Nuclear Export of FoxO1 Is Associated with ERK Signaling in ß-Cells Lacking Insulin Receptors.
J Biol Chem
; 291(41): 21485-21495, 2016 Oct 07.
Article
em En
| MEDLINE
| ID: mdl-27535223
ABSTRACT
The insulin/insulin-like growth factor (IGF) signaling pathway plays a critical role in the regulation of islet cell biology. However, the signaling pathway(s) utilized by insulin to directly modulate ß-cells is unclear. To interrogate whether insulin exerts endocrine effects in regulating proteins in the insulin/IGF-1 signaling cascade in vivo in physiological states via the insulin receptor, we designed two experimental approaches 1) glucose gavage and 2) hyperinsulinemic intravenous infusion, for studies in either ß-cell specific insulin receptor knock-out (ßIRKO) or control mice. Immunostaining of sections of pancreas (collected immediately after glucose gavage or insulin infusion) from controls showed significant increases in pAKT+, p-p70S6K+, and pERK+ ß-cells and a significant decrease in % nuclear FoxO1+ ß-cells compared with corresponding vehicle-treated groups. In contrast, in ßIRKOs, we observed no significant changes in pAKT+ or p-p70S6K+ ß-cells in either experiment; however, pERK+ ß-cells were significantly increased, and an attenuated decrease in % nuclear FoxO1+ ß cells was evident in response to glucose gavage or insulin infusion. Treatment of control and ßIRKO ß-cell lines with glucose or insulin showed significantly decreased % nuclear FoxO1+ ß-cells suggesting direct effects. Furthermore, blocking MAPK signaling had virtually no effect on FoxO1 nuclear export in controls, in contrast to attenuated export in ßIRKO ß-cells. These data suggest insulin acts on ß-cells in an endocrine manner in the normal situation; and that in ß-cells lacking insulin receptors, insulin and glucose minimally activate the Akt pathway, while ERK phosphorylation and FoxO1 nuclear export occur independently of insulin signaling.
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MEDLINE
Assunto principal:
Receptor de Insulina
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Sistema de Sinalização das MAP Quinases
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Células Secretoras de Insulina
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Proteínas Proto-Oncogênicas c-akt
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Proteína Forkhead Box O1
Tipo de estudo:
Risk_factors_studies
Limite:
Animals
Idioma:
En
Revista:
J Biol Chem
Ano de publicação:
2016
Tipo de documento:
Article