Insulin Inhibits Cardiac Contractility by Inducing a G(i)-Biased β(2)-Adrenergic Signaling in Hearts

Insulin and adrenergic stimulation are two divergent regulatory systems that may interact under certain pathophysiological circumstances. Here, we characterized a complex consisting of insulin receptor (IR) and β(2)-adrenergic receptor (β(2)AR) in the heart. The IR/β(2)AR complex undergoes dynamic dissociation under diverse conditions such as Langendorff perfusions of hearts with insulin or after euglycemic-hyperinsulinemic clamps in vivo. Activation of IR with insulin induces protein kinase A (PKA) and G-protein receptor kinase 2 (GRK2) phosphorylation of the β(2)AR, which promotes β(2)AR coupling to the inhibitory G-protein, G(i). The insulin-induced phosphorylation of β(2)AR is dependent on IRS1 and IRS2. After insulin pretreatment, the activated β(2)AR-G(i) signaling effectively attenuates cAMP/PKA activity after β-adrenergic stimulation in cardiomyocytes and consequently inhibits PKA phosphorylation of phospholamban and contractile responses in myocytes in vitro and in Langendorff perfused hearts. These data indicate that increased IR signaling, as occurs in hyperinsulinemic states, may directly impair βAR-regulated cardiac contractility. This β(2)AR-dependent IR and βAR signaling cross-talk offers a molecular basis for the broad interaction between these signaling cascades in the heart and other tissues or organs that may contribute to the pathophysiology of metabolic and cardiovascular dysfunction in insulin-resistant states.