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Insulin resistance is a condition in which there are defects in the insulin actions to induce tissue glucose uptake. Overstimulation of β-adrenergic receptors (βARs) leads to the development of heart failure and is associated with the pathogenesis of insulin resistance in the heart. However, the mechanisms by which βARs overstimulation affect insulin resistance in the heart are incompletely understood. We examine the mechanism for insulin resistance regulated by overstimulation of βARs. In this study, we show that sustained βAR stimulation with isoproterenol (ISO) showed the inhibition of insulin-induce glucose uptake and glucose transporter-4 (GLUT4) expression is mediated by the β2AR subtype in cardiomyocytes and heart tissue. Moreover, ISO stimulation attenuated insulin-induced GLUT4 translocation in β2AR-overexpressing HEK-293 cells. Overstimulation of βARs plays a key role in the enhancement of insulin resistance in the heart through cyclic adenosine monophosphate (cAMP)-dependent and protein kinase A (PKA)-dependent pathways. Treatment with β-blockers is able to antagonize the action of ISO-mediated insulin resistance in the heart. The essential role for βARs and identification of the molecular mechanism of βARs on the induction of insulin resistance in the heart advances our understanding, leading to a new therapeutic target for heart diseases.