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

Fibroblast growth factor (FGF) signalling has been implicated in patterning , proliferation and cell differentiation in many organs, including the deve loping pancreas(1,2). Here we show that the FGF receptors (FGFRs) 1 and 2, together with the ligands FGF1, FGF2, FGF4, FGF5, FGF7 and FGF10, are expre ssed in adult mouse beta -cells, indicating that FGF signalling may have a role in differentiated beta -cells. When we perturbed signalling by express ing dominant-negative forms of the receptors, FGFR1c and FGFR2b, in the pan creas, we found that that mice with attenuated FGFR1c signalling, but not t hose with reduced FGFR2b signalling, develop diabetes with age and exhibit a decreased number of beta -cells, impaired expression of glucose transport er 2 and increased proinsulin content in beta -cells owing to impaired expr ession of prohormone convertases 1/3 and 2. These defects are all character istic 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 Ipf 1/Pdx1 is required for the expression of FGFR1 signalling components in bet a -cells, indicating that Ipf1/Pdx1 acts upstream of FGFR1 signalling in be ta -cells to maintain proper glucose sensing, insulin processing and glucos e homeostasis.