Targeting innate immune mediators in type 1 and type 2 diabetes

Article metrics


Type 1 and type 2 diabetes are characterized by chronic inflammation; both diseases involve pancreatic islet inflammation, while systemic low-grade inflammation is a feature of obesity and type 2 diabetes. Long-term activation of the innate immune system impairs insulin secretion and action, and inflammation also contributes to macrovascular and microvascular complications of diabetes. However, despite strong preclinical evidence and proof-of-principle clinical trials demonstrating that targeting inflammatory pathways can prevent cardiovascular disease and other complications in patients with diabetes, there are still no approved treatments for diabetes that target innate immune mediators. Here, we review recent advances in our understanding of the inflammatory pathogenesis of type 1 and type 2 diabetes from a translational angle and point out the critical gaps in knowledge that need to be addressed to guide drug development.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Model for targeting IL-1β in islets of patients with type 2 diabetes.
Fig. 2: Transition from innate immune metabolic homeostasis via systemic low-grade inflammation to local disease.
Fig. 3: Pathogenesis of type 2 diabetes and its associated complications.


  1. 1.

    Gaede, P., Lund-Andersen, H., Parving, H. H. & Pedersen, O. Effect of a multifactorial intervention on mortality in type 2 diabetes. New Engl. J. Med. 358, 580–591 (2008).

  2. 2.

    Zinman, B. et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. New Engl. J. Med. 373, 2117–2128 (2015).

  3. 3.

    Marso, S. P. et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. New Engl. J. Med. 375, 311–322 (2016).

  4. 4.

    Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. New Engl. J. Med. 377, 1119–1131 (2017). A milestone study showing that IL-1 antagonism prevents cardiovascular diseases.

  5. 5.

    Garber, A. J. Incretin effects on beta-cell function, replication, and mass: the human perspective. Diabetes Care 34, S258–S263 (2011).

  6. 6.

    Del Rey, A. & Besedovsky, H. O. Metabolic and neuroendocrine effects of pro-inflammatory cytokines. Eur. J. Clin. Invest. 22, 10–15 (1992).

  7. 7.

    Spinas, G. A. et al. The bimodal effect of interleukin 1 on rat pancreatic beta-cells–stimulation followed by inhibition–depends upon dose, duration of exposure, and ambient glucose concentration. Acta Endocrinol.(Copenh) 119, 307–311 (1988). The first study to demonstrate bimodal effect of IL-1 on β-cell secretory function.

  8. 8.

    Maedler, K. et al. FLIP switches Fas-mediated glucose signaling in human pancreatic ß cells from apoptosis to cell replication. Proc. Natl Acad. Sci. USA 99, 8236–8241 (2002).

  9. 9.

    Boni-Schnetzler, M. et al. beta cell-specific deletion of the IL-1 receptor antagonist impairs beta cell proliferation and insulin secretion. Cell Rep. 22, 1774–1786 (2018).

  10. 10.

    Dror, E. et al. Postprandial macrophage-derived IL-1β stimulates insulin, and both synergistically promote glucose disposal and inflammation. Nat. Immunol. 18, 283–292 (2017). First study assigning to IL-1β a physiological role in the regulation of insulin secretion.

  11. 11.

    Ellingsgaard, H. et al. Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nat. Med. 17, 1481–1489 (2011).

  12. 12.

    Dalmas, E. et al. Interleukin-33-activated islet-resident innate lymphoid cells promote insulin secretion through myeloid cell retinoic acid production. Immunity 47, 1774–1786 (2017).

  13. 13.

    Eizirik, D. L., Sandler, S., Welsh, N., Juntti-Berggren, L. & Berggren, P. O. Interleukin-1β-induced stimulation of insulin release in mouse pancreatic islets is related to diacylglycerol production and protein kinase C activation. Mol Cell Endocrinol. 111, 159–165 (1995).

  14. 14.

    Mandrup-Poulsen, T., Pickersgill, L. & Donath, M. Y. Blockade of interleukin 1 in type 1 diabetes mellitus. Nat. Rev. Endocrinol. 6, 158–166 (2010).

  15. 15.

    Donath, M. Y. & Shoelson, S. E. Type 2 diabetes as an inflammatory disease. Nat. Rev. Immunol. 11, 98–107 (2011).

  16. 16.

    Kolb, H. & Mandrup-Poulsen, T. An immune origin of type 2 diabetes? Diabetologia 48, 1038–1050 (2005).

  17. 17.

    Donath, M. Y., Storling, J., Berchtold, L. A., Billestrup, N. & Mandrup-Poulsen, T. Cytokines and beta-cell biology: from concept to clinical translation. Endocr. Rev. 29, 334–350 (2008).

  18. 18.

    Boni-Schnetzler, M. et al. Free fatty acids induce a proinflammatory response in islets via the abundantly expressed interleukin-1 receptor I. Endocrinology 150, 5218–5229 (2009).

  19. 19.

    Corbett, J. A., Kwon, G., Misko, T. P., Rodi, C. P. & McDaniel, M. L. Tyrosine kinase involvement in IL-1 beta-induced expression of iNOS by beta-cells purified from islets of Langerhans. Am. J. Physiol. 267, C48–C54 (1994).

  20. 20.

    Ortis, F. et al. Cytokine-induced proapoptotic gene expression in insulin-producing cells is related to rapid, sustained, and nonoscillatory nuclear factor-kappaB activation. Mol. Endocrinol. 20, 1867–1879 (2006).

  21. 21.

    Meyerovich, K. et al. The non-canonical NF-kappaB pathway is induced by cytokines in pancreatic beta cells and contributes to cell death and proinflammatory responses in vitro. Diabetologia 59, 512–521 (2016).

  22. 22.

    Hansen, J. B. et al. Divalent metal transporter 1 regulates iron-mediated ROS and pancreatic beta cell fate in response to cytokines. Cell Metab. 16, 449–461 (2012). This study indicates the link between low-grade inflammation, ROS formation, iron handling and β-cell damage, and also explains the selective toxic effect of IL-1 on β-cells.

  23. 23.

    Lenzen, S., Drinkgern, J. & Tiedge, M. Low antioxidant enzyme gene expression in pancreatic islets compared with various other mouse tissues. Free Radic. Biol. Med. 20, 463–466 (1996).

  24. 24.

    Berchtold, L. A., Prause, M., Storling, J. & Mandrup-Poulsen, T. Cytokines and pancreatic beta-cell apoptosis. Adv. Clin. Chem. 75, 99–158 (2016).

  25. 25.

    Hotamisligil, G. S., Shargill, N. S. & Spiegelman, B. M. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259, 87–91 (1993). First study implicating cytokines in insulin resistance in animals.

  26. 26.

    Munoz-Canoves, P., Scheele, C., Pedersen, B. K. & Serrano, A. L. Interleukin-6 myokine signaling in skeletal muscle: a double-edged sword? FEBS J. 280, 4131–4148 (2013).

  27. 27.

    Pedersen, B. K. et al. The metabolic role of IL-6 produced during exercise: is IL-6 an exercise factor? Proc. Nutr. Soc. 63, 263–267 (2004).

  28. 28.

    Carey, A. L. & Febbraio, M. A. Interleukin-6 and insulin sensitivity: friend or foe? Diabetologia 47, 1135–1142 (2004).

  29. 29.

    Hotamisligil, G. S. & Erbay, E. Nutrient sensing and inflammation in metabolic diseases. Nat. Rev. Immunol. 8, 923–934 (2008).

  30. 30.

    Donath, M. Y., Storling, J., Maedler, K. & Mandrup-Poulsen, T. Inflammatory mediators and islet beta-cell failure: a link between type 1 and type 2 diabetes. J. Mol. Med. 81, 455–470 (2003).

  31. 31.

    Ehses, J. A., Ellingsgaard, H., Boni-Schnetzler, M. & Donath, M. Y. Pancreatic islet inflammation in type 2 diabetes: from alpha and beta cell compensation to dysfunction. Arch. Physiol. Biochem. 115, 240–247 (2009).

  32. 32.

    Westwell-Roper, C. Y., Ehses, J. A. & Verchere, C. B. Resident macrophages mediate islet amyloid polypeptide-induced islet IL-1beta production and beta cell dysfunction. Diabetes 63, 1697–1711 (2014).

  33. 33.

    Westwell-Roper, C. et al. IL-1 blockade attenuates islet amyloid polypeptide-induced proinflammatory cytokine release and pancreatic islet graft dysfunction. J. Immunol. 187, 2755–2765 (2011).

  34. 34.

    Masters, S. L. et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1beta in type 2 diabetes. Nat. Immunol. 11, 897–904 (2010). First article showing how a secreted product of β- cells serves as a damage-associated molecular pattern and activates the inflammasome to produce IL-1β and IL-18.

  35. 35.

    Jourdan, T. et al. Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes. Nat. Med. 19, 1132–1140 (2013).

  36. 36.

    Oslowski, C. M. et al. Thioredoxin-interacting protein mediates ER stress-induced beta cell death through initiation of the inflammasome. Cell Metab. 16, 265–273 (2012).

  37. 37.

    Lerner, A. G. et al. IRE1alpha induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress. Cell Metab. 16, 250–264 (2012).

  38. 38.

    Maedler, K. et al. Glucose-induced beta-cell production of interleukin-1beta contributes to glucotoxicity in human pancreatic islets. J. Clin. Invest. 110, 851–860 (2002). First study showing a role for IL-1β in the pathogenesis of T2D.

  39. 39.

    Zhou, R., Tardivel, A., Thorens, B., Choi, I. & Tschopp, J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat. Immunol. 11, 136–140 (2010).

  40. 40.

    Pal, D. et al. Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nat. Med. 18, 1279–1285 (2012).

  41. 41.

    Maedler, K. et al. FLIP switches Fas-mediated glucose signaling in human pancreatic beta cells from apoptosis to cell replication. Proc. Natl Acad. Sci. USA 99, 8236–8241 (2002).

  42. 42.

    Boni-Schnetzler, M. et al. Increased interleukin (IL)-1β messenger ribonucleic acid expression in β-cells of individuals with type 2 diabetes and regulation of IL-1β in human islets by glucose and autostimulation. J. Clin. Endocrinol. Metab. 93, 4065–4074 (2008).

  43. 43.

    Robertson, R. P., Harmon, J., Tran, P. O. & Poitout, V. Beta-cell glucose toxicity, lipotoxicity, and chronic oxidative stress in type 2 diabetes. Diabetes 53, S119–S124 (2004).

  44. 44.

    Weir, G. C. & Bonner-Weir, S. Five stages of evolving beta-cell dysfunction during progression to diabetes. Diabetes 53, S16–S21 (2004).

  45. 45.

    Prentki, M. & Nolan, C. J. Islet beta cell failure in type 2 diabetes. J. Clin. Invest. 116, 1802–1812 (2006).

  46. 46.

    Hull, R. L., Westermark, G. T., Westermark, P. & Kahn, S. E. Islet amyloid: a critical entity in the pathogenesis of type 2 diabetes. J. Clin. Endocrinol. Metab. 89, 3629–3643 (2004).

  47. 47.

    Harding, H. P. & Ron, D. Endoplasmic reticulum stress and the development of diabetes: a review. Diabetes 51, S455–S461 (2002).

  48. 48.

    Donath, M. Y., Gross, D. J., Cerasi, E. & Kaiser, N. Hyperglycemia-induced beta-cell apoptosis in pancreatic islets of Psammomys obesus during development of diabetes. Diabetes 48, 738–744 (1999).

  49. 49.

    Maedler, K. et al. Distinct effects of saturated and monounsaturated fatty acids on beta-cell turnover and function. Diabetes 50, 69–76 (2001).

  50. 50.

    Di Marzo, V. et al. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 410, 822–825 (2001).

  51. 51.

    Hotamisligil, G. S. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 140, 900–917 (2010).

  52. 52.

    Martinez, J., Verbist, K., Wang, R. & Green, D. R. The relationship between metabolism and the autophagy machinery during the innate immune response. Cell Metab. 17, 895–900 (2013).

  53. 53.

    Skurk, T., Alberti-Huber, C., Herder, C. & Hauner, H. Relationship between adipocyte size and adipokine expression and secretion. J. Clin. Endocrinol. Metab. 92, 1023–1033 (2007).

  54. 54.

    Stienstra, R. et al. The inflammasome-mediated caspase-1 activation controls adipocyte differentiation and insulin sensitivity. Cell Metab. 12, 593–605 (2010).

  55. 55.

    Koenen, T. B. et al. Hyperglycemia activates caspase-1 and TXNIP-mediated IL-1beta transcription in human adipose tissue. Diabetes 60, 517–524 (2011).

  56. 56.

    Wen, H. et al. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat. Immunol. 12, 408–415 (2011).

  57. 57.

    Cinti, S. et al. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J. Lipid Res. 46, 2347–2355 (2005).

  58. 58.

    Weisberg, S. P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796–1808 (2003).

  59. 59.

    Xu, H. et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest. 112, 1821–1830 (2003).

  60. 60.

    Ye, J. Emerging role of adipose tissue hypoxia in obesity and insulin resistance. Int. J. Obes. 33, 54–66 (2009).

  61. 61.

    Cox, L. M. & Blaser, M. J. Pathways in microbe-induced obesity. Cell Metab. 17, 883–894 (2013).

  62. 62.

    Ley, R. E. et al. Obesity alters gut microbial ecology. Proc. Natl Acad. Sci. USA 102, 11070–11075 (2005).

  63. 63.

    Turnbaugh, P. J. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006).

  64. 64.

    Ley, R. E., Turnbaugh, P. J., Klein, S. & Gordon, J. I. Microbial ecology: human gut microbes associated with obesity. Nature 444, 1022–1023 (2006).

  65. 65.

    Cani, P. D. et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56, 1761–1772 (2007).

  66. 66.

    Cani, P. D. et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 57, 1470–1481 (2008).

  67. 67.

    Hotamisligil, G. S. Inflammation, metaflammation and immunometabolic disorders. Naure. 542, 177–185 (2017).

  68. 68.

    Sun, B. & Karin, M. Obesity, inflammation, and liver cancer. J. Hepatol. 56, 704–713 (2012).

  69. 69.

    Libby, P., Ridker, P. M. & Hansson, G. K., Leducq Transatlantic Network on, Atherothrombosis. Inflammation in atherosclerosis: from pathophysiology to practice. J. Am. Coll. Cardiol. 54, 2129–2138 (2009).

  70. 70.

    Stahel, M., Becker, M., Graf, N. & Michels, S. Systemic interleukin 1β inhibition in proliferative diabetic retinopathy: a prospective open-label study using canakinumab. Retina 36, 385–391 (2016).

  71. 71.

    So, A., De Smedt, T., Revaz, S. & Tschopp, J. A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res. Ther. 9, R28 (2007).

  72. 72.

    Greenwood, R. H., Mahler, R. F. & Hales, C. N. Improvement in insulin secretion in diabetes after diazoxide. Lancet 1, 444–447 (1976).

  73. 73.

    Kelly, B., Tannahill, G. M., Murphy, M. P. & O’Neill, L. A. Metformin inhibits the production of reactive oxygen species from NADH:ubiquinone oxidoreductase to limit induction of interleukin-1beta (IL-1beta) and boosts interleukin-10 (IL-10) in lipopolysaccharide (LPS)-activated macrophages. J. Biol. Chem. 290, 20348–20359 (2015).

  74. 74.

    Cavelti-Weder, C. et al. Effects of gevokizumab on glycemia and inflammatory markers in type 2 diabetes. Diabetes Care 35, 1654–1662 (2012).

  75. 75.

    Everett, B. M. et al. Anti-inflammatory therapy with canakinumab for the prevention and management of diabetes. J. Am. Coll. Cardiol. 71, 2392–2401 (2018).

  76. 76.

    Jorns, A. et al. Islet infiltration, cytokine expression and beta cell death in the NOD mouse, BB rat, Komeda rat, LEW.1AR1-iddm rat and humans with type 1 diabetes. Diabetologia 57, 512–521 (2014).

  77. 77.

    Reddy, S. et al. Distribution of IL-1beta immunoreactive cells in pancreatic biopsies from living volunteers with new-onset type 1 diabetes: comparison with donors without diabetes and with longer duration of disease. Diabetologia 61, 1362–1373 (2018).

  78. 78.

    Ablamunits, V. et al. Synergistic reversal of type 1 diabetes in NOD mice with anti-CD3 and interleukin-1 blockade: evidence of improved immune regulation. Diabetes 61, 145–154 (2012).

  79. 79.

    Mastrandrea, L. et al. Etanercept treatment in children with new-onset type 1 diabetes: pilot randomized, placebo-controlled, double-blind study. Diabetes Care 32, 1244–1249 (2009).

  80. 80.

    Moran, A. et al. Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials. Lancet 381, 1905–1915 (2013).

  81. 81.

    Mandrup-Poulsen, T. et al. Monokine antagonism is reduced in patients with IDDM. Diabetes 43, 1242–1247 (1994).

  82. 82.

    US National Library of Medicine. (2019).

  83. 83.

    Cabrera, S. M. et al. Interleukin-1 antagonism moderates the inflammatory state associated with type 1 diabetes during clinical trials conducted at disease onset. Eur. J. Immunol. 46, 1030–1046 (2016).

  84. 84.

    Cardozo, A. K. et al. A comprehensive analysis of cytokine-induced and nuclear factor-κB-dependent genes in primary rat pancreatic β-cells. J. Biol. Chem. 276, 48879–48886 (2001).

  85. 85.

    Christensen, D. P. et al. Histone deacetylase (HDAC) inhibition as a novel treatment for diabetes mellitus. Mol. Med. 17, 378–390 (2011).

  86. 86.

    Larsen, L. et al. Inhibition of histone deacetylases prevents cytokine-induced toxicity in beta cells. Diabetologia 50, 779–789 (2007). First study showing the β-cell protective effects of HDAC inhibitors.

  87. 87.

    Lundh, M. et al. Lysine deacetylases are produced in pancreatic beta cells and are differentially regulated by proinflammatory cytokines. Diabetologia 53, 2569–2578 (2010).

  88. 88.

    Lundh, M. et al. Histone deacetylases 1 and 3 but not 2 mediate cytokine-induced beta cell apoptosis in INS-1 cells and dispersed primary islets from rats and are differentially regulated in the islets of type 1 diabetic children. Diabetologia 55, 2421–2431 (2012).

  89. 89.

    Christensen, D. P. et al. Lysine deacetylase inhibition prevents diabetes by chromatin-independent immunoregulation and beta-cell protection. Proc. Natl Acad. Sci. USA 111, 1055–1059 (2014).

  90. 90.

    Chou, D. H. et al. Inhibition of histone deacetylase 3 protects beta cells from cytokine-induced apoptosis. Chem. Biol. 19, 669–673 (2012).

  91. 91.

    Patel, T., Patel, V., Singh, R. & Jayaraman, S. Chromatin remodeling resets the immune system to protect against autoimmune diabetes in mice. Immunol. Cell Biol. 89, 640–649 (2011).

  92. 92.

    Lundh, M., Galbo, T., Poulsen, S. S. & Mandrup-Poulsen, T. Histone deacetylase 3 inhibition improves glycaemia and insulin secretion in obese diabetic rats. Diabetes Obes. Metab. 17, 703–707 (2015).

  93. 93.

    Wagner, F. F. et al. An isochemogenic set of inhibitors to define the therapeutic potential of histone deacetylases in beta-cell protection. ACS Chem. Biol. 11, 363–374 (2016).

  94. 94.

    Dinarello, C. A. et al. Suppression of innate inflammation and immunity by interleukin-37. Eur. J. Immunol. 46, 1067–1081 (2016).

  95. 95.

    Ballak, D. B. et al. IL-37 protects against obesity-induced inflammation and insulin resistance. Nat. Commun. 5, 4711 (2014). First study showing protection against insulin resistance and inflammation by IL-37.

  96. 96.

    Jonigk, D. et al. Anti-inflammatory and immunomodulatory properties of alpha1-antitrypsin without inhibition of elastase. Proc. Natl Acad. Sci. USA 110, 15007–15012 (2013).

  97. 97.

    Ter Horst, R. et al. Host and environmental factors influencing individual human cytokine responses. Cell 167, 1111–1124.e1113 (2016).

  98. 98.

    Lewis, E. C. et al. α1-Antitrypsin monotherapy induces immune tolerance during islet allograft transplantation in mice. Proc. Natl Acad. Sci. USA 105, 16236–16241 (2008). First study showing that AAT protects against inflammation-induced β-cell destruction.

  99. 99.

    Koulmanda, M. et al. Curative and beta cell regenerative effects of alpha1-antitrypsin treatment in autoimmune diabetic NOD mice. Proc. Natl Acad. Sci. USA 105, 16242–16247 (2008).

  100. 100.

    Gottlieb, P. A. et al. alpha1-Antitrypsin therapy downregulates toll-like receptor-induced IL-1beta responses in monocytes and myeloid dendritic cells and may improve islet function in recently diagnosed patients with type 1 diabetes. J. Clin. Endocrinol. Metab. 99, E1418–E1426 (2014).

  101. 101.

    Donath, M. Y. Targeting inflammation in the treatment of type 2 diabetes: time to start. Nat. Rev. Drug Discov. 13, 465–476 (2014).

  102. 102.

    Larsen, C. M. et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. New Engl. J. Med. 356, 1517–1526 (2007). First clinical trial demonstrating proof of concept for the role of IL-1 in glycaemic control and β-cell function in type 2 diabetes.

  103. 103.

    van Asseldonk, E. J. et al. Treatment with anakinra improves disposition index but not insulin sensitivity in nondiabetic subjects with the metabolic syndrome: a randomized, double-blind, placebo-controlled study. J. Clin. Endocrinol. Metab. 96, 2119–2126 (2011).

  104. 104.

    van Poppel, P. C. et al. The interleukin-1 receptor antagonist anakinra improves first-phase insulin secretion and insulinogenic index in subjects with impaired glucose tolerance. Diabetes Obes. Metab. 16, 1269–1273 (2014).

  105. 105.

    Rissanen, A., Howard, C. P., Botha, J. & Thuren, T. Effect of anti-IL-1beta antibody (canakinumab) on insulin secretion rates in impaired glucose tolerance or type 2 diabetes: results of a randomized, placebo-controlled trial. Diabetes Obes. Metab. 14, 1088–1096 (2012).

  106. 106.

    Hensen, J., Howard, C. P., Walter, V. & Thuren, T. Impact of interleukin-1beta antibody (canakinumab) on glycaemic indicators in patients with type 2 diabetes mellitus: results of secondary endpoints from a randomized, placebo-controlled trial. Diabetes Metab. 39, 524–531 (2013).

  107. 107.

    Sloan-Lancaster, J. et al. Double-blind, randomized study evaluating the glycemic and anti-inflammatory effects of subcutaneous LY2189102, a neutralizing IL-1beta antibody, in patients with type 2 diabetes. Diabetes Care 36, 2239–2246 (2013).

  108. 108.

    Green, J. B. et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. New Engl. J. Med. 373, 232–242 (2015).

  109. 109.

    Everett, B. M. et al. Anti-inflammatory therapy with canakinumab for the prevention of hospitalization for heart failure. Circulation 139, 1289–1299 (2019).

  110. 110.

    Abbate, A. et al. Interleukin-1 blockade with anakinra to prevent adverse cardiac remodeling after acute myocardial infarction (Virginia Commonwealth University Anakinra Remodeling Trial [VCU-ART] pilot study). Am. J. Cardiol. 105, 1371–1377.e1371 (2010). A milestone study showing that IL-1 antagonism may prevent heart failure.

  111. 111.

    Abbate, A. et al. Comparative safety of interleukin-1 blockade with anakinra in patients with ST-segment elevation acute myocardial infarction (from the VCU-ART and VCU-ART2 pilot studies). Am. J. Cardiol. 115, 288–292 (2015).

  112. 112.

    Van Tassell, B. W. et al. Interleukin-1 blockade in recently decompensated systolic heart failure: results from REDHART (Recently Decompensated Heart Failure Anakinra Response Trial). Circ. Heart Fail. 10, e004373 (2017).

  113. 113.

    Van Tassell, B. W. et al. Rationale and design of the Virginia Commonwealth University-Anakinra Remodeling Trial-3 (VCU-ART3): a randomized, placebo-controlled, double-blinded, multicenter study. Clin. Cardiol. 41, 1004–1008 (2018).

  114. 114.

    Kataria, Y., Ellervik, C. & Mandrup-Poulsen, T. Treatment of type 2 diabetes by targeting interleukin-1 – a meta-analysis of 2921 patients. Semin. Immunopathol. 41, 413–425 (2019).

  115. 115.

    Febbraio, M. A. et al. Preclinical models for studying NASH-driven HCC: how useful are they? Cell Metab. 29, 18–26 (2018).

  116. 116.

    Schlesinger, S. et al. General and abdominal obesity and incident distal sensorimotor polyneuropathy: insights into inflammatory biomarkers as potential mediators in the KORA F4/FF4 cohort. Diabetes Care 42, 240–247 (2019).

  117. 117.

    Herder, C. et al. A systemic inflammatory signature reflecting cross talk between innate and adaptive immunity is associated with incident polyneuropathy: KORA F4/FF4 study. Diabetes 67, 2434–2442 (2018).

  118. 118.

    Herder, C. et al. Proinflammatory cytokines predict the incidence and progression of distal sensorimotor polyneuropathy: KORA F4/FF4 study. Diabetes care 40, 569–576 (2017).

  119. 119.

    Herder, C. et al. Association of subclinical inflammation with polyneuropathy in the older population: KORA F4 study. Diabetes Care 36, 3663–3670 (2013).

  120. 120.

    Herder, C. et al. Subclinical inflammation and diabetic polyneuropathy: MONICA/KORA Survey F3 (Augsburg, Germany). Diabetes Care 32, 680–682 (2009).

  121. 121.

    Tesch, G. H. Diabetic nephropathy - is this an immune disorder? Clin. Sci. 131, 2183–2199 (2017).

  122. 122.

    Mesquida, M., Leszczynska, A., Llorenc, V. & Adan, A. Interleukin-6 blockade in ocular inflammatory diseases. Clin. Exp. Immunol. 176, 301–309 (2014).

  123. 123.

    Ebrahimi, F. et al. Interleukin-1 antagonism in men with metabolic syndrome and low testosterone - a randomized clinical trial. J. Clin. Endocrinol. Metab. 103, 3466–3476 (2018).

  124. 124.

    Urwyler, S. A., Schuetz, P., Ebrahimi, F., Donath, M. Y. & Christ-Crain, M. Interleukin-1 antagonism decreases cortisol levels in obese individuals. J. Clin. Endocrinol. Metab. 102, 1712–1718 (2017).

  125. 125.

    Lehrskov, L. L. et al. The role of IL-1 in postprandial fatigue. Mol. Metab. 12, 107–112 (2018).

  126. 126.

    Cavelti-Weder, C. et al. Inhibition of IL-1beta improves fatigue in type 2 diabetes. Diabetes Care 34, e158 (2011).

  127. 127.

    Ruscitti, P.a.A. et al. Anti-interleukin-1 treatment in patients with rheumatoid arthritis and type 2 diabetes (TRACK): a multicentre, randomised, open, prospective, controlled, parallel-group trial. PLoS Med in press.

  128. 128.

    Yuan, M. et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science 293, 1673–1677 (2001). A seminal article showing reversal of insulin resistance by salsalate.

  129. 129.

    Fleischman, A., Shoelson, S. E., Bernier, R. & Goldfine, A. B. Salsalate improves glycemia and inflammatory parameters in obese young adults. Diabetes Care 31, 289–294 (2008).

  130. 130.

    Pedersen, B. K. & Febbraio, M. A. Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol. Rev. 88, 1379–1406 (2008).

  131. 131.

    Pedersen, B. K. & Febbraio, M. A. Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat. Rev. Endocrinol. 8, 457–465 (2012).

  132. 132.

    Carey, A. L. et al. 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 (2006).

  133. 133.

    Jansson, J. O. & Wallenius, V. Point-counterpoint: Interleukin-6 does/does not have a beneficial role in insulin sensitivity and glucose homeostasis. J. Appl. Physiol. 102, 821; author reply 825 (2007).

  134. 134.

    Mooney, R. A. Counterpoint: interleukin-6 does not have a beneficial role in insulin sensitivity and glucose homeostasis. J. Appl. Physiol. 102, 816-818; discussion 818-819 (2007).

  135. 135.

    Pedersen, B. K. & Febbraio, M. A. Point: interleukin-6 does have a beneficial role in insulin sensitivity and glucose homeostasis. J. Appl. Physiol. 102, 814–816 (2007).

  136. 136.

    Sabio, G. et al. A stress signaling pathway in adipose tissue regulates hepatic insulin resistance. Science 322, 1539–1543 (2008).

  137. 137.

    Weigert, C., Lehmann, R. & Schleicher, E. D. Point-counterpoint: interleukin-6 does/does not have a beneficial role in insulin sensitivity and glucose homeostasis. J. Appl. Physiol. 102, 820-821; author reply 825 (2007).

  138. 138.

    Wunderlich, F. T. et al. Interleukin-6 signaling in liver-parenchymal cells suppresses hepatic inflammation and improves systemic insulin action. Cell Metab. 12, 237–249 (2010).

  139. 139.

    Lazar, M. A. How obesity causes diabetes: not a tall tale. Science 307, 373–375 (2005).

  140. 140.

    Marchetti, C. et al. OLT1177, a beta-sulfonyl nitrile compound, safe in humans, inhibits the NLRP3 inflammasome and reverses the metabolic cost of inflammation. Proc. Natl Acad. Sci. USA 115, E1530–E1539 (2018). Key translational study showing metabolic benefits of inflammasome inhibition.

  141. 141.

    Coll, R. C. et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat. Med. 21, 248–255 (2015).

  142. 142.

    Lewis, E. C. & Dinarello, C. A. Responses of IL-18- and IL-18 receptor-deficient pancreatic islets with convergence of positive and negative signals for the IL-18 receptor. Proc. Natl Acad. Sci. USA 103, 16852–16857 (2006).

  143. 143.

    Moschen, A. R. et al. Adipose and liver expression of interleukin (IL)-1 family members in morbid obesity and effects of weight loss. Mol. Med. 17, 840–845 (2011).

  144. 144.

    Ballak, D. B. et al. Interleukin-37 treatment of mice with metabolic syndrome improves insulin sensitivity and reduces pro-inflammatory cytokine production in adipose tissue. J. Biol. Chem. 293, 14224–14236 (2018).

  145. 145.

    Whitham, M. & Febbraio, M. A. The ever-expanding myokinome: discovery challenges and therapeutic implications. Nat. Rev. Drug Discov. 15, 719–729 (2016).

  146. 146.

    Febbraio, M. Invited talk: IC7: a novel therapy for the treatment of metabolic disease. Obes. Res. Clin. Pract. 13, 39 (2019).

  147. 147.

    Ehses, J. A. et al. Increased number of islet-associated macrophages in type 2 diabetes. Diabetes 56, 2356–2370 (2007). Pioneering study showing macrophage infiltration in islets of humans and animals with T2D.

  148. 148.

    Chan, J. Y., Lee, K., Maxwell, E. L., Liang, C. & Laybutt, D. R. Macrophage alterations in islets of obese mice linked to beta cell disruption in diabetes. Diabetologia 62, 993–999 (2019).

  149. 149.

    Ying, W. et al. Expansion of islet-resident macrophages leads to inflammation affecting beta cell proliferation and function in obesity. Cell Metab. 29, 457–474.e5 (2019).

  150. 150.

    Xiao, X. et al. M2 macrophages promote beta-cell proliferation by up-regulation of SMAD7. Proc. Natl Acad. Sci. USA 111, E1211–E1220 (2014).

  151. 151.

    Cao, X., Han, Z. B., Zhao, H. & Liu, Q. Transplantation of mesenchymal stem cells recruits trophic macrophages to induce pancreatic beta cell regeneration in diabetic mice. Int. J. Biochem. Cell Biol. 53, 372–379 (2014).

  152. 152.

    Ying, W. et al. Expansion of islet-resident macrophages leads to inflammation affecting beta cell proliferation and function in obesity. Cell Metab. 29, 457–474.e455 (2019).

  153. 153.

    Lee, Y. S., Wollam, J. & Olefsky, J. M. An integrated view of immunometabolism. Cell 172, 22–40 (2018).

  154. 154.

    Deng, Y. & Scherer, P. E. Adipokines as novel biomarkers and regulators of the metabolic syndrome. Ann. N. Y. Acad. Sci. 1212, E1–E19 (2010).

  155. 155.

    Smith, U. & Kahn, B. B. Adipose tissue regulates insulin sensitivity: role of adipogenesis, de novo lipogenesis and novel lipids. J. Intern. Med. 280, 465–475 (2016).

  156. 156.

    Febbraio, M. A. Role of interleukins in obesity: implications for metabolic disease. Trends Endocrinol. Metab. 25, 312–319 (2014).

  157. 157.

    Chawla, A. Control of macrophage activation and function by PPARs. Circ. Res. 106, 1559–1569 (2010).

  158. 158.

    Breccia, M., Muscaritoli, M., Aversa, Z., Mandelli, F. & Alimena, G. Imatinib mesylate may improve fasting blood glucose in diabetic Ph+ chronic myelogenous leukemia patients responsive to treatment. J. Clin. Oncol. 22, 4653–4655 (2004).

  159. 159.

    AlAsfoor, S. et al. Imatinib reduces non-alcoholic fatty liver disease in obese mice by targeting inflammatory and lipogenic pathways in macrophages and liver. Sci. Rep. 8, 15331 (2018).

  160. 160.

    Moraes-Vieira, P. M., Saghatelian, A. & Kahn, B. B. GLUT4 expression in adipocytes regulates de novo lipogenesis and levels of a novel class of lipids with antidiabetic and anti-inflammatory effects. Diabetes 65, 1808–1815 (2016).

  161. 161.

    Bersoff-Matcha, S. J., Chamberlain, C., Cao, C., Kortepeter, C. & Chong, W. H. Fournier gangrene associated with sodium-glucose cotransporter-2 inhibitors: a review of spontaneous postmarketing cases. Ann. Intern. Med. 17, 764–769 (2019).

  162. 162.

    Ferguson, F. M. & Gray, N. S. Kinase inhibitors: the road ahead. Nat. Rev. Drug Discov. 17, 353–377 (2018).

  163. 163.

    Ridker, P. M. et al. Effect of interleukin-1beta inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. Lancet 390, 1833–1842 (2017).

  164. 164.

    Besancon, A. et al. Oral histone deacetylase inhibitor synergises with T cell targeted immunotherapy to preserve beta cell metabolic function and induce stable remission of new-onset autoimmune diabetes in NOD mice. Diabetologia 61, 389–398 (2018).

Download references

Author information

The authors contributed equally to all aspects of the article.

Correspondence to Marc Y. Donath.

Ethics declarations

Competing interests

M.Y.D. is listed as the inventor on a patent filed in 2003 for the use of an IL-1 receptor antagonist for the treatment of or prophylaxis for type 2 diabetes. C.A.D. and T.M.-P. declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

KAMADA T1D focus area:


Glucagon-like peptide 1

(GLP1). An intestinal incretin hormone that induces satiety and potentiates glucose-stimulated insulin secretion on oral feeding.

Sodium–glucose cotransporter 2 (SGLT2) inhibitors

Antidiabetic drugs that lower blood glucose levels by inhibiting renal reuptake of glucose.

Metabolic syndrome

A condition characterized by increased blood pressure, impaired glucose metabolism (prediabetes or type 2 diabetes), excess body weight and abnormal blood levels of lipids (cholesterol and triglycerides). It is associated with increased risk of cardiovascular diseases.

β-cell ‘rest’

Concept implying that inactive β-cells are resistant to metabolic, inflammatory and oxidative stress.

Haemoglobin A1c

(HbA1c). HbA1c (or glycated haemoglobin) level represents the average amount of glucose attached to haemoglobin and reflects the average level of blood glucose over the past 2–3 months.


A human monoclonal antibody targeting IL-1β.

Homeostatic model assessment

Model assessment of insulin sensitivity and secretion.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Further reading