title: 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.
authors: Department of Neurology, Medical University Innsbruck, Innsbruck, Austria. stefan.kiechl@i-med.ac.at
authors: Stefan
authors: S
authors: Kiechl
authors: Jürgen
authors: J
authors: Wittmann
authors: Andrea
authors: A
authors: Giaccari
authors: Michael
authors: M
authors: Knoflach
authors: Peter
authors: P
authors: Willeit
authors: Aline
authors: A
authors: Bozec
authors: Alexander R
authors: AR
authors: Moschen
authors: Giovanna
authors: G
authors: Muscogiuri
authors: Gian Pio
authors: GP
authors: Sorice
authors: Trayana
authors: T
authors: Kireva
authors: Monika
authors: M
authors: Summerer
authors: Stefan
authors: S
authors: Wirtz
authors: Julia
authors: J
authors: Luther
authors: Dirk
authors: D
authors: Mielenz
authors: Ulrike
authors: U
authors: Billmeier
authors: Georg
authors: G
authors: Egger
authors: Agnes
authors: A
authors: Mayr
authors: Friedrich
authors: F
authors: Oberhollenzer
authors: Florian
authors: F
authors: Kronenberg
authors: Michael
authors: M
authors: Orthofer
authors: Josef M
authors: JM
authors: Penninger
authors: James B
authors: JB
authors: Meigs
authors: Enzo
authors: E
authors: Bonora
authors: Herbert
authors: H
authors: Tilg
authors: Johann
authors: J
authors: Willeit
authors: Georg
authors: G
authors: Schett
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000517:prevention & control*; D004789:Enzyme Activation; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D011446:Prospective Studies; D053245:RANK Ligand / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D053245:RANK Ligand
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