Prolonged stimulation of β₂-adrenergic receptor with β₂-agonists impairs insulin actions in H9c2 cells

Insulin resistance is a condition in which there is a defect in insulin actions to induce glucose uptake into the cells. Overstimulation of β₂-adrenergic receptors (β₂ARs) is associated with the pathogenesis of insulin resistance in the heart. However, the mechanisms by which β₂-agonists affect insulin resistance in the heart are incompletely understood. The β₂-agonists are used for treatment of asthma due to bronchodilating effects. We also investigated the effects of β₂-agonists in human bronchial smooth muscle (HBSM) cells. In this study, we demonstrate that chronic treatment with salbutamol, salmeterol, and formoterol inhibited insulin-induced glucose uptake and GLUT4 synthesis in H9c2 myoblast cells. Sustained β₂AR stimulation also attenuated GLUT4 translocation to the plasma membrane, whereas short-term stimulation had no effect. In HBSM cells, prolonged treatment with β₂-agonists had no effect on insulin-induced glucose uptake and did not alter insulin-induced expressions of GLUT1, GLUT4, and GLUT10. In addition, genetic polymorphisms at amino acid positions 16 and 27 of β₂AR are linked to insulin resistance by significant suppression of GLUT4 translocation compared to wild-type. Thus, prolonged β₂AR stimulation by β₂-agonists impairs insulin actions through suppression of GLUT synthesis and translocation only in H9c2 cells.