Type 2 diabetes mellitus—an autoimmune disease?

Abstract

Inflammation-induced inhibition of the insulin signalling pathway can lead to insulin resistance and contribute to the development of type 2 diabetes mellitus (T2DM). Obesity and insulin resistance are associated with a chronic but subclinical inflammatory process that impairs insulin action in most tissues and could also hamper pancreatic β-cell function. The involvement of monocytic cells and the profiles of the chemokines and cytokines induced by this inflammation suggest an innate immune response. However, emerging data indicate that elements of the adaptive immune system could also be involved. As activation of an adaptive response requires antigen specificity, some researchers have hypothesized that T2DM evolves from an innate immune response to an autoimmune condition. In this Perspectives article, we present the arguments for and against this hypothesis and discuss which mechanisms could be involved in a putative switch from innate immunity to autoimmunity.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Putative pathways of progression from innate to adaptive immune responses in obesity and type 2 diabetes mellitus.

References

  1. 1

    Danaei, G. et al. National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants. Lancet 378, 31–40 (2011).

    CAS  Article  Google Scholar 

  2. 2

    Schulz, M. et al. Food groups as predictors for short-term weight changes in men and women of the EPIC-Potsdam cohort. J. Nutr. 132, 1335–1340 (2002).

    CAS  Article  Google Scholar 

  3. 3

    Shoelson, S. E., Lee, J. & Goldfine, A. B. Inflammation and insulin resistance. J. Clin. Invest. 116, 1793–1801 (2006).

    CAS  Article  Google Scholar 

  4. 4

    Tsukumo, D. M. et al. Loss-of-function mutation in Toll-like receptor 4 prevents diet-induced obesity and insulin resistance. Diabetes 56, 1986–1998 (2007).

    CAS  Article  Google Scholar 

  5. 5

    Ozcan, U. et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306, 457–461 (2004).

    Article  Google Scholar 

  6. 6

    Milanski, M. et al. Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: implications for the pathogenesis of obesity. J. Neurosci. 29, 359–370 (2009).

    CAS  Article  Google Scholar 

  7. 7

    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).

    CAS  Article  Google Scholar 

  8. 8

    Gregor, M. F. & Hotamisligil, G. S. Inflammatory mechanisms in obesity. Annu. Rev. Immunol. 29, 415–445 (2011).

    CAS  Article  Google Scholar 

  9. 9

    Cnop, M., Foufelle, F. & Velloso, L. A. Endoplasmic reticulum stress, obesity and diabetes. Trends Mol. Med. 18, 59–68 (2012).

    CAS  Article  Google Scholar 

  10. 10

    Eizirik, D. L., Miani, M. & Cardozo, A. K. Signalling danger: endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation. Diabetologia 56, 234–241 (2013).

    CAS  Article  Google Scholar 

  11. 11

    Osborn, O. & Olefsky, J. M. The cellular and signaling networks linking the immune system and metabolism in disease. Nat. Med. 18, 363–374 (2012).

    CAS  Article  Google Scholar 

  12. 12

    Guarda, G. et al. T cells dampen innate immune responses through inhibition of NLRP1 and NLRP3 inflammasomes. Nature 460, 269–273 (2009).

    CAS  Article  Google Scholar 

  13. 13

    Feuerer, M. et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat. Med. 15, 930–939 (2009).

    CAS  Article  Google Scholar 

  14. 14

    Winer, S. et al. Normalization of obesity-associated insulin resistance through immunotherapy. Nat. Med. 15, 921–929 (2009).

    CAS  Article  Google Scholar 

  15. 15

    Witebsky, E., Rose, N. R., Terplan, K., Paine, J. R. & Egan, R. W. Chronic thyroiditis and autoimmunization. J. Am. Med. Assoc. 164, 1439–1447 (1957).

    CAS  Article  Google Scholar 

  16. 16

    Ziegler, A. G. & Nepom, G. T. Prediction and pathogenesis in type 1 diabetes. Immunity 32, 468–478 (2010).

    CAS  Article  Google Scholar 

  17. 17

    Yang, Y. & Santamaria, P. Lessons on autoimmune diabetes from animal models. Clin. Sci. (Lond.) 110, 627–639 (2006).

    CAS  Article  Google Scholar 

  18. 18

    Roep, B. O. & Peakman, M. Diabetogenic T lymphocytes in human type 1 diabetes. Curr. Opin. Immunol. 23, 746–753 (2011).

    CAS  Article  Google Scholar 

  19. 19

    von Herrath, M., Peakman, M. & Roep, B. Progress in immune-based therapies for type 1 diabetes. Clin. Exp. Immunol. 172, 186–202 (2013).

    CAS  Article  Google Scholar 

  20. 20

    Eizirik, D. L., Colli, M. L. & Ortis, F. The role of inflammation in insulitis and β-cell loss in type 1 diabetes. Nat. Rev. Endocrinol. 5, 219–226 (2009).

    CAS  Article  Google Scholar 

  21. 21

    Winer, D. A. et al. B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nat. Med. 17, 610–617 (2011).

    CAS  Article  Google Scholar 

  22. 22

    Brooks-Worrell, B. M., Juneja, R., Minokadeh, A., Greenbaum, C. J. & Palmer, J. P. Cellular immune responses to human islet proteins in antibody-positive type 2 diabetic patients. Diabetes 48, 983–988 (1999).

    CAS  Article  Google Scholar 

  23. 23

    Barrett, J. C. et al. Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat. Genet. 41, 703–707 (2009).

    CAS  Article  Google Scholar 

  24. 24

    Dupuis, J. et al. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat. Genet. 42, 105–116 (2010).

    CAS  Article  Google Scholar 

  25. 25

    Rafiq, S. et al. Gene variants influencing measures of inflammation or predisposing to autoimmune and inflammatory diseases are not associated with the risk of type 2 diabetes. Diabetologia 51, 2205–2213 (2008).

    CAS  Article  Google Scholar 

  26. 26

    Winkler, C., Raab, J., Grallert, H. & Ziegler, A. G. Lack of association of type 2 diabetes susceptibility genotypes and body weight on the development of islet autoimmunity and type 1 diabetes. PLoS One 7, e35410 (2012).

    CAS  Article  Google Scholar 

  27. 27

    Speliotes, E. K. et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat. Genet. 42, 937–948 (2010).

    CAS  Article  Google Scholar 

  28. 28

    Hempel, P. et al. Sera from patients with type 2 diabetes contain agonistic autoantibodies against G protein-coupled receptors. Scand. J. Immunol. 70, 159–160 (2009).

    CAS  Article  Google Scholar 

  29. 29

    Zimering, M. B. & Pan, Z. Autoantibodies in type 2 diabetes induce stress fiber formation and apoptosis in endothelial cells. J. Clin. Endocrinol. Metab. 94, 2171–2177 (2009).

    CAS  Article  Google Scholar 

  30. 30

    Fosgerau, K. et al. Interleukin-6 autoantibodies are involved in the pathogenesis of a subset of type 2 diabetes. J. Endocrinol. 204, 265–273 (2010).

    CAS  Article  Google Scholar 

  31. 31

    Wu, H. et al. T-cell accumulation and regulated on activation, normal T cell expressed and secreted upregulation in adipose tissue in obesity. Circulation 115, 1029–1038 (2007).

    CAS  Article  Google Scholar 

  32. 32

    Corre, J. et al. Human subcutaneous adipose cells support complete differentiation but not self-renewal of hematopoietic progenitors. J. Cell Physiol. 208, 282–288 (2006).

    CAS  Article  Google Scholar 

  33. 33

    Rocha, V. Z. et al. Interferon-gamma, a Th1 cytokine, regulates fat inflammation: a role for adaptive immunity in obesity. Circ. Res. 103, 467–476 (2008).

    CAS  Article  Google Scholar 

  34. 34

    Nishimura, S. et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat. Med. 15, 914–920 (2009).

    CAS  Article  Google Scholar 

  35. 35

    Ilan, Y. et al. Induction of regulatory T cells decreases adipose inflammation and alleviates insulin resistance in ob/ob mice. Proc. Natl Acad. Sci. USA 107, 9765–9770 (2010).

    CAS  Article  Google Scholar 

  36. 36

    Yang, H. et al. Obesity increases the production of proinflammatory mediators from adipose tissue T cells and compromises TCR repertoire diversity: implications for systemic inflammation and insulin resistance. J. Immunol. 185, 1836–1845 (2010).

    CAS  Article  Google Scholar 

  37. 37

    Savic, S., Dickie, L. J., Wittmann, M. & McDermott, M. F. Autoinflammatory syndromes and cellular responses to stress: pathophysiology, diagnosis and new treatment perspectives. Best Pract. Res. Clin. Rheumatol. 26, 505–533 (2012).

    CAS  Article  Google Scholar 

  38. 38

    Araujo, E. P. et al. Infliximab restores glucose homeostasis in an animal model of diet-induced obesity and diabetes. Endocrinology 148, 5991–5997 (2007).

    CAS  Article  Google Scholar 

  39. 39

    Larsen, C. M. et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N. Engl. J. Med. 356, 1517–1526 (2007).

    CAS  Article  Google Scholar 

  40. 40

    Goldfine, A. B. et al. The effects of salsalate on glycemic control in patients with type 2 diabetes: a randomized trial. Ann. Intern. Med. 152, 346–357 (2010).

    Article  Google Scholar 

  41. 41

    Tuncman, G. et al. Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance. Proc. Natl Acad. Sci. USA 103, 10741–10746 (2006).

    CAS  Article  Google Scholar 

  42. 42

    Perreault, M. & Marette, A. Targeted disruption of inducible nitric oxide synthase protects against obesity-linked insulin resistance in muscle. Nat. Med. 7, 1138–1143 (2001).

    CAS  Article  Google Scholar 

  43. 43

    Thaler, J. P. et al. Obesity is associated with hypothalamic injury in rodents and humans. J. Clin. Invest. 122, 153–162 (2012).

    CAS  Article  Google Scholar 

  44. 44

    Velloso, L. A. & Schwartz, M. W. Altered hypothalamic function in diet-induced obesity. Int. J. Obes (Lond.) 35, 1455–1465 (2011).

    CAS  Article  Google Scholar 

  45. 45

    Milanski, M. et al. Inhibition of hypothalamic inflammation reverses diet-induced insulin resistance in the liver. Diabetes 61, 1455–1462 (2012).

    CAS  Article  Google Scholar 

  46. 46

    Calegari, V. C. et al. Inflammation of the hypothalamus leads to defective pancreatic islet function. J. Biol. Chem. 286, 12870–12880 (2011).

    CAS  Article  Google Scholar 

  47. 47

    Purkayastha, S., Zhang, G. & Cai, D. Uncoupling the mechanisms of obesity and hypertension by targeting hypothalamic IKK-β and NF-κB. Nat. Med. 17, 883–887 (2011).

    CAS  Article  Google Scholar 

  48. 48

    Calay, E. S. & Hotamisligil, G. S. Turning off the inflammatory, but not the metabolic, flames. Nat. Med. 19, 265–267 (2013).

    CAS  Article  Google Scholar 

  49. 49

    Brooks-Worrell, B., Narla, R. & Palmer, J. P. Biomarkers and immune-modulating therapies for type 2 diabetes. Trends Immunol. 33, 546–553 (2012).

    CAS  Article  Google Scholar 

  50. 50

    Barbarroja, N. et al. Progression from high insulin resistance to type 2 diabetes does not entail additional visceral adipose tissue inflammation. PLoS One 7, e48155 (2012).

    CAS  Article  Google Scholar 

  51. 51

    Ehses, J. A. et al. Increased number of islet-associated macrophages in type 2 diabetes. Diabetes 56, 2356–2370 (2007).

    CAS  Article  Google Scholar 

  52. 52

    Richardson, S. J., Willcox, A., Bone, A. J., Foulis, A. K. & Morgan, N. G. Islet-associated macrophages in type 2 diabetes. Diabetologia 52, 1686–1688 (2009).

    CAS  Article  Google Scholar 

  53. 53

    Masters, S. L. et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes. Nat. Immunol. 11, 897–904 (2010).

    CAS  Article  Google Scholar 

  54. 54

    Igoillo-Esteve, M. et al. Palmitate induces a pro-inflammatory response in human pancreatic islets that mimics CCL2 expression by β cells in type 2 diabetes. Diabetologia 53, 1395–1405 (2010).

    CAS  Article  Google Scholar 

  55. 55

    Mahdi, T. et al. Secreted frizzled-related protein 4 reduces insulin secretion and is overexpressed in type 2 diabetes. Cell Metab. 16, 625–633 (2012).

    CAS  Article  Google Scholar 

  56. 56

    Tuomi, T. et al. Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with a non-insulin-dependent onset of disease. Diabetes 42, 359–362 (1993).

    CAS  Article  Google Scholar 

  57. 57

    Brooks-Worrell, B. & Palmer, J. P. Immunology in the Clinic Review Series; focus on metabolic diseases: development of islet autoimmune disease in type 2 diabetes patients: potential sequelae of chronic inflammation. Clin. Exp. Immunol. 167, 40–46 (2012).

    CAS  Article  Google Scholar 

  58. 58

    Cnop, M. et al. Mechanisms of pancreatic β-cell death in type 1 and type 2 diabetes: many differences, few similarities. Diabetes 54 (Suppl. 2), S97–S107 (2005).

    CAS  Article  Google Scholar 

  59. 59

    Reilly, S. M. et al. An inhibitor of the protein kinases TBK1 and IKK-ε improves obesity-related metabolic dysfunctions in mice. Nat. Med. 19, 313–321 (2013).

    CAS  Article  Google Scholar 

  60. 60

    Brassard, P. et al. Modulation of T-cell signalling by non-esterified fatty acids. Prostaglandins Leukot. Essent. Fatty Acids 77, 337–343 (2007).

    CAS  Article  Google Scholar 

  61. 61

    Beckman, E. M. et al. Recognition of a lipid antigen by CD1-restricted αβ+ T cells. Nature 372, 691–694 (1994).

    CAS  Article  Google Scholar 

  62. 62

    Cohen, N. R., Garg, S. & Brenner, M. B. Antigen presentation by CD1 lipids, T cells, and NKT cells in microbial immunity. Adv. Immunol. 102, 1–94 (2009).

    CAS  Article  Google Scholar 

  63. 63

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

    CAS  Article  Google Scholar 

  64. 64

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

    Article  Google Scholar 

  65. 65

    Caricilli, A. M. et al. Gut microbiota is a key modulator of insulin resistance in TLR 2 knockout mice. PLoS Biol. 9, e1001212 (2011).

    CAS  Article  Google Scholar 

  66. 66

    Geddes, K. et al. Identification of an innate T helper type 17 response to intestinal bacterial pathogens. Nat. Med. 17, 837–844 (2011).

    CAS  Article  Google Scholar 

  67. 67

    Atarashi, K. & Honda, K. Microbiota in autoimmunity and tolerance. Curr. Opin. Immunol. 23, 761–768 (2011).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

The authors' research is supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (Brazil), the Communauté Française de Belgique—Actions de Recherche Concertées, and the European Union projects Naimit and BetaBat, in the Framework Programme 7 of the European Community. The authors are also grateful to Mark Peakman of King's College London, UK, and Bart Roep of Leiden University Medical Centre, The Netherlands, for helpful discussions.

Author information

Affiliations

Authors

Contributions

The authors contributed equally to all aspects of this article.

Corresponding author

Correspondence to Lício A. Velloso.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Velloso, L., Eizirik, D. & Cnop, M. Type 2 diabetes mellitus—an autoimmune disease?. Nat Rev Endocrinol 9, 750–755 (2013). https://doi.org/10.1038/nrendo.2013.131

Download citation

Further reading

Search

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing