Type 1 diabetes mellitus

Abstract

Type 1 diabetes mellitus (T1DM), also known as autoimmune diabetes, is a chronic disease characterized by insulin deficiency due to pancreatic β-cell loss and leads to hyperglycaemia. Although the age of symptomatic onset is usually during childhood or adolescence, symptoms can sometimes develop much later. Although the aetiology of T1DM is not completely understood, the pathogenesis of the disease is thought to involve T cell-mediated destruction of β-cells. Islet-targeting autoantibodies that target insulin, 65 kDa glutamic acid decarboxylase, insulinoma-associated protein 2 and zinc transporter 8 — all of which are proteins associated with secretory granules in β-cells — are biomarkers of T1DM-associated autoimmunity that are found months to years before symptom onset, and can be used to identify and study individuals who are at risk of developing T1DM. The type of autoantibody that appears first depends on the environmental trigger and on genetic factors. The pathogenesis of T1DM can be divided into three stages depending on the absence or presence of hyperglycaemia and hyperglycaemia-associated symptoms (such as polyuria and thirst). A cure is not available, and patients depend on lifelong insulin injections; novel approaches to insulin treatment, such as insulin pumps, continuous glucose monitoring and hybrid closed-loop systems, are in development. Although intensive glycaemic control has reduced the incidence of microvascular and macrovascular complications, the majority of patients with T1DM are still developing these complications. Major research efforts are needed to achieve early diagnosis, prevent β-cell loss and develop better treatment options to improve the quality of life and prognosis of those affected.

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Figure 1: Staging of T1DM.
Figure 2: The incidence and prevalence of T1DM in children.
Figure 3: Age-specific incidence rates of T1DM.
Figure 4: Pathogenesis of T1DM.
Figure 5: Pancreatic inflammation and insulitis in T1DM.
Figure 6: Mechanisms of hyperglycaemia-induced cellular damage.

References

  1. 1

    SEARCH Study Group. SEARCH for Diabetes in Youth: a multicenter study of the prevalence, incidence and classification of diabetes mellitus in youth. Control. Clin. Trials 25, 458–471 (2004).

    Google Scholar 

  2. 2

    Gepts, W. Pathologic anatomy of the pancreas in juvenile diabetes mellitus. Diabetes 14, 619–633 (1965). This paper represents the hallmark investigation and rediscovery of insulitis in individuals who died shortly after the clinical diagnosis of T1DM.

    Google Scholar 

  3. 3

    Eisenbarth, G. S. Type I diabetes mellitus. A chronic autoimmune disease. N. Engl. J. Med. 314, 1360–1368 (1986). This review describes the concept of T1DM pathogenesis that eventually resulted in the staging of T1DM depicted in Figure 1 of this Primer.

    Google Scholar 

  4. 4

    Atkinson, M. A., Eisenbarth, G. S. & Michels, A. W. Type 1 diabetes. Lancet 383, 69–82 (2014).

    Google Scholar 

  5. 5

    American Diabetes Association. 2. Classification and diagnosis of diabetes. Diabetes Care 38, S8–S16 (2015).

    Google Scholar 

  6. 6

    Ziegler, A. G., Hummel, M., Schenker, M. & Bonifacio, E. Autoantibody appearance and risk for development of childhood diabetes in offspring of parents with type 1 diabetes: the 2-year analysis of the German BABYDIAB Study. Diabetes 48, 460–468 (1999).

    Google Scholar 

  7. 7

    Ilonen, J. et al. Patterns of β-cell autoantibody appearance and genetic associations during the first years of life. Diabetes 62, 3636–3640 (2013). This is the first investigation to dissect the temporal pattern of the first-appearing β-cell-targeting autoantibody as a biomarker of T1DM.

    Google Scholar 

  8. 8

    Krischer, J. P. et al. The 6 year incidence of diabetes-associated autoantibodies in genetically at-risk children: the TEDDY study. Diabetologia 58, 980–987 (2015).

    Google Scholar 

  9. 9

    Ziegler, A. G. et al. Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA 309, 2473–2479 (2013). These authors merge data from three independent longitudinal studies that followed children from birth and demonstrate that the presence of multiple β-cell-targeting autoantibodies inevitably leads to the clinical onset of T1DM.

    Google Scholar 

  10. 10

    Rewers, M. et al. Newborn screening for HLA markers associated with IDDM: diabetes autoimmunity study in the young (DAISY). Diabetologia 39, 807–812 (1996).

    Google Scholar 

  11. 11

    Nejentsev, S. et al. Population-based genetic screening for the estimation of type 1 diabetes mellitus risk in Finland: selective genotyping of markers in the HLA-DQB1, HLA-DQA1 and HLA-DRB1 loci. Diabet. Med. 16, 985–992 (1999).

    Google Scholar 

  12. 12

    TEDDY Study Group. The Environmental Determinants of Diabetes in the Young (TEDDY) study: study design. Pediatr. Diabetes 8, 286–298 (2007).

    Google Scholar 

  13. 13

    Insel, R. A. et al. Staging presymptomatic type 1 diabetes: a scientific statement of JDRF, the Endocrine Society, and the American Diabetes Association. Diabetes Care 38, 1964–1974 (2015).

    Google Scholar 

  14. 14

    International Diabetes Federation. IDF diabetes atlas. IDF http://www.diabetesatlas.org/component/attachments/?task=download&id=116 (2015).

  15. 15

    Diaz-Valencia, P. A., Bougneres, P. & Valleron, A. J. Global epidemiology of type 1 diabetes in young adults and adults: a systematic review. BMC Public Health 15, 255 (2015).

    Google Scholar 

  16. 16

    Askar, M. et al. 16th IHIW: global distribution of extended HLA haplotypes. Int. J. Immunogenet. 40, 31–38 (2013).

    Google Scholar 

  17. 17

    Erlich, H. A. et al. HLA class II alleles and susceptibility and resistance to insulin dependent diabetes mellitus in Mexican-American families. Nat. Genet. 3, 358–364 (1993).

    Google Scholar 

  18. 18

    Delli, A. J. et al. Type 1 diabetes patients born to immigrants to Sweden increase their native diabetes risk and differ from Swedish patients in HLA types and islet autoantibodies. Pediatr. Diabetes 11, 513–520 (2010).

    Google Scholar 

  19. 19

    Serrano-Rios, M., Goday, A. & Martinez Larrad, T. Migrant populations and the incidence of type 1 diabetes mellitus: an overview of the literature with a focus on the Spanish-heritage countries in Latin America. Diabetes Metab. Res. Rev. 15, 113–132 (1999).

    Google Scholar 

  20. 20

    Kondrashova, A., Seiskari, T., Ilonen, J., Knip, M. & Hyoty, H. The ‘hygiene hypothesis’ and the sharp gradient in the incidence of autoimmune and allergic diseases between Russian Karelia and Finland. APMIS 121, 478–493 (2013). Along with other studies by the same authors, this study demonstrates the importance of gene–environment interactions in the risk of developing both allergies and cell-specific autoimmune diseases such as T1DM.

    Google Scholar 

  21. 21

    Patterson, C. C., Dahlquist, G. G., Gyurus, E., Green, A. & Soltesz, G. Incidence trends for childhood type 1 diabetes in Europe during 1989–2003 and predicted new cases 2005–20: a multicentre prospective registration study. Lancet 373, 2027–2033 (2009).

    Google Scholar 

  22. 22

    Thunander, M. et al. Incidence of type 1 and type 2 diabetes in adults and children in Kronoberg, Sweden. Diabetes Res. Clin. Pract. 82, 247–255 (2008).

    Google Scholar 

  23. 23

    Turner, R. et al. UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. UK Prospective Diabetes Study Group. Lancet 350, 1288–1293 (1997).

    Google Scholar 

  24. 24

    Landin-Olsson, M., Nilsson, K. O., Lernmark, Å. & Sundkvist, G. Islet cell antibodies and fasting C-peptide predict insulin requirement at diagnosis of diabetes mellitus. Diabetologia 33, 561–568 (1990).

    Google Scholar 

  25. 25

    Hagopian, W. A. et al. Quantitative assay using recombinant human islet glutamic acid decarboxylase (GAD65) shows that 64K autoantibody positivity at onset predicts diabetes type. J. Clin. Invest. 91, 368–374 (1993).

    Google Scholar 

  26. 26

    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).

    Google Scholar 

  27. 27

    Svensson, J., Carstensen, B., Mortensen, H. B. & Borch-Johnsen, K. Early childhood risk factors associated with type 1 diabetes — is gender important? Eur. J. Epidemiol. 20, 429–434 (2005).

    Google Scholar 

  28. 28

    Patterson, C. C. et al. Trends in childhood type 1 diabetes incidence in Europe during 1989–2008: evidence of non-uniformity over time in rates of increase. Diabetologia 55, 2142–2147 (2012).

    Google Scholar 

  29. 29

    Soltesz, G., Patterson, C. C. & Dahlquist, G. Worldwide childhood type 1 diabetes incidence — what can we learn from epidemiology? Pediatr. Diabetes 8 (Suppl. 6), 6–14 (2007).

    Google Scholar 

  30. 30

    Rawshani, A. et al. The incidence of diabetes among 0–34 year olds in Sweden: new data and better methods. Diabetologia 57, 1375–1381 (2014).

    Google Scholar 

  31. 31

    Bonifacio, E. et al. Harmonization of glutamic acid decarboxylase and islet antigen-2 autoantibody assays for National Institute of Diabetes and Digestive and Kidney Diseases consortia. J. Clin. Endocrinol. Metab. 95, 3360–3367 (2010).

    Google Scholar 

  32. 32

    Vehik, K. et al. Development of autoantibodies in the TrialNet Natural History Study. Diabetes Care 34, 1897–1901 (2011).

    Google Scholar 

  33. 33

    Sosenko, J. M. et al. The prediction of type 1 diabetes by multiple autoantibody levels and their incorporation into an autoantibody risk score in relatives of type 1 diabetic patients. Diabetes Care 36, 2615–2620 (2013).

    Google Scholar 

  34. 34

    Xu, P. & Krischer, J. P. Prognostic classification factors associated with development of multiple autoantibodies, dysglycemia, and type 1 diabetes — a recursive partitioning analysis. Diabetes Care 39, 1036–1044 (2016).

    Google Scholar 

  35. 35

    Bonifacio, E. Predicting type 1 diabetes using biomarkers. Diabetes Care 38, 989–996 (2015).

    Google Scholar 

  36. 36

    LaGasse, J. M. et al. Successful prospective prediction of type 1 diabetes in schoolchildren through multiple defined autoantibodies: an 8-year follow-up of the Washington State Diabetes Prediction Study. Diabetes Care 25, 505–511 (2002).

    Google Scholar 

  37. 37

    Schlosser, M. et al. The Karlsburg type 1 diabetes risk study of a normal schoolchild population: association of β-cell autoantibodies and human leukocyte antigen-DQB1 alleles in antibody-positive individuals. J. Clin. Endocrinol. Metab. 87, 2254–2261 (2002).

    Google Scholar 

  38. 38

    Mahon, J. L. et al. The TrialNet Natural History Study of the development of type 1 diabetes: objectives, design, and initial results. Pediatr. Diabetes 10, 97–104 (2009).

    Google Scholar 

  39. 39

    Gorus, F. K. et al. Influence of age on the associations among insulin autoantibodies, islet cell antibodies, and HLA DAQ1*0301-DQB1*0302 in siblings of patients with type 1 (insulin-dependent) diabetes mellitus. Belgian Diabetes Registry. J. Clin. Endocrinol. Metab. 78, 1172–1178 (1994).

    Google Scholar 

  40. 40

    Rolandsson, O. et al. Glutamate decarboxylase (GAD65) and tyrosine phosphatase-like protein (IA-2) autoantibodies index in a regional population is related to glucose intolerance and body mass index. Diabetologia 42, 555–559 (1999).

    Google Scholar 

  41. 41

    Rewers, M. et al. β-cell autoantibodies in infants and toddlers without IDDM relatives: Diabetes Autoimmunity Study in the Young (DAISY). J. Autoimmun. 9, 405–410 (1996).

    Google Scholar 

  42. 42

    Hagopian, W. A. et al. The Environmental Determinants of Diabetes in the Young (TEDDY): genetic criteria and international diabetes risk screening of 421 000 infants. Pediatr. Diabetes 12, 733–743 (2011).

    Google Scholar 

  43. 43

    Wenzlau, J. M. et al. A common nonsynonymous single nucleotide polymorphism in the SLC30A8 gene determines ZnT8 autoantibody specificity in type 1 diabetes. Diabetes 57, 2693–2697 (2008).

    Google Scholar 

  44. 44

    Savola, K. et al. IA-2 antibodies — a sensitive marker of IDDM with clinical onset in childhood and adolescence. Childhood Diabetes in Finland Study Group. Diabetologia 41, 424–429 (1998).

    Google Scholar 

  45. 45

    Lampasona, V. et al. Zinc transporter 8 antibodies complement GAD and IA-2 antibodies in the identification and characterization of adult-onset autoimmune diabetes: non insulin requiring autoimmune diabetes (NIRAD) 4. Diabetes Care 33, 104–108 (2010).

    Google Scholar 

  46. 46

    Skarstrand, H. et al. Zinc transporter 8 (ZnT8) autoantibody epitope specificity and affinity examined with recombinant ZnT8 variant proteins in specific ZnT8R and ZnT8W autoantibody-positive type 1 diabetes patients. Clin. Exp. Immunol. 179, 220–229 (2015).

    Google Scholar 

  47. 47

    Tuomilehto, J. The emerging global epidemic of type 1 diabetes. Curr. Diab. Rep. 13, 795–804 (2013).

    Google Scholar 

  48. 48

    Redondo, M. J., Jeffrey, J., Fain, P. R., Eisenbarth, G. S. & Orban, T. Concordance for islet autoimmunity among monozygotic twins. N. Engl. J. Med. 359, 2849–2850 (2008).

    Google Scholar 

  49. 49

    Nerup, J. et al. HL-A antigens and diabetes mellitus. Lancet 2, 864–866 (1974).

    Google Scholar 

  50. 50

    Singal, D. P. & Blajchman, M. A. Histocompatibility (HL-A) antigens, lymphocytotoxic antibodies and tissue antibodies in patients with diabetes mellitus. Diabetes 22, 429–432 (1973).

    Google Scholar 

  51. 51

    Cudworth, A. G. & Woodrow, J. C. Evidence for HL-A-linked genes in “juvenile” diabetes mellitus. Br. Med. J. 3, 133–135 (1975).

    Google Scholar 

  52. 52

    Erlich, H. A. et al. Next generation sequencing reveals the association of DRB3*02:02 with type 1 diabetes. Diabetes 62, 2618–2622 (2013).

    Google Scholar 

  53. 53

    Caillat-Zucman, S. et al. Age-dependent HLA genetic heterogeneity of type 1 insulin-dependent diabetes mellitus. J. Clin. Invest. 90, 2242–2250 (1992).

    Google Scholar 

  54. 54

    Cucca, F. et al. The distribution of DR4 haplotypes in Sardinia suggests a primary association of type I diabetes with DRB1 and DQB1 loci. Hum. Immunol. 43, 301–308 (1995).

    Google Scholar 

  55. 55

    Zhao, L. P. et al. Next-generation sequencing reveals that HLA-DRB3, -DRB4, and -DRB5 may be associated with islet autoantibodies and risk for childhood type 1 diabetes. Diabetes 65, 710–718 (2016).

    Google Scholar 

  56. 56

    Graham, J. et al. Genetic effects on age-dependent onset and islet cell autoantibody markers in type 1 diabetes. Diabetes 51, 1346–1355 (2002). This major investigation of patients with newly diagnosed T1DM (1–34 years of age) demonstrates that the age-dependent onset of T1DM is strongly related to the presence of β-cell-targeting autoantibodies, which is associated with specific HLA-DR-DQ genotypes.

    Google Scholar 

  57. 57

    Dahlquist, G. et al. The epidemiology of diabetes in Swedish children 0–14 years — a six-year prospective study. Diabetologia 28, 802–808 (1985).

    Google Scholar 

  58. 58

    Parkkola, A., Harkonen, T., Ryhanen, S. J., Ilonen, J. & Knip, M. Extended family history of type 1 diabetes and phenotype and genotype of newly diagnosed children. Diabetes Care 36, 348–354 (2013).

    Google Scholar 

  59. 59

    Torn, C. et al. Role of type 1 diabetes-associated SNPs on risk of autoantibody positivity in the TEDDY study. Diabetes 64, 1818–1829 (2015).

    Google Scholar 

  60. 60

    Wester, A. et al. An increased diagnostic sensitivity of truncated GAD65 autoantibodies in type 1 diabetes may be related to HLA-DQ8. Diabetes 66, 735–740 (2016).

    Google Scholar 

  61. 61

    Cooper, J. D. et al. Confirmation of novel type 1 diabetes risk loci in families. Diabetologia 55, 996–1000 (2012).

    Google Scholar 

  62. 62

    Pociot, F. & Lernmark, Å. Genetic risk factors for type 1 diabetes. Lancet 387, 2331–2339 (2016).

    Google Scholar 

  63. 63

    Rich, S. S. et al. Overview of the Type I Diabetes Genetics Consortium. Genes Immun. 10, S1–S4 (2009).

    Google Scholar 

  64. 64

    Bell, G. I., Pictet, R. & Rutter, W. J. Analysis of the regions flanking the human insulin gene and sequence of an Alu family member. Nucleic Acids Res. 8, 4091–4109 (1980).

    Google Scholar 

  65. 65

    Polychronakos, C. & Li, Q. Understanding type 1 diabetes through genetics: advances and prospects. Nat. Rev. Genet. 12, 781–792 (2011).

    Google Scholar 

  66. 66

    Pugliese, A. et al. The insulin gene is transcribed in the human thymus and transcription levels correlated with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes. Nat. Genet. 15, 293–297 (1997).

    Google Scholar 

  67. 67

    Beyerlein, A., Donnachie, E., Jergens, S. & Ziegler, A. G. Infections in early life and development of type 1 diabetes. JAMA 315, 1899–1901 (2016).

    Google Scholar 

  68. 68

    Ashton, M. P. et al. Incomplete immune response to coxsackie B viruses associates with early autoimmunity against insulin. Sci. Rep. 6, 32899 (2016).

    Google Scholar 

  69. 69

    Hyoty, H. Viruses in type 1 diabetes. Pediatr. Diabetes 17 (Suppl. 22), 56–64 (2016).

    Google Scholar 

  70. 70

    Knip, M., Virtanen, S. M. & Akerblom, H. K. Infant feeding and the risk of type 1 diabetes. Am. J. Clin. Nutr. 91, 1506S–1513S (2010).

    Google Scholar 

  71. 71

    La Torre, D. et al. Decreased cord-blood phospholipids in young age-at-onset type 1 diabetes. Diabetes 62, 3951–3956 (2013).

    Google Scholar 

  72. 72

    Oresic, M. et al. Cord serum lipidome in prediction of islet autoimmunity and type 1 diabetes. Diabetes 62, 3268–3274 (2013).

    Google Scholar 

  73. 73

    Lynch, K. F. et al. Cord blood islet autoantibodies and seasonal association with the type 1 diabetes high-risk genotype. J. Perinatol. 28, 211–217 (2008).

    Google Scholar 

  74. 74

    Resic Lindehammer, S. et al. Seroconversion to islet autoantibodies after enterovirus infection in early pregnancy. Viral Immunol. 25, 254–261 (2012).

    Google Scholar 

  75. 75

    Viskari, H. R. et al. Maternal first-trimester enterovirus infection and future risk of type 1 diabetes in the exposed fetus. Diabetes 51, 2568–2571 (2002).

    Google Scholar 

  76. 76

    Bonifacio, E. et al. Maternal type 1 diabetes reduces the risk of islet autoantibodies: relationships with birthweight and maternal HbA1c . Diabetologia 51, 1245–1252 (2008).

    Google Scholar 

  77. 77

    Hofer, J. et al. Elevated proportions of recent thymic emigrants in children and adolescents with type 1 diabetes. Rejuvenation Res. 12, 311–320 (2009).

    Google Scholar 

  78. 78

    Wong, F. S. How does B-cell tolerance contribute to the protective effects of diabetes following induced mixed chimerism in autoimmune diabetes? Diabetes 63, 1855–1857 (2014).

    Google Scholar 

  79. 79

    Roep, B. O. & Peakman, M. Antigen targets of type 1 diabetes autoimmunity. Cold Spring Harb. Perspect. Med. 2, a007781 (2012).

    Google Scholar 

  80. 80

    Oling, V., Reijonen, H., Simell, O., Knip, M. & Ilonen, J. Autoantigen-specific memory CD4+ T cells are prevalent early in progression to type 1 diabetes. Cell. Immunol. 273, 133–139 (2012).

    Google Scholar 

  81. 81

    van Lummel, M. et al. Post-translational modification of HLA-DQ binding islet-autoantigens in type 1 diabetes. Diabetes 63, 237–247 (2014).

    Google Scholar 

  82. 82

    Delong, T. et al. Pathogenic CD4 T cells in type 1 diabetes recognize epitopes formed by peptide fusion. Science 351, 711–714 (2016).

    Google Scholar 

  83. 83

    McLaughlin, R. J., Spindler, M. P., van Lummel, M. & Roep, B. O. Where, how, and when: positioning posttranslational modification within type 1 diabetes pathogenesis. Curr. Diab. Rep. 16, 63 (2016).

    Google Scholar 

  84. 84

    Yang, J. et al. Autoreactive T cells specific for insulin B:11–23 recognize a low-affinity peptide register in human subjects with autoimmune diabetes. Proc. Natl Acad. Sci. USA 111, 14840–14845 (2014).

    Google Scholar 

  85. 85

    Yang, J., James, E. A., Sanda, S., Greenbaum, C. & Kwok, W. W. CD4+ T cells recognize diverse epitopes within GAD65: implications for repertoire development and diabetes monitoring. Immunology 138, 269–279 (2013).

    Google Scholar 

  86. 86

    Miani, M., Colli, M. L., Ladriere, L., Cnop, M. & Eizirik, D. L. Mild endoplasmic reticulum stress augments the proinflammatory effect of IL-1β in pancreatic rat β-cells via the IRE1α/XBP1s pathway. Endocrinology 153, 3017–3028 (2012).

    Google Scholar 

  87. 87

    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).

    Google Scholar 

  88. 88

    James, E. A. et al. Immunology of Diabetes Society T-cell workshop: HLA class II tetramer-directed epitope validation initiative. Diabetes Metab. Res. Rev. 27, 727–736 (2011).

    Google Scholar 

  89. 89

    McGinty, J. W. et al. Recognition of posttranslationally modified GAD65 epitopes in subjects with type 1 diabetes. Diabetes 63, 3033–3040 (2014).

    Google Scholar 

  90. 90

    Wiberg, A. et al. Characterization of human organ donors testing positive for type 1 diabetes-associated autoantibodies. Clin. Exp. Immunol. 182, 278–288 (2015).

    Google Scholar 

  91. 91

    Babon, J. A. et al. Analysis of self-antigen specificity of islet-infiltrating T cells from human donors with type 1 diabetes. Nat. Med. 22, 1482–1487 (2016).

    Google Scholar 

  92. 92

    Campbell-Thompson, M. Organ donor specimens: what can they tell us about type 1 diabetes? Pediatr. Diabetes 16, 320–330 (2015).

    Google Scholar 

  93. 93

    In't Veld, P. et al. Screening for insulitis in adult autoantibody-positive organ donors. Diabetes 56, 2400–2404 (2007).

    Google Scholar 

  94. 94

    Richardson, S. J. et al. Islet cell hyperexpression of HLA class I antigens: a defining feature in type 1 diabetes. Diabetologia 59, 2448–2458 (2016).

    Google Scholar 

  95. 95

    Sosenko, J. M. et al. A new approach for diagnosing type 1 diabetes in autoantibody-positive individuals based on prediction and natural history. Diabetes Care 38, 271–276 (2015).

    Google Scholar 

  96. 96

    Helminen, O. et al. OGTT and random plasma glucose in the prediction of type 1 diabetes and time to diagnosis. Diabetologia 58, 1787–1796 (2015).

    Google Scholar 

  97. 97

    Sosenko, J. M. et al. Acceleration of the loss of the first-phase insulin response during the progression to type 1 diabetes in diabetes prevention trial-type 1 participants. Diabetes 62, 4179–4183 (2013).

    Google Scholar 

  98. 98

    Helminen, O. et al. HbA1c predicts time to diagnosis of type 1 diabetes in children at risk. Diabetes 64, 1719–1727 (2015).

    Google Scholar 

  99. 99

    Magnuson, A. M. et al. Population dynamics of islet-infiltrating cells in autoimmune diabetes. Proc. Natl Acad. Sci. USA 112, 1511–1516 (2015).

    Google Scholar 

  100. 100

    Engin, F. et al. Restoration of the unfolded protein response in pancreatic β cells protects mice against type 1 diabetes. Sci. Transl Med. 5, 211ra156 (2013).

    Google Scholar 

  101. 101

    Mordes, J. P., Bortell, R., Blankenhorn, E. P., Rossini, A. A. & Greiner, D. L. Rat models of type 1 diabetes: genetics, environment, and autoimmunity. ILAR J. 45, 278–291 (2004).

    Google Scholar 

  102. 102

    Kaldunski, M. et al. Identification of a serum-induced transcriptional signature associated with type 1 diabetes in the BioBreeding rat. Diabetes 59, 2375–2385 (2010).

    Google Scholar 

  103. 103

    Bogdani, M. et al. BioBreeding rat islets exhibit reduced antioxidative defense and N-acetyl cysteine treatment delays type 1 diabetes. J. Endocrinol. 216, 111–123 (2013).

    Google Scholar 

  104. 104

    Krogvold, L. et al. Insulitis and characterisation of infiltrating T cells in surgical pancreatic tail resections from patients at onset of type 1 diabetes. Diabetologia 59, 492–501 (2016).

    Google Scholar 

  105. 105

    Imagawa, A. et al. Pancreatic biopsy as a procedure for detecting in situ autoimmune phenomena in type 1 diabetes: close correlation between serological markers and histological evidence of cellular autoimmunity. Diabetes 50, 1269–1273 (2001).

    Google Scholar 

  106. 106

    Krogvold, L. et al. Pancreatic biopsy by minimal tail resection in live adult patients at the onset of type 1 diabetes: experiences from the DiViD study. Diabetologia 57, 841–843 (2014).

    Google Scholar 

  107. 107

    Bottazzo, G. F. et al. In situ characterization of autoimmune phenomena and expression of HLA molecules in the pancreas in diabetic insulitis. N. Engl. J. Med. 313, 353–360 (1985).

    Google Scholar 

  108. 108

    Lernmark, Å. et al. Heterogeneity of islet pathology in two infants with recent onset diabetes mellitus. Virchows Arch. 425, 631–640 (1995).

    Google Scholar 

  109. 109

    Bottazzo, G. F. & Lendrum, R. Separate autoantibodies to human pancreatic glucagon and somatostatin cells. Lancet 2, 873–876 (1976).

    Google Scholar 

  110. 110

    Pugliese, A. et al. The Juvenile Diabetes Research Foundation Network for Pancreatic Organ Donors with Diabetes (nPOD) Program: goals, operational model and emerging findings. Pediatr. Diabetes 15, 1–9 (2014).

    Google Scholar 

  111. 111

    Akirav, E., Kushner, J. A. & Herold, K. C. β-Cell mass and type 1 diabetes: going, going, gone? Diabetes 57, 2883–2888 (2008).

    Google Scholar 

  112. 112

    Bjork, E. et al. Glucose regulation of the autoantigen GAD65 in human pancreatic islets. J. Clin. Endocrinol. Metab. 75, 1574–1576 (1992).

    Google Scholar 

  113. 113

    Melendez-Ramirez, L. Y., Richards, R. J. & Cefalu, W. T. Complications of type 1 diabetes. Endocrinol. Metab. Clin. North Am. 39, 625–640 (2010).

    Google Scholar 

  114. 114

    Miki, T., Yuda, S., Kouzu, H. & Miura, T. Diabetic cardiomyopathy: pathophysiology and clinical features. Heart Fail. Rev. 18, 149–166 (2013).

    Google Scholar 

  115. 115

    Lind, M. et al. Glycaemic control and incidence of heart failure in 20,985 patients with type 1 diabetes: an observational study. Lancet 378, 140–146 (2011).

    Google Scholar 

  116. 116

    Rosengren, A. et al. Long-term excess risk of heart failure in people with type 1 diabetes: a prospective case-control study. Lancet Diabetes Endocrinol. 3, 876–885 (2015).

    Google Scholar 

  117. 117

    McMurray, J. J., Gerstein, H. C., Holman, R. R. & Pfeffer, M. A. Heart failure: a cardiovascular outcome in diabetes that can no longer be ignored. Lancet Diabetes Endocrinol. 2, 843–851 (2014).

    Google Scholar 

  118. 118

    Jacobson, A. M. et al. Long-term effect of diabetes and its treatment on cognitive function. N. Engl. J. Med. 356, 1842–1852 (2007). This comprehensive investigation demonstrates that long-term T1DM and recurrent hypoglycaemic episodes do not affect cognitive function.

    Google Scholar 

  119. 119

    Shah, A. D. et al. Type 2 diabetes and incidence of cardiovascular diseases: a cohort study in 1.9 million people. Lancet Diabetes Endocrinol. 3, 105–113 (2015).

    Google Scholar 

  120. 120

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

    Google Scholar 

  121. 121

    Wanner, C. et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N. Engl. J. Med. 375, 323–334 (2016).

    Google Scholar 

  122. 122

    Sattar, N., McLaren, J., Kristensen, S. L., Preiss, D. & McMurray, J. J. SGLT2 inhibition and cardiovascular events: why did EMPA-REG outcomes surprise and what were the likely mechanisms? Diabetologia 59, 1333–1339 (2016).

    Google Scholar 

  123. 123

    ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker versus diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 288, 2981–2997 (2002).

    Google Scholar 

  124. 124

    de Ferranti, S. D. et al. Type 1 diabetes mellitus and cardiovascular disease: a scientific statement from the American Heart Association and American Diabetes Association. Diabetes Care 37, 2843–2863 (2014).

    Google Scholar 

  125. 125

    de Ferranti, S. D. et al. Type 1 diabetes mellitus and cardiovascular disease: a scientific statement from the American Heart Association and American Diabetes Association. Circulation 130, 1110–1130 (2014).

    Google Scholar 

  126. 126

    Giacco, F. & Brownlee, M. Oxidative stress and diabetic complications. Circ. Res. 107, 1058–1070 (2010).

    Google Scholar 

  127. 127

    Paneni, F., Beckman, J. A., Creager, M. A. & Cosentino, F. Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I. Eur. Heart J. 34, 2436–2443 (2013).

    Google Scholar 

  128. 128

    Saydah, S. H. et al. Trends and characteristics of self-reported case presentation of diabetes diagnosis among youth from 2002 to 2010: findings from the SEARCH for diabetes in youth study. Diabetes Care 38, e84–e85 (2015).

    Google Scholar 

  129. 129

    American Diabetes Association. 2. Classification and diagnosis of diabetes. Diabetes Care 39, S13–S22 (2016).

    Google Scholar 

  130. 130

    American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 36, S67–S74 (2013).

    Google Scholar 

  131. 131

    Hattersley, A. T. & Ashcroft, F. M. Activating mutations in Kir6.2 and neonatal diabetes: new clinical syndromes, new scientific insights, and new therapy. Diabetes 54, 2503–2513 (2005).

    Google Scholar 

  132. 132

    Flanagan, S. E. et al. Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease. Nat. Genet. 46, 812–814 (2014).

    Google Scholar 

  133. 133

    Johnson, M. B., Hattersley, A. T. & Flanagan, S. E. Monogenic autoimmune diseases of the endocrine system. Lancet Diabetes Endocrinol. 4, 862–872 (2016).

    Google Scholar 

  134. 134

    Johansson, B. B. et al. Targeted next-generation sequencing reveals MODY in up to 6.5% of antibody-negative diabetes cases listed in the Norwegian Childhood Diabetes Registry. Diabetologia 60, 625 (2017).

    Google Scholar 

  135. 135

    Mire-Sluis, A. R., Gaines Das, R. & Lernmark, Å. The World Health Organization International Collaborative Study for islet cell antibodies. Diabetologia 43, 1282–1292 (2000).

    Google Scholar 

  136. 136

    Strauss, R. S. & Pollack, H. A. Epidemic increase in childhood overweight, 1986–1998. JAMA 286, 2845–2848 (2001).

    Google Scholar 

  137. 137

    Liu, L. L. et al. Prevalence of overweight and obesity in youth with diabetes in USA: the SEARCH for Diabetes in Youth study. Pediatr. Diabetes 11, 4–11 (2010).

    Google Scholar 

  138. 138

    Carlsson, A. et al. Low risk HLA-DQ and increased body mass index in newly diagnosed type 1 diabetes children in the Better Diabetes Diagnosis study in Sweden. Int. J. Obes. (Lond.) 36, 718–724 (2012).

    Google Scholar 

  139. 139

    Dahlquist, G. et al. The Swedish childhood diabetes study — results from a nine year case register and a one year case-referent study indicating that type 1 (insulin-dependent) diabetes mellitus is associated with both type 2 (non-insulin-dependent) diabetes mellitus and autoimmune disorders. Diabetologia 32, 2–6 (1989).

    Google Scholar 

  140. 140

    Pinhas-Hamiel, O., Dolan, L. M. & Zeitler, P. S. Diabetic ketoacidosis among obese African-American adolescents with NIDDM. Diabetes Care 20, 484–486 (1997).

    Google Scholar 

  141. 141

    Sellers, E. A. & Dean, H. J. Diabetic ketoacidosis: a complication of type 2 diabetes in Canadian aboriginal youth. Diabetes Care 23, 1202–1204 (2000).

    Google Scholar 

  142. 142

    Hathout, E. H., Thomas, W., El-Shahawy, M., Nahab, F. & Mace, J. W. Diabetic autoimmune markers in children and adolescents with type 2 diabetes. Pediatrics 107, E102 (2001).

    Google Scholar 

  143. 143

    Libman, I. M. & Becker, D. J. Coexistence of type 1 and type 2 diabetes mellitus: “double” diabetes? Pediatr. Diabetes 4, 110–113 (2003).

    Google Scholar 

  144. 144

    Dabelea, D. et al. Etiological approach to characterization of diabetes type: the SEARCH for Diabetes in Youth Study. Diabetes Care 34, 1628–1633 (2011).

    Google Scholar 

  145. 145

    Dabelea, D. et al. Development, validation and use of an insulin sensitivity score in youths with diabetes: the SEARCH for Diabetes in Youth study. Diabetologia 54, 78–86 (2011).

    Google Scholar 

  146. 146

    Nathan, D. M. The diabetes control and complications trial/epidemiology of diabetes interventions and complications study at 30 years: overview. Diabetes Care 37, 9–16 (2014).

    Google Scholar 

  147. 147

    Lind, M. et al. Glycemic control and excess mortality in type 1 diabetes. N. Engl. J. Med. 371, 1972–1982 (2014). This registry-based observational study finds that the risk of death from any cause or from cardiovascular causes among patients with T1DM who have a HbA1c level of ≤6.9% is twice as high as the risk among matched controls.

    Google Scholar 

  148. 148

    Livingstone, S. J. et al. Estimated life expectancy in a Scottish cohort with type 1 diabetes, 2008–2010. JAMA 313, 37–44 (2015).

    Google Scholar 

  149. 149

    Huxley, R. R., Peters, S. A., Mishra, G. D. & Woodward, M. Risk of all-cause mortality and vascular events in women versus men with type 1 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 3, 198–206 (2015).

    Google Scholar 

  150. 150

    Lachin, J. M., Genuth, S., Nathan, D. M., Zinman, B. & Rutledge, B. N. Effect of glycemic exposure on the risk of microvascular complications in the diabetes control and complications trial — revisited. Diabetes 57, 995–1001 (2008).

    Google Scholar 

  151. 151

    Anderzen, J., Samuelsson, U., Gudbjornsdottir, S., Hanberger, L. & Akesson, K. Teenagers with poor metabolic control already have a higher risk of microvascular complications as young adults. J. Diabetes Complicat. 30, 533–536 (2016).

    Google Scholar 

  152. 152

    Yau, J. W. et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care 35, 556–564 (2012).

    Google Scholar 

  153. 153

    Frank, R. N. Diabetic retinopathy. N. Engl. J. Med. 350, 48–58 (2004).

    Google Scholar 

  154. 154

    Raile, K. et al. Diabetic nephropathy in 27,805 children, adolescents, and adults with type 1 diabetes: effect of diabetes duration, A1C, hypertension, dyslipidemia, diabetes onset, and sex. Diabetes Care 30, 2523–2528 (2007).

    Google Scholar 

  155. 155

    Gross, J. L. et al. Diabetic nephropathy: diagnosis, prevention, and treatment. Diabetes Care 28, 164–176 (2005).

    Google Scholar 

  156. 156

    Valmadrid, C. T., Klein, R., Moss, S. E. & Klein, B. E. The risk of cardiovascular disease mortality associated with microalbuminuria and gross proteinuria in persons with older-onset diabetes mellitus. Arch. Intern. Med. 160, 1093–1100 (2000).

    Google Scholar 

  157. 157

    Vasan, R. S. et al. Impact of high-normal blood pressure on the risk of cardiovascular disease. N. Engl. J. Med. 345, 1291–1297 (2001).

    Google Scholar 

  158. 158

    Hovind, P. et al. Predictors for the development of microalbuminuria and macroalbuminuria in patients with type 1 diabetes: inception cohort study. BMJ 328, 1105 (2004).

    Google Scholar 

  159. 159

    Caramori, M. L., Fioretto, P. & Mauer, M. The need for early predictors of diabetic nephropathy risk: is albumin excretion rate sufficient? Diabetes 49, 1399–1408 (2000).

    Google Scholar 

  160. 160

    Perkins, B. A. et al. Regression of microalbuminuria in type 1 diabetes. N. Engl. J. Med. 348, 2285–2293 (2003).

    Google Scholar 

  161. 161

    Voulgari, C. et al. The association between cardiac autonomic neuropathy with metabolic and other factors in subjects with type 1 and type 2 diabetes. J. Diabetes Complicat. 25, 159–167 (2011).

    Google Scholar 

  162. 162

    Gerstein, H. C. Diabetes: dysglycaemia as a cause of cardiovascular outcomes. Nat. Rev. Endocrinol. 11, 508–510 (2015).

    Google Scholar 

  163. 163

    Gerstein, H. C. & Werstuck, G. H. Dysglycaemia, vasculopenia, and the chronic consequences of diabetes. Lancet Diabetes Endocrinol. 1, 71–78 (2013).

    Google Scholar 

  164. 164

    Nathan, D. M. et al. Intensive diabetes therapy and carotid intima-media thickness in type 1 diabetes mellitus. N. Engl. J. Med. 348, 2294–2303 (2003).

    Google Scholar 

  165. 165

    Dabelea, D. et al. Effect of type 1 diabetes on the gender difference in coronary artery calcification: a role for insulin resistance? The Coronary Artery Calcification in Type 1 Diabetes (CACTI) study. Diabetes 52, 2833–2839 (2003).

    Google Scholar 

  166. 166

    Jarvisalo, M. J. et al. Carotid artery intima-media thickness in children with type 1 diabetes. Diabetes 51, 493–498 (2002).

    Google Scholar 

  167. 167

    Margeirsdottir, H. D., Stensaeth, K. H., Larsen, J. R., Brunborg, C. & Dahl-Jorgensen, K. Early signs of atherosclerosis in diabetic children on intensive insulin treatment: a population-based study. Diabetes Care 33, 2043–2048 (2010).

    Google Scholar 

  168. 168

    Secrest, A. M., Becker, D. J., Kelsey, S. F., Laporte, R. E. & Orchard, T. J. Cause-specific mortality trends in a large population-based cohort with long-standing childhood-onset type 1 diabetes. Diabetes 59, 3216–3222 (2010).

    Google Scholar 

  169. 169

    Soedamah-Muthu, S. S. et al. High risk of cardiovascular disease in patients with type diabetes in the U.K.: a cohort study using the general practice research database. Diabetes Care 29, 798–804 (2006).

    Google Scholar 

  170. 170

    Jonasson, J. M. et al. Risks of nontraumatic lower-extremity amputations in patients with type 1 diabetes: a population-based cohort study in Sweden. Diabetes Care 31, 1536–1540 (2008).

    Google Scholar 

  171. 171

    Deckert, T., Poulsen, J. E. & Larsen, M. The prognosis of insulin dependent diabetes mellitus and the importance of supervision. Acta Med. Scand. Suppl. 624, 48–53 (1979).

    Google Scholar 

  172. 172

    Keenan, H. A. et al. Residual insulin production and pancreatic β-cell turnover after 50 years of diabetes: Joslin Medalist study. Diabetes 59, 2846–2853 (2010).

    Google Scholar 

  173. 173

    Hahl, J., Simell, T., Ilonen, J., Knip, M. & Simell, O. Costs of predicting IDDM. Diabetologia 41, 79–85 (1998).

    Google Scholar 

  174. 174

    Kukko, M. et al. Geographical variation in risk HLA-DQB1 genotypes for type 1 diabetes and signs of β-cell autoimmunity in a high-incidence country. Diabetes Care 27, 676–681 (2004).

    Google Scholar 

  175. 175

    Larsson, H. E. et al. Diabetes-associated HLA genotypes affect birthweight in the general population. Diabetologia 48, 1484–1491 (2005).

    Google Scholar 

  176. 176

    Carmichael, S. K. et al. Prospective assessment in newborns of diabetes autoimmunity (PANDA): maternal understanding of infant diabetes risk. Genet. Med. 5, 77–83 (2003).

    Google Scholar 

  177. 177

    Elding Larsson, H. et al. Reduced prevalence of diabetic ketoacidosis at diagnosis of type 1 diabetes in young children participating in longitudinal follow-up. Diabetes Care 34, 2347–2352 (2011).

    Google Scholar 

  178. 178

    Elding Larsson, H. et al. Children followed in the TEDDY study are diagnosed with type 1 diabetes at an early stage of disease. Pediatr. Diabetes 15, 118–126 (2014).

    Google Scholar 

  179. 179

    Raab, J. et al. Capillary blood islet autoantibody screening for identifying pre-type 1 diabetes in the general population: design and initial results of the Fr1da study. BMJ Open 6, e011144 (2016).

    Google Scholar 

  180. 180

    Knip, M. et al. Hydrolyzed infant formula and early β-cell autoimmunity: a randomized clinical trial. JAMA 311, 2279–2287 (2014).

    Google Scholar 

  181. 181

    Bonifacio, E. et al. Effects of high-dose oral insulin on immune responses in children at high risk for type 1 diabetes: the Pre-POINT randomized clinical trial. JAMA 313, 1541–1549 (2015).

    Google Scholar 

  182. 182

    Chase, H. P. et al. Nutritional Intervention to Prevent (NIP) type 1 diabetes a pilot trial. Infant Child Adolesc. Nutr. 1, 98–107 (2009).

    Google Scholar 

  183. 183

    Skyler, J. S. et al. Effects of oral insulin in relatives of patients with type 1 diabetes: the Diabetes Prevention Trial — Type 1. Diabetes Care 28, 1068–1076 (2005).

    Google Scholar 

  184. 184

    Vehik, K. et al. Long-term outcome of individuals treated with oral insulin: Diabetes Prevention Trial-Type 1 (DPT-1) oral insulin trial. Diabetes Care 34, 1585–1590 (2011).

    Google Scholar 

  185. 185

    American Diabetes Association. 5. Glycemic targets. Diabetes Care 39, S39–S46 (2016).

    Google Scholar 

  186. 186

    Rewers, A. et al. Presence of diabetic ketoacidosis at diagnosis of diabetes mellitus in youth: the Search for Diabetes in Youth Study. Pediatrics 121, e1258–e1266 (2008).

    Google Scholar 

  187. 187

    Wolfsdorf, J., Glaser, N. & Sperling, M. A. Diabetic ketoacidosis in infants, children, and adolescents: a consensus statement from the American Diabetes Association. Diabetes Care 29, 1150–1159 (2006).

    Google Scholar 

  188. 188

    Tonyushkina, K. N., Visintainer, P. F., Jasinski, C. F., Wadzinski, T. L. & Allen, H. F. Site of initial diabetes education does not affect metabolic outcomes in children with T1DM. Pediatr. Diabetes 15, 135–141 (2014).

    Google Scholar 

  189. 189

    Jasinski, C. F., Rodriguez-Monguio, R., Tonyushkina, K. & Allen, H. Healthcare cost of type 1 diabetes mellitus in new-onset children in a hospital compared to an outpatient setting. BMC Pediatr. 13, 55 (2013).

    Google Scholar 

  190. 190

    Lowes, L. & Gregory, J. W. Management of newly diagnosed diabetes: home or hospital? Arch. Dis. Child. 89, 934–937 (2004).

    Google Scholar 

  191. 191

    Simell, T., Kaprio, E. A., Maenpaa, J., Tuominen, J. & Simell, O. Randomised prospective study of short-term and long-term initial stay in hospital by children with diabetes mellitus. Lancet 337, 656–660 (1991).

    Google Scholar 

  192. 192

    Dhaliwal, R. & Weinstock, R. S. Management of type 1 diabetes in older adults. Diabetes Spectr. 27, 9–20 (2014).

    Google Scholar 

  193. 193

    Auer, R. N. Hypoglycemic brain damage. Metab. Brain Dis. 19, 169–175 (2004).

    Google Scholar 

  194. 194

    Auer, R. N. Hypoglycemic brain damage. Forensic Sci. Int. 146, 105–110 (2004).

    Google Scholar 

  195. 195

    Barnard, K., Thomas, S., Royle, P., Noyes, K. & Waugh, N. Fear of hypoglycaemia in parents of young children with type 1 diabetes: a systematic review. BMC Pediatr. 10, 50 (2010).

    Google Scholar 

  196. 196

    Miller, K. M. et al. Evidence of a strong association between frequency of self-monitoring of blood glucose and hemoglobin A1c levels in T1D exchange clinic registry participants. Diabetes Care 36, 2009–2014 (2013).

    Google Scholar 

  197. 197

    Skyler, J. S. Immune intervention for type 1 diabetes mellitus. Int. J. Clin. Pract. Suppl. 65, 61–70 (2011).

    Google Scholar 

  198. 198

    The Canadian-European Randomized Control Trial Group. Cyclosporin-induced remission of IDDM after early intervention. Association of 1 yr of cyclosporin treatment with enhanced insulin secretion. Diabetes 37, 1574–1582 (1988).

    Google Scholar 

  199. 199

    Cook, J. J. et al. Double-blind controlled trial of azathioprine in children with newly diagnosed type I diabetes. Diabetes 38, 779–783 (1989).

    Google Scholar 

  200. 200

    Herold, K. C. et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N. Engl. J. Med. 346, 1692–1698 (2002).

    Google Scholar 

  201. 201

    Keymeulen, B. et al. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N. Engl. J. Med. 352, 2598–2608 (2005).

    Google Scholar 

  202. 202

    Pescovitz, M. D. et al. Rituximab, B-lymphocyte depletion, and preservation of β-cell function. N. Engl. J. Med. 361, 2143–2152 (2009). This paper describes the first randomized controlled trial of a monoclonal antibody against the B cell surface protein CD20; this antibody preserved residual β-cell function better than did T cell-targeting antibodies, which contradicts the long-held dogma that T1DM is a T cell-mediated disease. This study underscores the importance of taking the entire immune response depicted in Figure 4 of this Primer into account when studying the aetiology and pathogenesis of T1DM.

    Google Scholar 

  203. 203

    Orban, T. et al. Costimulation modulation with abatacept in patients with recent-onset type 1 diabetes: follow-up 1 year after cessation of treatment. Diabetes Care 37, 1069–1075 (2014).

    Google Scholar 

  204. 204

    Gottlieb, P. A. et al. Failure to preserve β-cell function with mycophenolate mofetil and daclizumab combined therapy in patients with new-onset type 1 diabetes. Diabetes Care 33, 826–832 (2010).

    Google Scholar 

  205. 205

    Long, S. A. et al. Rapamycin/IL-2 combination therapy in patients with type 1 diabetes augments Tregs yet transiently impairs β-cell function. Diabetes 61, 2340–2348 (2012).

    Google Scholar 

  206. 206

    Agardh, C. D., Lynch, K. F., Palmer, M., Link, K. & Lernmark, Å. GAD65 vaccination: 5 years of follow-up in a randomised dose-escalating study in adult-onset autoimmune diabetes. Diabetologia 52, 1363–1368 (2009).

    Google Scholar 

  207. 207

    Ludvigsson, J. et al. GAD treatment and insulin secretion in recent-onset type 1 diabetes. N. Engl. J. Med. 359, 1909–1920 (2008).

    Google Scholar 

  208. 208

    Ludvigsson, J. et al. GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus. N. Engl. J. Med. 366, 433–442 (2012).

    Google Scholar 

  209. 209

    Wherrett, D. K. et al. Antigen-based therapy with glutamic acid decarboxylase (GAD) vaccine in patients with recent-onset type 1 diabetes: a randomised double-blind trial. Lancet 378, 319–327 (2011).

    Google Scholar 

  210. 210

    Haller, M. J. et al. Anti-thymocyte globulin plus G-CSF combination therapy leads to sustained immunomodulatory and metabolic effects in a subset of responders with established type 1 diabetes. Diabetes 65, 3765–3775 (2016).

    Google Scholar 

  211. 211

    Haller, M. J. et al. Autologous umbilical cord blood infusion for type 1 diabetes. Exp. Hematol. 36, 710–715 (2008).

    Google Scholar 

  212. 212

    Bott, U., Muhlhauser, I., Overmann, H. & Berger, M. Validation of a diabetes-specific quality-of-life scale for patients with type 1 diabetes. Diabetes Care 21, 757–769 (1998).

    Google Scholar 

  213. 213

    Rubin, R. R. Diabetes and quality of life. Diabetes Spectr. 13, 21–22 (2000).

    Google Scholar 

  214. 214

    Speight, J., Reaney, M. D. & Barnard, K. D. Not all roads lead to Rome — a review of quality of life measurement in adults with diabetes. Diabet. Med. 26, 315–327 (2009).

    Google Scholar 

  215. 215

    Hilliard, M. E., Mann, K. A., Peugh, J. L. & Hood, K. K. How poorer quality of life in adolescence predicts subsequent type 1 diabetes management and control. Patient Educ. Couns. 91, 120–125 (2013).

    Google Scholar 

  216. 216

    Hoey, H. et al. Good metabolic control is associated with better quality of life in 2,101 adolescents with type 1 diabetes. Diabetes Care 24, 1923–1928 (2001).

    Google Scholar 

  217. 217

    Hood, K. K. et al. Psychosocial burden and glycemic control during the first 6 years of diabetes: results from the SEARCH for Diabetes in Youth study. J. Adolesc. Health 55, 498–504 (2014).

    Google Scholar 

  218. 218

    Laffel, L. M. et al. General quality of life in youth with type 1 diabetes: relationship to patient management and diabetes-specific family conflict. Diabetes Care 26, 3067–3073 (2003).

    Google Scholar 

  219. 219

    Delamater, A. M. Psychological care of children and adolescents with diabetes. Pediatr. Diabetes 10 (Suppl. 12), 175–184 (2009).

    Google Scholar 

  220. 220

    Lohr, K. N. & Zebrack, B. J. Using patient-reported outcomes in clinical practice: challenges and opportunities. Qual. Life Res. 18, 99–107 (2009).

    Google Scholar 

  221. 221

    Lernmark, Å. The streetlight effect — is there light at the end of the tunnel? Diabetes 64, 1105–1107 (2015).

    Google Scholar 

  222. 222

    Rolandsson, O. & Palmer, J. P. Latent autoimmune diabetes in adults (LADA) is dead: long live autoimmune diabetes! Diabetologia 53, 1250–1253 (2010).

    Google Scholar 

  223. 223

    Garg, S. K. et al. Glucose outcomes with the in-home use of a hybrid closed-loop insulin delivery system in adolescents and adults with type 1 diabetes. Diabetes Technol. Ther. http://dx.doi.org/10.1089/dia.2016.0421 (2017).

  224. 224

    Bally, L. et al. Day-and-night glycaemic control with closed-loop insulin delivery versus conventional insulin pump therapy in free-living adults with well controlled type 1 diabetes: an open-label, randomised, crossover study. Lancet Diabetes Endocrinol. http://dx.doi.org/10.1016/S2213-8587(17)30001-3 (2017).

  225. 225

    de Wit, M. et al. Monitoring and discussing health related quality of life in adolescents with type 1 diabetes improve psychosocial well-being: a randomized controlled trial. Diabetes Care 31, 1521–1526 (2008).

    Google Scholar 

  226. 226

    Little, R. R. & Rohlfing, C. L. The long and winding road to optimal HbA1c measurement. Clin. Chim. Acta 418, 63–71 (2013).

    Google Scholar 

  227. 227

    Diabetes Prevention Trial — Type 1 Diabetes Study Group. Effects of insulin in relatives of patients with type 1 diabetes mellitus. N. Engl. J. Med. 346, 1685–1691 (2002).

    Google Scholar 

  228. 228

    Nanto-Salonen, K. et al. Nasal insulin to prevent type 1 diabetes in children with HLA genotypes and autoantibodies conferring increased risk of disease: a double-blind, randomised controlled trial. Lancet 372, 1746–1755 (2008).

    Google Scholar 

  229. 229

    Gale, E. A., Bingley, P. J., Emmett, C. L. & Collier, T. European Nicotinamide Diabetes Intervention Trial (ENDIT): a randomised controlled trial of intervention before the onset of type 1 diabetes. Lancet 363, 925–931 (2004).

    Google Scholar 

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Acknowledgements

The authors were supported by the US NIH (grants K12DK097696 and R21DK106505 to B.J.A.; DK60987, DK60987, DK104216 and UL1TR001427 to D.A.S. and L.M.J.; and DK063861 to Å.L.), The Leona M. and Harry B. Helmsley Charitable Trust (grants 2015PG-T1D084 and 2016PG-T1D011 to B.J.A.) and the Swedish Research Council (Å.L., S.G. and A.R.).

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Introduction (A.K. and Å.L.); Epidemiology (A.K., Å.L. and D.D.); Mechanisms/pathophysiology (E.B.); Diagnosis, screening and prevention (A.K., Å.L., E.B. and D.D.); Management (D.A.S., L.M.J., S.G. and A.R.); Quality of life (B.J.A.); Outlook (Å.L.); Overview of Primer (Å.L.).

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Correspondence to Åke Lernmark.

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Å.L. is a member of the Scientific Advisory Board of Diamyd Medical, Stockholm, Sweden. All other authors declare no conflicts of interest.

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Katsarou, A., Gudbjörnsdottir, S., Rawshani, A. et al. Type 1 diabetes mellitus. Nat Rev Dis Primers 3, 17016 (2017). https://doi.org/10.1038/nrdp.2017.16

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