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

Abstract

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 ␤-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/Ca 2ϩ -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/Ca 2ϩ 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.

Novel mechanisms of the regulation of Protein kinase B in adipocytes; implications for Protein kinase A, Epac, Phosphodiesterases 3 and 4

“…In contrast to our results in adipocytes, however, Epac appeared to be a positive, and PKA a negative, regulator of this process. On the other hand, in cardiomyocytes, short term stimulation with adrenaline increased insulininduced PKB phosphorylation via PKA [37], in agreement with our findings in adipocytes. Also the study on hepatocytes showed possible involvement of PKA in insulin+glucagon or leptin+glucagon-induced PKB activation [20].…”

“…In other cell types various results have been obtained. In cardiomyocytes [37], isoproterenol-induced phosphorylation of PKB was PKA and PI3K dependent, whereas, in COS cells [19], cAMP-induced PKB activation was PKA-dependent but PI3K-independent, and in Sertoli cells [39], dbcAMP-induced activation of PKB was PKAindependent but PI3K-dependent. These data strengthen the hypothesis about the specificity of certain signalling events with regard to different tissues.…”

A stress response pathway in mice upregulates somatostatin level and transcription in pancreatic delta cells through Gs and β-arrestin 1

“…3d). In addition to inducing CREB phosphorylation, β-adrenergic agonism also activates Akt and extracellular signal-related kinase (ERK) [5,17,18]. In contrast to the two phases of ERK activation by glucagonlike peptide 1 in the pancreatic beta cells, ERK activation induced by isoprenaline treatment in TGP52 cells is monophasic [19].…”

Propranolol Improves Impaired Hepatic Phosphatidylinositol 3-Kinase/Akt Signaling after Burn Injury

“…Given that prolonged β adrenergic receptor stimulation in cardiomyocytes inhibited insulin receptor signaling (22), we hypothesized that β adrenergic receptor blockade might improve insulin receptor signaling. As expected, in addition to reducing inhibitory IRS-1 phosphorylation, propranolol administration promoted tyrosine phosphorylation of IRS-1 and phosphorylation of Akt.…”