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

Ermina Bach; Bent Roni Ranghøj Nielsen; Mikkel Vendelbo; Andreas Buch Møller; Niels Jessen; Mads Buhl; Thomas Krusenstjerna- Hafstrøm; Lars Holm; Steen B. Pedersen; Henriette Pilegaard; Rasmus Sjørup Biensø; Jens Otto Lunde Jørgensen; Niels Møller

doi:10.2337/db13-0138

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

Ermina Bach, Bent Roni Ranghøj Nielsen, Mikkel Vendelbo, Andreas Buch Møller, Niels Jessen, Mads Buhl, Thomas Krusenstjerna- Hafstrøm, Lars Holm, Steen B. Pedersen, Henriette Pilegaard, Rasmus Sjørup Biensø, Jens Otto Lunde Jørgensen, Niels Møller

Molecular Integrative Physiology

31 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Diabetes
Volume	62
Issue number	12
Pages (from-to)	4023-4029
Number of pages	8
ISSN	0012-1797
DOIs	https://doi.org/10.2337/db13-0138
Publication status	Published - Dec 2013

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Bach, E., Nielsen, B. R. R., Vendelbo, M., Møller, A. B., Jessen, N., Buhl, M., Hafstrøm, T. K., Holm, L., Pedersen, S. B., Pilegaard, H., Biensø, R. S., Jørgensen, J. O. L., & Møller, N. (2013). 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. Diabetes, 62(12), 4023-4029. https://doi.org/10.2337/db13-0138

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. / Bach, Ermina; Nielsen, Bent Roni Ranghøj; Vendelbo, Mikkel et al.
In: Diabetes, Vol. 62, No. 12, 12.2013, p. 4023-4029.

Research output: Contribution to journal › Journal article › Research › peer-review

Bach, E, Nielsen, BRR, Vendelbo, M, Møller, AB, Jessen, N, Buhl, M, Hafstrøm, TK, Holm, L, Pedersen, SB, Pilegaard, H, Biensø, RS, Jørgensen, JOL & Møller, N 2013, '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', Diabetes, vol. 62, no. 12, pp. 4023-4029. https://doi.org/10.2337/db13-0138

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title = "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-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.",

author = "Ermina Bach and Nielsen, {Bent Roni Rangh{\o}j} and Mikkel Vendelbo and M{\o}ller, {Andreas Buch} and Niels Jessen and Mads Buhl and Hafstr{\o}m, {Thomas Krusenstjerna-} and Lars Holm and Pedersen, {Steen B.} and Henriette Pilegaard and Biens{\o}, {Rasmus Sj{\o}rup} and J{\o}rgensen, {Jens Otto Lunde} and Niels M{\o}ller",

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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

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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.

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