Underlying mechanisms of glucocorticoid-induced beta-cell death and dysfunction: a new role for glycogen synthase kinase 3

Etienne Delangre (1) , Junjun Liu (1) , Stefania Tolu (1) , Kamel Maouche (1) , Mathieu Armanet (2) , Pierre Cattan (2) , Gaelle Pommier (1) , Danielle Bailbe (1) , Jamileh Movassat (1)

1 BFA (UMR_8251 / U1133) - Unité de Biologie Fonctionnelle et Adaptative
2 AP-HP - Hopital Saint-Louis [AP-HP]

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 beta-cells are not well understood. In this study we investigated the role of glycogen synthase kinase 3 (GSK3) in the mediation of beta-cell death and dysfunction induced by GCs. Using genetic and pharmacological approaches we showed that GSK3 is involved in GC-induced beta-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 GSK3 beta isoform is sufficient to mediate the pro-apoptotic effects of GCs in beta-cells. Collectively, in this work we identified GSK3 as a viable target to mitigate GC deleterious effects in pancreatic beta-cells.

Keywords: INSULIN-SECRETING CELLS; GLUCOSE-HOMEOSTASIS; INDUCED INHIBITION; PANCREATIC-ISLET; PHOSPHORYLATION; ACTIVATION; KINASE-3-BETA; EXPRESSION; INFLAMMATION; REGENERATION

Domains: Life Sciences [q-bio]

Etienne Delangre, Junjun Liu, Stefania Tolu, Kamel Maouche, Mathieu Armanet, et al.. Underlying mechanisms of glucocorticoid-induced beta-cell death and dysfunction: a new role for glycogen synthase kinase 3. Cell Death and Disease, 2021, 12 (12), ⟨10.1038/s41419-021-04419-8⟩. ⟨hal-03677215⟩