Epidermal Growth Factor Receptor Signaling Promotes Pancreatic β-Cell Proliferation in Response to Nutrient Excess in Rats through mTOR and FOXM1
- Bader Zarrouki1,2,3,
- Isma Benterki1,2,4,
- Ghislaine Fontés1,2,
- Marie-line Peyot1,2,
- Ondrej Seda1,2,
- Marc Prentki1,2,4,5 and
- Vincent Poitout1,2,3,4,5⇑
- 1Montreal Diabetes Research Center, University of Montreal, QC, Canada;
- 2CRCHUM, University of Montreal, QC, Canada;
- 3Department of Medicine, University of Montreal, QC, Canada;
- 4Department of Biochemistry, University of Montreal, QC, Canada;
- 5Department of Nutrition, University of Montreal, QC, Canada;
- Corresponding Author:Vincent Poitout, Email:
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.
- © 2013 by the American Diabetes Association.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.