Université de Paris, BFA, UMR 8251, CNRS, Team « Biologie et Pathologie du Pancréas Endocrine », Paris, France.
Shandong Institute of Endocrine & Metabolic Diseases, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China.
Cell Death Dis. 2021 Dec 7;12(12):1136. doi: 10.1038/s41419-021-04419-8.
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.
糖皮质激素（GCs）因其抗炎和免疫抑制特性而被广泛用于治疗各种疾病。GC 的使用与重要的副作用有关，包括致糖尿病作用。然而，GC 介导的β细胞致糖尿病作用的潜在机制尚不清楚。在这项研究中，我们研究了糖原合酶激酶 3（GSK3）在 GC 诱导的β细胞死亡和功能障碍中的作用。通过遗传和药理学方法，我们表明 GSK3 参与了 GC 诱导的β细胞死亡和胰岛素分泌受损。此外，我们揭示了 GC-GSK3 相互作用的潜在机制。我们表明 GSK3 轻微参与了配体结合时 GC 受体（GR）的核定位。此外，我们表明 GSK3 调节 GR 在 mRNA 和蛋白质水平的表达。最后，我们剖析了每个 GSK3 同工型的适当贡献，并表明 GSK3β 同工型足以介导 GC 在β细胞中的促凋亡作用。总之，在这项工作中，我们确定 GSK3 是减轻胰腺β细胞中 GC 有害作用的可行靶标。
