| First Author | Fu Q | Year | 2014 |
| Journal | Diabetes | Volume | 63 |
| Issue | 8 | Pages | 2676-89 |
| PubMed ID | 24677713 | Mgi Jnum | J:229791 |
| Mgi Id | MGI:5754465 | Doi | 10.2337/db13-1763 |
| Citation | Fu Q, et al. (2014) Insulin inhibits cardiac contractility by inducing a Gi-biased beta2-adrenergic signaling in hearts. Diabetes 63(8):2676-89 |
| abstractText | 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 beta2-adrenergic receptor (beta2AR) in the heart. The IR/beta2AR 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 beta2AR, which promotes beta2AR coupling to the inhibitory G-protein, Gi. The insulin-induced phosphorylation of beta2AR is dependent on IRS1 and IRS2. After insulin pretreatment, the activated beta2AR-Gi signaling effectively attenuates cAMP/PKA activity after beta-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 betaAR-regulated cardiac contractility. This beta2AR-dependent IR and betaAR 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. |
