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).
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).
Shoelson, S. E., Lee, J. & Goldfine, A. B. Inflammation and insulin resistance. J. Clin. Invest. 116, 1793–1801 (2006).
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).
Ozcan, U. et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306, 457–461 (2004).
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).
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).
Gregor, M. F. & Hotamisligil, G. S. Inflammatory mechanisms in obesity. Annu. Rev. Immunol. 29, 415–445 (2011).
Cnop, M., Foufelle, F. & Velloso, L. A. Endoplasmic reticulum stress, obesity and diabetes. Trends Mol. Med. 18, 59–68 (2012).
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).
Osborn, O. & Olefsky, J. M. The cellular and signaling networks linking the immune system and metabolism in disease. Nat. Med. 18, 363–374 (2012).
Guarda, G. et al. T cells dampen innate immune responses through inhibition of NLRP1 and NLRP3 inflammasomes. Nature 460, 269–273 (2009).
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).
Winer, S. et al. Normalization of obesity-associated insulin resistance through immunotherapy. Nat. Med. 15, 921–929 (2009).
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).
Ziegler, A. G. & Nepom, G. T. Prediction and pathogenesis in type 1 diabetes. Immunity 32, 468–478 (2010).
Yang, Y. & Santamaria, P. Lessons on autoimmune diabetes from animal models. Clin. Sci. (Lond.) 110, 627–639 (2006).
Roep, B. O. & Peakman, M. Diabetogenic T lymphocytes in human type 1 diabetes. Curr. Opin. Immunol. 23, 746–753 (2011).
von Herrath, M., Peakman, M. & Roep, B. Progress in immune-based therapies for type 1 diabetes. Clin. Exp. Immunol. 172, 186–202 (2013).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Nishimura, S. et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat. Med. 15, 914–920 (2009).
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).
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).
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).
Araujo, E. P. et al. Infliximab restores glucose homeostasis in an animal model of diet-induced obesity and diabetes. Endocrinology 148, 5991–5997 (2007).
Larsen, C. M. et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N. Engl. J. Med. 356, 1517–1526 (2007).
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).
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).
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).
Thaler, J. P. et al. Obesity is associated with hypothalamic injury in rodents and humans. J. Clin. Invest. 122, 153–162 (2012).
Velloso, L. A. & Schwartz, M. W. Altered hypothalamic function in diet-induced obesity. Int. J. Obes (Lond.) 35, 1455–1465 (2011).
Milanski, M. et al. Inhibition of hypothalamic inflammation reverses diet-induced insulin resistance in the liver. Diabetes 61, 1455–1462 (2012).
Calegari, V. C. et al. Inflammation of the hypothalamus leads to defective pancreatic islet function. J. Biol. Chem. 286, 12870–12880 (2011).
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).
Calay, E. S. & Hotamisligil, G. S. Turning off the inflammatory, but not the metabolic, flames. Nat. Med. 19, 265–267 (2013).
Brooks-Worrell, B., Narla, R. & Palmer, J. P. Biomarkers and immune-modulating therapies for type 2 diabetes. Trends Immunol. 33, 546–553 (2012).
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).
Ehses, J. A. et al. Increased number of islet-associated macrophages in type 2 diabetes. Diabetes 56, 2356–2370 (2007).
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).
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).
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).
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).
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).
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).
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).
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).
Brassard, P. et al. Modulation of T-cell signalling by non-esterified fatty acids. Prostaglandins Leukot. Essent. Fatty Acids 77, 337–343 (2007).
Beckman, E. M. et al. Recognition of a lipid antigen by CD1-restricted αβ+ T cells. Nature 372, 691–694 (1994).
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).
Cani, P. D. et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56, 1761–1772 (2007).
Turnbaugh, P. J. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006).
Caricilli, A. M. et al. Gut microbiota is a key modulator of insulin resistance in TLR 2 knockout mice. PLoS Biol. 9, e1001212 (2011).
Geddes, K. et al. Identification of an innate T helper type 17 response to intestinal bacterial pathogens. Nat. Med. 17, 837–844 (2011).
Atarashi, K. & Honda, K. Microbiota in autoimmunity and tolerance. Curr. Opin. Immunol. 23, 761–768 (2011).