@article{911c8022c5974a51b50b37e022028895,
title = "HB-EGF signaling is required for glucose-induced pancreatic β-cell proliferation in rats",
abstract = "The molecular mechanisms of β-cell compensation to metabolic stress are poorly understood. We previously observed that nutrient-induced β-cell proliferation in rats is dependent on epidermal growth factor receptor (EGFR) signaling. The aim of this study was to determine the role of the EGFR ligand heparin-binding EGF-like growth factor (HB-EGF) in the β-cell proliferative response to glucose, a β-cell mitogen and key regulator of β-cell mass in response to increased insulin demand. We show that exposure of isolated rat and human islets to HB-EGF stimulates β-cell proliferation. In rat islets, inhibition of EGFR or HB-EGF blocks the proliferative response not only to HB-EGF but also to glucose. Furthermore, knockdown of HB-EGF in rat islets blocks β-cell proliferation in response to glucose ex vivo and in vivo in transplanted glucose-infused rats. Mechanistically, we demonstrate that HB-EGF mRNA levels are increased in β-cells in response to glucose in a carbohydrate-response element–binding protein (ChREBP)–dependent manner. In addition, chromatin immunoprecipitation studies identified ChREBP binding sites in proximity to the HB-EGF gene. Finally, inhibition of Src family kinases, known to be involved in HB-EGF processing, abrogated glucose-induced β-cell proliferation. Our findings identify a novel glucose/HB-EGF/EGFR axis implicated in β-cell compensation to increased metabolic demand.",
author = "Hasna Maachi and Grace Fergusson and Melanie Ethier and Brill, {Gabriel N.} and Katz, {Liora S.} and Honig, {Lee B.} and Metukuri, {Mallikarjuna R.} and Scott, {Donald K.} and Julien Ghislain and Vincent Poitout",
note = "Funding Information: Acknowledgments. The authors thank A. Levert (CRCHUM, Montreal, Quebec, Canada) for technical assistance with isolated experiments and R. Screaton (Sunnybrook Research Institute, Toronto, Ontario, Canada) for advice on human islet culture. Funding. H.M. was supported by a doctoral studentship from the Fonds de Recherche du Qu{\'e}bec-Sant{\'e}. This study was supported by the National Institutes of Health (grants R01-DK-108905 to D.K.S. and R01-DK-58096 to V.P.) and the Canadian Institutes of Health Research (grant MOP 77686 to V.P.). V.P. holds the Canada Research Chair in Diabetes and Pancreatic Beta-Cell Function. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. H.M. and M.R.M. designed the experiments and acquired the data. H.M., M.R.M., D.K.S., J.G., and V.P. researched data, analyzed the results, and wrote the manuscript. All authors revised the manuscript and approved the final version. V.P. is the guarantor of this work and, as such, takes full responsibility for the work. Funding Information: H.M. was supported by a doctoral studentship from the Fonds de Recherche du Qu?bec-Sant?. This study was supported by the National Institutes of Health (grants R01-DK-108905 to D.K.S. and R01-DK-58096 to V.P.) and the Canadian Institutes of Health Research (grant MOP 77686 to V.P.). V.P. holds the Canada Research Chair in Diabetes and Pancreatic Beta-Cell Function. Publisher Copyright: {\textcopyright} 2019 by the American Diabetes Association.",
year = "2020",
month = mar,
day = "1",
doi = "10.2337/db19-0643",
language = "English",
volume = "69",
pages = "369--380",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "3",
}