Abstract
Pyrethroids, a class of widely used insecticides, have been linked to diabetes. However, it remains unclear whether and how environmentally relevant exposure to pyrethroids aggravates diet-induced diabetic symptoms. In this study, we investigated the diabetogenic effects of exposure to environmentally relevant doses of cypermethrin (CP), one of the most commonly used pyrethroids, and a high calorie diet (HCD) in adult male mice. Notably, HCD consumption significantly facilitated the bioaccumulation of CP in the liver. CP exposure at the lowest dose in the range of human daily intake exacerbated HCD-induced insulin resistance. In HCD-fed mice, CP treatment significantly decreased hepatic glucose uptake by impairing the translocation of glucose transporter GLUT2. CP exposure regulated hepatic AKT2/GSK3β/GYS2 pathway, thereby reducing glycogenesis and stimulating gluconeogenesis in the livers of HCD-fed mice. Hepatic transcriptome data showed that CP exposure of HCD-fed mice increased hepatic expression of thioredoxin-interacting protein (Txnip) and vanin-1 (VnnI) genes, which were involved in regulating GLUT2 translocation and AKT2/GSK3β/GYS2 pathway activity, respectively. CP treatment significantly decreased hepatic glucose uptake in HCD-fed mice by impairing the translocation of glucose transporter GLUT2, which was modulated by upregulation of TXNIP. CP exposure regulated hepatic AKT2/GSK3β/GYS2 pathway through upregulation of VNNI, thereby reducing glycogenesis and stimulating gluconeogenesis in the livers of HCD-fed mice. This is the first study to show that HCD led to an enrichment of lipophilic CP in the liver, which significantly disrupted glucose homeostasis and caused prediabetic phenotype. Our findings suggest that when assessing the health risks of lipophilic environmental chemicals, especially for metabolism-related outcomes, the interaction between contaminants and diet factors should be considered, otherwise the health risks may be underestimated.