Epidermal Growth Factor Receptor Signaling Promotes Pancreatic β-Cell Proliferation in Response to Nutrient Excess in Rats through mTOR and FOXM1

  1. Vincent Poitout1,2,3,4,5
  1. 1Montreal Diabetes Research Center, University of Montreal, QC, Canada;
  2. 2CRCHUM, University of Montreal, QC, Canada;
  3. 3Department of Medicine, University of Montreal, QC, Canada;
  4. 4Department of Biochemistry, University of Montreal, QC, Canada;
  5. 5Department of Nutrition, University of Montreal, QC, Canada;
  1. Corresponding Author:Vincent Poitout, Email: vincent.poitout{at}


The cellular and molecular mechanisms underpinning the compensatory increase in β-cell mass in response to insulin resistance are essentially unknown. We previously reported that a 72-h co-infusion of glucose and Intralipid (GLU+IL) induces insulin resistance and a marked increase in β-cell proliferation in 6-mo-old but not in 2-mo-old Wistar rats. The aim of the present study was to identify the mechanisms underlying nutrient-induced β-cell proliferation in this model. A transcriptomic analysis identified a central role for the forkhead transcription factor FOXM1 and its targets, and for heparin binding EGF-like growth factor (HB-EGF), a ligand of the EGF receptor (EGFR), in nutrient-induced β-cell proliferation. Phosphorylation of ribosomal S6 kinase, an mTOR target, was increased in islets from GLU+IL-infused 6-mo-old rats. HB-EGF induced proliferation of insulin-secreting MIN6 cells and isolated rat islets, and this effect was blocked in MIN6 cells by the EGFR inhibitor AG1478 or the mTOR inhibitor rapamycin. Co-infusion of either AG1478 or rapamycin blocked the increase in FOXM1 signaling, β-cell proliferation, and β-cell mass and size in response to GLU+IL infusion in 6-mo-old rats. We conclude that chronic nutrient excess promotes β-cell mass expansion via a pathway that involves EGFR signaling, mTOR activation, and FOXM1-mediated cell proliferation.

  • Received March 15, 2013.
  • Accepted October 31, 2013.

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