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Glucose regulates Foxo1 through insulin receptor signaling in the pancreatic islet beta-cell

Sara C Martinez1, Corentin Cras-Méneur, Ernesto Bernal-Mizrachi

  • 1Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8127, St. Louis, MO 63110, USA.

Diabetes
|May 30, 2006
PubMed

Insights

Glucose regulates Foxo1 activity in beta-cells via insulin signaling. This process involves insulin receptor activation, affecting Foxo1 phosphorylation and translocation, and ultimately influencing beta-cell function and metabolism.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Cell Biology

Background:

  • Glucose is a key regulator of pancreatic islet beta-cell function and mass.
  • The phosphatidylinositol 3-kinase (PI3K)/Akt pathway, downstream of insulin signaling, plays a crucial role in glucose-mediated beta-cell control.
  • Foxo proteins are transcription factors regulated by Akt and influence cell proliferation and metabolism.

Purpose of the Study:

  • To investigate the hypothesis that glucose regulates Foxo1 activity in beta-cells through an autocrine/paracrine insulin signaling loop.
  • To elucidate the role of the insulin receptor in mediating glucose-induced Foxo1 regulation.
  • To identify Foxo1 targets and understand its transcriptional activity in response to nutritional changes.

Main Methods:

  • Utilized mouse insulinoma cells (MIN6) subjected to varying glucose concentrations and starvation.
  • Employed phosphorylation site-specific antibodies and Western blotting to assess Foxo1 phosphorylation.
  • Used inhibitors of depolarization, calcium influx, and PI3K signaling.
  • Performed nuclear-to-cytoplasmic translocation assays.
  • Conducted luciferase reporter assays to measure Foxo1 transcriptional activity and identify targets like Chop.
  • Generated an insulin receptor knockdown cell line to confirm the mediation pathway.

Main Results:

  • Glucose refeeding rapidly induced Foxo1 phosphorylation in MIN6 cells in a time- and dose-dependent manner.
  • Glucose-induced Foxo1 phosphorylation was dependent on depolarization, calcium influx, and PI3K signaling.
  • Increased glucose concentrations led to nuclear-to-cytoplasmic translocation of Foxo1.
  • The effects of glucose on Foxo1 were abolished in insulin receptor knockdown cells, highlighting the insulin receptor's critical role.
  • Foxo1 transcriptional activity increased with decreased glucose concentrations.
  • Chop was identified as a putative Foxo1 target gene.

Conclusions:

  • Nutritional alterations in beta-cells are associated with significant changes in Foxo1 transcriptional activity.
  • Glucose-stimulated insulin secretion, acting through the insulin receptor, predominantly mediates these changes in Foxo1 activity.
  • This signaling pathway is crucial for integrating metabolic cues and regulating beta-cell function and potentially mass.

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