Published online before print December 9, 2004, doi: 10.1161/01.RES.0000152968.71868.c3
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Submitted on December 9, 2003
Revised on November 17, 2004
Accepted on November 29, 2004
Akt Mediates the Cross-Talk Between 
-Adrenergic and Insulin Receptors in Neonatal Cardiomyocytes
Carmine Morisco ;
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.
* To whom correspondence should be addressed. 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 
-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 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 -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 -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 subunit of the insulin receptor and blunted tyrosine autophosphorylation of the -subunit of the insulin receptor after insulin stimulation. These results indicate that, in cardiomyocytes, -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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