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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

journal contribution
posted on 2023-05-17, 01:38 authored by Yuen, DYC, Renee RossRenee Ross, Matthews, VB, Lejun ZhangLejun Zhang, Drew, BG, Neill, B, Kingwell, BA, Michael ClarkMichael Clark, Stephen RattiganStephen Rattigan, Febbraio, MA
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

History

Publication title

Diabetes

Volume

58

Issue

May

Pagination

1086-1095

ISSN

0012-1797

Department/School

Tasmanian School of Medicine

Publisher

Amer Diabetes Assoc

Place of publication

1701 N Beauregard St, Alexandria, USA, Va, 22311-1717

Rights statement

© 2009 by the American Diabetes Association.

Repository Status

  • Restricted

Socio-economic Objectives

Clinical health not elsewhere classified

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