Bach, Ermina2; Nielsen, Bent Roni Ranghøj3; Vendelbo, Mikkel4; Møller, Andreas Buch5; Jessen, Niels6; Buhl, Mads7; Hafstrøm, Thomas Krusenstjerna-8; Holm, Lars9; Pedersen, Steen B.10; Pilegaard, Henriette13; Biensø, Rasmus Sjørup14; Jørgensen, Jens Otto Lunde4; Møller, Niels12
1 Molecular Integrative Physiology, Department of Biology, Faculty of Science, Københavns Universitet2 Institut for Klinisk Medicin - Medicinsk Endokrinologisk afdeling MEA, NBG3 Hjertemedicinsk Afdeling B, SKS4 Institut for Klinisk Medicin - Medicinsk Endokrinologisk Afd., MEA, NBG5 Institut for Klinisk Medicin6 Molekylær medicinsk afdeling (MOMA)7 Institut for Klinisk Medicin - Børneafdeling A, SKS8 Medicinsk Endokrinologisk Afd., MEA, NBG9 Center of Healthy Aging, Faculty of Health and Medical Sciences10 Institut for Klinisk Medicin - Medicinsk Endokrinologisk Afd., MEA, THG11 Cell Biology and Physiology, Department of Biology, Faculty of Science, Københavns Universitet12 Institut for Klinisk Medicin - Medicinsk Forskningslaboratorium13 Cell Biology and Physiology, Department of Biology, Faculty of Science, Københavns Universitet14 Molecular Integrative Physiology, Department of Biology, Faculty of Science, Københavns Universitet
increased insulin sensitivity, increased net protein breakdown and increased IL-6 release
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.