Abstract
Fibroblast growth factor (FGF) signalling has been implicated in patterning, proliferation and cell differentiation in many organs, including the developing pancreas1,2. 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 β-cells, indicating that FGF signalling may have a role in differentiated β-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 β-cells, impaired expression of glucose transporter 2 and increased proinsulin content in β-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 β-cells, indicating that Ipf1/Pdx1 acts upstream of FGFR1 signalling in β-cells to maintain proper glucose sensing, insulin processing and glucose homeostasis.
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Acknowledgements
We thank C. Granberg, K. Falk, U. B. Backman, the Umeå Transgene Core Facility, Mouse Camp, Karolinska Institute and U. Valtersson for technical assistance; T. Edlund for critical reading and comments; P. Hart and members from our laboratory for helpful discussions. We are grateful to A. Rosenthal for the dnFGFR1c-construct; W. LaRochelle for the dnFGFR2b-construct; O. Madsen for the proinsulin antisera and the C-peptide 1 and 2 antisera; D. Steiner for PC2 and PC1/3 antisera; B. Thorens for Glut2 antisera; and P. Serup for Nkx6.1 antisera. This work was supported by grants from the Swedish Medical Research Council and the Juvenile Diabetes Foundation, New York (to H.E.).
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Hart, A., Baeza, N., Apelqvist, Å. et al. Attenuation of FGF signalling in mouse β-cells leads to diabetes. Nature 408, 864–868 (2000). https://doi.org/10.1038/35048589
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DOI: https://doi.org/10.1038/35048589
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