Inhibiting insulin-mediated β 2-adrenergic receptor activation prevents diabetes-associated cardiac dysfunction

Qingtong Wang, Yongming Liu, Qin Fu, Bing Xu, Yuan Zhang, Sungjin Kim, Ruensern Tan, Federica Barbagallo, Toni West, Ethan Anderson, Wei Wei, E. Dale Abel, Yang Kevin Xiang

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

Background: Type 2 diabetes mellitus (DM) and obesity independently increase the risk of heart failure by incompletely understood mechanisms. We propose that hyperinsulinemia might promote adverse consequences in the hearts of subjects with type-2 DM and obesity. Methods: High-fat diet feeding was used to induce obesity and DM in wild-type mice or mice lacking β 2 -adrenergic receptor (β 2 AR) or β-arrestin2. Wild-type mice fed with high-fat diet were treated with a β-blocker carvedilol or a GRK2 (G-protein-coupled receptor kinase 2) inhibitor. We examined signaling and cardiac contractile function. Results: High-fat diet feeding selectively increases the expression of phosphodiesterase 4D (PDE4D) in mouse hearts, in concert with reduced protein kinase A phosphorylation of phospholamban, which contributes to systolic and diastolic dysfunction. The expression of PDE4D is also elevated in human hearts with DM. The induction of PDE4D expression is mediated by an insulin receptor, insulin receptor substrate, and GRK2 and β-arrestin2-dependent transactivation of a β 2 AR-extracellular regulated protein kinase signaling cascade. Thus, pharmacological inhibition of β 2 AR or GRK2, or genetic deletion of β 2 AR or β-arrestin2, all significantly attenuate insulin-induced phosphorylation of extracellular regulated protein kinase and PDE4D induction to prevent DM-related contractile dysfunction. Conclusions: These studies elucidate a novel mechanism by which hyperinsulinemia contributes to heart failure by increasing PDE4D expression and identify β 2 AR or GRK2 as plausible therapeutic targets for preventing or treating heart failure in subjects with type 2 DM.

Original languageEnglish (US)
Pages (from-to)73-88
Number of pages16
JournalCirculation
Volume135
Issue number1
DOIs
StatePublished - Jan 3 2017

Keywords

  • diabetic cardiomyopathy
  • heart failure
  • insulin
  • phosphodiesterase
  • β-adrenergic receptors

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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  • Cite this

    Wang, Q., Liu, Y., Fu, Q., Xu, B., Zhang, Y., Kim, S., Tan, R., Barbagallo, F., West, T., Anderson, E., Wei, W., Abel, E. D., & Xiang, Y. K. (2017). Inhibiting insulin-mediated β 2-adrenergic receptor activation prevents diabetes-associated cardiac dysfunction. Circulation, 135(1), 73-88. https://doi.org/10.1161/CIRCULATIONAHA.116.022281