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

  1. Niels Møller1,2
  1. 1Medical Research Laboratories, Institute for Clinical Medicine, Aarhus University, Aarhus, Denmark
  2. 2Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
  3. 3Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
  4. 4Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark
  5. 5Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark
  6. 6Institute of Sports Medicine and Department of Orthopedic Surgery M, Bispebjerg Hospital, and Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  7. 7Department of Biology, University of Copenhagen, Copenhagen, Denmark
  1. Corresponding author: Niels Møller, nielsem{at}


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.

  • Received January 25, 2013.
  • Accepted June 24, 2013.

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  1. Diabetes vol. 62 no. 12 4023-4029
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