Abstract
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.
Highlights
Glucocorticoids (GCs) are steroid hormones produced by the adrenal gland, under the control of the hypothalamo-pituitary axis [1]
We investigated the possible implication of Glycogen Synthase Kinase 3 (GSK3) in the mediation of diabetogenic effects of GCs in β-cells
We found that the down-regulation of GSK3β, but not INS-1 832/13 cells or primary islets with Dexa did not result in GSK3α, is sufficient to reduce glucocorticoid receptor (GR) protein levels in INS-1 832/13 cells significant changes in mRNA (Fig. 3A, B) and protein levels of (Fig. 6B), to a similar extent as that observed with pharmacological
Summary
Glucocorticoids (GCs) are steroid hormones produced by the adrenal gland, under the control of the hypothalamo-pituitary axis [1]. They regulate a large number of physiological processes and are widely used in therapy for their anti-inflammatory, immunomodulatory and anti-allergic properties [2]. Their clinical usage remains irreplaceable, especially in case of transplantation [3], or for treating chronic inflammatory diseases such as rheumatoid arthritis [4], asthma [5] or multiple sclerosis [6]. Its liganddependent nuclear translocation is known to be regulated by post-translational modifications, especially by phosphorylation [8]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
