In vivo activation of the PI3K-Akt pathway in mouse beta cells by the EGFR mutation L858R protects against diabetes.
OBJECTIVE
EGF receptor (EGFR) signalling is required for normal beta cell development and postnatal beta cell proliferation. We tested whether beta cell proliferation can be triggered by EGFR activation at any age and whether this can protect beta cells against apoptosis induced by diabetogenic insults in a mouse model.


METHODS
We generated transgenic mice with doxycycline-inducible expression of constitutively active EGFR (L858R) (CA-EGFR) under the insulin promoter. Mice were given doxycycline at various ages for different time periods, and beta cell proliferation and mass were analysed. Mice were also challenged with streptozotocin and isolated islets exposed to cytokines.


RESULTS
Expression of EGFR (L858R) led to increased phosphorylation of EGFR and Akt in pancreatic islets. CA-EGFR expression during pancreatic development (embryonic day [E]12.5 to postnatal day [P]1) increased beta cell proliferation and mass in newborn mice. However, CA-EGFR expression in adult mice did not affect beta cell mass. Expression of the transgene improved glycaemia and markedly inhibited beta cell apoptosis after a single high dose, as well as after multiple low doses of streptozotocin. In vitro mechanistic studies showed that CA-EGFR protected isolated islets from cytokine-mediated beta cell death, possibly by repressing the proapoptotic protein BCL2-like 11 (BIM).


CONCLUSIONS
Our findings show that the expression of CA-EGFR in the developing, but not in the adult pancreas stimulates beta cell replication and leads to increased beta cell mass. Importantly, CA-EGFR protects beta cells against streptozotocin- and cytokine-induced death.
Research Programs Unit, Molecular Neurology, Biomedicum Stem Cell Center, University of Helsinki, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), 00014, Helsinki, Finland, elina.hakonen@helsinki.fi.
Elina
E
Hakonen
Jarkko
J
Ustinov
Décio L
DL
Eizirik
Hannu
H
Sariola
Päivi J
PJ
Miettinen
Timo
T
Otonkoski
D000818:Animals; D017209:Apoptosis; D001786:Blood Glucose / Q000032:analysis; D016923:Cell Death; D049109:Cell Proliferation; D002470:Cell Survival; D003920:Diabetes Mellitus / Q000201:enzymology / Q000235:genetics*; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000235:genetics*; D006706:Homeostasis; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D010179:Pancreas / Q000196:embryology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction
D001786:Blood Glucose; D019869:Phosphatidylinositol 3-Kinases; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt