Insulin Inhibits Cardiac Contractility by Inducing a Gi-Biased β2-Adrenergic Signaling in Hearts

  1. Yang K. Xiang1,3
  1. 1Department of Pharmacology, University of California, Davis, Davis, CA
  2. 2Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
  3. 3Department of Molecular and Integrative Physiology, University of Illinois at Urbana, Urbana, IL
  4. 4Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
  5. 5Department of Physiology and Cardiovascular Research Center, Temple University Medical Center, Philadelphia, PA
  6. 6Division of Endocrinology, Metabolism, and Diabetes, Program in Molecular Medicine, University of Utah, Salt Lake City, UT
  7. 7Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA
  8. 8Department of Integrative Biology and Pharmacology, University of Texas Houston Medical Center, Houston, TX
  1. Corresponding author: Yang K. Xiang, ykxiang{at}


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) phosphorylation of the β2AR, which promotes β2AR coupling to the inhibitory G-protein, Gi. The insulin-induced phosphorylation of β2AR is dependent on IRS1 and IRS2. After insulin pretreatment, the activated β2AR-Gi 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.


  • Received November 19, 2013.
  • Accepted March 19, 2014.
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  1. Diabetes vol. 63 no. 8 2676-2689
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