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

被引：249

作者：

Kiechl, Stefan ^{[1
]}

Wittmann, Juergen ^{[2
]}

Giaccari, Andrea ^{[3
,4
]}

Knoflach, Michael ^{[1
]}

Willeit, Peter ^{[1
,5
]}

Bozec, Aline ^{[6
]}

Moschen, Alexander R. ^{[7
]}

Muscogiuri, Giovanna ^{[3
]}

Sorice, Gian Pio ^{[3
]}

Kireva, Trayana ^{[6
]}

Summerer, Monika ^{[8
]}

Wirtz, Stefan ^{[9
]}

Luther, Julia ^{[6
]}

Mielenz, Dirk ^{[2
]}

Billmeier, Ulrike ^{[9
]}

Egger, Georg ^{[10
]}

Mayr, Agnes ^{[11
]}

Oberhollenzer, Friedrich ^{[10
]}

Kronenberg, Florian ^{[8
]}

Orthofer, Michael ^{[12
]}

Penninger, Josef M. ^{[12
]}

Meigs, James B. ^{[13
,14
]}

Bonora, Enzo ^{[15
]}

Tilg, Herbert ^{[7
]}

Willeit, Johann ^{[1
]}

Schett, Georg ^{[6
]}

机构：

[1] Med Univ Innsbruck, Dept Neurol, A-6020 Innsbruck, Austria

[2] Univ Erlangen Nurnberg, Dept Internal Med 3, Div Mol Immunol, D-91054 Erlangen, Germany

[3] Univ Cattolica Sacro Cuore, Div Endocrinol & Metab Dis, Policlin A Gemelli, Rome, Italy

[4] Fdn Don C Gnocchi, Milan, Italy

[5] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England

[6] Univ Erlangen Nurnberg, Dept Internal Med 3, D-91054 Erlangen, Germany

[7] Med Univ Innsbruck, Div Endocrinol Gastroenterol & Metab, Dept Med 1, A-6020 Innsbruck, Austria

[8] Med Univ Innsbruck, Div Genet Epidemiol Mol & Clin Pharmacol, Dept Med Genet, A-6020 Innsbruck, Austria

[9] Univ Erlangen Nurnberg, Dept Internal Med 1, D-91054 Erlangen, Germany

[10] Bruneck Hosp, Dept Internal Med, Brunico, Italy

[11] Bruneck Hosp, Dept Lab Med, Brunico, Italy

[12] Austrian Acad Sci, IMBA, Inst Mol Biotechnol, A-1010 Vienna, Austria

[13] Harvard Univ, Dept Internal Med, Boston, MA 02115 USA

[14] Massachusetts Gen Hosp, Dept Med, Div Gen Med, Boston, MA 02114 USA

[15] Univ & Hosp Trust Verona, Div Endocrinol Diabet & Metab Dis, Verona, Italy

来源：

NATURE MEDICINE | 2013年 / 19卷 / 03期

基金：

欧洲研究理事会;

关键词：

CARDIOVASCULAR-DISEASE; IKK-BETA; OSTEOPROTEGERIN; RISK; LIGAND; OBESITY; LIVER; INFLAMMATION; OSTEOBLASTS; METABOLISM;

D O I：

10.1038/nm.3084

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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(1-3). There is compelling evidence that activation of the transcription factor nuclear factor-kappa B (NF-kappa B) and downstream inflammatory signaling pathways systemically and in the liver are key events in the etiology of hepatic insulin resistance and p-cell dysfunction, although the molecular mechanisms involved are incompletely understood(3-6). We here test the hypothesis that receptor activator of NE-kappa B ligand (RANKL), a prototypic activator of NF-kappa B, 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.

引用

页码：358 / 363

页数：6

共 40 条

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A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function [J].