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

Abstract

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)-α 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-α 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-α (started 10 min before insulin) with a more pronounced inhibition of glucose extraction than of blood flow. Furthermore, TNF-α 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-α was smaller ( P <0.001); TNF-α had no effect on the SNP response without insulin infusion. Thus, TNF-α 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-α could play a role in the development of insulin resistance in humans, both in muscle and in vascular tissue.