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

Andrea Giaccari, Giovanna Muscogiuri, Gianpio Sorice, Stefan Kiechl, Jürgen Wittmann, Michael Knoflach, Peter Willeit, Aline Bozec, Alexander R Moschen, Trayana Kireva, Monika Summerer, Stefan Wirtz, Julia Luther, Dirk Mielenz, Ulrike Billmeier, Georg Egger, Agnes Mayr, Friedrich Oberhollenzer, Florian Kronenberg, Michael OrthoferJosef M Penninger, James B Meigs, Enzo Bonora, Herbert Tilg, Johann Willeit, Georg Schett

Risultato della ricerca: Contributo in rivistaArticolo in rivistapeer review

138 Citazioni (Scopus)

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 liver. 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 understood. 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.
Lingua originaleEnglish
pagine (da-a)358-363
Numero di pagine6
RivistaNature Medicine
Volume19
DOI
Stato di pubblicazionePubblicato - 2013

Keywords

  • RANK
  • RANK-LINGAND
  • RANK-ligando
  • diabete mellito
  • diabetes
  • insulin resistance
  • insulino-resistenza

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