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|16||Direct effects of TNF-alpha 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.|
Bach E; Nielsen RR; Vendelbo MH; Moller AB; Jessen N; Buhl M; K-Hafstrom T; Holm L; Pedersen SB; Pilegaard H; Bienso RS; Jorgensen JO; Moller N
Diabetes 2013; 62(12): 4023-9
PubMed ID: 23835341
Tumor necrosis factor-alpha (TNF-alpha) has widespread metabolic actions. Systemic TNF-alpha administration, however, generates a complex hormonal and metabolic response. Our study was designed to test whether regional, placebo-controlled TNF-alpha 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-alpha. During the clamp, TNF-alpha 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-alpha perfusion with concomitant increases in appearance and disappearance rates. Free fatty acid kinetics was not affected by TNF-alpha, whereas interleukin-6 (IL-6) release increased. Insulin and protein signaling in muscle biopsies was not affected by TNF-alpha. TNF-alpha 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-alpha among the rare insulin mimetics of human origin. Bach, Ermina