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

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