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

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Islets of Langerhans
Epidermal Growth Factor Receptor
Down-Regulation
Growth
Fetal Development
Transgenic Mice
Cell Proliferation
Glucose
Cell Physiological Phenomena
Glucagon-Like Peptide 1
Homeobox Genes
Transgenes
Hyperglycemia
Signal Transduction
Phosphotransferases
Phosphorylation
Parturition
Insulin

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., ... 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

Downregulation of EGF receptor signaling in pancreatic islets causes diabetes due to impaired postnatal β-cell growth. / Miettinen, Päivi J.; Ustinov, Jarkko; Ormio, Päivi; Gao, Ru; Palgi, Jaan; Hakonen, Elina; Juntti-Berggren, Lisa; Berggren, Per Olof; Otonkoski, Timo.

In: Diabetes, Vol. 55, No. 12, 01.12.2006, p. 3299-3308.

Research output: Contribution to journalArticle

Miettinen, PJ, Ustinov, J, Ormio, P, Gao, R, Palgi, J, Hakonen, E, Juntti-Berggren, L, Berggren, PO & Otonkoski, T 2006, 'Downregulation of EGF receptor signaling in pancreatic islets causes diabetes due to impaired postnatal β-cell growth', Diabetes, vol. 55, no. 12, pp. 3299-3308. https://doi.org/10.2337/db06-0413
Miettinen, Päivi J. ; Ustinov, Jarkko ; Ormio, Päivi ; Gao, Ru ; Palgi, Jaan ; Hakonen, Elina ; Juntti-Berggren, Lisa ; Berggren, Per Olof ; Otonkoski, Timo. / Downregulation of EGF receptor signaling in pancreatic islets causes diabetes due to impaired postnatal β-cell growth. In: Diabetes. 2006 ; Vol. 55, No. 12. pp. 3299-3308.
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