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 language | English |
|---|---|
| Pages (from-to) | 180-188 |
| Number of pages | 9 |
| Journal | Circulation Research |
| Volume | 96 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - Feb 4 2005 |
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Keywords
- Glucose uptake
- Insulin resistance
- Isoproterenol
- L-type Ca channel
- Protein kinase A
ASJC Scopus subject areas
- Physiology
- Cardiology and Cardiovascular Medicine
Cite this
Akt mediates the cross-talk between β-adrenergic and insulin receptors in neonatal cardiomyocytes. / Morisco, Carmine; Condorelli, Gerolama; Trimarco, Valentina; Bellis, Alessandro; Marrone, Chiara; Condorelli, Gianluigi; Sadoshima, Junichi; Trimarco, Bruno.
In: Circulation Research, Vol. 96, No. 2, 04.02.2005, p. 180-188.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Akt mediates the cross-talk between β-adrenergic and insulin receptors in neonatal cardiomyocytes
AU - Morisco, Carmine
AU - Condorelli, Gerolama
AU - Trimarco, Valentina
AU - Bellis, Alessandro
AU - Marrone, Chiara
AU - Condorelli, Gianluigi
AU - Sadoshima, Junichi
AU - Trimarco, Bruno
PY - 2005/2/4
Y1 - 2005/2/4
N2 - 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.
AB - 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.
KW - Glucose uptake
KW - Insulin resistance
KW - Isoproterenol
KW - L-type Ca channel
KW - Protein kinase A
UR - http://www.scopus.com/inward/record.url?scp=13444291022&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=13444291022&partnerID=8YFLogxK
U2 - 10.1161/01.RES.0000152968.71868.c3
DO - 10.1161/01.RES.0000152968.71868.c3
M3 - Article
C2 - 15591229
AN - SCOPUS:13444291022
VL - 96
SP - 180
EP - 188
JO - Circulation Research
JF - Circulation Research
SN - 0009-7330
IS - 2
ER -