Published Online
on October 6, 2003

A more recent version of this article appeared on October 14, 2003

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Submitted on October 14, 2002
Revised on May 28, 2003
Accepted on July 17, 2003

Tumor Necrosis Factor- Inhibits Insulin's Stimulating Effect on Glucose Uptake and Endothelium-Dependent Vasodilation in Humans

Christian Rask-Madsen MD, PhD^*, Helena Domínguez MD, Nikolaj Ihlemann MD, Thomas Hermann MD, Lars Køber MD, DSc, and Christian Torp-Pedersen MD, DSc

From Joslin Diabetes Center (C.R.-M.), Boston, Mass; Department of Cardiology Y (H.D., N.I., T.H. C.T.-P.), Bispebjerg University Hospital, Copenhagen, Denmark; and The Heart Center (L.K.), Rigshospitalet University Hospital, Copenhagen, Denmark.

^* To whom correspondence should be addressed. E-mail: christian.rask-madsen{at}joslin.harvard.edu.

Background--Inflammatory mechanisms could be involved in the pathogenesis of both insulin resistance and atherosclerosis. Therefore, we aimed at examining whether the proinflammatory cytokine tumor necrosis factor (TNF)- inhibits insulin-stimulated glucose uptake and insulin-stimulated endothelial function in humans.

Methods and Results--Healthy, lean male volunteers were studied. On each study day, 3 acetylcholine (ACh) or sodium nitroprusside (SNP) dose-response studies were performed by infusion into the brachial artery. Before and during the last 2 dose-response studies, insulin and/or TNF- were coinfused. During infusion of insulin alone for 20 minutes, forearm glucose uptake increased by 220±44%. This increase was completely inhibited during coinfusion of TNF- (started 10 min before insulin) with a more pronounced inhibition of glucose extraction than of blood flow. Furthermore, TNF- inhibited the ACh forearm blood flow response (P<0.001), and this inhibition was larger during insulin infusion (P=0.01) but not further increased by N^G-monomethyl-L-arginine acetate (P=0.2). Insulin potentiated the SNP response less than the ACh response and the effect of TNF- was smaller (P<0.001); TNF- had no effect on the SNP response without insulin infusion. Thus, TNF- inhibition of the combined response to insulin and ACh was likely mediated through inhibition of NO production.

Conclusion--These results support the concept that TNF- could play a role in the development of insulin resistance in humans, both in muscle and in vascular tissue.

Key words: tumor necrosis factor • insulin • acetylcholine • blood flow • endothelium-derived factors

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