochondrial function and GSIS. INS-1 pancreatic β-cells were exposed to PFOS (10 and 100 µM), with or without MitoQ pretreatment (100 nM), and assessed using cell viability assays, GSIS assays, quantitative PCR, Western blotting, and ATP bioluminescence assays. PFOS exposure did not affect cell viability, indicating that the observed defects reflect functional β-cell impairment rather than cytotoxicity. Compared with controls, PFOS-exposed INS-1 cells exhibited decreased GSIS at both low (2.2 mM) and high (16.7 mM) glucose. PFOS exposure did not alter insulin mRNA or insulin protein expression, indicating that the decreased insulin secretion was not due to reduced insulin gene transcription or translation. However, PFOS exposure significantly decreased the expression of mitochondrial complex II, which was associated with a reduction in cellular ATP content. Pretreatment of INS-1 cells with the mitochondria-targeted antioxidant MitoQ effectively restored ATP production and GSIS in PFOS-exposed β-cells. These findings demonstrate that PFOS directly impairs β-cell function by targeting mitochondrial complex II and ATP production, thereby compromising insulin secretion, and highlight mitochondria-targeted antioxidants such as MitoQ as potential preventive strategies for PFOS-exposed populations.

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