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The Cancer-Associated FGFR4-G388R Polymorphism Enhances Pancreatic Insulin Secretion and Modifies the Risk of Diabetes

MPG-Autoren
http://pubman.mpdl.mpg.de/cone/persons/resource/persons78381

Mayr,  Thomas
Ullrich, Axel / Molecular Biology, Max Planck Institute of Biochemistry, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons78812

Ullrich,  Axel
Ullrich, Axel / Molecular Biology, Max Planck Institute of Biochemistry, Max Planck Society;

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Zitation

Ezzat, S., Zheng, L., Florez, J. C., Stefan, N., Mayr, T., Hliang, M. M., et al. (2013). The Cancer-Associated FGFR4-G388R Polymorphism Enhances Pancreatic Insulin Secretion and Modifies the Risk of Diabetes. CELL METABOLISM, 17(6), 929-940. doi:10.1016/j.cmet.2013.05.002.


Zitierlink: http://hdl.handle.net/11858/00-001M-0000-0014-C2A4-7
Zusammenfassung
The fibroblast growth factor receptor 4 (FGFR4)-R388 single-nucleotide polymorphism has been associated with cancer risk and prognosis. Here we show that the FGFR4-R388 allele yields a receptor variant that preferentially promotes STAT3/5 signaling. This STAT activation transcriptionally induces Grb14 in pancreatic endocrine cells to promote insulin secretion. Knockin mice with the FGFR4 variant allele develop pancreatic islets that secrete more insulin, a feature that is reversed through Grb14 deletion and enhanced with FGF19 administration. We also show in humans that the FGFR4-R388 allele enhances islet function and may protect against type 2 diabetes. These data support a common genetic link underlying cancer and hyperinsulinemia.