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MicroRNA-203a regulates pancreatic β cell proliferation and apoptosis by targeting IRS2

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Abstract

The main pathogenesis of type 1 diabetes mellitus (T1DM) is autoimmune-mediated apoptosis of pancreatic islet β cells. We sought to characterize the function of microRNA-203a (miR-203a) on pancreatic islet β cell proliferation and apoptosis. In situ hybridization was used to detect the expression of miR-203a in islet β cells in normal and hyperglycaemic non-obese diabetic (NOD) mice. Cell proliferation was measured by cell counting kit eight and cell apoptosis was detected using flow cytometry. Insulin receptor substrate 2 (IRS2/Irs2) was determined to be a direct target of miR-203a by Luciferase reporter assay. We detected the effects of miR-203a overexpression or inhibition on proliferation and apoptosis of IRS2-overexpressing or IRS2-knockdown MIN6 cells respectively, and preliminarily explored the downstream targets of the IRS2 pathway. NOD mice model was used to detect miR-203a inhibitor treatment for diabetes. Our experiment showed miR-203a was upregulated in pancreatic β cells of hyperglycaemic NOD mice. Elevated miR-203a expression inhibited the proliferation and promoted the apoptosis of MIN6 cells. IRS2/Irs2 is a novel target gene directly regulated by miR-203a and miR-203a overexpression downregulated the expression of IRS2. Irs2 silencing reduced cell proliferation and increased apoptosis. Irs2 overexpression could abolish the pro-apoptotic and anti-proliferative effects of miR-203a on MIN6 cells. Hyperglycemia in newly hyperglycemic NOD mice was under control after treatment with miR-203a inhibitor. Our study suggests that miR-203a regulates pancreatic β cell proliferation and apoptosis by targeting IRS2, treatment with miR-203a inhibitors and IRS2 might provide a new therapeutic strategy for T1DM.

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Abbreviations

T1DM:

Type 1 diabetes mellitus

miR-203a:

MicroRNA-203a

NOD mice:

Non-obese diabetic mice

IRS2:

Insulin receptor substrate 2

mTOR:

Mammalian target of rapamycin

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Funding

This study was funded by the National Natural Science Youth Foundation of China (81402272, 81702797), the Hunan Provincial Natural Science Foundation of China (2018JJ3745,2018JJ2213) and the New **angya Talent Project Funding of the Third **angya Hospital of Central South University (JY201627).

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Author notes

  1. **anlan Duan, Lian Zhao, contributed equally to this work.

Authors and Affiliations

  1. Department of Metabolism and Endocrinology, The Second **angya Hospital, Central South University, Changsha, 410011, Hunan, China

    **anlan Duan, Qinxin **ao, Yani Peng, Gan Huang, **a Li, Haibo Yu & Zhiguang Zhou

  2. National Clinical Research Center for Metabolic Diseases, Changsha, 410011, Hunan, China

    **anlan Duan, Qinxin **ao, Yani Peng, Gan Huang, **a Li, Haibo Yu & Zhiguang Zhou

  3. Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, Changsha, 410011, Hunan, China

    **anlan Duan, Qinxin **ao, Yani Peng, Gan Huang, **a Li, Haibo Yu & Zhiguang Zhou

  4. Department of Gastroenterology, Central South University, The Third **angya Hospital, Changsha, 410013, Hunan, China

    Lian Zhao

  5. Department of Echocardiography, The Second **angya Hospital, Central South University, Changsha, 410011, Hunan, China

    Wancun **

  6. Department of Obstetrics and Gynecology, Center for Abnormal Placentation, Hackensack University Medical Center, Hackensack, NJ, USA

    Sonia DaSilva-Arnold

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  1. **anlan Duan
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  2. Lian Zhao
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  9. Haibo Yu
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  10. Zhiguang Zhou
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Corresponding author

Correspondence to Haibo Yu.

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This article does not contain any studies with human participants or animals performed by any of the authors. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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Duan, X., Zhao, L., **, W. et al. MicroRNA-203a regulates pancreatic β cell proliferation and apoptosis by targeting IRS2. Mol Biol Rep 47, 7557–7566 (2020). https://doi.org/10.1007/s11033-020-05818-4

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  • DOI: https://doi.org/10.1007/s11033-020-05818-4

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