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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adipose Tissue / metabolism
-
Animals
-
Cell Line
-
Cystic Fibrosis / metabolism
-
Cystic Fibrosis / pathology
-
Cystic Fibrosis Transmembrane Conductance Regulator / antagonists & inhibitors
-
Cystic Fibrosis Transmembrane Conductance Regulator / genetics
-
Cystic Fibrosis Transmembrane Conductance Regulator / metabolism
-
Female
-
Forkhead Box Protein O1
-
Forkhead Transcription Factors / metabolism*
-
Insulin Receptor Substrate Proteins / metabolism
-
Insulin-Like Growth Factor I / genetics
-
Insulin-Like Growth Factor I / metabolism
-
Insulin-Like Growth Factor I / pharmacology*
-
Mice
-
Mice, Inbred CFTR
-
Mitogen-Activated Protein Kinase 1 / metabolism
-
Mitogen-Activated Protein Kinase 3 / metabolism
-
Muscle, Skeletal / metabolism
-
Phosphatidylinositol 3-Kinases / metabolism
-
Phosphorylation / drug effects
-
Proto-Oncogene Proteins c-akt / metabolism
-
Recombinant Proteins / biosynthesis
-
Recombinant Proteins / genetics
-
Recombinant Proteins / pharmacology
-
Signal Transduction / drug effects*
-
Suppressor of Cytokine Signaling Proteins / metabolism
Substances
-
Forkhead Box Protein O1
-
Forkhead Transcription Factors
-
Foxo1 protein, mouse
-
Insulin Receptor Substrate Proteins
-
Recombinant Proteins
-
Socs2 protein, mouse
-
Suppressor of Cytokine Signaling Proteins
-
Cystic Fibrosis Transmembrane Conductance Regulator
-
Insulin-Like Growth Factor I
-
Phosphatidylinositol 3-Kinases
-
Proto-Oncogene Proteins c-akt
-
Mitogen-Activated Protein Kinase 1
-
Mitogen-Activated Protein Kinase 3