title: FOXO1 content is reduced in cystic fibrosis and increases with IGF-I treatment.
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.
authors.affiliation: Department of Pediatrics, University Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy. arianna.smerieri@unipr.it.
authors.forename: Arianna
authors.initials: A
authors.lastname: Smerieri
authors.affiliation: Department of Pediatrics, University Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy. luisa.montanini@unipr.it.
authors.forename: Luisa
authors.initials: L
authors.lastname: Montanini
authors.affiliation: European Institute for Research in Cystic Fibrosis, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy. maiuri@unina.it.
authors.forename: Luigi
authors.initials: L
authors.lastname: Maiuri
authors.affiliation: Department of Pediatrics, University Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy. SBernasconi@ao.pr.it.
authors.forename: Sergio
authors.initials: S
authors.lastname: Bernasconi
authors.affiliation: Department of Pediatrics, University Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy. mariaelisabeth.street@unipr.it.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Street
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D003550:Cystic Fibrosis / Q000378:metabolism / Q000473:pathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D018181:Mice, Inbred CFTR; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D055504:Insulin Receptor Substrate Proteins; D011994:Recombinant Proteins; C491409:Socs2 protein, mouse; D050826:Suppressor of Cytokine Signaling Proteins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3