Nuclear Export of FoxO1 Is Associated with ERK Signaling in β-Cells Lacking Insulin Receptors

J Biol Chem. 2016 Oct 7;291(41):21485-21495. doi: 10.1074/jbc.M116.735738. Epub 2016 Aug 17.


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 β-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 β-cell specific insulin receptor knock-out (βIRKO) 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+ β-cells and a significant decrease in % nuclear FoxO1+ β-cells compared with corresponding vehicle-treated groups. In contrast, in βIRKOs, we observed no significant changes in pAKT+ or p-p70S6K+ β-cells in either experiment; however, pERK+ β-cells were significantly increased, and an attenuated decrease in % nuclear FoxO1+ β cells was evident in response to glucose gavage or insulin infusion. Treatment of control and βIRKO β-cell lines with glucose or insulin showed significantly decreased % nuclear FoxO1+ β-cells suggesting direct effects. Furthermore, blocking MAPK signaling had virtually no effect on FoxO1 nuclear export in controls, in contrast to attenuated export in βIRKO β-cells. These data suggest insulin acts on β-cells in an endocrine manner in the normal situation; and that in β-cells lacking insulin receptors, insulin and glucose minimally activate the Akt pathway, while ERK phosphorylation and FoxO1 nuclear export occur independently of insulin signaling.

Keywords: FOXO; beta cell (β-cell); insulin; insulin receptor; signal transduction.

MeSH terms

  • Active Transport, Cell Nucleus / physiology
  • Animals
  • Forkhead Box Protein O1 / genetics
  • Forkhead Box Protein O1 / metabolism*
  • Glucose / genetics
  • Glucose / metabolism
  • Insulin-Secreting Cells / metabolism*
  • MAP Kinase Signaling System / physiology*
  • Mice
  • Mice, Knockout
  • Phosphorylation / physiology
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Receptor, Insulin / genetics
  • Receptor, Insulin / metabolism*


  • Forkhead Box Protein O1
  • Foxo1 protein, mouse
  • Receptor, Insulin
  • Proto-Oncogene Proteins c-akt
  • Glucose