Journal
DIABETES
Volume 58, Issue 5, Pages 1086-1095Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db08-0775
Keywords
-
Categories
Funding
- National Health and Medical Research Council of Australia (NHMRC) [342115]
- Baker Heart Research Institute Early Career Scientist Grant
Ask authors/readers for more resources
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 (Ser(1177)), and NO production and reduced phosphorylation of AMPK in HAEC in vitro and capillary recruitment in vivo. In contrast, IL-6 increased Akt phosphorylation (Ser(473)) 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)-alpha protein expression in HAECs without any effect on TNF-alpha in skeletal muscle. When HAECs were incubated with a TNF-alpha-neutralizing antibody, the negative effects of 11,6 on eNOS signaling were abolished. CONCLUSIONS-In the presence of insulin, IL-6 contributes to aberrant endothelial cell signaling because of increased TNF-alpha expression. Diabetes 58:1086-1095, 2009
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available