Downregulation of EGF receptor signaling in pancreatic islets causes diabetes due to impaired postnatal β-cell growth

Päivi J. Miettinen, Jarkko Ustinov, Päivi Ormio, Ru Gao, Jaan Palgi, Elina Hakonen, Lisa Juntti-Berggren, Per Olof Berggren, Timo Otonkoski

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Abstract

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 β-cell signal transduction in the adult. To study the functional roles of EGF-R in β-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 β- and δ-cells but not in α-cells, as expected, and it resulted in an ∼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 β-cell surface area of E1-DN mice was highly reduced at the age of 2 months, while α-cell surface area was not changed. This defect was essentially postnatal, since the differences in β-cell area of newborn mice were much smaller. An apparent explanation for this is impaired postnatal β-cell proliferation; the normal surge of β-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 β-cells, which leads to the development of diabetes.

Original languageEnglish (US)
Pages (from-to)3299-3308
Number of pages10
JournalDiabetes
Volume55
Issue number12
DOIs
StatePublished - Dec 1 2006

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ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Miettinen, P. J., Ustinov, J., Ormio, P., Gao, R., Palgi, J., Hakonen, E., Juntti-Berggren, L., Berggren, P. O., & Otonkoski, T. (2006). Downregulation of EGF receptor signaling in pancreatic islets causes diabetes due to impaired postnatal β-cell growth. Diabetes, 55(12), 3299-3308. https://doi.org/10.2337/db06-0413