HB-EGF Signaling is Required for Glucose-Induced Pancreatic β-Cell Proliferation in Rats

Maachi, H.; Fergusson, G.; Ethier, M.; Brill, G. N.; Katz, L. S.; Honig, L. B.; Metukuri, M. R.; Scott, D. K.; Ghislain, J.; Poitout, V.

doi:10.1101/683003

bioRxiv · 10.1101/683003

HB-EGF Signaling is Required for Glucose-Induced Pancreatic β-Cell Proliferation in Rats

Maachi, H.·Fergusson, G.·Ethier, M.·Brill, G. N.·Katz, L. S.·Honig, L. B.·Metukuri, M. R.·Scott, D. K.·Ghislain, J.·Poitout, V.

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Abstract

The molecular mechanisms of {beta}-cell compensation to metabolic stress are poorly understood. We previously observed that nutrient-induced {beta}-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 {beta}-cell proliferative response to glucose, a {beta}-cell mitogen and key regulator of {beta}-cell mass in response to increased insulin demand. We show that exposure of isolated rat and human islets to HB-EGF stimulates {beta}-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 {beta}-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 {beta} 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 {beta}-cell proliferation. Our findings identify a novel glucose/HB-EGF/EGFR axis implicated in {beta}-cell compensation to increased metabolic demand.

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Maachi, H., Fergusson, G., Ethier, M., Brill, G. N., Katz, L. S., Honig, L. B., Metukuri, M. R., Scott, D. K., Ghislain, J., Poitout, V.. 2019-06-27. HB-EGF Signaling is Required for Glucose-Induced Pancreatic β-Cell Proliferation in Rats. https://doi.org/10.1101/683003

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