title: Direct effects of TNF-α on local fuel metabolism and cytokine levels in the placebo-controlled, bilaterally infused human leg: increased insulin sensitivity, increased net protein breakdown, and increased IL-6 release.
abstract: Tumor necrosis factor-α (TNF-α) has widespread metabolic actions. Systemic TNF-α administration, however, generates a complex hormonal and metabolic response. Our study was designed to test whether regional, placebo-controlled TNF-α infusion directly affects insulin resistance and protein breakdown. We studied eight healthy volunteers once with bilateral femoral vein and artery catheters during a 3-h basal period and a 3-h hyperinsulinemic-euglycemic clamp. One artery was perfused with saline and one with TNF-α. During the clamp, TNF-α perfusion increased glucose arteriovenous differences (0.91 ± 0.17 vs. 0.74 ± 0.15 mmol/L, P = 0.012) and leg glucose uptake rates. Net phenylalanine release was increased by TNF-α perfusion with concomitant increases in appearance and disappearance rates. Free fatty acid kinetics was not affected by TNF-α, whereas interleukin-6 (IL-6) release increased. Insulin and protein signaling in muscle biopsies was not affected by TNF-α. TNF-α directly increased net muscle protein loss, which may contribute to cachexia and general protein loss during severe illness. The finding of increased insulin sensitivity, which could relate to IL-6, is of major clinical interest and may concurrently act to provide adequate tissue fuel supply and contribute to the occurrence of systemic hypoglycemia. This distinct metabolic feature places TNF-α among the rare insulin mimetics of human origin.
authors.affiliation: Medical Research Laboratories, Institute for Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Ermina
authors.initials: E
authors.lastname: Bach
authors.forename: Roni R
authors.initials: RR
authors.lastname: Nielsen
authors.forename: Mikkel H
authors.initials: MH
authors.lastname: Vendelbo
authors.forename: Andreas B
authors.initials: AB
authors.lastname: Møller
authors.forename: Niels
authors.initials: N
authors.lastname: Jessen
authors.forename: Mads
authors.initials: M
authors.lastname: Buhl
authors.forename: Thomas
authors.initials: T
authors.lastname: K-Hafstrøm
authors.forename: Lars
authors.initials: L
authors.lastname: Holm
authors.forename: Steen B
authors.initials: SB
authors.lastname: Pedersen
authors.forename: Henriette
authors.initials: H
authors.lastname: Pilegaard
authors.forename: Rasmus S
authors.initials: RS
authors.lastname: Biensø
authors.forename: Jens O L
authors.initials: JO
authors.lastname: Jørgensen
authors.forename: Niels
authors.initials: N
authors.lastname: Møller
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D016207:Cytokines / Q000097:blood*; D004734:Energy Metabolism / Q000187:drug effects*; D005263:Femoral Artery / Q000187:drug effects / Q000378:metabolism; D015309:Glucose Clamp Technique; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D015850:Interleukin-6 / Q000378:metabolism*; D007866:Leg / Q000098:blood supply; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D016037:Single-Blind Method; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D016207:Cytokines; D007328:Insulin; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha