Tumor necrosis factor-alpha 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.


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.
Rask-Madsen
Christian
C
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
Domínguez
Helena
H
Ihlemann
Nikolaj
N
Hermann
Thomas
T
Køber
Lars
L
Torp-Pedersen
Christian
C
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
D007328:Insulin; D007329:Insulin Antagonists; D014409:Tumor Necrosis Factor-alpha; D009599:Nitroprusside; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D005947:Glucose; D000109:Acetylcholine