Article

Diabetologia

, Volume 54, Issue 7, pp 1735-1743

First online:

Epidermal growth factor (EGF)-receptor signalling is needed for murine beta cell mass expansion in response to high-fat diet and pregnancy but not after pancreatic duct ligation

  • E. HakonenAffiliated withResearch Programs Unit, Molecular Neurology, Biomedicum Stem Cell Centre, University of Helsinki Email author 
  • , J. UstinovAffiliated withResearch Programs Unit, Molecular Neurology, Biomedicum Stem Cell Centre, University of Helsinki
  • , I. MathijsAffiliated withCell Differentiation Laboratory, Vrije Universiteit
  • , J. PalgiAffiliated withResearch Programs Unit, Molecular Neurology, Biomedicum Stem Cell Centre, University of Helsinki
  • , L. BouwensAffiliated withCell Differentiation Laboratory, Vrije Universiteit
  • , P. J. MiettinenAffiliated withResearch Programs Unit, Molecular Neurology, Biomedicum Stem Cell Centre, University of HelsinkiHospital for Children and Adolescents, University of Helsinki and Helsinki University Central Hospital
  • , T. OtonkoskiAffiliated withResearch Programs Unit, Molecular Neurology, Biomedicum Stem Cell Centre, University of HelsinkiHospital for Children and Adolescents, University of Helsinki and Helsinki University Central Hospital

Abstract

Aims/hypothesis

Epidermal growth factor receptor (EGFR) signalling is essential for the proper fetal development of pancreatic islets and in the postnatal formation of an adequate beta cell mass. In this study we investigated the role of EGFR signalling in the physiological states of beta cell mass expansion in adults during metabolic syndrome and pregnancy, as well as in regeneration after pancreatic duct ligation.

Methods

Heterozygous Pdx1-EGFR-dominant-negative (E1-DN) mice, which have a kinase-negative EGFR under the Pdx1 promoter, and wild-type mice were both subjected to a high-fat diet, pregnancy and pancreatic duct ligation.

Results

The beta cell mass of wild-type mice fed the high-fat diet increased by 70% and the mice remained normoglycaemic; the E1-DN mice became diabetic and failed to show any compensatory beta cell mass expansion. Similarly, pregnant wild-type mice had four times more proliferating beta cells and a 75% increase in beta cell mass at mid-gestation, in contrast to the pregnant E1-DN mice, which did not show any significant beta cell compensation and were hyperglycaemic in an intraperitoneal glucose tolerance test. However, after pancreatic duct ligation, both the wild-type and E1-DN mice showed similar expression of Ngn3 (also known as Neurog3) and beta cell proliferation increased to a similar level in the ligated part of pancreas.

Conclusions/interpretations

EGFR signalling is essential in beta cell mass expansion during a high-fat diet and pregnancy where replication is the primary mechanism for compensatory beta cell mass expansion. In contrast, EGFR signalling appears not to be crucial to increased beta cell proliferation after pancreatic duct ligation.

Keywords

Beta cell mass EGFR High-fat diet Pancreatic duct ligation Pregnancy