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Open AccessArticle

FOXO1 Content Is Reduced in Cystic Fibrosis and Increases with IGF-I Treatment

1
Department of Pediatrics, University Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy
2
European Institute for Research in Cystic Fibrosis, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy
3
Institute of Pediatrics, University of Foggia, Via Pinto, 71100 Foggia, Italy
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2014, 15(10), 18000-18022; https://doi.org/10.3390/ijms151018000
Received: 19 May 2014 / Revised: 2 September 2014 / Accepted: 22 September 2014 / Published: 8 October 2014
(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells 2014)
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. View Full-Text
Keywords: cystic fibrosis-related diabetes; insulin; insulin resistance; IRS1; AKT; FOXO1; β2 arrestin; SOCS2; ERK1 and 2; IGF-I cystic fibrosis-related diabetes; insulin; insulin resistance; IRS1; AKT; FOXO1; β2 arrestin; SOCS2; ERK1 and 2; IGF-I
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Smerieri, A.; Montanini, L.; Maiuri, L.; Bernasconi, S.; Street, M.E. FOXO1 Content Is Reduced in Cystic Fibrosis and Increases with IGF-I Treatment. Int. J. Mol. Sci. 2014, 15, 18000-18022.

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