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

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.