Sustained ßAR Stimulation Mediates Cardiac Insulin Resistance in a PKA-Dependent Manner.

Insulin resistance is a condition in which cells are defective in response to the actions of insulin in tissue glucose uptake. Overstimulation of ß-adrenergic receptors (ßARs) leads to the development of heart failure and is associated with the pathogenesis of insulin resistance in the heart. However, the mechanisms by which sustained ßAR stimulation affects insulin resistance in the heart are incompletely understood. In this study, we demonstrate that sustained ßAR stimulation resulted in the inhibition of insulin-induced glucose uptake, and a reduction of insulin induced glucose transporter (GLUT)4 expression that were mediated by the ß2AR subtype in cardiomyocytes and heart tissue. Overstimulation of ß2AR inhibited the insulin-induced translocation of GLUT4 to the plasma membrane of cardiomyocytes. Additionally, ßAR mediated cardiac insulin resistance by reducing glucose uptake and GLUT4 expression via the cAMP-dependent and protein kinase A-dependent pathways. Treatment with ß-blockers, including propranolol and metoprolol antagonized isoproterenol-mediated insulin resistance in the heart. The data in this present study confirm a critical role for protein kinase A in ßAR-mediated insulin resistance.