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

Sara C. Martinez, Corentin Cras-Méneur, Ernesto Bernal-Mizrachi, M. Alan Permutt

Research output: Contribution to journalArticle

78 Scopus citations

Abstract

Glucose controls islet β-cell mass and function at least in part through the phosphatidylinositol 3-kinase (PI3K)/Akt pathway downstream of insulin signaling. The Foxo proteins, transcription factors known in other tissues to be negatively regulated by Akt activation, affect proliferation and metabolism. In this study, we tested the hypothesis that glucose regulates Foxo1 activity in the β-cell via an autocrine/paracrine effect of released insulin on its receptor. Mouse insulinoma cells (MIN6) were starved overnight for glucose (5 mmol/l) then refed with glucose (25 mmol/l), resulting in rapid Foxo1 phosphorylation (30 min, P < 0.05 vs. untreated). This glucose response was demonstrated to be time (0.5-2 h) and dose (5-30 mmol/l) dependent. The use of inhibitors demonstrated that glucose-induced Foxo1 phosphorylation was dependent upon depolarization, calcium influx, and PI3K signaling. Additionally, increases in glucose concentration over a physiological range (2.5-20 mmol/l) resulted in nuclear to cytoplasmic translocation of Foxo1. Phosphorylation and translocation of Foxo1 following glucose refeeding were eliminated in an insulin receptor knockdown cell line, indicating that the glucose effects are mediated primarily through the insulin receptor. Activity of Foxo1 was observed to increase with decreased glucose concentrations, assessed by an IGF binding protein-1 promoter luciferase assay. Starvation of MIN6 cells identified a putative Foxo1 target, Chop, and a Chop-promoter luciferase assay in the presence of cotransfected Foxo1 supported this hypothesis. The importance of these observations was that nutritional alterations in the β-cell are associated with changes in Foxo1 transcriptional activity and that these changes are predominantly mediated through glucose-stimulated insulin secretion acting through its own receptor.

Original languageEnglish (US)
Pages (from-to)1581-1591
Number of pages11
JournalDiabetes
Volume55
Issue number6
DOIs
StatePublished - Sep 11 2006
Externally publishedYes

Keywords

  • DMEM, Dulbecco's modified Eagle's medium
  • FBS, fetal bovine serum
  • GFP, green florescence protein
  • IGFBP, IGF binding protein
  • IRKDΔ80, insulin receptor knockdown (-80%)
  • IRS, insulin receptor substrate

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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