期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 15, 期 10, 页码 18000-18022出版社
MDPI AG
DOI: 10.3390/ijms151018000
关键词
cystic fibrosis-related diabetes; insulin; insulin resistance; IRS1; AKT; FOXO1; beta 2 arrestin; SOCS2; ERK1 and 2; IGF-I
资金
- European Institute for Research in Cystic Fibrosis [IERFC Hsr inflammation 019]
- Emilia Romagna cystic fibrosis association
- Department of Pediatrics, University of Parma
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 beta 2 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.
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