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

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.

journal_name

Nat Med

journal_title

Nature medicine

authors

Kiechl S,Wittmann J,Giaccari A,Knoflach M,Willeit P,Bozec A,Moschen AR,Muscogiuri G,Sorice GP,Kireva T,Summerer M,Wirtz S,Luther J,Mielenz D,Billmeier U,Egger G,Mayr A,Oberhollenzer F,Kronenberg F,Orthofer M,Penni

doi

10.1038/nm.3084

subject

Has Abstract

pub_date

2013-03-01 00:00:00

pages

358-63

issue

3

eissn

1078-8956

issn

1546-170X

pii

nm.3084

journal_volume

19

pub_type

杂志文章

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