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Excessive iron inhibits insulin secretion via perturbing transcriptional regulation of SYT7 by OGG1

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Abstract

Although iron overload is closely related to the occurrence of type 2 diabetes mellitus (T2DM), the specific mechanism is unclear. Here, we found that excessive iron inhibited the secretion of insulin (INS) and impaired islet β cell function through downregulating Synaptotagmin 7 (SYT7) in iron overload model in vivo and in vitro. Our results further demonstrated that 8-oxoguanine DNA glycosylase (OGG1), a key protein in the DNA base excision repair, was an upstream regulator of SYT7. Interestingly, such regulation could be suppressed by excessive iron. Ogg1-null mice, iron overload mice and db/db mice exhibit reduced INS secretion, weakened β cell function and subsequently impaired glucose tolerance. Notably, SYT7 overexpression could rescue these phenotypes. Our data revealed an intrinsic mechanism by which excessive iron inhibits INS secretion through perturbing the transcriptional regulation of SYT7 by OGG1, which suggested that SYT7 was a potential target in clinical therapy for T2DM.

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Acknowledgements

We thank the scholars for their selfless help in this research. Dr. Rufeng Xu, Dr. Yunxia Zhu, and Prof. Xiao Han from Nanjing Medical University instructed the intraductal virus infusion. Prof. Wei Yu and Huicong Zhou from Taikang Xianlin Drum Tower Hospital helped to detect serum Fe2+. Prof. Xueqing Ba from Northeast Normal University provided the OGG1 overexpression plasmid. Dr. Lei Lan and Prof. Long Chen from Nanjing Normal University provided ultra-thin sectioning equipment. Dr. Jian Liu from Nanjing Normal University provided assistance with the experimental method. Dr. Lili Gu from Nanjing Normal University for answering the clinical questions.

Funding

This work was supported by National Natural Science Foundation of China (81872284, 32171407) and Jiangsu Graduate Research and Practice Innovation Program (KYCX20-1187).

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Authors and Affiliations

  1. Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 WenYuan Road, Nanjing, 210023, China

    Xingqi Zhao, Ying Ma, Munan Shi, Miaoling Huang, Jingyu Xin, Zhigang Hu, Lingfeng He, Feiyan Pan & Zhigang Guo

  2. School of Basic Medical Sciences, Nanjing Medical University, Nanjing, 211166, Jiangsu, China

    Shusheng Ci

  3. Department of Endocrinology, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210000, Jiangsu, China

    Meimei Chen

  4. Department of Geriatrics, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210000, Jiangsu, China

    Tao Jiang

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  1. Xingqi Zhao
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Contributions

XZ and FP designed the study. XZ and YM obtained the data. MS, JX, SC and ZH contributed to and supervised the in vivo experimentation. MH and LH helped with the imaging analysis. MC and TJ provided support for the collection of outpatient cases. ZG provided funding support and support for communication with the administrative department. XZ drafted the manuscript. FP provided support for cooperation with the technology platform and manuscript revision. All authors reviewed and approved the manuscript. FP and ZG are the guarantors of this work and, as such, had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

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Correspondence to Feiyan Pan or Zhigang Guo.

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Zhao, X., Ma, Y., Shi, M. et al. Excessive iron inhibits insulin secretion via perturbing transcriptional regulation of SYT7 by OGG1. Cell. Mol. Life Sci. 80, 159 (2023). https://doi.org/10.1007/s00018-023-04802-y

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