Abstract
Interleukin 6 (IL-6), a multifunctional cytokine, has been implicated in the pathophysiology of type 2 diabetes (T2D). The elevated circulating level of IL-6 is an independent predictor of T2D and is considered to be involved in the development of inflammation, insulin resistance and β-cell dysfunction. On the other hand, an increasing number of evidence suggests that IL-6 has an anti-inflammatory role and improves glucose metabolism. The complex signal transduction mechanism of IL-6 may help explain the pleiotropic nature of the cytokine. IL-6 acts via two distinct signalling pathways called classic signalling and trans-signalling. While both signalling modes lead to activation of the same receptor subunit, their final biological effects are completely different. The aim of this review is to summarize our current knowledge about the role of IL-6 in the development of T2D. We will also discuss the importance of specific blockade of IL-6 trans-signalling rather than inhibiting both signalling pathways as a therapeutic strategy for the treatment of T2D and its associated macrovascular complications.
Similar content being viewed by others
References
Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F (2007) Interleukins 1β and 6 but not transforming growth factor-β are essential for the differentiation of interleukin 17–producing human T helper cells. Nat Immunol 8:942–949
Afford SC, Pongracz J, Stockley RA, Crocker J, Burnett D (1992) The induction by human interleukin-6 of apoptosis in the promonocytic cell line U937 and human neutrophils. J Biol Chem 267:21612–21616
Al-Khalili L, Bouzakri K, Glund S, Lönnqvist F, Koistinen HA, Krook A (2006) Signaling specificity of interleukin-6 action on glucose and lipid metabolism in skeletal muscle. Mol Endocrinol 20:3364–3375
Andreozzi F et al (2007) Interleukin-6 impairs the insulin signaling pathway, promoting production of nitric oxide in human umbilical vein endothelial cells. Mol Cell Biol 27:2372–2383
Biffl WL, Moore EE, Moore FA, Barnett CC (1995) Interleukin-6 suppression of neutrophil apoptosis is neutrophil concentration dependent. J Leukoc Biol 58:582–584
Böni-Schnetzler M et al (2009) Free fatty acids induce a proinflammatory response in islets via the abundantly expressed interleukin-1 receptor I. Endocrinology 150:5218–5229
Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, Shoelson SE (2005) Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB. Nat Med 11:183–190
Carey AL et al (2006) Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase. Diabetes 55:2688–2697
Chawla A, Nguyen KD, Goh YS (2011) Macrophage-mediated inflammation in metabolic disease. Nat Rev Immunol 11:738–749
Chomarat P, Banchereau J, Davoust J, Palucka AK (2000) IL-6 switches the differentiation of monocytes from dendritic cells to macrophages. Nat Immunol 1:510–514
DeFuria J et al (2013) B cells promote inflammation in obesity and type 2 diabetes through regulation of T-cell function and an inflammatory cytokine profile. Proc Natl Acad Sci 110:5133–5138
Donath MY, Shoelson SE (2011) Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 11:98–107
Ehses JA et al (2007) Increased number of islet-associated macrophages in type 2 diabetes. Diabetes 56:2356–2370
Ellingsgaard H et al (2008) Interleukin-6 regulates pancreatic α-cell mass expansion. Proc Natl Acad Sci 105:13163–13168
Ellingsgaard H et al (2011) Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nat Med 17:1481–1489
Esser N, Legrand-Poels S, Piette J, Scheen AJ, Paquot N (2014) Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes Res Clin Pract 105:141–150
Fasshauer M, Kralisch S, Klier M, Lossner U, Bluher M, Klein J, Paschke R (2003) Adiponectin gene expression and secretion is inhibited by interleukin-6 in 3T3-L1 adipocytes. Biochem Biophys Res Commun 301:1045–1050
Feuerer M et al (2009) Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med 15:930–939
Fielding CA et al (2014) Interleukin-6 signaling drives fibrosis in unresolved inflammation. Immunity 40:40–50
Fischer M et al (1997) A bioactive designer cytokine for human hematopoietic progenitor cell expansion. Nat Biotechnol 15:142–145
Gallagher D et al (2009) Adipose tissue distribution is different in type 2 diabetes. Am J Clin Nutr 89:807–814
Glund S et al (2007) Interleukin-6 directly increases glucose metabolism in resting human skeletal muscle. Diabetes 56:1630–1637
Hegde S, Pahne J, Smola-Hess S (2004) Novel immunosuppressive properties of interleukin-6 in dendritic cells: inhibition of NF-κB binding activity and CCR7 expression. FASEB J 18:1439–1441
Hirano T et al (1985) Purification to homogeneity and characterization of human B-cell differentiation factor (BCDF or BSFp-2). Proc Natl Acad Sci USA 82(16):5490–5494
Hunter CA, Jones SA (2015) IL-6 as a keystone cytokine in health and disease. Nat Immunol 16:448–457
Illig T et al (2004) Significant association of the interleukin-6 gene polymorphisms C-174G and A-598G with type 2 diabetes. J Clin Endocrinol Metab 89:5053–5058
Jostock T et al (2001) Soluble gp130 is the natural inhibitor of soluble interleukin-6 receptor transsignaling responses. Eur J Biochem 268:160–167
Kado S, Nagase T, Nagata N (1999) Circulating levels of interleukin-6, its soluble receptor and interleukin-6/interleukin-6 receptor complexes in patients with type 2 diabetes mellitus. Acta Diabetol 36:67–72
Kamimura D, Ishihara K, Hirano T (2003) IL-6 signal transduction and its physiological roles: the signal orchestration model. Rev Physiol Biochem Pharmacol 149:1–38
Kim H-J et al (2004) Differential effects of interleukin-6 and -10 on skeletal muscle and liver insulin action in vivo. Diabetes 53:1060–1067
Kim J-H, Kim JE, Liu H-Y, Cao W, Chen J (2008) Regulation of interleukin-6-induced hepatic insulin resistance by mammalian target of rapamycin through the STAT3-SOCS3 pathway. J Biol Chem 283:708–715
Klouche M, Bhakdi S, Hemmes M, Rose-John S (1999) Novel path to activation of vascular smooth muscle cells: up-regulation of gp130 creates an autocrine activation loop by IL-6 and its soluble receptor. J Immunol 163:4583–4589
Klover PJ, Zimmers TA, Koniaris LG, Mooney RA (2003) Chronic exposure to interleukin-6 causes hepatic insulin resistance in mice. Diabetes 52:2784–2789
Kraakman MJ et al (2015) Blocking IL-6 trans-signaling prevents high-fat diet-induced adipose tissue macrophage recruitment but does not improve insulin resistance. Cell Metab 21:403–416
Lagathu C, Bastard J-P, Auclair M, Maachi M, Capeau J, Caron M (2003) Chronic interleukin-6 (IL-6) treatment increased IL-6 secretion and induced insulin resistance in adipocyte: prevention by rosiglitazone. Biochem Biophys Res Commun 311:372–379
Liu J et al (2009) Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice. Nat Med 15:940–945
Lust JA, Donovan KA, Kline MP, Greipp PR, Kyle RA, Maihle NJ (1992) Isolation of an mRNA encoding a soluble form of the human interleukin-6 receptor. Cytokine 4:96–100
Makki K, Froguel P, Wolowczuk I (2013) Adipose tissue in obesity-related inflammation and insulin resistance: cells, cytokines, and chemokines. ISRN Inflamm 2013:139239. https://doi.org/10.1155/2013/139239
Matthews V et al (2003) Cellular cholesterol depletion triggers shedding of the human interleukin-6 receptor by ADAM10 and ADAM17 (TACE). J Biol Chem 278:38829–38839
Matthews V et al (2010) Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance. Diabetologia 53:2431–2441
Mauer J et al (2014) Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin. Nat Immunol 15:423–430
Narazaki M et al (1993) Soluble forms of the interleukin-6 signal-transducing receptor component gp130 in human serum possessing a potential to inhibit signals through membrane-anchored gp130. Blood 82:1120–1126
Navarro-Gonzalez J, Mora-Fernandez C, Gomez-Chinchon M, Muros M, Herrera H, Garcia J (2010) Serum and gene expression profile of tumor necrosis factor-α and interleukin-6 in hypertensive diabetic patients: effect of amlodipine administration. Int J Immunopathol Pharmacol 23:51–59
Nieto-Vazquez I, Fernández-Veledo S, de Alvaro C, Lorenzo M (2008) Dual role of interleukin-6 in regulating insulin sensitivity in murine skeletal muscle. Diabetes 57:3211–3221
Nishimura S et al (2009) CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med 15:914–920
Ogata A et al (2010) Improvement of HbA1c during treatment with humanised anti-interleukin 6 receptor antibody, tocilizumab. Ann Rheum Dis 70(6):1164–1165
Pedersen BK, Febbraio MA (2007) Interleukin-6 does/does not have a beneficial role in insulin sensitivity and glucose homeostasis. J Appl Physiol 102:814–816
Pedersen BK, Febbraio MA (2008) Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol Rev 88(4):1379–1406
Pickup JC, Chusney GD, Thomas SM, Burt D (2000) Plasma interleukin-6, tumour necrosis factor α and blood cytokine production in type 2 diabetes. Life Sci 67:291–300
Romano M et al (1997) Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment. Immunity 6:315–325
Rose-John S (2012) IL-6 trans-signaling via the soluble IL-6 receptor: importance for the pro-inflammatory activities of IL-6. Int J Biol Sci 8(9):1237–1247
Rose-John S, Heinrich PC (1994) Soluble receptors for cytokines and growth factors: generation and biological function. Biochem J 300:281–290
Rose-John S, Winthrop K, Calabrese L (2017) The role of IL-6 in host defence against infections: immunobiology and clinical implications. Nat Rev Rheumatol 13(7):399–409
Rothaug M, Becker-Pauly C, Rose-John S (2016) The role of interleukin-6 signaling in nervous tissue. Biochim Biophys Acta 1863:1218–1227
Rotter Sopasakis V, Larsson B-M, Johansson A, Holmäng A, Smith U (2004) Short-term infusion of interleukin-6 does not induce insulin resistance in vivo or impair insulin signalling in rats. Diabetologia 47:1879–1887
Rotter V, Nagaev I, Smith U (2003) Interleukin-6 (IL-6) induces insulin resistance in 3T3-L1 adipocytes and is, like IL-8 and tumor necrosis factor-α, overexpressed in human fat cells from insulin-resistant subjects. J Biol Chem 278:45777–45784
Schaper F, Rose-John S (2015) Interleukin-6: biology, signaling and strategies of blockade. Cytokine Growth Factor Rev 26:475–487
Scheller J, Grotzinger J, Rose-John S (2006) Updating interleukin-6 classic-and trans-signaling. Signal Transduct 6:240–259
Schuett H et al (2012) Transsignaling of interleukin-6 crucially contributes to atherosclerosis in mice. Arterioscler Thromb Vasc Biol 32:281–290
Schultz O, Oberhauser F, Saech J, Rubbert-Roth A, Hahn M, Krone W, Laudes M (2010) Effects of inhibition of interleukin-6 signalling on insulin sensitivity and lipoprotein (a) levels in human subjects with rheumatoid diseases. PLoS ONE 5:e14328
Senn JJ, Klover PJ, Nowak IA, Mooney RA (2002) Interleukin-6 induces cellular insulin resistance in hepatocytes. Diabetes 51:3391–3399
Spindler MP et al (2016) Acute hyperglycemia impairs IL-6 expression in humans. Immun Inflamm Dis 4:91–97
Spranger J et al (2003) Inflammatory cytokines and the risk to develop type 2 diabetes. Diabetes 52:812–817
Steensberg A, Hall G, Osada T, Sacchetti M, Saltin B, Pedersen BK (2000) Production of interleukin-6 in contracting human skeletal muscles can account for the exercise-induced increase in plasma interleukin-6. J Physiol 529:237–242
Stouthard J, Elferink RO, Sauerwein H (1996) Interleukin-6 enhances glucose transport in 3T3-L1 adipocytes. Biochem Biophys Res Commun 220:241–245
Stumvoll M, Goldstein BJ, van Haeften TW (2005) Type 2 diabetes: principles of pathogenesis and therapy. Lancet 365:1333–1346
Taga T et al (1989) Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130. Cell 58:573–581
Takai Y, Wong G, Clark S, Burakoff S, Herrmann S (1988) B cell stimulatory factor-2 is involved in the differentiation of cytotoxic T lymphocytes. J Immunol 140:508–512
Tanaka T, Narazaki M, Kishimoto T (2012) Therapeutic targeting of the interleukin-6 receptor. Annu Rev Pharmacol Toxicol 52:199–219
Tanaka T, Narazaki M, Ogata A, Kishimoto T (2014) A new era for the treatment of inflammatory autoimmune diseases by interleukin-6 blockade strategy. Semin Immunol 26(1):88–96
Trujillo ME, Sullivan S, Harten I, Schneider SH, Greenberg AS, Fried SK (2004) Interleukin-6 regulates human adipose tissue lipid metabolism and leptin production in vitro. J Clin Endocrinol Metab 89:5577–5582
Tsiotra PC et al (2008) Peripheral mononuclear cell resistin mRNA expression is increased in type 2 diabetic women. Mediat Inflamm 2008:892864
Van Greevenbroek M, Schalkwijk C, Stehouwer C (2013) Obesity-associated low-grade inflammation in type 2 diabetes mellitus: causes and consequences. Neth J Med 71:174–187
Waetzig GH, Rose-John S (2012) Hitting a complex target: an update on interleukin-6 trans-signalling. Expert Opin Ther Targets 16:225–236
Wallenius V et al (2002) Interleukin-6-deficient mice develop mature-onset obesity. Nat Med 8:75–79
Weigert C et al (2006) Direct cross-talk of interleukin-6 and insulin signal transduction via insulin receptor substrate-1 in skeletal muscle cells. J Biol Chem 281:7060–7067
Winer S et al (2009) Normalization of obesity-associated insulin resistance through immunotherapy. Nat Med 15:921–929
Winer DA et al (2011) B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nat Med 17:610–617
Wright HL, Cross AL, Edwards SW, Moots RJ (2014) Effects of IL-6 and IL-6 blockade on neutrophil function in vitro and in vivo. Rheumatology 53:1321–1331
Wunderlich FT et al (2010) Interleukin-6 signaling in liver-parenchymal cells suppresses hepatic inflammation and improves systemic insulin action. Cell Metab 12:237–249
Acknowledgements
This work was supported by the Iran National Science Foundation with the Award Number 94000647.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Akbari, M., Hassan-Zadeh, V. IL-6 signalling pathways and the development of type 2 diabetes. Inflammopharmacol 26, 685–698 (2018). https://doi.org/10.1007/s10787-018-0458-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10787-018-0458-0