Advertisement

The role of interleukin-6 in glucose homeostasis and lipid metabolism

  • Louise Lang LehrskovEmail author
  • Regitse Højgaard Christensen
Review

Abstract

Low-grade inflammation is recognized as an important factor in the development and progression of a multitude of diseases including type 2 diabetes mellitus and cardiovascular disease. The potential of using antibody-based therapies that neutralize key players of low-grade inflammation has gained scientific momentum as a novel therapeutic strategy in metabolic diseases. As interleukin-6 (IL-6) is traditionally considered a key pro-inflammatory factor, the potential of expanding the use of anti-IL-6 therapies to metabolic diseases is intriguing. However, IL-6 is a molecule of a very pleiotropic nature that regulates many aspects of not only inflammation but also metabolism. In this review, we give a brief overview of the pro- and anti-inflammatory aspects of IL-6 and provide an update on its role in metabolic regulation, with a specific focus on glucose homeostasis and adipose tissue metabolism. Finally, we shall discuss the metabolic implications and clinical potential of blocking IL-6 signaling, focusing on glucose homeostasis and lipid metabolism.

Notes

Acknowledgments

We are grateful to Helga Ellingsgaard for providing us the opportunity to write this review. The Centre for Physical Activity Research (CFAS) is supported by a grant from TrygFonden.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

References

  1. 1.
    Pedersen BK (2009) The diseasome of physical inactivity--and the role of myokines in muscle--fat cross talk. J Physiol 587:5559–5568CrossRefGoogle Scholar
  2. 2.
    Pedersen BK, Akerström TCA, Nielsen AR, Fischer CP (2007) Role of myokines in exercise and metabolism. J Appl Physiol 103:1093–1098CrossRefGoogle Scholar
  3. 3.
    Pedersen BK (2019) Physical activity and muscle–brain crosstalk. Nat Rev Endocrinol.  https://doi.org/10.1038/s41574-019-0174-x
  4. 4.
    Kamimura D, Ishihara K, Hirano T (2003) IL-6 signal transduction and its physiological roles: the signal orchestration model. Rev Physiol Biochem Pharmacol 149:1–38Google Scholar
  5. 5.
    Mohamed-Ali V, Goodrick S, Rawesh A, Katz DR, Miles JM, Yudkin JS, Klein S, Coppack SW (1997) Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-α, in vivo. J Clin Endocrinol Metab 82:4196–4200Google Scholar
  6. 6.
    De Rossi M, Bernasconi P, Baggi F, de Waal Malefyt R, Mantegazza R (2000) Cytokines and chemokines are both expressed by human myoblasts: possible relevance for the immune pathogenesis of muscle inflammation. Int Immunol 12:1329–1335CrossRefGoogle Scholar
  7. 7.
    Pedersen BK, Febbraio MA (2008) Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol Rev 88:1379–1406CrossRefGoogle Scholar
  8. 8.
    Hojman P, Brolin C, Nørgaard-Christensen N, Dethlefsen C, Lauenborg B, Olsen CK, Åbom MM, Krag TO, Gehl J, Pedersen BK (2019) IL-6 release from muscles during exercise is stimulated by lactate-dependent protease activity. Am J Physiol Endocrinol Metab 19.  https://doi.org/10.1152/ajpendo.00414.2018
  9. 9.
    Rose-John S (2012) IL-6 trans-signaling via the soluble IL-6 receptor: importance for the proinflammatory activities of IL-6. Int J Biol Sci 8:1237–1247CrossRefGoogle Scholar
  10. 10.
    Rose-John S, Heinrich PC (1994) Soluble receptors for cytokines and growth factors: generation and biological function. Biochem J 300:281–290CrossRefGoogle Scholar
  11. 11.
    Hibi M, Murakami M, Saito M, Hirano T, Taga T, Kishimoto T (1990) Molecular cloning and expression of an IL-6 signal transducer, gp130. Cell 63:1149–1157CrossRefGoogle Scholar
  12. 12.
    Heinrich PC, Behrmann I, Haan S, Hermanns HM, Uller-newen GM (2003) Principles of IL 6 type cytokine signaling and its regulating. Biochem J 20:1–20CrossRefGoogle Scholar
  13. 13.
    Yang L, Wang L, Lin HK, Kan PY, Xie S, Tsai MY, Wang PH, Chen YT, Chang C (2003) Interleukin-6 differentially regulates androgen receptor transactivation via PI3K-Akt, STAT3, and MAPK, three distinct signal pathways in prostate cancer cells. Biochem Biophys Res Commun 305:462–469CrossRefGoogle Scholar
  14. 14.
    Zhong Z, Wen Z, Darnell JE (1994) Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6 author. Science. 264:95–98CrossRefGoogle Scholar
  15. 15.
    Barton BE (1997) IL-6: insights into novel biological activities. Clin Immunol Immunopathol 85:16–20CrossRefGoogle Scholar
  16. 16.
    Damas P et al (1992) Cytokine serum level during severe sepsis in human IL-6 as a marker of severity. Ann Surg 215:356–362CrossRefGoogle Scholar
  17. 17.
    Libermann TA, Baltimore D (1990) Activation of interleukin-6 gene expression through the NF-kappa B transcription factor. Mol Cell Biol 10:2327–2334CrossRefGoogle Scholar
  18. 18.
    Zhang YH, Lin JX, Vilcek J (1990) Interleukin-6 induction by tumor necrosis factor and interleukin-1 in human fibroblasts involves activation of a nuclear factor binding to a kappa B-like sequence. Mol Cell Biol 10:3818–3823CrossRefGoogle Scholar
  19. 19.
    Shimizu H, Mitomo K, Watanabe T, Okamoto S, Yamamoto K (1990) Involvement of a NF-kappa B-like transcription factor in the activation of the interleukin-6 gene by inflammatory lymphokines. Mol Cell Biol 10:561–568CrossRefGoogle Scholar
  20. 20.
    Benatti FB, Pedersen BK (2015) Exercise as an anti-inflammatory therapy for rheumatic diseases - myokine regulation. Nat Rev Rheumatol 11:86–97CrossRefGoogle Scholar
  21. 21.
    Unver N, McAllister F (2018) IL-6 family cytokines: key inflammatory mediators as biomarkers and potential therapeutic targets. Cytokine Growth Factor Rev 41:10–17CrossRefGoogle Scholar
  22. 22.
    T.W., D. C (2000) Function of C-reactive protein. Ann Med 32:274–278CrossRefGoogle Scholar
  23. 23.
    Wilund KR (2007) Is the anti-inflammatory effect of regular exercise responsible for reduced cardiovascular disease? Clin Sci (Lond) 112:543–555CrossRefGoogle Scholar
  24. 24.
    Bruunsgaard H (2005) Physical activity and modulation of systemic low-level inflammation. J Leukoc Biol 78:819–835CrossRefGoogle Scholar
  25. 25.
    Hotamisligil GS (2017) Inflammation, metaflammation and immunometabolic disorders. Nature 542:177–185CrossRefGoogle Scholar
  26. 26.
    Hotamisligil GS, Erbay E (2008) Nutrient sensing and inflammation in metabolic diseases. Nat Rev Immunol 8:923–934CrossRefGoogle Scholar
  27. 27.
    Sun K, Kusminski CM, Scherer PE (2011) Adipose tissue remodeling and obesity. J Clin Invest 121:2094–2101CrossRefGoogle Scholar
  28. 28.
    Donath MY (2014) Targeting inflammation in the treatment of type 2 diabetes: time to start. Nat Rev Drug Discov 13:465–476CrossRefGoogle Scholar
  29. 29.
    Steensberg A, Fischer CP, Keller C, Møller K, Pedersen BK (2015) IL-6 enhances plasma IL-1ra, IL-10, and cortisol in humans. Am J Physiol Metab 285:E433–E437Google Scholar
  30. 30.
    Steensberg A, Febbraio MA, Osada T, Schjerling P, van Hall G, Saltin B, Pedersen BK (2001) Interleukin-6 production in contracting human skeletal muscle is influenced by pre-exercise muscle glycogen content. J Physiol 537:633–639CrossRefGoogle Scholar
  31. 31.
    Pedersen BK, Steensberg A, Fischer C, Keller C, Ostrowski K, Schjerling P (2001) Exercise and cytokines with particular focus on muscle derived IL-6. Exerc Immunol Rev 7:18–31Google Scholar
  32. 32.
    Pedersen BK, Steensberg A, Fischer C, Keller C, Keller P, Plomgaard P, Febbraio M, Saltin B (2003) Searching for the exercise factor: is IL-6 a candidate? J Muscle Res Cell Motil 24:113–119CrossRefGoogle Scholar
  33. 33.
    Ostrowski K, Rohde T, Zacho M, Asp S, Pedersen B (1998) Evidence that IL-6 is produced in skeletal muscle during intense long-term muscle activity. J Physiol 508:949–953CrossRefGoogle Scholar
  34. 34.
    Steensberg A, van 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 529:237–242CrossRefGoogle Scholar
  35. 35.
    Fischer C (2006) Interleukin-6 in acute exercise and training: what is the biological relevance. Exerc Immunol Rev 12:6–33Google Scholar
  36. 36.
    Helge JW, Stallknecht B, Pedersen BK, Galbo H, Kiens B, Richter EA (2003) The effect of graded exercise on IL-6 release and glucose uptake in human skeletal muscle. J Physiol 546:299–305CrossRefGoogle Scholar
  37. 37.
    Pedersen BK (2013) Muscle as a secretory organ. Compr Physiol 3:1337–1362Google Scholar
  38. 38.
    Ullum H et al (1994) Bicycle exercise enhances plasma IL-6 but does not change IL-1α, IL-1β, IL-6, or TNF-α pre-mRNA in BMNC. Cytokines:93–97Google Scholar
  39. 39.
    Ostrowski K, Hermann C, Bangash A, Schjerling P, Nielsen JN, Pedersen BK (1998) A trauma-like elevation of plasma cytokines in humans in response to treadmill running. J Physiol 513:889–894CrossRefGoogle Scholar
  40. 40.
    Starkie R, Ostrowski SR, Jauffred S, Febbraio M, Pedersen BK (2003) Exercise and IL-6 infusion inhibit endotoxin-induced TNF-alpha production in humans. FASEB J 17:884–886CrossRefGoogle Scholar
  41. 41.
    Gershenwald JE, Fong YM, Fahey TJ, Calvano SE, Chizzonite R, Kilian PL, Lowry SF, Moldawer LL (1990) Interleukin 1 receptor blockade attenuates the host inflammatory response. Proc Natl Acad Sci U S A 87:4966–4970CrossRefGoogle Scholar
  42. 42.
    Petersen AMW, Pedersen BK (2006) The role of IL-6 in mediating the anti-inflammatory effects of exercise. J Physiol Pharmacol 57:43–51Google Scholar
  43. 43.
    Steensberg A, Fischer CP, Keller C, Møller K, Pedersen BK (2003) IL-6 enhances plasma IL-1ra, IL-10, and cortisol in humans. Am J Physiol Endocrinol Metab 285:E433–E437CrossRefGoogle Scholar
  44. 44.
    Wallenius V, Wallenius K, Ahrén B, Rudling M, Carlsten H, Dickson SL, Ohlsson C, Jansson JO (2002) Interleukin-6-deficient mice develop mature-onset obesity. Nat Med 8:75–79CrossRefGoogle Scholar
  45. 45.
    Matthews VB, Allen TL, Risis S, Chan MHS, Henstridge DC, Watson N, Zaffino LA, Babb JR, Boon J, Meikle PJ, Jowett JB, Watt MJ, Jansson JO, Bruce CR, Febbraio MA (2010) Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance. Diabetologia 53:2431–2441CrossRefGoogle Scholar
  46. 46.
    Kristiansen OP, Mandrup-poulsen T (2005) The good, the bad, or the indifferent? Diabetes 54:114–124CrossRefGoogle Scholar
  47. 47.
    Pedersen BK, Febbraio M a (2012) Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol 8:457–465CrossRefGoogle Scholar
  48. 48.
    Kim H-J, Higashimori T, Park SY, Choi H, Dong J, Kim YJ, Noh HL, Cho YR, Cline G, Kim YB, Kim JK (2004) Differential effects of interleukin-6 and -10 on skeletal muscle and liver insulin action in vivo. Diabetes 53:1060–1067CrossRefGoogle Scholar
  49. 49.
    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 11:183–190CrossRefGoogle Scholar
  50. 50.
    Senn JJ, Klover PJ, Nowak IA, Zimmers TA, Koniaris LG, Furlanetto RW, Mooney RA (2003) Suppressor of cytokine signaling-3 (SOCS-3), a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes. J Biol Chem 278:13740–13746CrossRefGoogle Scholar
  51. 51.
    Kraakman MJ, Allen TL, Whitham M, Iliades P, Kammoun HL, Estevez E, Lancaster GI, Febbraio MA (2013) Targeting gp130 to prevent inflammation and promote insulin action. Diabetes Obes Metab 15:170–175CrossRefGoogle Scholar
  52. 52.
    Ellingsgaard H, Ehses JA, Hammar EB, van Lommel L, Quintens R, Martens G, Kerr-Conte J, Pattou F, Berney T, Pipeleers D, Halban PA, Schuit FC, Donath MY (2008) Interleukin-6 regulates pancreatic α-cell mass expansion. Proc Natl Acad Sci 105:13163–13168CrossRefGoogle Scholar
  53. 53.
    Ellingsgaard H, Hauselmann I, Schuler B, Habib AM, Baggio LL, Meier DT, Eppler E, Bouzakri K, Wueest S, Muller YD, Hansen AMK, Reinecke M, Konrad D, Gassmann M, Reimann F, Halban PA, Gromada J, Drucker DJ, Gribble FM, Ehses JA, Donath MY (2011) Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nat Med 17:1481–1489CrossRefGoogle Scholar
  54. 54.
    Timper K, Dalmas E, Dror E, Rütti S, Thienel C, Sauter NS, Bouzakri K, Bédat B, Pattou F, Kerr-Conte J, Böni-Schnetzler M, Donath MY (2016) Glucose-dependent insulinotropic peptide stimulates glucagon-like peptide 1 production by pancreatic islets via interleukin 6, produced by α cells. Gastroenterology 151:165–179CrossRefGoogle Scholar
  55. 55.
    Mauer J, Chaurasia B, Goldau J, Vogt MC, Ruud J, Nguyen KD, Theurich S, Hausen AC, Schmitz J, Brönneke HS, Estevez E, Allen TL, Mesaros A, Partridge L, Febbraio MA, Chawla A, Wunderlich FT, Brüning JC (2014) Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin. Nat Immunol 15:423–430CrossRefGoogle Scholar
  56. 56.
    Timper K, Denson JL, Steculorum SM, Heilinger C, Engström-Ruud L, Wunderlich CM, Rose-John S, Wunderlich FT, Brüning JC (2017) IL-6 improves energy and glucose homeostasis in obesity via enhanced central IL-6 trans-signaling. Cell Rep 19:267–280CrossRefGoogle Scholar
  57. 57.
    Wunderlich FT, Ströhle P, Könner AC, Gruber S, Tovar S, Brönneke HS, Juntti-Berggren L, Li LS, van Rooijen N, Libert C, Berggren PO, Brüning JC (2010) Interleukin-6 signaling in liver-parenchymal cells suppresses hepatic inflammation and improves systemic insulin action. Cell Metab 12:237–249CrossRefGoogle Scholar
  58. 58.
    Carey AL, Bruce CR, Sacchetti M, Anderson MJ, Olsen DB, Saltin B, Hawley JA, Febbraio MA (2004) Interleukin-6 and tumor necrosis factor-α are not increased in patients with type 2 diabetes: evidence that plasma interleukin-6 is related to fat mass and not insulin responsiveness. Diabetologia 47:1029–1037Google Scholar
  59. 59.
    Lang Lehrskov L, Lyngbaek MP, Soederlund L, Legaard GE, Ehses JA, Heywood SE, Wewer Albrechtsen NJ, Holst JJ, Karstoft K, Pedersen BK, Ellingsgaard H (2018) Interleukin-6 delays gastric emptying in humans with direct effects on glycemic control. Cell Metab 27:1201–1211.e3CrossRefGoogle Scholar
  60. 60.
    Hirano T, Yasukawa K, Harada H, Taga T, Watanabe Y, Matsuda T, Kashiwamura SI, Nakajima K, Koyama K, Iwamatsu A, Tsunasawa S, Sakiyama F, Matsui H, Takahara Y, Taniguchi T, Kishimoto T (1986) Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature 324:73–76CrossRefGoogle Scholar
  61. 61.
    Van Snick J et al (1988) cDNA cloning of murine interleukin-HP1: homology with human interleukin 6. Eur J Immunol 18:193–197CrossRefGoogle Scholar
  62. 62.
    Knudsen SH, Pedersen BK (2015) Targeting inflammation through a physical active lifestyle and pharmaceuticals for the treatment of type 2 diabetes. Curr Diab Rep 15(1–9):82CrossRefGoogle Scholar
  63. 63.
    Carey AL, Steinberg GR, Macaulay SL, Thomas WG, Holmes AG, Ramm G, Prelovsek O, Hohnen-Behrens C, Watt MJ, James DE, Kemp BE, Pedersen BK, Febbraio MA (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 55:2688–2697CrossRefGoogle Scholar
  64. 64.
    Karstoft K, Pedersen BK (2016) Exercise and type 2 diabetes: focus on metabolism and inflammation. Immunol Cell Biol 94:146–150CrossRefGoogle Scholar
  65. 65.
    Tsigos C, Papanicolaou DA, Kyrou I, Defensor R, Mitsiadis CS, Chrousos GP (1997) Dose-dependent effects of recombinant human interleukin-6 on glucose regulation. J.Clin.Endocrinol.Metab 82:4167–4170CrossRefGoogle Scholar
  66. 66.
    Stouthard J et al (1995) Endocrinologic and metabolic effects of interleukin-6 in humans. Am J Phys 268:E813–E819Google Scholar
  67. 67.
    Lyngsø D, Simonsen L, Bülow J (2002) Interleukin-6 production in human subcutaneous abdominal adipose tissue: the effect of exercise. J Physiol 543:373–378CrossRefGoogle Scholar
  68. 68.
    Petersen a MW, Pedersen BK (2005) The anti-inflammatory effect of exercise. J Appl Physiol 98:1154–1162CrossRefGoogle Scholar
  69. 69.
    Febbraio MA, Hiscock N, Sacchetti M, Fischer CP, Pedersen BK (2004) Interleukin-6 is a novel factor mediating glucose homeostasis during skeletal muscle contraction. Diabetes 53:1643–1648CrossRefGoogle Scholar
  70. 70.
    Harder-Lauridsen NM et al (2014) Effect of IL-6 on the insulin sensitivity in patients with type 2 diabetes. Am J Physiol Metab 306:E769–E778Google Scholar
  71. 71.
    Fève B, Bastard J-P (2009) The role of interleukins in insulin resistance and type 2 diabetes mellitus. Nat Rev Endocrinol 5:305–311CrossRefGoogle Scholar
  72. 72.
    Sadagurski M, Norquay L, Farhang J, D’Aquino K, Copps K, White MF (2010) Human IL6 enhances leptin action in mice. Diabetologia 53:525–535CrossRefGoogle Scholar
  73. 73.
    Xu Y, Zhang Y, Ye J (2018) IL-6: a potential role in cardiac metabolic homeostasis. Int J Mol Sci 19.  https://doi.org/10.3390/ijms19092474
  74. 74.
    Petersen EW et al (2005) Acute IL-6 treatment increases fatty acid turnover in elderly humans in vivo and in tissue culture in vitro. Circulation 102:E155–E162Google Scholar
  75. 75.
    Van Hall G et al (2003) Interleukin-6 stimulates lipolysis and fat oxidation in humans. J Clin Endocrinol Metab 88:3005–3010CrossRefGoogle Scholar
  76. 76.
    Lyngsø D, Simonsen L, Bülow J (2002) Metabolic effects of interleukin-6 in human splanchnic and adipose tissue. J Physiol 543:379–386CrossRefGoogle Scholar
  77. 77.
    Nishimoto N et al (2005) Humanized anti – interleukin-6 receptor antibody treatment of multicentric Castleman disease. Blood 106:2627–2633CrossRefGoogle Scholar
  78. 78.
    Päth G et al (2007) Human breast adipocytes express interleukin-6 (IL-6) and its receptor system: increased IL-6 production by beta-adrenergic activation and effects of IL-6 on adipocyte function. J Clin Endocrinol Metab 86:0–7Google Scholar
  79. 79.
    Al-Khalili L et al (2006) Signaling specificity of interleukin-6 action on glucose and lipid metabolism in skeletal muscle. Mol Endocrinol 20:3364–3375CrossRefGoogle Scholar
  80. 80.
    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 89:5577–5582CrossRefGoogle Scholar
  81. 81.
    Ruderman NB, Keller C, Richard AM, Saha AK, Luo Z, Xiang X, Giralt M, Ritov VB, Menshikova EV, Kelley DE, Hidalgo J, Pedersen BK, Kelly M (2006) Interleukin-6 regulation of AMP-activated protein kinase: potential role in the systemic response to exercise and prevention of the metabolic syndrome. Diabetes 55:S48–S54CrossRefGoogle Scholar
  82. 82.
    Hardie DG, Ross FA, Hawley SA (2017) AMPK - a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 13:251–262CrossRefGoogle Scholar
  83. 83.
    Jeon SM (2016) Regulation and function of AMPK in physiology and diseases. Exp Mol Med 48:e245CrossRefGoogle Scholar
  84. 84.
    Longo N, Frigeni M, Pasquali M (2016) Carnitine transport and fatty acid oxidation. Biochim Biophys Acta 1863:2422–2435CrossRefGoogle Scholar
  85. 85.
    Tanaka T, Hishitani Y, Ogata A (2014) Monoclonal antibodies in rheumatoid arthritis: comparative effectiveness of tocilizumab with tumor necrosis factor inhibitors. Biologics 8:141-53.  https://doi.org/10.2147/BTT.S37509
  86. 86.
    Shetty A et al (2014) Tocilizumab in the treatment of rheumatoid arthritis and beyond. Drug Des Devel Ther 8:349–364Google Scholar
  87. 87.
    Iking-Konert C et al (2014) Interleukin-6 inhibition as a potential therapeutic target in rheumatic diseases. Rheumatol. 73:269–276Google Scholar
  88. 88.
    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 105:141–150CrossRefGoogle Scholar
  89. 89.
    Esser N, Paquot N, Scheen AJ (2014) Anti-inflammatory agents to treat or prevent type 2 diabetes, metabolic syndrome and cardiovascular disease. Expert Opin Investig Drugs 24:283–307CrossRefGoogle Scholar
  90. 90.
    Ogata A, Morishima A, Hirano T, Hishitani Y, Hagihara K, Shima Y, Narazaki M, Tanaka T (2011) Improvement of HbA1c during treatment with humanised anti-interleukin 6 receptor antibody, tocilizumab. Ann Rheum Dis 70:1164–1165CrossRefGoogle Scholar
  91. 91.
    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:e14328CrossRefGoogle Scholar
  92. 92.
    Ursini F, Russo E, Ruscitti P, Giacomelli R, De Sarro G (2018) The effect of non–TNF-targeted biologics and small molecules on insulin resistance in inflammatory arthritis. Autoimmun Rev 17:399–404CrossRefGoogle Scholar
  93. 93.
    Castañeda S, Remuzgo-Martínez S, López-Mejías R, Genre F, Calvo-Alén J, Llorente I, Aurrecoechea E, Ortiz AM, Triguero A, Blanco R, Llorca J, González-Gay MA (2018) Rapid beneficial effect of the IL-6 receptor blockade on insulin resistance and insulin sensitivity in non-diabetic patients with rheumatoid arthritis. Clin Exp RheumatolGoogle Scholar
  94. 94.
    Otsuka Y, Kiyohara C, Kashiwado Y, Sawabe T, Nagano S, Kimoto Y, Ayano M, Mitoma H, Akahoshi M, Arinobu Y, Niiro H, Akashi K, Horiuchi T (2018) Effects of tumor necrosis factor inhibitors and tocilizumab on the glycosylated hemoglobin levels in patients with rheumatoid arthritis; an observational study. PLoS One 13:e0196368CrossRefGoogle Scholar
  95. 95.
    Everett BM, Donath MY, Pradhan AD, Thuren T, Pais P, Nicolau JC, Glynn RJ, Libby P, Ridker PM (2018) Anti-inflammatory therapy with canakinumab for the prevention and management of diabetes. J Am Coll Cardiol 71:2392–2401CrossRefGoogle Scholar
  96. 96.
    Choy E, Sattar N (2009) Interpreting lipid levels in the context of high-grade inflammatory states with a focus on rheumatoid arthritis: a challenge to conventional cardiovascular risk actions. Ann Rheum Dis 68:460–469CrossRefGoogle Scholar
  97. 97.
    Wedell-Neergaard A-S et al (2018) Exercise-induced changes in visceral adipose tissue mass are regulated by IL-6 signaling: a randomized controlled trial. Cell Metab:1–12Google Scholar
  98. 98.
    Smolen JS, Beaulieu A, Rubbert-Roth A, Ramos-Remus C, Rovensky J, Alecock E, Woodworth T, Alten R (2008) Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet 371:987–997CrossRefGoogle Scholar
  99. 99.
    Genovese MC, McKay JD, Nasonov EL, Mysler EF, da Silva NA, Alecock E, Woodworth T, Gomez-Reino JJ (2008) Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum 58:2968–2980CrossRefGoogle Scholar
  100. 100.
    Rao VU, Pavlov A, Klearman M, Musselman D, Giles JT, Bathon JM, Sattar N, Lee JS (2015) An evaluation of risk factors for major adverse cardiovascular events during tocilizumab therapy. Arthritis Rheum 67:372–380CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.The Centre of Inflammation and Metabolism (CIM) and the Centre for Physical Activity Research (CFAS), Rigshospitalet 7641University of CopenhagenCopenhagenDenmark

Personalised recommendations