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.

Nature
|December 29, 2000
PubMed

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.

Related Concept Videos

Cell Specific Gene Expression01:58

Cell Specific Gene Expression

Multicellular organisms contain a variety of structurally and functionally distinct cell types, but the DNA in all the cells originated from the same parent cells. The differences in the cells can be attributed to the differential gene expression. Liver cells, whose functions include detoxification of blood, production of bile to metabolize fats, and synthesis of proteins essential for metabolism, must express a specific set of genes to perform their functions. Gene expression also varies with...
Glucose Transporters01:27

Glucose Transporters

Glucose transporters facilitate the transport of glucose across the cell membrane. In addition to glucose, some glucose transporters can also aid the movement of other hexoses such as fructose, mannose, and galactose.
Facilitated diffusion-glucose transporters (GLUTs) are encoded by the solute-linked carrier (SLC) family 2, subfamily A gene family, or SLC2A. The 14 GLUT protein members are distributed into three classes:
TGF - β Signaling Pathway01:16

TGF - β Signaling Pathway

The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors are of three kinds RI, RII, and RIII. The RI...
Hormones Regulating Blood Glucose01:16

Hormones Regulating Blood Glucose

Insulin is released by beta cells of the pancreas when blood glucose levels are high. It facilitates glucose absorption and utilization in insulin-dependent cells with insulin receptors on their plasma membranes. Insulin promotes glucose uptake by increasing the number of glucose transport proteins in the cell membrane, allowing glucose to enter the cell. As a result, glucose utilization and ATP production are enhanced.
In addition to accelerating glucose uptake and utilization, insulin has...
Glucose Homeostasis: Pancreatic Islets and Insulin Secretion01:27

Glucose Homeostasis: Pancreatic Islets and Insulin Secretion

The pancreatic islets comprising only 1%-2% of the volume are highly vascularized and innervated mini-organs. They contain five endocrine cell types, including β cells that secrete insulin, which is synthesized as a single polypeptide chain, preproinsulin, processed to proinsulin, and finally to insulin and C-peptide. This process is complex and regulated, involving the Golgi complex, the endoplasmic reticulum, and the secretory granules of the β cell.
Insulin and C-peptide are co-secreted in...
Diabetic Neuropathy01:22

Diabetic Neuropathy

DefinitionDiabetic neuropathy is nerve damage caused by long-standing diabetes mellitus. It results directly from prolonged high blood sugar levels.PathophysiologyThe pathophysiology of diabetic neuropathy involves both metabolic and vascular disturbances triggered by chronic hyperglycemia.Metabolic injury: Elevated glucose levels activate the polyol pathway within nerve cells, leading to the accumulation of sorbitol and fructose. This increases oxidative stress, disrupts normal nerve...