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

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.

The effects of metformin on fibroblast growth factor 19, 21 and fibroblast growth factor receptor 1 in high-fat diet and streptozotocin induced diabetic rats

“…However, the effects and mechanisms of metformin on FGFR1 have not been fully elucidated and further research is required. Previous study has shown that pancreatic and duodenol homeobox 1 (PDX1) is required for the expression of FGFR1 in the pancreas and metformin could induce PDX1 in embryonic pancreas [14]. Since PDX1 involves in the development and functions of β cells [14], the normalization of FGFR1 after metformin treatment may indicate the improved functions of β cells.…”

“…Previous study has shown that pancreatic and duodenol homeobox 1 (PDX1) is required for the expression of FGFR1 in the pancreas and metformin could induce PDX1 in embryonic pancreas [14]. Since PDX1 involves in the development and functions of β cells [14], the normalization of FGFR1 after metformin treatment may indicate the improved functions of β cells. Besides, gen analysis suggested that FGFR1 may be a regulator of adipogenesis by increasing fat cell numbers [27].…”

“…Hart et al suggested that in the pancreas, FGFR1 is predominantly located in the β cell and attenuation of FGFR1 signaling leads to β cell dysfunction, thus leading to diabetes [14]. Besides, ablation of FGFR1 in adipose tissue resulted in impaired lipid profile [15].…”

Linkage Analysis of Diabetes Status Among Hypertensive Families

“…CRH secretion by the paraventricular nucleus of the hypothalamus is one of the first steps in the mammalian stress response. Hart et al (19) perturbed FGFR1 dominant-negative signaling in the mouse pancreas and observed a phenotype typical of type 2 diabetes. They demonstrated that mice with attenuated FGFR1 signaling developed diabetes with age, exhibited decreased numbers of ␤-cells, and had increased proinsulin content in ␤-cells.…”

Gene- and cell-based therapeutics for type I diabetes mellitus

“…171 185,186 and, to a limited extent, TGF-a, 179,187,188 can promote pancreatic cell growth and islet cell proliferation. Hart and co-workers 189,190 colleagues have produced evidence suggesting that fibroblast growth factor (FGF) signalling is important for b-cell generation. 189,190 Strategies aimed at engineering b-cell progenitors from pancreatic ductular epithelium with FGF in the presence of a permissive PDX-1 expression could promote expansion of b-cell progentors or a differentiation of progenitors into a pre-b-cell lineage.…”