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

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.