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: Ermina Bach, Roni R Nielsen, Mikkel H Vendelbo, Andreas B Møller, Niels Jessen, Mads Buhl, Thomas K-Hafstrøm, Lars Holm, Steen B Pedersen, Henriette Pilegaard, Rasmus S Biensø, Jens O L Jørgensen, Niels Møller
• Journal: Diabetes (Diabetes) Vol. 62 Issue 12 Pg. 4023-9 (Dec 2013) ISSN: 1939-327X [Electronic] United States
• PMID: 23835341 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose
• Cytokines
• Insulin
• Interleukin-6
• Tumor Necrosis Factor-alpha

Topics

• Adult
• Blood Glucose (metabolism)
• Cytokines (blood)
• Energy Metabolism (drug effects)
• Femoral Artery (drug effects, metabolism)
• Glucose Clamp Technique
• Humans
• Insulin (metabolism)
• Insulin Resistance (physiology)
• Interleukin-6 (metabolism)
• Leg (blood supply)
• Male
• Muscle, Skeletal (drug effects, metabolism)
• Single-Blind Method
• Tumor Necrosis Factor-alpha (pharmacology)