GLP-1 receptor agonists synergize with DYRK1A inhibitors to potentiate functional human β cell regeneration.
Détails
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Accès restreint UNIL
Etat: Public
Version: de l'auteur⸱e
Licence: Non spécifiée
ID Serval
serval:BIB_4E3C5CE86DB9
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
GLP-1 receptor agonists synergize with DYRK1A inhibitors to potentiate functional human β cell regeneration.
Périodique
Science translational medicine
ISSN
1946-6242 (Electronic)
ISSN-L
1946-6234
Statut éditorial
Publié
Date de publication
12/02/2020
Peer-reviewed
Oui
Volume
12
Numéro
530
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Résumé
Glucagon-like peptide-1 receptor (GLP1R) agonists and dipeptidyl peptidase 4 inhibitors are widely prescribed diabetes drugs due to their ability to stimulate insulin secretion from remaining β cells and to reduce caloric intake. Unfortunately, they fail to increase human β cell proliferation. Small-molecule inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) are able to induce adult human β cell proliferation, but rates are modest (~2%), and their specificity to β cells is limited. Here, we provide evidence that combining any member of the GLP1R agonist class with any member of the DYRK1A inhibitor class induces a synergistic increase in human β cell replication (5 to 6%) accompanied by an actual increase in numbers of human β cells. GLP1R agonist-DYRK1A inhibitor synergy required combined inhibition of DYRK1A and an increase in cAMP and did not lead to β cell dedifferentiation. These beneficial effects on proliferation were seen in both normal human β cells and β cells derived from individuals with type 2 diabetes. The ability of the GLP1R agonist-DYRK1A inhibitor combination to enhance human β cell proliferation, human insulin secretion, and blood glucose control extended in vivo to studies of human islets transplanted into euglycemic and streptozotocin-diabetic immunodeficient mice. No adverse events were observed in the mouse studies during a 1-week period. Because of the relative β cell specificity of GLP1R agonists, the combination provides an improved, although not complete, degree of human β cell specificity.
Mots-clé
Adult, Animals, Diabetes Mellitus, Type 2, Glucagon-Like Peptide-1 Receptor/agonists, Humans, Insulin-Secreting Cells, Mice, Protein Kinase Inhibitors/pharmacology, Protein Serine-Threonine Kinases/antagonists & inhibitors, Protein-Tyrosine Kinases/antagonists & inhibitors, Regeneration
Pubmed
Web of science
Open Access
Oui
Création de la notice
29/06/2021 15:05
Dernière modification de la notice
12/03/2022 7:29