Acute interleukin-6 administration does not impair muscle glucose uptake or whole-body glucose disposal in healthy humans

Abstract

Elevated plasma levels of the cytokines tumour necrosis factor-α and interleukin (IL)-6 have been consistently observed in patients with type 2 diabetes mellitus, and as a consequence both have been related to insulin resistance and/or impaired glucose disposal (for review see Hotamisligil, 1999; Febbraio & Pedersen, 2002). Research from our laboratory has focussed on the effect of muscle contraction on the IL-6 response (for review see Pedersen et al. 2001). We have demonstrated that contracting muscle releases IL-6, and that this release can account for much of the systemic increase in [IL-6] found in response to exercise (Steensberg et al. 2000), even though the brain (Nybo et al. 2002) and the peritendon (Langberg et al. 2002) can release small amounts of IL-6 during exercise. In addition, IL-6 mRNA is upregulated in contracting muscle (Keller et al. 2001; Starkie et al. 2001; Steensberg et al. 2001). Of note, IL-6 mRNA expression, the nuclear transcriptional rate of IL-6, and release of this protein from human skeletal muscle are enhanced when exercising with low intramuscular glycogen stores (Keller et al. 2001; Steensberg et al. 2001). In addition, Helge et al. (2002) recently demonstrated that IL-6 release was positively correlated with leg-glucose uptake during graded exercise. Thus, IL-6 appears to be upregulated in the muscle when the requirement for glucose uptake is augmented. Hence, rather than indicate that IL-6 impairs glucose uptake, our recent data suggest that IL-6 levels are augmented during periods of enhanced glucose uptake, although it must be noted that IL-6 release occurs after 60 min of exercise, whereas glucose uptake is increased at the onset of muscle contraction (Steensberg et al. 2001). Recently, Wallenius et al. (2002) demonstrated that IL-6-deficient mice developed markedly impaired glucose disposal, compared with littermate control mice during an intravenous glucose tolerance test. In addition, Stouthard et al. (1996) demonstrated that IL-6 enhanced both basal and insulin-stimulated glucose uptake in cultured 3T3-L1 adipocytes, while Hardin et al. (2000) observed increased glucose transport in jejunal tissue incubated with IL-6 compared with controls. The effect of acute IL-6 administration on whole-body glucose metabolism is unclear. Tsigos et al. (1997) demonstrated that recombinant human IL-6 (rhIL-6) administration to healthy volunteers increased circulating plasma glucose in a dose-dependent manner. Although these authors could not determine whether rhIL-6 resulted in increased glucose production or decreased glucose disposal, they speculated that IL-6 might have produced peripheral resistance to insulin action. This hypothesis is plausible given the fact that acute rhIL-6 infusion increases circulating free fatty acids (FFA; Lyngsoet al. 2002), which according to the classic glucose-fatty acid cycle can lead to impaired glucose disposal (Randle et al. 1963). In contrast, Stouthard et al. (1995) studied patients with metastatic renal cell cancer receiving rhIL-6 infusion, and observed an increase in glucose appearance and whole-body glucose disposal using the isotopic tracer dilution method. Importantly, however, in this study (Stouthard et al. 1995) all subjects experienced clinical symptoms, such as fever, and consequently increased their whole-body oxygen consumption (VO2). In addition, circulating levels of hormones such as glucagon, adrenaline (epinephrine) and noradrenaline (norepinephrine) were elevated. Therefore, the authors could not determine whether the enhanced glucose disposal was a direct effect of IL-6, whether skeletal muscle was the site of the enhanced disposal, or whether the response was characteristic of healthy humans. Hence, the aim of the present study was to investigate the role of acute IL-6 administration on whole-body glucose disposal and leg-glucose uptake in healthy humans by using the isotopic tracer dilution method and arterial- femoral venous (a-fv) differences across the legs. In order to determine whether any effect of IL-6 was direct, or secondary to changes in energy turnover and/or regulatory hormones, we chose to infuse both a low and a high dose of rhIL-6. The low dose elicited plasma concentrations of IL-6 comparable with the highest concentrations observed during prolonged strenuous exercise (Pedersen et al. 2001). We hypothesized that IL-6 infusion would increase glucose uptake by the muscle.