Exendin‑4 protects INS‑1 cells against palmitate‑induced apoptosis through the IRE1α‑Xbp1 signaling pathway

Jiang,Dongdong; Wan,Fang

doi:10.3892/etm.2018.6240

Exendin‑4 protects INS‑1 cells against palmitate‑induced apoptosis through the IRE1α‑Xbp1 signaling pathway

Authors:
- Dongdong Jiang
- Fang Wan
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Affiliations: Department of Endocrinology and Metabolism, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, P.R. China, Department of Orthopedic Sports Medicine, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
Published online on: May 30, 2018 https://doi.org/10.3892/etm.2018.6240
Pages: 1029-1035

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Abstract

The anti-apoptotic effect of the incretin analog, exendin-4 (EX-4) on pancreatic β cells is mediated via the activation of protein kinase B (Akt) signaling, and its effect is partly produced through the inhibition of endoplasmic reticulum (ER) stress. However, the molecular mechanisms that underlie the effect of EX‑4 on the suppression of ER stress and the upregulation of Akt signaling are poorly understood. Inositol‑requiring enzyme 1 (IRE1), a member of the ER‑localized transmembrane protein family, activates its downstream transcription factor X‑box binding protein 1 (XBP1) to mediate a key part of the cellular unfolded protein response in order to cope with ER stress. Using the clonal rat pancreatic β cell line INS‑1, the present study produced an in vitro model of ER stress using palmitate (PA) in order to determine whether the beneficial effect of EX‑4 under ER stress was regulated by the IRE1α‑Xbp1 signaling pathway. The results demonstrated that the reduction in ER stress and the activation Akt by EX‑4 may be associated with the upregulation of IRE1α phosphorylation and the splicing of Xbp1 mRNA, which improved PA‑reduced cell viability. This effect was partially abrogated by the knockdown of IRE1α with small interfering RNA. Additionally, cellular IRE1α was phosphorylated by the protein kinase A (PKA) associated with EX‑4 and the activation of IRE1α, as IRE1α phosphorylation was attenuated by the inhibition of PKA with its inhibitor. In conclusion, the data identified the IRE1α‑Xbp1 signaling pathway as an essential mediator that associates EX‑4 with the intracellular mechanism that inhibits ER stress and activates Akt in order to regulate β cell survival. This may provide important evidence for the use of EX‑4 in treatments for type 2 diabetes.

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