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

TY - JOUR

T1 - Direct effects of TNF-α on local fuel metabolism and cytokine levels in the placebo controlled bilaterally infused human leg

T2 - increased insulin sensitivity, increased net protein breakdown and increased IL-6 release

AU - Bach, Ermina

AU - Nielsen, Bent Roni Ranghøj

AU - Vendelbo, Mikkel

AU - Møller, Andreas Buch

AU - Jessen, Niels

AU - Buhl, Mads

AU - Hafstrøm, Thomas Krusenstjerna-

AU - Holm, Lars

AU - Pedersen, Steen B.

AU - Pilegaard, Henriette

AU - Biensø, Rasmus Sjørup

AU - Jørgensen, Jens Otto Lunde

AU - Møller, Niels

PY - 2013/12

Y1 - 2013/12

N2 - Tumor necrosis factor-a (TNF-a) has widespread metabolic actions. Systemic TNF-a administration, however, generates a complex hormonal and metabolic response. Our study was designed to test whether regional, placebo-controlled TNF-a 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-a. During the clamp, TNF-a perfusion increased glucose arteriovenous differences (0.91 6 0.17 vs. 0.74 6 0.15 mmol/L, P = 0.012) and leg glucose uptake rates. Net phenylalanine release was increased by TNF-a perfusion with concomitant increases in appearance and disappearance rates. Free fatty acid kinetics was not affected by TNF-a, whereas interleukin-6 (IL-6) release increased. Insulin and protein signaling in muscle biopsies was not affected by TNF-a. TNF-a 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-a among the rare insulin mimetics of human origin.

AB - Tumor necrosis factor-a (TNF-a) has widespread metabolic actions. Systemic TNF-a administration, however, generates a complex hormonal and metabolic response. Our study was designed to test whether regional, placebo-controlled TNF-a 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-a. During the clamp, TNF-a perfusion increased glucose arteriovenous differences (0.91 6 0.17 vs. 0.74 6 0.15 mmol/L, P = 0.012) and leg glucose uptake rates. Net phenylalanine release was increased by TNF-a perfusion with concomitant increases in appearance and disappearance rates. Free fatty acid kinetics was not affected by TNF-a, whereas interleukin-6 (IL-6) release increased. Insulin and protein signaling in muscle biopsies was not affected by TNF-a. TNF-a 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-a among the rare insulin mimetics of human origin.

U2 - 10.2337/db13-0138

DO - 10.2337/db13-0138

M3 - Journal article

C2 - 23835341

SN - 0012-1797

VL - 62

SP - 4023

EP - 4029

JO - Diabetes

JF - Diabetes

IS - 12

ER -