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Interleukin-6 attenuates insulin-mediated increases in endothelial cell signaling but augments skeletal muscle insulin action via differential effects on tumor necrosis factor-á expression

Citation

Yuen, DYC and Dwyer, RM and Matthews, VB and Zhang, L and Drew, BG and Neill, B and Kingwell, BA and Clark, MG and Rattigan, S and Febbraio, MA, Interleukin-6 attenuates insulin-mediated increases in endothelial cell signaling but augments skeletal muscle insulin action via differential effects on tumor necrosis factor-a expression, Diabetes, 58, (May) pp. 1086-1095. ISSN 0012-1797 (2009) [Refereed Article]


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Copyright Statement

© 2009 by the American Diabetes Association.

DOI: doi:10.2337/db08-0775

Abstract

OBJECTIVE—The cytokine interleukin-6 (IL-6) stimulates AMP-activated protein kinase (AMPK) and insulin signaling in skeletal muscle, both of which result in the activation of endothelial nitric oxide synthase (eNOS). We hypothesized that IL-6 promotes endothelial cell signaling and capillary recruitment in vivo, contributing to increased glucose uptake. RESEARCH DESIGN AND METHODS—The effect of IL-6 with and without insulin on AMPK, insulin, and eNOS signaling in and nitric oxide (NO) release from human aortic endothelial cells (HAECs) was examined. The physiological significance of these in vitro signaling events was assessed by measuring capillary recruitment in rats during control and euglycemic-hyperinsulinemic clamps with or without IL-6 infusion. RESULTS—IL-6 blunted increases in insulin signaling, eNOS phosphorylation (Ser1177), and NO production and reduced phosphorylation of AMPK in HAEC in vitro and capillary recruitment in vivo. In contrast, IL-6 increased Akt phosphorylation (Ser473) in hindlimb skeletal muscle and enhanced whole-body glucose disappearance and glucose uptake during the clamp. The differences in endothelial cell and skeletal muscle signaling were mediated by the cell-specific, additive effects of IL-6 and insulin because this treatment markedly increased tumor necrosis factor (TNF)- protein expression in HAECs without any effect on TNF- in skeletal muscle. When HAECs were incubated with a TNF-–neutralizing antibody, the negative effects of IL-6 on eNOS signaling were abolished. CONCLUSIONS—In the presence of insulin, IL-6 contributes to aberrant endothelial cell signaling because of increased TNF- expression. Diabetes 58:1086–1095, 2009

Item Details

Item Type:Refereed Article
Research Division:Medical and Health Sciences
Research Group:Cardiorespiratory Medicine and Haematology
Research Field:Cardiology (incl. Cardiovascular Diseases)
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Diabetes
Author:Dwyer, RM (Dr Renee Dwyer)
Author:Zhang, L (Mr Lejun Zhang)
Author:Clark, MG (Professor Michael Clark)
Author:Rattigan, S (Professor Stephen Rattigan)
ID Code:61323
Year Published:2009
Web of Science® Times Cited:32
Deposited By:Medicine
Deposited On:2010-03-02
Last Modified:2010-03-30
Downloads:0

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