Low-grade chronic inflammation is a feature of Type 2 diabetes and appears to play a pathogenetic role in insulin resistance. It is well known that cytokines, besides their immunoregulatory roles, are important players in metabolism. Moreover, it has become evident that skeletal muscles express several cytokines, which belong to distinct cytokine classes. IL-6 (interleukin-6) is a pleiotropic cytokine produced by virtually all multinucleated cells including skeletal myocytes where it is produced in response to contraction. IL-6 is subsequently released into the circulation, where it works in a hormone-like fashion to induce lipolysis and fat oxidation. In more recent experiments, it has been shown that IL-6 infusion increases glucose disposal during a hyperinsulinaemic euglycaemic clamp in healthy humans. IL-6 treatment of myotubes increases fatty acid oxidation, basal and insulin-stimulated glucose uptake and translocation of GLUT4 to the plasma membrane. Furthermore, IL-6 rapidly and markedly increases AMPK (AMP-activated protein kinase) and the metabolic effects of IL-6 were abrogated in AMPK dominant negative-infected cells. Finally, IL-6 mediates anti-inflammatory effects by stimulating the production of anti-inflammatory cytokines and by suppressing TNFα (tumour necrosis factor α) production. We suggest that IL-6 and other muscle-derived cytokines (myokines) may play a role in defending Type 2 diabetes.
- adipose tissue
- insulin resistance
- skeletal muscle
Over the past decade, there has been an increasing focus on the role of inflammation in the pathogenesis of several chronic diseases. Low-grade chronic inflammation is reflected by a 2–3-fold increase in the systemic levels of some cytokines  as well as CRP (C-reactive protein), and several reports investigating various markers of inflammation have confirmed an association between low-grade systemic inflammation and Type 2 diabetes . Interestingly, regular physical activity offers protection against and may be useful as a treatment for a wide variety of chronic diseases associated with low-grade inflammation, including Type 2 diabetes . Recent findings demonstrate that physical activity induces an increase in the systemic levels of a number of cytokines with anti-inflammatory properties [4,5]. It has been suggested that IL-6 (interleukin-6) promotes insulin resistance due to the observation that plasma IL-6 is often elevated in patients with metabolic disease. However, it is now well established that IL-6 is rapidly released into the circulation following exercise  and it seems paradoxical that working muscle would release a factor that inhibits insulin signalling when insulin action is enhanced in the immediate post-exercise period . We have challenged the generally held view that IL-6 is primarily a pro-inflammatory cytokine based on recently conducted experiments both in vitro and, importantly, in humans in vivo [8–11].
Effects of IL-6 on glucose and lipid metabolism
While IL-6 appears to play a role in EGP (endogenous glucose production) during exercise in humans, its action on the liver is dependent on a yet unidentified muscle contraction-induced factor . In healthy humans under the basal condition, acute rhIL-6 (recombinant human IL-6) administration at physiological concentrations does not impair whole-body glucose disposal or net leg-glucose uptake, nor does it increase EGP [13–15]. In patients with Type 2 diabetes, rhIL-6 decreases circulating insulin, suggesting an insulin-sensitizing effect of IL-6 . To test this hypothesis, we recently demonstrated that IL-6 increased glucose infusion rate and glucose oxidation without affecting the suppression of EGP during a hyperinsulinaemic euglycaemic clamp in healthy humans . These results are in contrast with observations reported in mice . The finding of an insulin-sensitizing effect of IL-6 under conditions where EGP was completely suppressed underlines that in humans, the main effects of IL-6 with regard to glucose metabolism are likely to be in peripheral tissues (muscle and adipose), whereas IL-6 does not influence glucose output from the liver.
Infusion of rhIL-6 into healthy humans to obtain physiological concentrations of IL-6 caused an increase in lipolysis in the absence of hypertriglyceridaemia or changes in catecholamines, glucagon, insulin or any adverse effects in healthy individuals [14,15,18] and in patients with Type 2 diabetes . These findings together with cell culture experiments demonstrating that IL-6 alone increases both lipolysis and fat oxidation identify IL-6 as a novel lipolytic factor . Moreover, blocking IL-6 in clinical trials with patients with rheumatoid arthritis leads to enhanced cholesterol and plasma glucose levels, indicating that functional lack of IL-6 may lead to insulin resistance and an atherogenic lipid profile [19–21]. In accordance, IL-6-knockout mice develop late onset obesity and impaired glucose tolerance .
Mechanisms of action
IL-6 has a negative effect on hepatic insulin-sensitivity, when investigated in isolated hepatocytes and in mice in vivo. These findings may be of limited clinical relevance as in vivo studies in humans clearly demonstrate that neither splanchnic glucose output measured by arteriovenous balance across the hepatosplanchnic tissue nor isotopic tracer-determined EGP is increased by acute infusion of rhIL-6 [13–15]. In vitro, IL-6 either enhances [16,23] or does not enhance [24,25] glucose transport in adipocytes. The fact that IL-6 infusion increases subcutaneous adipose tissue glucose uptake in humans  argues against IL-6 as an insulin resistance-inducing agent in adipocytes. In addition, several studies reported that IL-6 increases intramyocellular or whole body fatty acid oxidation, which in turn is likely to decrease intramyocellular fatty acid accumulation, which may impair insulin signalling (reviewed in ). With regard to myocytes, IL-6 enhances insulin-stimulated glucose transport  and glycogen synthesis . IL-6 directly promotes skeletal-muscle differentiation of primary human skeletal-muscle cells and regulates muscle substrate utilization, promoting glycogen storage and lipid oxidation . When muscle strips were incubated with or without IL-6, it was found that acute IL-6 exposure increased glucose metabolism, whereas insulin-stimulated glucose transport and insulin signalling were unchanged after IL-6 exposure . When rat epitrochlearis and soleus muscles were incubated with various doses of IL-6, only high doses were able to increase glucose transport and insulin-sensitivity . In vivo experiments demonstrated that IL-6 increases basal and insulin-stimulated glucose uptake via an increased GLUT4 translocation .
In recent years, much attention has been given to the role of AMPK (AMP-activated protein kinase) as a potential therapeutic target for the treatment of obesity and Type 2 diabetes. There is now accumulating evidence to suggest a link between IL-6 and AMPK [30,31].
AMPK activation stimulates fatty acid oxidation and increases glucose uptake . IL-6 was shown to enhance AMPK in both skeletal muscle and adipose tissue  and, more recently, the effects of IL-6 on enhanced glucose uptake in skeletal myotubes were abolished in cells infected with an AMPK dominant-negative construct . Studies have shown that IL-6 can enhance lipid oxidation in vitro , ex vivo  and in vivo [15,18]. AMPK phosphorylates ACC (acetyl-CoA carboxylase) resulting in inhibition of ACC activity, which in turn leads to a decrease in malonyl-CoA content, relieving inhibition of CPT-1 (carnitine palmitoyltransferase-1) and increasing fatty acid oxidation . We showed recently that the IL-6-mediated phosphorylation of ACC and subsequent palmitate oxidation is AMPK-dependent . Together with recent findings regarding CNTF (ciliary neurotrophic factor), another member of the IL-6 cytokine family, which markedly enhances lipid oxidation via activation of AMPK , these results suggest that ligands that bind to the gp130 (glycoprotein 130) receptor complex may enhance glucose uptake and fat oxidation via activation of AMPK.
IL-6 has been shown to activate SOCS (suppressor of cytokine signalling) proteins in liver, leading to hepatic insulin resistance . IL-6 increased SOCS3 expression in myotubes, but concomitantly increased glucose uptake in these cells . While IL-6 increased SOCS3 2-fold in muscle, it was increased ∼25-fold in liver, suggesting that the capacity of IL-6 to induce SOCS3 is much greater in hepatic tissue . The possibility exists that the negative effects of IL-6 on SOCS3 may be overridden by the positive effects on AMPK.
The anti-inflammatory effects of IL-6
A couple of studies suggest that IL-6 may exert inhibitory effects on TNFα (tumour necrosis factor α) . IL-6 inhibits LPS (lipopolysaccharide)-induced TNFα production both in cultured human monocytes and in the human monocytic line U937. Furthermore, levels of TNFα are markedly elevated in anti-IL-6-treated mice and in IL-6-knockout mice, indicating that circulating IL-6 is involved in the regulation of TNFα levels. In addition, rhIL-6 infusion inhibits the endotoxin-induced increase in the circulating levels of TNFα in healthy humans. Direct evidence for a role of TNF in insulin resistance in humans has been obtained  and it is likely that muscle-derived IL-6 may offer protection against TNF-induced insulin resistance .
The anti-inflammatory effects of IL-6 are also demonstrated by the fact that IL-6 stimulates the production of IL-1ra (IL-1 receptor antagonist) and IL-10. IL-10 inhibits the production of IL-1α, IL-1β and TNFα as well as the production of chemokines, including IL-8 and MIPα (macrophage inflammatory protein α) from LPS-activated human monocytes. These cytokines and chemokines play a critical role in the activation of granulocytes, monocytes/macrophages and lymphocytes and in their recruitment to the sites of inflammation. The biological role of IL-1ra is to inhibit signalling transduction through the IL-1 receptor complex.
We have identified skeletal muscle as an endocrine organ and suggest that the long-term effect of exercise on the progression of chronic diseases associated with low-grade inflammation, such as Type 2 diabetes, may in part be mediated by muscle-derived IL-6 or other muscle-derived factors. In addition, we have suggested that cytokines and other peptides that are produced, expressed and released by muscle fibres and exert either paracrine or endocrine effects should be classified as ‘myokines’.
The Centre of Inflammation and Metabolism is supported by a grant from the Danish National Research Foundation (DG 02-512-555); the Copenhagen Muscle Research Centre is supported by grants from the University of Copenhagen, the Faculty of Science and the Faculty of Health Sciences at this university, and the Copenhagen Hospital Corporation. Support was further obtained from the Danish Medical Research Foundation and the Commission of the European Communities (contract no. LSHM-CT-2004-005272 EXGENESIS).
Exercise: A Focus Topic at Life Sciences 2007, held at SECC Glasgow, U.K., 9–12 July 2007. Edited by C. Downes (Dundee, U.K.), P. Greenhaff (Nottingham, U.K.) and P. Taylor (Dundee, U.K.).
Abbreviations: ACC, acetyl-CoA carboxylase; AMPK, AMP-activated protein kinase; EGP, endogenous glucose production; IL, interleukin; IL-1ra, IL-1 receptor antagonist; LPS, lipopolysaccharide; rhIL-6, recombinant human IL-6; SOCS, suppressor of cytokine signalling; TNFα, tumour necrosis factor α
- © The Authors Journal compilation © 2007 Biochemical Society