Underlying mechanisms of glucocorticoid-induced β-cell death and dysfunction: a new role for glycogen synthase kinase 3.
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
07 12 2021
07 12 2021
Historique:
received:
22
06
2021
accepted:
18
11
2021
revised:
10
11
2021
entrez:
8
12
2021
pubmed:
9
12
2021
medline:
9
4
2022
Statut:
epublish
Résumé
Glucocorticoids (GCs) are widely prescribed for their anti-inflammatory and immunosuppressive properties as a treatment for a variety of diseases. The use of GCs is associated with important side effects, including diabetogenic effects. However, the underlying mechanisms of GC-mediated diabetogenic effects in β-cells are not well understood. In this study we investigated the role of glycogen synthase kinase 3 (GSK3) in the mediation of β-cell death and dysfunction induced by GCs. Using genetic and pharmacological approaches we showed that GSK3 is involved in GC-induced β-cell death and impaired insulin secretion. Further, we unraveled the underlying mechanisms of GC-GSK3 crosstalk. We showed that GSK3 is marginally implicated in the nuclear localization of GC receptor (GR) upon ligand binding. Furthermore, we showed that GSK3 regulates the expression of GR at mRNA and protein levels. Finally, we dissected the proper contribution of each GSK3 isoform and showed that GSK3β isoform is sufficient to mediate the pro-apoptotic effects of GCs in β-cells. Collectively, in this work we identified GSK3 as a viable target to mitigate GC deleterious effects in pancreatic β-cells.
Identifiants
pubmed: 34876563
doi: 10.1038/s41419-021-04419-8
pii: 10.1038/s41419-021-04419-8
pmc: PMC8651641
doi:
Substances chimiques
Glucocorticoids
0
Glycogen Synthase Kinase 3 beta
EC 2.7.11.1
Glycogen Synthase Kinase 3
EC 2.7.11.26
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1136Informations de copyright
© 2021. The Author(s).
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