The cancer-associated FGFR4-G388R polymorphism enhances pancreatic insulin secretion and modifies the risk of diabetes

Shereen Ezzat; Lei Zheng; Jose C Florez; Norbert Stefan; Thomas Mayr; Maw Maw Hliang; Kathleen Jablonski; Maegan Harden; Alena Stančáková; Markku Laakso; Hans-Ulrich Haring; Axel Ullrich; Sylvia L Asa

doi:10.1016/j.cmet.2013.05.002

The cancer-associated FGFR4-G388R polymorphism enhances pancreatic insulin secretion and modifies the risk of diabetes

Cell Metab. 2013 Jun 4;17(6):929-940. doi: 10.1016/j.cmet.2013.05.002.

Authors

Affiliations

¹ Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2M9, Canada. Electronic address: [email protected].
² Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2M9, Canada.
³ Center for Human Genetic Research and Diabetes Research Center (Diabetes Unit), Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Harvard Medical School, Boston, MA 02142, USA.
⁴ University of Tübingen, 72076 Tübingen, Germany.
⁵ Department of Molecular Biology, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
⁶ The Biostatistics Center, George Washington University, Rockville, MD 20852, USA.
⁷ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁸ Department of Medicine, University of Eastern Finland, 70210 Kuopio, Finland.

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Retracted Publication

MeSH terms

Adaptor Proteins, Signal Transducing
Animals
Cells, Cultured
Diabetes Mellitus, Type 2 / genetics
Diabetes Mellitus, Type 2 / metabolism
Diabetes Mellitus, Type 2 / prevention & control
Gene Expression Profiling
Gene Knock-In Techniques
Humans
Hyperinsulinism
Insulin / biosynthesis
Insulin / metabolism*
Insulin Secretion
Mice
Mice, Knockout
Neoplasms / genetics
Neoplasms / metabolism
Pancreas / metabolism
Polymorphism, Single Nucleotide
Proteins / genetics
Proteins / metabolism*
RNA Interference
RNA, Small Interfering
Rats
Receptor, Fibroblast Growth Factor, Type 4 / genetics
Receptor, Fibroblast Growth Factor, Type 4 / metabolism*
Receptor, Insulin / metabolism
STAT3 Transcription Factor / metabolism*
STAT5 Transcription Factor / metabolism*
Signal Transduction / genetics

Substances

Adaptor Proteins, Signal Transducing
Grb14 protein, mouse
Insulin
Proteins
RNA, Small Interfering
STAT3 Transcription Factor
STAT5 Transcription Factor
Stat3 protein, mouse
Fgfr4 protein, mouse
Receptor, Fibroblast Growth Factor, Type 4
Receptor, Insulin

Abstract

Publication types

MeSH terms

Substances

Grants and funding