Downregulation of EGF receptor signaling in pancreatic islets causes diabetes due to impaired postnatal beta-cell growth.
Epidermal growth factor receptor (EGF-R) signaling is essential for proper fetal development and growth of pancreatic islets, and there is also evidence for its involvement in beta-cell signal transduction in the adult. To study the functional roles of EGF-R in beta-cell physiology in postnatal life, we have generated transgenic mice that carry a mutated EGF-R under the pancreatic duodenal homeobox-1 promoter (E1-DN mice). The transgene was expressed in islet beta- and delta-cells but not in alpha-cells, as expected, and it resulted in an approximately 40% reduction in pancreatic EGF-R, extracellular signal-related kinase, and Akt phosphorylation. Homozygous E1-DN mice were overtly diabetic after the age of 2 weeks. The hyperglycemia was more pronounced in male than in female mice. The relative beta-cell surface area of E1-DN mice was highly reduced at the age of 2 months, while alpha-cell surface area was not changed. This defect was essentially postnatal, since the differences in beta-cell area of newborn mice were much smaller. An apparent explanation for this is impaired postnatal beta-cell proliferation; the normal surge of beta-cell proliferation during 2 weeks after birth was totally abolished in the transgenic mice. Heterozygous E1-DN mice were glucose intolerant in intraperitoneal glucose tests. This was associated with a reduced insulin response. However, downregulation of EGF-R signaling had no influence on the insulinotropic effect of glucagon-like peptide-1 analog exendin-4. In summary, our results show that even a modest attenuation of EGF-R signaling leads to a severe defect in postnatal growth of the beta-cells, which leads to the development of diabetes.
Miettinen
Päivi J
PJ
Program of Developmental and Reproductive Biology, Biomedicum Helsinki, Room B530b, P.O. Box 63, FIN-00014 University of Helsinki, Helsinki, Finland. paivi.miettinen@helsinki.fi
Ustinov
Jarkko
J
Ormio
Päivi
P
Gao
Ru
R
Palgi
Jaan
J
Hakonen
Elina
E
Juntti-Berggren
Lisa
L
Berggren
Per-Olof
PO
Otonkoski
Timo
T
D000818:Animals; D015536:Down-Regulation; D066246:ErbB Receptors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000473:pathology / Q000502:physiology*; D007515:Islets of Langerhans / Q000502:physiology*; D008099:Liver / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction
D066246:ErbB Receptors