title: O-GlcNAcylation of FoxO1 in pancreatic β cells promotes Akt inhibition through an IGFBP1-mediated autocrine mechanism.
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.
authors.affiliation: 1Department of Endocrinology, Metabolism, and Diabetes, Institut Cochin, 22 rue Méchain, 75014, Paris, France. tarik.issad@inserm.fr.
authors.forename: Yann
authors.initials: Y
authors.lastname: Fardini
authors.forename: Elodie
authors.initials: E
authors.lastname: Masson
authors.forename: Ouassila
authors.initials: O
authors.lastname: Boudah
authors.forename: Rania
authors.initials: R
authors.lastname: Ben Jouira
authors.forename: Camille
authors.initials: C
authors.lastname: Cosson
authors.forename: Cécile
authors.initials: C
authors.lastname: Pierre-Eugene
authors.forename: Mei-Shiue
authors.initials: MS
authors.lastname: Kuo
authors.forename: Tarik
authors.initials: T
authors.lastname: Issad
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology; D047468:Immunoprecipitation; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D000071161:Forkhead Box Protein O1
chemical_list: D051858:Forkhead Transcription Factors; D005947:Glucose; D018970:Insulin-Like Growth Factor Binding Protein 1; D009419:Nerve Tissue Proteins; D051057:Proto-Oncogene Proteins c-akt; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1
keywords: Forkhead transcription factor O1; PI3K signaling; apoptosis; glucotoxicity; insulin-like growth factor-binding protein 1