Journal
DIABETES
Volume 67, Issue 3, Pages 461-472Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db17-0595
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Funding
- Agence Nationale de la Recherche (Laboratoire d'Excellence Revive, Investissement d'Avenir) [ANR-10-LABX-73]
- Cochin Internal Program PIC
- Agence Nationale de la Recherche [ANR-10-LABX-73]
- Bettencourt Schueller Foundation
- Innovative Medicines Initiative 2 Joint Undertaking [115881]
- European Union's Horizon research and innovation programme
- Swiss State Secretariat for Education Research and Innovation (SERI) [16.0097]
- EFPIA
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Although the mechanisms by which glucose regulates insulin secretion from pancreatic beta-cells are now well described, the way glucose modulates gene expression in such cells needs more understanding. Here, we demonstrate that MondoA, but not its paralog carbohydrate-responsive element-binding protein, is the predominant glucose-responsive transcription factor in human pancreatic beta-EndoC-beta H1 cells and in human islets. In high-glucose conditions, MondoA shuttles to the nucleus where it is required for the induction of the glucose-responsive genes arrestin domain-containing protein 4 (ARRDC4) and thioredoxin interacting protein (TXNIP), the latter being a protein strongly linked to beta-cell dysfunction and diabetes. Importantly, increasing cAMP signaling in human beta-cells, using forskolin or the glucagon-like peptide 1 mimetic Exendin-4, inhibits the shuttling of MondoA and potently inhibits TXNIP and ARRDC4 expression. Furthermore, we demonstrate that silencing MondoA expression improves glucose uptake in EndoC-beta H1 cells. These results highlight MondoA as a novel target in beta-cells that coordinates transcriptional response to elevated glucose levels.
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