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Rotenone protects against β-cell apoptosis and attenuates type 1 diabetes mellitus

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Abstract

Type 1 diabetes mellitus (T1DM) is caused by pancreatic β-cell dysfunction and apoptosis, with consequent severe insulin deficiency. Thus, β-cell protection may be a primary target in the treatment of T1DM. Evidence has demonstrated that defective mitochondrial function plays an important role in pancreatic β-cell dysfunction and apoptosis; however, the fundamental effect of mitochondrial complex I action on β-cells and T1DM remains unclear. In the current study, the pancreas protective effect of complex I inhibitor rotenone (ROT) and its potential mechanism were assessed in a streptozotocin (STZ)-induced mouse model of T1DM and in cultured mouse pancreatic β-cell line, Min6. ROT treatment exerted a hypoglycemic effect, restored the insulin level, and decreased inflammation and cell apoptosis in the pancreas. In vitro experiments also showed that ROT decreased STZ- and inflammatory cytokines-induced β-cell apoptosis. These protective effects were accompanied by attenuation of reactive oxygen species, increased mitochondrial membrane potential, and upregulation of transcriptional coactivator PPARα coactivator 1α (PGC-1α)-controlled mitochondrial biogenesis. These findings suggest that mitochondrial complex I inhibition may represent a promising strategy for β-cell protection in T1DM.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation (Nos. 81800599, 81830020, 81873599, 81600352, 81670678, 81530023), the Natural Science Foundation of Jiangsu Province (No. BK20180145), the China Postdoctoral Science Foundation (No. 2018M632342) and Nanjing City Key Medical Research Project (No. ZKX18039).

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Authors and Affiliations

  1. Department of Nephrology, Children’s Hospital of Nanjing Medical University, Guangzhou Road #72, Gulou District, Nanjing, 210008, China

    Mengqiu Wu, Weiyi Chen, Shengnan Zhang, Songming Huang, Aihua Zhang, Yue Zhang & Zhanjun Jia

  2. Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Hanzhong Road #140, Gulou District, Nanjing, 210029, China

    Mengqiu Wu, Weiyi Chen, Shengnan Zhang, Songming Huang, Aihua Zhang, Yue Zhang & Zhanjun Jia

  3. Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical University, Gulou District, Guangzhou Road #72, Nanjing, 210008, China

    Mengqiu Wu, Weiyi Chen, Shengnan Zhang, Songming Huang, Aihua Zhang, Yue Zhang & Zhanjun Jia

  4. State Key Laboratory of Kidney Diseases, Fuxing Road #28, Haidian District, Beijing, 100853, China

    Mengqiu Wu

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  1. Mengqiu Wu
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Contributions

Z.J., Y. Z., S.H., and A.Z coordinated and oversaw the study. M.W., W.C., and S.Z. performed the experiments, collected the samples, and analyzed the data. M.W., Y. Z., and Z.J. wrote the manuscript.

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Correspondence to Yue Zhang or Zhanjun Jia.

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All animal experiments are in accordance with International Guidelines and Protocols and approved by the Nanjing Medical University Institutional Animal Care and Use Committee.

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Wu, M., Chen, W., Zhang, S. et al. Rotenone protects against β-cell apoptosis and attenuates type 1 diabetes mellitus. Apoptosis 24, 879–891 (2019). https://doi.org/10.1007/s10495-019-01566-4

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