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

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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 arterio-venous differences (0.91±0.17 mmol/l 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 were not affected by TNF-α, whereas 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.
Original languageEnglish
Publication statusPublished - 8 Jul 2013

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