Local effects of cytokine TNF-alpha on glucose, lipid and protein metabolism in the placebo controlled bilaterally perfused human leg
E. Bosnjak, M. Buhl, R. Nielsen, T. Hafstrøm, M. Vandelbo, E. Tønnesen & N. Møller
Introduction: Cytokine TNF-alpha has widespread metabolic actions, including induction of insulin resistance, lipolysis and cachexia. Systemic TNF-alpha administration, however, generates complex hormonal and metabolic scenario. No studies employing regional, placebo controlled TNF-alpha infusion exist. Our study was designed to test the hypothesis that local leg perfusion with TNF-alpha directly induces insulin resistance, lipolysis and protein breakdown.
Methods: We studied eight healthy volunteers with bilateral femoral vein and artery catheters during 3-h basal period and 3-h insulin stimulation (hyperinsulinemic euglycemic clamp). One femoral artery was perfused with saline and the other with TNF-alpha (Beromun, Boehringer-Ingelheim, 6 ng/kg/h). Amino acid metabolism was quantified with 15N-Phenylalanine tracer, lipid metabolism with 3H-Palmitate tracer and arterio-venous differences of free fatty acids and glucose metabolism was quantified by arterio-venous differences.
Results: TNF-alpha perfusion significantly increased local leg glucose uptake during the clamp. Basal glucose arterio-venous difference was unaltered, but substantially increased during the clamp (P<0.001), with 0.925±0.49 mmol/1 in the TNF-alpha leg, and 0.744±0.43 mmol/1 in the placebo leg.
Net phenylalanine release was increased by TNF-alpha perfusion (P=0.023). During the basal period there was an increased phenylalanine release (P=0.003), with 4466±1390 μg/min in the TNF-alpha leg, and 3794±1122 μg/min in the placebo leg, and an increased phenylalanine uptake (P=0.023) with 2951±1134 μg/min in the TNF-alpha leg, and 2464±708 μg/min in the placebo leg.
Free fatty acids and palmitate kinetics were not affected by TNF-alpha.
Conclusion: TNF-alpha directly increased muscle protein breakdown and local muscle insulin sensitivity in terms of increased muscle glucose uptake. The finding of increased muscle loss may contribute to general protein loss during severe illness. The finding of increased insulin sensitivity is unexpected and highlights the necessity of differentiation between direct local cytokine effects as in this study and those secondary to release of stress cascades including hormones such as epinephrine, glucagon and cortisol.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This work was supported, however funding details unavailable.