Abstract
Cystic fibrosis-related diabetes is to date the most frequent complication in cystic fibrosis (CF). The mechanisms underlying this condition are not well understood, and a possible role of insulin resistance is debated. We investigated insulin signal transduction in CF. Total insulin receptor, IRS1, p85 PI3K, and AKT contents were substantially normal in CF cells (CFBE41o-), whereas winged helix forkhead (FOX)O1 contents were reduced both in baseline conditions and after insulin stimulation. In addition, CF cells showed increased ERK1/2, and reduced β2 arrestin contents. No significant change in SOCS2 was observed. By using a CFTR inhibitor and siRNA, changes in FOXO1 were related to CFTR loss of function. In a CF-affected mouse model, FOXO1 content was reduced in the muscle while no significant difference was observed in liver and adipose tissue compared with wild-type. Insulin-like growth factor 1 (IGF-I) increased FOXO1 content in vitro and in vivo in muscle and adipose tissue. In conclusion; we present the first description of reduced FOXO1 content in CF, which is compatible with reduced gluconeogenesis and increased adipogenesis, both features of insulin insensitivity. IGF-I treatment was effective in increasing FOXO1, thereby suggesting that it could be considered as a potential treatment in CF patients possibly to prevent and treat cystic fibrosis-related diabetes.
Highlights
Cystic fibrosis (CF) is the most common life-threatening inherited recessive disease in the white population, and is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene encoding a protein involved in the homeostasis of ions and other metabolites [1].Cystic fibrosis-related diabetes (CFRD) is to date the major co-morbidity of CF [1,2,3], and its prevalence has dramatically increased in recent years
We provide evidence that insulin signal transduction in CF cells is impaired, is characterized mainly by reduced FOXO1 content, that these changes are related with CFTR loss of function, and that IGF-I
The activated/total IRS1 ratio was similar in the 16HBE14o- cells and in the CFBE41o- cells, and did not show significant changes after treatment with insulin (Figure 1B)
Summary
Cystic fibrosis-related diabetes (CFRD) is to date the major co-morbidity of CF [1,2,3], and its prevalence has dramatically increased in recent years. This condition is commonly ascribed to a progressive reduction in insulin secretion; the mechanisms underlying this progression are not understood, and a possible role of insulin resistance is debated [4,5,6,7]. It is very difficult to study insulin resistance clinically in these patients because of confounding factors as progressive insulin deficiency, malabsorption, and variable blood glucose concentrations [10]
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