Tumor necrosis factor-α inhibits insulin's stimulating effect on glucose uptake and endothelium-dependent vasodilation in humans

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