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Attenuation of FGF signalling in mouse beta-cells leads to diabetes
A W Hart1, N Baeza, A Apelqvist
1Department of Microbiology and ULMM, Umeå University, Sweden.
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.
Insights
Fibroblast growth factor receptor 1c (FGFR1c) signaling is crucial for maintaining adult mouse beta-cell function. Impaired FGFR1c signaling leads to diabetes, mimicking type-2 diabetes characteristics.
Area of Science:
- Endocrinology
- Molecular Biology
- Diabetes Research
Background:
- Fibroblast growth factor (FGF) signaling plays a role in organ development and cell differentiation.
- FGF signaling components are expressed in adult mouse beta-cells, suggesting a role in differentiated cells.
Purpose of the Study:
- To investigate the role of FGF signaling, specifically FGFR1c and FGFR2b, in adult mouse beta-cell function.
- To determine the relationship between FGFR1 signaling and the homeobox gene Ipf1/Pdx1 in glucose homeostasis.
Main Methods:
- Expression analysis of FGF ligands and receptors in adult mouse beta-cells.
- Perturbation of FGFR1c and FGFR2b signaling using dominant-negative receptor expression in mouse pancreas.
- Assessment of diabetes phenotypes, beta-cell number, glucose transporter 2, proinsulin, and prohormone convertase expression.
Main Results:
- Attenuated FGFR1c signaling, but not FGFR2b signaling, in mice led to age-dependent diabetes.
- FGFR1c signaling deficiency resulted in decreased beta-cell number, impaired glucose transporter 2 expression, and increased proinsulin content.
- Ipf1/Pdx1 is essential for FGFR1 signaling component expression in beta-cells, acting upstream to regulate glucose sensing and insulin processing.
Conclusions:
- FGFR1c signaling is vital for maintaining differentiated beta-cell function and glucose homeostasis in adult mice.
- Defects in FGFR1c signaling mimic key pathological features of type-2 diabetes.
- Ipf1/Pdx1 acts upstream of FGFR1 signaling, highlighting a critical regulatory pathway for beta-cell function.
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