BPA exposure in L6 myotubes increased basal glucose metabolism in an estrogen receptor-dependent manner but induced insulin resistance.

Exposure to bisphenol A (BPA) is associated with insulin resistance and type 2 diabetes (T2D). Since muscle insulin resistance is the primary defect in T2D, we aimed to determine whether BPA alters glucose metabolism in L6 muscle cells. L6 or L6-GLUT4-myc cells were exposed to 1-10 ⁴ nM BPA or the vehicle (0.1% DMSO) for 7 days. BPA at 10 ³ -10 ⁴ nM significantly decreased the levels of the muscle differentiation markers troponin- T and myosin heavy chain 3. Insulin-stimulated phosphorylation of Akt and GSK3, insulin-stimulated glucose uptake, and insulin-stimulated GLUT4 translocation were significantly decreased with 10 ³ -10 ⁴ nM BPA. Basal glucose uptake and glycolysis (extracellular acidification rates measured by Seahorse XFe96) were increased with 10 ³ -10 ⁴ nM BPA. Levels of ROS detoxifying enzymes were increased with BPA >10 nM, while catalase activity was increased with 10 ³ -10 ⁴ nM BPA. However, BPA did not induce oxidative stress (measured by protein carbonylation and lipid peroxidation) nor mitochondrial dysfunction. The effects of BPA on basal glucose uptake and catalase activity, but not on insulin sensitivity, were restored when estrogen receptors (ERs) were inhibited with ICI. These findings suggest that high concentrations of BPA increase muscle glucose uptake through the ERs but induce insulin resistance through another pathway.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Celine Aguer reports financial support was provided by Natural Sciences and Engineering Research Council of Canada. Ilham Mekkioui reports financial support was provided by BioTalent.
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