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

Diabetes. 2020 Mar;69(3):369-380. doi: 10.2337/db19-0643. Epub 2019 Dec 27.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics*
  • Chromatin Immunoprecipitation
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / metabolism*
  • Gene Knockdown Techniques
  • Glucose / metabolism*
  • Glucose / pharmacology
  • Heparin-binding EGF-like Growth Factor / genetics*
  • Heparin-binding EGF-like Growth Factor / metabolism
  • Humans
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism*
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism
  • RNA, Messenger / metabolism
  • Rats
  • Signal Transduction
  • src-Family Kinases / antagonists & inhibitors


  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Heparin-binding EGF-like Growth Factor
  • Mlxipl protein, rat
  • RNA, Messenger
  • EGFR protein, human
  • Egfr protein, rat
  • ErbB Receptors
  • src-Family Kinases
  • Glucose