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Pré-Publication, Document De Travail Année : 2021

A crosstalk between E2F1 and GLP-1 signaling pathways modulates insulin secretion

Résumé

Abstract Compromised β-cell function contributes to type 2 diabetes (T2D) development. The glucagon like peptide 1 (Glp-1) has emerged as a hormone with broad pharmacological potential toward T2D treatment, notably by improving β-cell functions. Recent data have shown that the transcription factor E2f1, besides its role as a cell cycle regulator, is involved in glucose homeostasis by modulating β-cell mass, function and identity. Here, we demonstrate a crosstalk between the E2F1, phosphorylation of retinoblastoma protein (pRb) and Glp-1 signaling pathways. We found that β-cell specific E2f1 deficient mice ( E2f1 β−/− ) presented with impaired glucose homeostasis and decreased glucose stimulated-insulin secretion mediated by exendin 4 ( i . e ., GLP1R agonist), which were associated with decreased expression of Glp1r encoding Glp-1 receptor (GLP1R) in E2f1 β−/− pancreatic islets. Decreasing E2F1 transcriptional activity with an E2F inhibitor in islets from nondiabetic humans decreased GLP1R levels and blunted the incretin effect of exendin 4 on insulin secretion. Conversely, overexpressing E2f1 in pancreatic β cells increased Glp1r expression associated with enhanced insulin secretion mediated by GLP1R agonist. Interestingly, kinome analysis of mouse islets demonstrated that an acute treatment with exendin 4 increased pRb phosphorylation and subsequent E2f1 transcriptional activity. This study suggests a molecular crosstalk between the E2F1/pRb and GLP1R signaling pathways that modulates insulin secretion and glucose homeostasis.
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Dates et versions

hal-04365604 , version 1 (28-12-2023)

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Cyril Bourouh, Emilie Courty, Gianni Pasquetti, Xavier Gromada, Nabil Rabhi, et al.. A crosstalk between E2F1 and GLP-1 signaling pathways modulates insulin secretion. 2023. ⟨hal-04365604⟩
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