ArticleJournal of biomedical science2014
Valproate pretreatment protects pancreatic β-cells from palmitate-induced ER stress and apoptosis by inhibiting glycogen synthase kinase-3β.
Article in Journal of biomedical science, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 36 citations in OpenAlex.
- Reciprocal rescue of Wolfram syndrome by two causative genes.EMBO reports · 2025Article
- Neuroprotective mechanisms of valproic acid and alpha-lipoic acid in ALS: a network pharmacology-based investigation.Frontiers in pharmacology · 2025Article
- Targeting Protein Kinases to Protect Beta-Cell Function and Survival in Diabetes.International journal of molecular sciences · 2024Review
- Pharmacological inhibitors of β-cell dysfunction and death as therapeutics for diabetes.Frontiers in endocrinology · 2023Review
- Endoplasmic reticulum stress associates with the development of intervertebral disc degeneration.Frontiers in endocrinology · 2022Review
- Protein Kinases Signaling in Pancreatic Beta-cells Death and Type 2 Diabetes.Advances in experimental medicine and biology · 2021Article
- Effect of 4-phenylbutyrate and valproate on dominant mutations of WFS1 gene in Wolfram syndrome.Journal of endocrinological investigation · 2020Article
- Regulation of Glycogen Content in Astrocytes via Cav-1/PTEN/AKT/GSK-3β Pathway by Three Anti-bipolar Drugs.Neurochemical research · 2018Article
- Review
- GSK3β and VDAC Involvement in ER Stress and Apoptosis Modulation during Orthotopic Liver Transplantation.International journal of molecular sciences · 2017Article
- DR5 but not miRNA-181 or miRNA-211 is involved in ER stress-mediated apoptosis induced by palmitate in islet β cells.International journal of clinical and experimental pathology · 2017Article
- Bipolar disorder and diabetes mellitus: evidence for disease-modifying effects and treatment implications.International journal of bipolar disorders · 2016Review
- GSK-3β mediates dexamethasone-induced pancreatic β cell apoptosis.Life sciences · 2016Article
- Role of histone deacetylases in pancreas: Implications for pathogenesis and therapy.World journal of gastrointestinal oncology · 2015Review
- How the location of superoxide generation influences the β-cell response to nitric oxide.The Journal of biological chemistry · 2015Article
- Valproate Attenuates 25-kDa C-Terminal Fragment of TDP-43-Induced Neuronal Toxicity via Suppressing Endoplasmic Reticulum Stress and Activating Autophagy.International journal of biological sciences · 2015Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundReduction of pancreatic β-cells mass, major secondary to increased β-cells apoptosis, is increasingly recognized as one of the main contributing factors to the pathogenesis of type 2 diabetes (T2D), and saturated free fatty acid palmitate has been shown to induce endoplasmic reticulum (ER) stress that may contribute to promoting β-cells apoptosis. Recent literature suggests that valproate, a diffusely prescribed drug in the treatment of epilepsy and bipolar disorder, can inhibit glycogen synthase kinase-3β (GSK-3β) activity and has cytoprotective effects in neuronal cells and HepG2 cells. Thus, we hypothesized that valproate may protect INS-1 β-cells from palmitate-induced apoptosis via inhibiting GSK-3β.
resultsValproate pretreatment remarkable prevented palmitate-mediated cytotoxicity and apoptosis (lipotoxicity) as well as ER distension. Furthermore, palmitate triggered ER stress as evidenced by increased mRNA levels of C/EBP homologous protein (CHOP) and activating transcription factor 4 (ATF4) in a time-dependent fashion. However, valproate not only reduced the mRNA and protein expression of CHOP but also inhibited GSK-3β and caspase-3 activity induced by palmitate, whereas, the mRNA expression of ATF4 was not affected. Interestingly, TDZD-8, a specific GSK-3β inhibitor, also showed the similar effect on lipotoxicity and ER stress as valproate in INS-1 cells. Finally, compared with CHOP knockdown, valproate displayed better cytoprotection against palmitate.
conclusionsValproate may protect β-cells from palmitate-induced apoptosis and ER stress via GSK-3β inhibition, independent of ATF4/CHOP pathway. Besides, GSK-3β, rather than CHOP, may be a more promising therapeutic target for T2D.
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