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Blockade of receptor activator of nuclear factor-κB (RANKL) signaling improves hepatic insulin resistance and prevents development of diabetes mellitus

Nature Medicine volume 19, pages 358–363 (2013)Cite this article

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Abstract

Hepatic insulin resistance is a driving force in the pathogenesis of type 2 diabetes mellitus (T2DM) and is tightly coupled with excessive storage of fat and the ensuing inflammation within the liver1,2,3. There is compelling evidence that activation of the transcription factor nuclear factor-κB (NF-κB) and downstream inflammatory signaling pathways systemically and in the liver are key events in the etiology of hepatic insulin resistance and β-cell dysfunction, although the molecular mechanisms involved are incompletely understood3,4,5,6. We here test the hypothesis that receptor activator of NF-κB ligand (RANKL), a prototypic activator of NF-κB, contributes to this process using both an epidemiological and experimental approach. In the prospective population-based Bruneck Study, a high serum concentration of soluble RANKL emerged as a significant (P < 0.001) and independent risk predictor of T2DM manifestation. In close agreement, systemic or hepatic blockage of RANKL signaling in genetic and nutritional mouse models of T2DM resulted in a marked improvement of hepatic insulin sensitivity and amelioration or even normalization of plasma glucose concentrations and glucose tolerance. Overall, this study provides evidence for a role of RANKL signaling in the pathogenesis of T2DM. If so, translation to the clinic may be feasible given current pharmacological strategies to lower RANKL activity to treat osteoporosis.

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Figure 1: Effect of inhibition of RANKL signaling on fasting glucose concentration and insulin resistance in mouse diabetes models.
Figure 2: Effects of inhibition of Rank on hepatic glucose production, insulin signaling and NF-κB activation.
Figure 3: Effects of RANKL-stimulated hepatocytes on Kupffer cell activation.

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Acknowledgements

This study was supported by the Deutsche Forschungsgemeinschaft (SPP1468-IMMUNOBONE to G.S.), the Bundesministerium für Bildung und Forschung (Bundesministerium für Bildung und Forschung project ANCYLOSS to G.S.), the European Union (Masterswitch to G.S.), the Innovative Medicines Initiative funded project BTCure (to G.S.), the National Institute of Diabetes and Digestive and Kidney Diseases (K24 DK080140 to J.B.M.), the Genomics of Lipid-associated Disorders of the Austrian Genome Research Programme GEN-AU (to F.K.), the 'Pustertaler Verein zur Prävention von Herz- und Hirngefässerkrankungen', the 'Gesundheitsbetrieb Bruneck' and the 'Assessorat für Gesundheitswesen, Familie und Soziales, Bolzano'. G.M. is recipient of the Umberto Di Mario Prize by the Società Italiana di Diabetologia 2011. A.G. was supported by grants from Fondazione Don Gnocchi, Università Cattolica del Sacro Cuore (Fondi Ateneo Linea D.3.2 Sindrome Metabolica) and the Italian Ministry of Education, University and Research (PRIN 2010JS3PMZ_011). A.M. and H.T. were supported by the Christian Doppler Research Society. E.B. is recipient of grants from the Italian Ministry of Education, University and Research and the University of Verona. J.M.P. holds an advanced European Research Council grant and is supported by the Austrian Academy of Sciences, a Grant by the National Bank Foundation and Era of Hope/US Department of Defense. We thank B. Enrich for technical support.

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Author notes

  1. Stefan Kiechl and Georg Schett: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Medical University Innsbruck, Innsbruck, Austria

    Stefan Kiechl, Michael Knoflach, Peter Willeit & Johann Willeit

  2. Department of Internal Medicine 3, Division of Molecular Immunology, University of Erlangen-Nuremberg, Erlangen, Germany

    Jürgen Wittmann & Dirk Mielenz

  3. Division of Endocrinology and Metabolic Diseases, Università Cattolica del Sacro Cuore, Policlinico 'A. Gemelli', Rome, Italy

    Andrea Giaccari, Giovanna Muscogiuri & Gian Pio Sorice

  4. Fondazione Don Gnocchi, Milan, Italy

    Andrea Giaccari

  5. Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK

    Peter Willeit

  6. Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany

    Aline Bozec, Trayana Kireva, Julia Luther & Georg Schett

  7. Department of Medicine I, Division of Endocrinology, Gastroenterology and Metabolism, Medical University Innsbruck, Innsbruck, Austria

    Alexander R Moschen & Herbert Tilg

  8. Department of Medical Genetics, Division of Genetic Epidemiology, Molecular and Clinical Pharmacology, Medical University Innsbruck, Innsbruck, Austria

    Monika Summerer & Florian Kronenberg

  9. Department of Internal Medicine I, University of Erlangen-Nuremberg, Erlangen, Germany

    Stefan Wirtz & Ulrike Billmeier

  10. Department of Internal Medicine, Bruneck Hospital, Bruneck, Italy

    Georg Egger & Friedrich Oberhollenzer

  11. Department of Laboratory Medicine, Bruneck Hospital, Bruneck, Italy

    Agnes Mayr

  12. Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria

    Michael Orthofer & Josef M Penninger

  13. Department of Internal Medicine, Harvard University, Boston, Massachusetts, USA

    James B Meigs

  14. Department of Medicine, General Medicine Division, Massachusetts General Hospital, Boston, Massachusetts, USA

    James B Meigs

  15. Division of Endocrinology, Diabetes and Metabolic Diseases, University and Hospital Trust of Verona, Verona, Italy

    Enzo Bonora

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  1. Stefan Kiechl
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Contributions

S.K., G.S. and J. Willeit had the idea for this research, took responsibility for the epidemiological and experimental design of this work and wrote the manuscript. G.S. designed all analyses for the experiments. S.K. and P.W. performed all analyses of the epidemiological portion of the study and were supported by M.K. J. Willeit is the principle investigator of the Bruneck Study. J. Wittman, A.G., A.B., A.R.M., G.M., G.P.S., T.K., S.W., J.L., D.M., U.B. and H.T. performed the in vitro and in vivo experimental analysis. A.G., G.M. and G.P.S. performed the animal clamp studies and contributed to the interpretation of the data. G.E., A.M. and F.O. participated in data collection, laboratory analyses, fund raising and conception of the Bruneck Study. M.S. and F.K. performed genetic analyses and contributed to the interpretation of these data. E.B. contributed to researching data. E.B. and J.B.M. gave their advice regarding study design and analysis. J.M.P. and M.O. conducted the experiments involving Msk-Rank and Rip-Rank mice. E.B., J.B.M., H.T., A.G., J.M.P. and all other authors made a critical revision of the final manuscript.

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Correspondence to Stefan Kiechl or Georg Schett.

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J.M.P. has received funding from Amgen.

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Kiechl, S., Wittmann, J., Giaccari, A. et al. Blockade of receptor activator of nuclear factor-κB (RANKL) signaling improves hepatic insulin resistance and prevents development of diabetes mellitus. Nat Med 19, 358–363 (2013). https://doi.org/10.1038/nm.3084

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