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 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.
Hart
A W
AW
Department of Microbiology and ULMM, Umeå University, Sweden.
Baeza
N
N
Apelqvist
A
A
Edlund
H
H
D000375:Aging / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000209:etiology / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D051272:Glucose Transporter Type 1; D051273:Glucose Transporter Type 2; D018398:Homeodomain Proteins; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D010179:Pancreas / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
D001786:Blood Glucose; D051272:Glucose Transporter Type 1; D051273:Glucose Transporter Type 2; D018398:Homeodomain Proteins; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D017468:Receptors, Fibroblast Growth Factor; C495677:SLC2A1 protein, human; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D005346:Fibroblast Growth Factors; C496348:FGFR1 protein, human; C496353:FGFR2 protein, human; C496349:Fgfr1 protein, mouse; C496354:Fgfr2 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2