A crosstalk between E2F1 and GLP-1 signaling pathways modulates insulin secretion
| Autor: | François Pattou, Patrick Meffre, Zohra Benfodda, Frédérik Oger, Gianni Pasquetti, Xavier Gromada, Julie Kerr-Conte, Amélie Bonnefond, Emilie Courty, Charlène Carney, Laure Rolland, Cyril Bourouh, Philippe Froguel, Emilie Caron, Jean-Sébastien Annicotte, Maeva Moreno, Raphael Boutry, Nabil Rabhi |
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| Rok vydání: | 2021 |
| Předmět: |
endocrine system
medicine.medical_specialty biology Chemistry Pancreatic islets Retinoblastoma protein Incretin Glucagon-like peptide-1 Crosstalk (biology) Endocrinology medicine.anatomical_structure Internal medicine medicine biology.protein Glucose homeostasis biological phenomena cell phenomena and immunity Signal transduction E2F |
| Popis: | 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 specificE2f1deficient mice (E2f1β−/−) 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 ofGlp1rencoding Glp-1 receptor (GLP1R) inE2f1β−/−pancreatic islets. Decreasing E2F1 transcriptional activity with an E2F inhibitor in islets from nondiabetic humans decreasedGLP1Rlevels and blunted the incretin effect of exendin 4 on insulin secretion. Conversely, overexpressingE2f1in pancreatic β cells increasedGlp1rexpression 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. |
| Databáze: | OpenAIRE |
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