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Decreased Sirt3 contributes to cyclic production of reactive oxygen species and islet β-cell apoptosis in high glucose conditions

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Abstract

Background

Reactive oxygen species (ROS) plays a vital role in the apoptosis of islet β-cells in type 2 diabetes mellitus (T2DM). Sirt3 (Sirtuin 3, a deacetylase) and FoxO1 (a transcription factor) might be involved in ROS production. This study was to investigate mechanism of ROS production and β-cell apoptosis in T2DM.

Methods

Oxidative stress and apoptosis in islets of db/db mice and high glucose cultured β-cells were observed by terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay and western blotting. Then, H2O2 was used to ascertain the effect of ROS on the expression of Sirt3. Meanwhile, FoxO1, antioxidant enzymes – catalase (CAT) and manganese superoxide dismutase (MnSOD) and β-cell apoptosis were also determined by western blotting. Finally, Sirt3 was knocked down to evaluate the effect on oxidative stress and apoptosis of β-cells.

Results

Under high glucose environment, enhanced ROS made a decrease of Sirt3 expression, which increased acetylation of FoxO1, thus reduced the expression of its target proteins –MnSOD and CAT, and further significantly increased ROS levels. Increased ROS finally led to the apoptosis of β-cells.

Conclusion

Down-regulation of Sirt3 plays an important role in the cyclic production of ROS and β-cell apoptosis. Targeting Sirt3 may be favorable for the treatment of T2DM.

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Abbreviations

Catalase:

CAT

Forkhead Box O1:

FoxO1

hydrogen peroxide:

H2O2

high glucose:

HG

manganese superoxide dismutase:

MnSOD

middle glucose:

MG

normal glucose:

NG

Reactive oxygen species:

ROS

Sirtuin 3:

Sirt3

type 2 diabetes mellitus:

T2DM

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Funding

This study was funded by the National Natural Science Foundation of China (Grant No. 81903681); the Xuzhou Science and Technology Program, China (Grant No. KC19029); the Director Project of Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy (Grant No. ZR-XY201502).

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Author notes

  1. Zhichen Cai, Shuqing Liu and Yaxing Nie these authors contributed equally to this work.

Authors and Affiliations

  1. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China

    Zhichen Cai, Shuqing Liu, Yaxing Nie, Chenglin Li, Jinyuan Zhang, Chunya Xia, Lei Du, Xiaoxing Yin & Jianyun Wang

  2. Department of Urology, Xuzhou Central Hospital, The Affiliated School of Clinical Medicine, Xuzhou Medical University, Xuzhou, 221009, Jiangsu, China

    Bingzheng Dong

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  1. Zhichen Cai
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Contributions

CZ drafted the manuscript; LS and NY performed the in vitro experiments; DB participated the in vivo experiments; ZJ and XC performed immunofluorescence staining and imaging; LC provided some technical assistance; DL bought the agents; YX contributed to the interpretation of the data; WJ revised manuscript critically. All authors agreed with this submitted version.

Corresponding author

Correspondence to Jianyun Wang.

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Conflict of interest

The authors have not disclosed any competing interests.

Ethical approval

The animal study was reviewed and approved by Xuzhou Medical University on December 18, 2018 (approval number 201812W008).

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Cai, Z., Liu, S., Nie, Y. et al. Decreased Sirt3 contributes to cyclic production of reactive oxygen species and islet β-cell apoptosis in high glucose conditions. Mol Biol Rep 49, 10479–10488 (2022). https://doi.org/10.1007/s11033-022-07916-x

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  • DOI: https://doi.org/10.1007/s11033-022-07916-x

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