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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.
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: | Biomedical and Clinical Sciences |
| Research Group: | Cardiovascular medicine and haematology |
| Research Field: | Cardiology (incl. cardiovascular diseases) |
| Objective Division: | Health |
| Objective Group: | Clinical health |
| Objective Field: | Clinical health not elsewhere classified |
| UTAS Author: | Dwyer, RM (Dr Renee Ross) |
| UTAS Author: | Zhang, L (Dr Lejun Zhang) |
| UTAS Author: | Clark, MG (Professor Michael Clark) |
| UTAS Author: | Rattigan, S (Professor Stephen Rattigan) |
| ID Code: | 61323 |
| Year Published: | 2009 |
| Web of Science® Times Cited: | 36 |
| Deposited By: | School of Medicine |
| Deposited On: | 2010-03-02 |
| Last Modified: | 2010-03-30 |
| Downloads: | 0 |
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