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 Montréal, Montréal, Québec, Canada
- 2University of Montréal Hospital Research Centre, Montréal, Québec, Canada
- 3Department of Medicine, University of Montréal, Montréal, Québec, Canada
- 4Department of Biochemistry, University of Montréal, Montréal, Québec, Canada
- 5Department of Nutrition, University of Montréal, Montréal, Québec, Canada
- Corresponding author: Vincent Poitout, .
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 coinfusion of glucose and Intralipid (GLU+IL) induces insulin resistance and a marked increase in β-cell proliferation in 6-month-old, but not in 2-month-old, Wistar rats. The aim of the current 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 epidermal growth factor (EGF)-like growth factor (HB-EGF), a ligand of the EGF receptor (EGFR), in nutrient-induced β-cell proliferation. Phosphorylation of ribosomal S6 kinase, a mammalian target of rapamycin (mTOR) target, was increased in islets from GLU+IL–infused 6-month-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. Coinfusion 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-month-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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-0425/-/DC1.
- Received March 15, 2013.
- Accepted November 1, 2013.
- © 2014 by the American Diabetes Association.
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