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The microRNA-200 family regulates pancreatic beta cell survival in type 2 diabetes

Nature Medicine volume 21, pages 619–627 (2015)Cite this article

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Abstract

Pancreatic beta cell death is a hallmark of type 1 (T1D) and type 2 (T2D) diabetes, but the molecular mechanisms underlying this aspect of diabetic pathology are poorly understood. Here we report that expression of the microRNA (miR)-200 family is strongly induced in islets of diabetic mice and that beta cell–specific overexpression of miR-200 in mice is sufficient to induce beta cell apoptosis and lethal T2D. Conversely, mir-200 ablation in mice reduces beta cell apoptosis and ameliorates T2D. We show that miR-200 negatively regulates a conserved anti-apoptotic and stress-resistance network that includes the essential beta cell chaperone Dnajc3 (also known as p58IPK) and the caspase inhibitor Xiap. We also observed that mir-200 dosage positively controls activation of the tumor suppressor Trp53 and thereby creates a pro-apoptotic gene-expression signature found in islets of diabetic mice. Consequently, miR-200–induced T2D is suppressed by interfering with the signaling of Trp53 and Bax, a proapoptotic member of the B cell lymphoma 2 protein family. Our results reveal a crucial role for the miR-200 family in beta cell survival and the pathophysiology of diabetes.

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Figure 1: Overexpression of miR-200 causes beta cell death and diabetes.
Figure 2: Ablation of mir-200 protects against STZ-induced beta cell death and diabetes.
Figure 3: Ablation of mir-200 ameliorates beta cell death and diabetes in Akita (Ak) mice.
Figure 4: miR-200 downregulates expression of beta cell survival genes.
Figure 5: miR-200–mediated regulation of Trp53 activity.
Figure 6: miR-200–induced diabetes is dependent on Trp53 and Bax.

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Gene Expression Omnibus

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Acknowledgements

We wish to thank B. Kaps and R. Kubsch for excellent technical and animal husbandry assistance. We thank the Functional Genomics Center Zurich and the Light Microscopy and Screening Center Zurich for support, and N. Danial (Dana Farber Cancer Institute, Boston, USA), D. Hanahan (Swiss Institute for Experimental Cancer Research, Lausanne, Switzerland) and P. Herrera (University of Geneva, Switzerland) for sharing Bad−/−, Rip-Tag2 and Rip-Cre mice, respectively. This work was supported by European Molecular Biology Organization Long-Term Fellowships (to B.-F.B. and K.A.), the Austrian Genome Research Programme GEN-AU II and III (Austromouse) (to T.R.) and the European Genomic Institute for Diabetes (ANR-10-LABX-46 to F.P.) and in part sponsored by a Juvenile Diabetes Research Foundation (JDRF) Scholar award, European Research Council grant 'Metabolomirs', the Starr Foundation International and the Swiss National Science Foundation, and the National Center of Competence in Research on RNA Biology and Disease (all to M.S.). Human islets for research were provided thanks to the European Consortium for Islet Transplantation funded by the JDRF (31-2012-783 to F.P.).

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Author notes

  1. Ferdinand von Meyenn

    Present address: Present addresses: Babraham Institute, Cambridge, UK.,

  2. Mathieu Latreille: MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London, UK.

  3. Bengt-Frederik Belgardt, Kashan Ahmed and Martina Spranger: These authors contributed equally to this work.

  4. stoffel@biol.ethz.ch

Authors and Affiliations

  1. Institute of Molecular Health Sciences, Swiss Federal Institute of Technology, Zurich, Switzerland

    Bengt-Frederik Belgardt, Kashan Ahmed, Martina Spranger, Mathieu Latreille, Remy Denzler, Nadiia Kondratiuk, Ferdinand von Meyenn, Felipe Nunez Villena, Karolin Herrmanns & Markus Stoffel

  2. Competence Center for Systems Physiology and Metabolic Disease, Swiss Federal Institute of Technology, Zurich, Switzerland

    Bengt-Frederik Belgardt, Kashan Ahmed, Martina Spranger, Mathieu Latreille, Remy Denzler, Nadiia Kondratiuk, Ferdinand von Meyenn, Felipe Nunez Villena, Karolin Herrmanns & Markus Stoffel

  3. Department of Surgery, Cell Isolation and Transplantation Center, University Hospitals and University of Geneva, Geneva, Switzerland

    Domenico Bosco

  4. Université de Lille 2, INSERM, European Genomic Institute for Diabetes, Lille Cedex, France

    Julie Kerr-Conte & Francois Pattou

  5. Institute of Laboratory Animal Science, University of Veterinary Medicine Vienna, Vienna, Austria

    Thomas Rülicke

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Contributions

B.-F.B. and K.A. performed most of the experiments, analyzed and interpreted data and wrote the manuscript; K.A. generated conditional miR-200aflox/flox mice; M.S. generated Rip141/200c and mir-141/200c−/− animals and performed the initial characterizations; M.L. generated miR expression data in islets of obese mice; R.D. performed the bioinformatics analysis; N.K., F.v.M., F.N.V. and K.H. helped with some of the in vivo experiments and immunohistochemistry; D.B., J.K.-C. and F.P. obtained human islets and performed quality controls; T.R. performed pronuclei and blastocyst injections; M.S. analyzed and interpreted data, supervised the project and wrote the manuscript.

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M.S. is a member of the scientific advisory boards of Regulus Therapeutics and Alnylam Pharmaceuticals

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Belgardt, BF., Ahmed, K., Spranger, M. et al. The microRNA-200 family regulates pancreatic beta cell survival in type 2 diabetes. Nat Med 21, 619–627 (2015). https://doi.org/10.1038/nm.3862

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