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.

Trial registration: ClinicalTrials.gov NCT01452958.

Figures

FIG. 1.

Glucose a-v differences during infusion of TNF-α in one femoral artery and saline in the other femoral artery in healthy volunteers. Mean values from triplicate sampling at times 160, 170, and 180 min (basal) and 340, 350, and 360 min (clamp). *P value <0.05, placebo vs. TNF-α; #P value <0.05, basal vs. clamp.

FIG. 2.

Intramyocellular signaling during infusion of TNF-α in one femoral artery and saline in the other femoral artery in healthy volunteers. Muscle biopsies were obtained simultaneously from both lateral vastus muscles at t = 120 min (basal period) and t = 210 min (clamp). Phosphorylation of Akt Ser473 (A), AS160 (B), PDH site 1 (C) and 2 (D), AMPK (E), ACC (F), and mTOR (G); expression of GLUT1 (H) and GLUT4 (I). White bars, basal period; black bars, clamp. *P value <0.05, basal vs. clamp.