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HB-EGF Signaling Is Required for Glucose-Induced Pancreatic ?-Cell Proliferation in Rats.


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

SUBMITTER: Maachi H 

PROVIDER: S-EPMC7034189 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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

Maachi Hasna H   Fergusson Grace G   Ethier Melanie M   Brill Gabriel N GN   Katz Liora S LS   Honig Lee B LB   Metukuri Mallikarjuna R MR   Scott Donald K DK   Ghislain Julien J   Poitout Vincent V  

Diabetes 20191227 3


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  ...[more]

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