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CXXC4 mediates glucose-induced β-cell proliferation

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Abstract

Aims

CXXC finger protein 4 (CXXC4) is an identified negative regulator of the Wnt/β-catenin pathway, and it is involved in cancer cell proliferation. In this study, we sought to clarify whether CXXC4 is involved in glucose-stimulated β-cell proliferation.

Materials and methods

We investigated the biological function of CXXC4 in glucose-induced β-cell proliferation, and we investigated the underlying mechanism of this activity. First, we analyzed CXXC4 expression in established rat models treated for 24 h with a high glucose infusion and in INS-1 cells and primary rat islets treated with different concentrations of glucose. Subsequently, we used an adenovirus to overexpress CXXC4 in INS-1 cells and primary islets. The proliferation rate of β-cells was evaluated by CCK-8 and EdU incorporation methods. Cell cycle analysis was performed by flow cytometry. Finally, the Wnt signaling pathway and its downstream genes were assessed by Western blot.

Results

CXXC4 mRNA levels were significantly lower in islets isolated from glucose-infused rats than they were in those isolated from saline-infused rats. Decreased expression of CXXC4 also correlated with high glucose treatment of INS-1 cells and primary rat β-cells. Furthermore, adenovirus-mediated overexpression of CXXC4 inhibited cell proliferation induced by the high glucose treatment in vitro, which was mechanistically mediated by Wnt signaling and a decrease in cyclin D2 expression.

Conclusions

Glucose inhibits CXXC4 expression and hence promotes pancreatic β-cell proliferation. Our findings may provide a new potential target for the treatment of diabetes.

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Acknowledgements

We thank Dr. Hongli Zhang (No. 7 Hospital, Shanghai) and Dr. Wenyi Li (Ruijin Hospital, Shanghai) for their excellent technical assistance. This work was supported by the Natural Science Foundation of Fujian (2017Y9047, 2016J01547) and the Foundation of Fujian Provincial Health Commission (2018ZQN32).

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  1. Binbin Guan and Zhidong Zhan contributed equally to this work.

Authors and Affiliations

  1. Department of Endocrinology, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, 350001, Fujian, China

    Binbin Guan, Zhidong Zhan, Lijing Wang, Linxi Wang & Libin Liu

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  1. Binbin Guan
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  2. Zhidong Zhan
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  3. Lijing Wang
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  4. Linxi Wang
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Contributions

B G and Z Z were responsible for the collection of data, data assembly, data analysis, interpretation, and manuscript writing. LX W and LJ W were responsible for data collection and contributed to the discussion. B G and L L were responsible for the conception, manuscript revision, and financial support. All authors have read and approved the final version of the manuscript.

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Correspondence to Binbin Guan.

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The authors have no financial conflicts of interest.

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All procedures were performed in accordance with the principles of the Guide for the Care and Use of Experimental Animals of Fujian Medical University and were approved by the Animal Care Committee at Fujian Medical University.

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Guan, B., Zhan, Z., Wang, L. et al. CXXC4 mediates glucose-induced β-cell proliferation. Acta Diabetol 57, 1101–1109 (2020). https://doi.org/10.1007/s00592-020-01525-5

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