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Thioredoxin-interacting protein regulates insulin transcription through microRNA-204

Nature Medicine volume 19, pages 1141–1146 (2013)Cite this article

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Abstract

Beta-cell dysfunction and impaired insulin production are hallmarks of diabetes1, but despite the growing diabetes epidemic, the molecular mechanisms underlying this disease have remained unclear. We identified thioredoxin-interacting protein (TXNIP), a cellular redox regulator, as a crucial factor in beta-cell biology and show that beta-cell TXNIP is upregulated in diabetes, whereas TXNIP deficiency protects against diabetes by preventing beta-cell apoptosis2,3. Here we show that TXNIP and diabetes induce beta-cell expression of a specific microRNA, miR-204, which in turn blocks insulin production by directly targeting and downregulating MAFA, a known insulin transcription factor. In particular, we first discovered the regulation of miR-204 by TXNIP by microarray analysis, followed by validation studies in INS-1 beta cells, islets of Txnip-deficient mice, diabetic mouse models and primary human islets. We then further found that TXNIP induces miR-204 by inhibiting the activity of signal transducer and activator of transcription 3 (STAT3), a transcription factor that is involved in miR-204 regulation4,5. We also identified MAFA as a target that is downregulated by miR-204. Taken together, our results demonstrate that TXNIP controls microRNA expression and insulin production and that miR-204 is involved in beta-cell function. The newly identified TXNIP–miR-204–MAFA–insulin pathway may contribute to diabetes progression and provides new insight into TXNIP function and microRNA biology in health and disease.

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Figure 1: The effects of TXNIP and diabetes on beta-cell miR-204 expression.
Figure 2: The effects of miR-204 on insulin production.
Figure 3: MAFA as a target of miR-204.
Figure 4: The effects of TXNIP on MAFA and insulin production.

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Acknowledgements

This work was supported by grants to A.S. from the US National Institutes of Health (R01DK-078752), the American Diabetes Association (7-12-BS-167) and the Juvenile Diabetes Research Foundation and JNJSI (40-2011-1). A-ZIP/F mice were a generous gift of C. Vinson, US National Institutes of Health.

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Authors and Affiliations

  1. Department of Medicine, Division of Endocrinology, Comprehensive Diabetes Center, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, Alabama, USA

    Guanlan Xu, Junqin Chen, Gu Jing & Anath Shalev

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  1. Guanlan Xu
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  2. Junqin Chen
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  3. Gu Jing
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  4. Anath Shalev
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Contributions

G.X. designed, performed and analyzed the experiments and helped prepare the manuscript. J.C. was responsible for the mouse studies and islet isolations. G.J. performed most of the cloning and helped with some of the experiments. A.S. conceived the project, supervised the work and wrote the manuscript.

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Correspondence to Anath Shalev.

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The authors declare no competing financial interests.

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Xu, G., Chen, J., Jing, G. et al. Thioredoxin-interacting protein regulates insulin transcription through microRNA-204. Nat Med 19, 1141–1146 (2013). https://doi.org/10.1038/nm.3287

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