title: Tumor necrosis factor-alpha 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)-alpha inhibits insulin-stimulated glucose uptake and insulin-stimulated endothelial function in humans.
  
  
  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 NG-monomethyl-L-arginine acetate (P=0.2). Insulin potentiated the SNP response less than the ACh response and the effect of TNF-alpha 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Joslin Diabetes Center, Section on Vascular Cell Biology and Complications, One Joslin Place, Room 4504, Boston, Mass 02215, USA. christian.rask-madsen@joslin.harvard.edu
authors.forename: Christian
authors.initials: C
authors.lastname: Rask-Madsen
authors.forename: Helena
authors.initials: H
authors.lastname: Domínguez
authors.forename: Nikolaj
authors.initials: N
authors.lastname: Ihlemann
authors.forename: Thomas
authors.initials: T
authors.lastname: Hermann
authors.forename: Lars
authors.initials: L
authors.lastname: Køber
authors.forename: Christian
authors.initials: C
authors.lastname: Torp-Pedersen
mesh_terms: D000109:Acetylcholine / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000328:Adult; D001161:Arteriosclerosis / Q000209:etiology* / Q000503:physiopathology; D001783:Blood Flow Velocity / Q000187:drug effects; D001916:Brachial Artery; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects*; D005542:Forearm / Q000098:blood supply; D005947:Glucose / Q000493:pharmacokinetics*; D006801:Humans; D007249:Inflammation / Q000150:complications* / Q000503:physiopathology; D007261:Infusions, Intra-Arterial; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology*; D007329:Insulin Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis; D009599:Nitroprusside / Q000009:adverse effects / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D007328:Insulin; D007329:Insulin Antagonists; D014409:Tumor Necrosis Factor-alpha; D009599:Nitroprusside; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D005947:Glucose; D000109:Acetylcholine