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.

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