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(Circulation Research. 2005;96:180.)
© 2005 American Heart Association, Inc.

Cellular Biology

Akt Mediates the Cross-Talk Between ß-Adrenergic and Insulin Receptors in Neonatal Cardiomyocytes

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

From the Dipartimento di Medicina Clinica, Scienze Cardiovascolari ed Immunologiche (C. Morisco, V.T., A.B., C. Marrone, B.T.), Dipartimento di Biologia e Patologia Cellulare e Molecolare (Ge.C.), Università Federico II, Napoli, Italy; San Raffaele Biomedical Science Park of Rome (Gi.C.), Italy; and the Department of Cell Biology and Molecular Medicine (J.S.), University of Medicine and Dentistry of New Jersey, Newark.

Correspondence to Bruno Trimarco, MD, Dipartimento di Medicina Clinica, Scienze Cardiovascolari ed Immunologiche, Università Federico II, Napoli, Via S. Pansini n. 5, 80131 Napoli, Italy. E-mail trimarco{at}unina.it

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 ß-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 ß 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 ß-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 ß-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 ß subunit of the insulin receptor and blunted tyrosine autophosphorylation of the ß-subunit of the insulin receptor after insulin stimulation. These results indicate that, in cardiomyocytes, ß-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.

Key Words: glucose uptake • isoproterenol • insulin resistance • protein kinase A • L-type Ca²⁺ channel

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