Di-(2-ethylhexyl) phthalate exposure disrupts glucose homeostasis through inhibition of PI3K/Akt/FoxO1 pathway triggering β-cell dedifferentiation in male rats.

Di-(2-ethylhexyl) phthalate (DEHP), a widely used environmental endocrine disruptor, has been associated with an increased risk of Type 2 Diabetes Mellitus (T2DM). However, it remains unclear whether exposure to DEHP and its active metabolite can disrupt metabolic homeostasis by inducing pancreatic β-cell dedifferentiation. To evaluate the effects of DEHP on glucose homeostasis and β-cell dedifferentiation, we established an in vivo exposure model using male SD rats, administered with varying concentrations of DEHP (0, 2, 20 and 200 mg/kg/day) over six weeks. Our findings suggest that DEHP exposure leads to elevated blood glucose levels, insulin resistance, and β-cell dedifferentiation, which are associated with the suppression of the PI3K/Akt/FoxO1 signaling pathway. Subsequent in vitro experiments demonstrated that exposure of INS-1 cells to mono (2-ethylhexyl) phthalate (MEHP), the primary bioactive metabolite of DEHP, impaired glucose-stimulated insulin secretion (GSIS). This impairment was associated with β-cell dedifferentiation, the nuclear translocation of FoxO1, and suppression of the PI3K/Akt signaling pathway. Notably, these detrimental effects were ameliorated by PI3K agonist treatment or the transfection of FoxO1 overexpression plasmids. Our findings indicate that DEHP induces β-cell dedifferentiation by inhibiting the PI3K/Akt/FoxO1 signaling pathway, thereby disrupting glucose homeostasis. These findings provide mechanistic insight into the disruption of glucose regulation following DEHP exposure.