Insulin inhibits cardiac contractility by inducing a Gi-Biased β2-adrenergic signaling in hearts

Qin Fu, Bing Xu, Yongming Liu, Dippal Parikh, Jing Li, Ying Li, Yuan Zhang, Christian Riehle, Yi Zhu, Tenley Rawlings, Qian Shi, Richard B. Clark, Xiongwen Chen, E. Dale Abel, Yang K. Xiang

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

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 β2-adrenergic receptor (β2AR) in the heart. The IR/β2AR 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) phos-phorylation of the β2AR, which promotes β2AR coupling to the inhibitory G-protein, Gi. The insulin-induced phos-phorylation of β2AR is dependent on IRS1 and IRS2. After insulin pretreatment, the activated β2AR-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 β2AR-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.

Original languageEnglish (US)
Pages (from-to)2676-2689
Number of pages14
JournalDiabetes
Volume63
Issue number8
DOIs
StatePublished - Aug 2014

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Fingerprint Dive into the research topics of 'Insulin inhibits cardiac contractility by inducing a G<sub>i</sub>-Biased β<sub>2</sub>-adrenergic signaling in hearts'. Together they form a unique fingerprint.

  • Cite this

    Fu, Q., Xu, B., Liu, Y., Parikh, D., Li, J., Li, Y., Zhang, Y., Riehle, C., Zhu, Y., Rawlings, T., Shi, Q., Clark, R. B., Chen, X., Abel, E. D., & Xiang, Y. K. (2014). Insulin inhibits cardiac contractility by inducing a Gi-Biased β2-adrenergic signaling in hearts. Diabetes, 63(8), 2676-2689. https://doi.org/10.2337/db13-1763