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

Research output: Contribution to journalArticlepeer-review

Authors

  • E. Bach
  • Roni R. Nielsen
  • M Vendelbo
  • Andreas Buch Møller
  • N Jessen
  • M Buhl
  • Thomas Krusenstjerna- Hafstrøm
  • Steen Bønløkke Pedersen
  • H Pilegaard
  • Rasmus S Biensøe
  • Jens O L Jørgensen
  • N Møller

Colleges, School and Institutes

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.

Details

Original languageEnglish
Pages (from-to)4023-4029
Number of pages7
JournalDiabetes
Volume62
Issue number12
Publication statusPublished - Dec 2013

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