Akt mediates the cross-talk between β-adrenergic and insulin receptors in neonatal cardiomyocytes

Carmine Morisco, Gerolama Condorelli, Valentina Trimarco, Alessandro Bellis, Chiara Marrone, Gianluigi Condorelli, Junichi Sadoshima, Bruno Trimarco

Research output: Contribution to journalArticle

Abstract

Upregulation of the sympathetic nervous system plays a key role in the pathogenesis of insulin resistance. Although the heart is a target organ of insulin, few studies have examined the mechanisms by which β-adrenergic stimulation affects insulin sensitivity in cardiac muscle. In this study, we explored the molecular mechanisms involved in the regulation of the cross-talk between β adrenergic and insulin receptors in neonatal rat cardiomyocytes and in transgenic mice with cardiac overexpression of a constitutively active mutant of Akt (E40K Tg). The results of this study show that β-adrenergic receptor stimulation has a biphasic effect on insulin-stimulated glucose uptake. Short-term stimulation induces an additive effect on insulin-induced glucose uptake, and this effect is mediated by phosphorylation of Akt in threonine 308 through PKA/Ca2+-dependent and PI3K-independent pathway, whereas insulin-evoked threonine phosphorylation of Akt is exclusively PI3K-dependent. On the other hand, long-term stimulation of β-adrenergic receptors inhibits both insulin-stimulated glucose uptake and insulin-induced autophosphorylation of the insulin receptor, and at the same time promotes threonine phosphorylation of the insulin receptor. This is mediated by serine 473 phosphorylation of Akt through PKA/Ca2+ and PI3K-dependent pathways. Under basal conditions, E40K Tg mice show increased levels of threonine phosphorylation of the β subunit of the insulin receptor and blunted tyrosine autophosphorylation of the β-subunit of the insulin receptor after insulin stimulation. These results indicate that, in Cardiomyocytes, β-adrenergic receptor stimulation impairs insulin signaling transduction machinery through an Akt-dependent pathway, suggesting that Akt is critically involved in the regulation of insulin sensitivity.

Original languageEnglish
Pages (from-to)180-188
Number of pages9
JournalCirculation Research
Volume96
Issue number2
DOIs
Publication statusPublished - Feb 4 2005

Keywords

  • Glucose uptake
  • Insulin resistance
  • Isoproterenol
  • L-type Ca channel
  • Protein kinase A

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Morisco, C., Condorelli, G., Trimarco, V., Bellis, A., Marrone, C., Condorelli, G., Sadoshima, J., & Trimarco, B. (2005). Akt mediates the cross-talk between β-adrenergic and insulin receptors in neonatal cardiomyocytes. Circulation Research, 96(2), 180-188. https://doi.org/10.1161/01.RES.0000152968.71868.c3