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FASEB J. 2014 Feb;28(2):1010-21. doi: 10.1096/fj.13-238378. Epub 2013 Oct 30.

O-GlcNAcylation of FoxO1 in pancreatic β cells promotes Akt inhibition through an IGFBP1-mediated autocrine mechanism.

Author information

1
1Department of Endocrinology, Metabolism, and Diabetes, Institut Cochin, 22 rue Méchain, 75014, Paris, France. tarik.issad@inserm.fr.

Abstract

O-GlcNAcylation on serine/threonine is a post-translational modification that controls the activity of nucleocytoplasmic proteins according to glucose availability. We previously showed that O-GlcNAcylation of FoxO1 in liver cells increases its transcriptional activity. In the present study, we evaluated the potential involvement of FoxO1 O-GlcNAcylation in the context of pancreatic β-cell glucotoxicity. FoxO1 was O-GlcNAcylated in INS-1 832/13 β cells and isolated rat pancreatic islets. O-GlcNAcylation of FoxO1 resulted in a 2-fold increase in its transcriptional activity toward a FoxO1 reporter gene and a 3-fold increase in the expression of the insulin-like growth factor-binding protein 1 (Igfbp1) gene at the mRNA level, resulting in IGFBP1 protein oversecretion by the cells. Of note, increased IGFBP1 in the culture medium inhibited the activity of the insulin-like growth factor 1 receptor (IGF1R)/phosphatidyl inositol 3 kinase (PI3K)/Akt pathway. We reveal in this report a novel mechanism by which O-GlcNAcylation inhibits Akt activity through an autocrine mechanism. However, although inhibition of IGFBP1 expression using siRNA restored the PI3 kinase/Akt pathway, it did not rescue INS-1 832/13 cells from high-glucose- or O-glcNAcylation-induced cell death. In contrast, FoxO1 down-regulation by siRNA led to 30 to 60% protection of INS-1 832/13 cells from death mediated by glucotoxic conditions. Therefore, whereas FoxO1 O-GlcNAcylation inhibits Akt through an IGFBP1-mediated autocrine pathway, the deleterious effects of FoxO1 O-GlcNAcylation on cell survival appeared to be independent of this pathway.

KEYWORDS:

Forkhead transcription factor O1; PI3K signaling; apoptosis; glucotoxicity; insulin-like growth factor-binding protein 1

PMID:
24174424
DOI:
10.1096/fj.13-238378
[Indexed for MEDLINE]

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