Insulin Inhibits Cardiac Contractility by Inducing a Gi-Biased b2-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 b2adrenergic receptor (b2AR) in the heart. The IR/b2AR 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 b2AR, which promotes b2AR coupling to the inhibitory G-protein, Gi. The insulin-induced phosphorylation of b2AR is dependent on IRS1 and IRS2. After insulin pretreatment, the activated b2AR-Gi signaling effectively attenuates cAMP/PKA activity after b-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 bAR-regulated cardiac contractility. This b2AR-dependent IR and bAR 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.