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Int. J. Mol. Sci. 2014, 15(10), 18000-18022; doi:10.3390/ijms151018000

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.
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)
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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. 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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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

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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