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  • Nicorandil attenuates high glucose-induced insulin resistance by suppressing oxidative stress-mediated ER stress PERK signaling pathway

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Signal transduction
Nicorandil attenuates high glucose-induced insulin resistance by suppressing oxidative stress-mediated ER stress PERK signaling pathway
  1. Zhongwei Liu1,
  2. Haitao Zhu2,
  3. Chunhui He3,
  4. Ting He3,
  5. Shuo Pan1,
  6. Na Zhao1,
  7. Ling Zhu1,
  8. Gongchang Guan1,
  9. Peng Liu1,
  10. Yong Zhang1,
  11. Junkui Wang1
  1. 1Department of Cardiology, Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, China
  2. 2Department of Pediatrics, Northwest Women’s and Children’s Hospital, Xi'an, China
  3. 3Department of Cardiology, Fuwai Hospital State Key Laboratory of Cardiovascular Disease, Beijing, China
  1. Correspondence to Dr Junkui Wang; junkuiwang{at}yeah.net; Dr Yong Zhang; zhangyong971292{at}163.com

Abstract

Introduction Glucose-induced insulin resistance is a typical character of diabetes. Nicorandil is now widely used in ischemic heart disease. Nicorandil shows protective effects against oxidative and endoplasmic reticulum (ER) stress, which are involved in insulin resistance. Here, we investigated mechanisms of nicorandil’s novel pharmacological activity on insulin resistance in diabetes.

Research design and methods Nicorandil was administrated to streptozotocin-induced animals with diabetes and high glucose exposed skeletal muscle cells. Insulin resistance and glucose tolerance were evaluated. Molecular mechanisms concerning oxidative stress, ER stress signaling activation and glucose uptake were assessed.

Results Nicorandil attenuated high glucose-induced insulin resistance without affecting fasting blood glucose and glucose tolerance in whole body and skeletal muscle in rats with diabetes. Nicorandil treatment suppressed protein kinase C/nicotinamide adenine dinucleotide phosphate oxidases system activities by reducing cytoplasmic free calcium level in skeletal muscle cells exposed to high glucose. As a result, the oxidative stress-mediated ER stress protein kinase RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2α/activating transcription factor 4/CEBP homologous protein/tribbles homolog (TRB)3 signaling pathway activation was inhibited. Nicorandil downregulated expression of TRB3 and thus facilitated Akt phosphorylation in response to insulin stimulation, leading to glucose transporter4 plasma membrane translocation which promoted glucose uptake capability of skeletal muscle cells.

Conclusions By reducing cytoplasmic calcium, nicorandil alleviated high glucose-induced insulin resistance by inhibiting oxidative stress-mediated ER stress PERK pathway.

  • diabetes complications
  • insulin resistance
  • endoplasmic reticulum

Data availability statement

Data are available on reasonable request.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/bmjdrc-2020-001884

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    Data availability statement

    Data are available on reasonable request.

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    Footnotes

    • Contributors ZL, PL and YZ designed the study, performed experiments, analyzed the data and wrote the manuscript. HZ accomplished the statistics. CH, TH, SP, LZ, NZ and GG participated in the experiments. JW reviewed, revised and edited the manuscript.

    • Funding This study was supported by Innovative Talents Promotion Project of Shaanxi Province (2019KJXX-019); Fundamental Scientific Research Foundation of Xi’an Jiaotong University (xzy012019131); Health Scientific Foundation of Shaanxi Province (2018E11); Natural Science Basic Research Foundation of Shaanxi Province (2020JQ-941).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.