Standing at the crossroads: How does amino acids function in the crosstalk between pancreas and the kidney under exposure to per- and polyfluoroalkyl substances?

Diabetes and kidney diseases are complex disorders influenced by organ-specific abnormalities and systemic dysregulation. Previous research suggests per- and polyfluoroalkyl substances (PFAS) can interfere with glucose metabolism and kidney function, but their impact on pancreas-kidney inter-organ crosstalk is unclear. In this study, we conducted a three-wave repeated-measures analysis, in a non-diabetic, non-chronic kidney disease (CKD) cohort. We assessed 23 PFAS, 23 amino acids, 5 glucose indicators, and 3 renal biomarkers across three visits. Our findings showed that perfluorooctane sulfonate (PFOS) was linked to both glucose and renal biomarkers, suggesting its potential role in impairing pancreas-kidney crosstalk. We also identified amino acids, particularly serine and citrulline, as key mediators in this process, implicating amino acid metabolism as a common mechanism through which PFOS influences inter-organ communication. Serine was found to positively mediate approximately 50 % of the total effect of PFOS exposure on insulin and glucose metabolism, while citrulline negatively mediated about 15 % of PFOS's effects on kidney function biomarkers. These results highlight PFOS's role in disrupting pancreas-kidney crosstalk within a non-diabetic, non-CKD cohort and provide new insights into amino acid regulation in metabolic and kidney diseases. This is the first study to demonstrate PFAS involvement in this inter-organ crosstalk and suggests a novel mechanism involving amino acids.