Attenuation of FGF signalling in mouse beta-cells leads to diabetes

Alan Hart, N Baeza, A Apelqvist, H Edlund

Research output: Contribution to journalArticlepeer-review

Abstract

Fibroblast growth factor (FGF) signalling has been implicated in patterning, proliferation and cell differentiation in many organs, including the developing pancreas. Here we show that the FGF receptors (FGFRs) 1 and 2, together with the ligands FGF1, FGF2, FGF4, FGF5, FGF7 and FGF10, are expressed in adult mouse beta-cells, indicating that FGF signalling may have a role in differentiated beta-cells. When we perturbed signalling by expressing dominant-negative forms of the receptors, FGFR1c and FGFR2b, in the pancreas, we found that that mice with attenuated FGFR1c signalling, but not those with reduced FGFR2b signalling, develop diabetes with age and exhibit a decreased number of beta-cells, impaired expression of glucose transporter 2 and increased proinsulin content in beta-cells owing to impaired expression of prohormone convertases 1/3 and 2. These defects are all characteristic of patients with type-2 diabetes. Mutations in the homeobox gene Ipf1/Pdx1 are linked to diabetes in both mouse and human. We also show that Ipf1/Pdx1 is required for the expression of FGFR1 signalling components in beta-cells, indicating that Ipf1/Pdx1 acts upstream of FGFR1 signalling in beta-cells to maintain proper glucose sensing, insulin processing and glucose homeostasis.
Original languageEnglish
Pages (from-to)864-8
Number of pages5
JournalNature
Volume408
Issue number6814
DOIs
Publication statusPublished - 14 Dec 2000

Keywords

  • Animals
  • Glucose Transporter Type 1
  • Homeodomain Proteins
  • Pancreas
  • Humans
  • Aging
  • Islets of Langerhans
  • Mice
  • Mice, Transgenic
  • Receptors, Fibroblast Growth Factor
  • Glucose Transporter Type 2
  • Insulin
  • Blood Glucose
  • Receptor, Fibroblast Growth Factor, Type 1
  • Receptor Protein-Tyrosine Kinases
  • Receptor, Fibroblast Growth Factor, Type 2
  • Diabetes Mellitus, Type 2
  • Trans-Activators
  • Signal Transduction
  • Monosaccharide Transport Proteins
  • Fibroblast Growth Factors
  • Diabetes Mellitus, Experimental

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