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Chronic treatment with valproate protects INS1 cell from palmitate-induced ER stress and apoptosis by inhibiting GSK3β


Reduction of β-cell mass is increasingly recognized as one of the main contributing factors to the pathogenesis of type 2 diabetes. Chronic free fatty acid (FFA) exposure has been shown to induce endoplasmic reticulum (ER) stress that may contribute to promoting pancreatic β-cell apoptosis. In the present study, we first investigated whether anticonvulsant sodium valproate (VPA), at clinically relevant doses, protects pancreatic β-cell from palmitate-induced apoptosis and the mechanism underlying anti-apoptosis.

Methods and results

INS1 cells exposed to 0.25~1.0mM palmitate for 24~48h under serum-free conditions showed marked apoptosis in time- and concentration-dependent as assessed by CCK-8 assay, Hoechst 33342 / PI, flow cytometric cell apoptosis assay and electron microscopy. Palmitate triggered ER stress and apoptosis in INS1 cells as evidenced by increased mRNA levels of C/EBP homologous transcription factor (CHOP), activating transcription factor 4 (ATF4) and X box-binding protein 1 (XBP-1) in a time-dependent fashion. Western blot analysis also showed significant increase of CHOP and caspase-3 in protein level. We also found that palmitate activated GSK3β by inhibiting phosphorylation at serine 9. While chronic, not acute, 1~2mM VPA and 2mM LiCl remarkable reduced palmitate-induced cytotoxicity. Furthermore, INS1 cells treated with 10~20μM TDZD-8, a specific GSK3β inhibitor, also elicited cytoprotective responses against 0.25~0.5mM palmitate for 6~48h and decreased mRNA level of CHOP, but not ATF4 or XBP-1. The protein levels of CHOP, caspase-3 and GSK3β activity were remarkable reduced by co-treatment of INS1 cells with 0.25mM palmitate and 1mM VPA, compared with 0.25mM palmitate only. Finally, down-regulation of CHOP expression in INS1 cells by small interfering RNA (SiRNA) did not show apparent cytoprotective responses against 0.25mM palmitate.


ER stress and GSK3β involved in palmitate-induced β-cell apoptosis, however, GSK3β other than ER stress is likely playing a more prominent role. Valproate protected pancreatic β-cell from palmitate-induced apoptosis and ER stress by inhibiting GSK3β.

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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Huang, S., Wu, W., Liang, Y. et al. Chronic treatment with valproate protects INS1 cell from palmitate-induced ER stress and apoptosis by inhibiting GSK3β. Int J Pediatr Endocrinol 2013 (Suppl 1), O21 (2013).

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  • Endoplasmic Reticulum Stress
  • Valproate
  • Sodium Valproate
  • INS1 Cell
  • Cytoprotective Response