Type 1 diabetes mellitus - Nature Reviews Disease Primers
- ️Lernmark, Åke
- ️Thu Mar 30 2017
References
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).
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.
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.
Atkinson, M. A., Eisenbarth, G. S. & Michels, A. W. Type 1 diabetes. Lancet 383, 69–82 (2014).
American Diabetes Association. 2. Classification and diagnosis of diabetes. Diabetes Care 38, S8–S16 (2015).
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).
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.
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).
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.
Rewers, M. et al. Newborn screening for HLA markers associated with IDDM: diabetes autoimmunity study in the young (DAISY). Diabetologia 39, 807–812 (1996).
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).
TEDDY Study Group. The Environmental Determinants of Diabetes in the Young (TEDDY) study: study design. Pediatr. Diabetes 8, 286–298 (2007).
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).
International Diabetes Federation. IDF diabetes atlas. IDF http://www.diabetesatlas.org/component/attachments/?task=download&id=116 (2015).
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).
Askar, M. et al. 16th IHIW: global distribution of extended HLA haplotypes. Int. J. Immunogenet. 40, 31–38 (2013).
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).
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).
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).
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.
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Vehik, K. et al. Development of autoantibodies in the TrialNet Natural History Study. Diabetes Care 34, 1897–1901 (2011).
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).
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).
Bonifacio, E. Predicting type 1 diabetes using biomarkers. Diabetes Care 38, 989–996 (2015).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Tuomilehto, J. The emerging global epidemic of type 1 diabetes. Curr. Diab. Rep. 13, 795–804 (2013).
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).
Nerup, J. et al. HL-A antigens and diabetes mellitus. Lancet 2, 864–866 (1974).
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).
Cudworth, A. G. & Woodrow, J. C. Evidence for HL-A-linked genes in “juvenile” diabetes mellitus. Br. Med. J. 3, 133–135 (1975).
Erlich, H. A. et al. Next generation sequencing reveals the association of DRB3*02:02 with type 1 diabetes. Diabetes 62, 2618–2622 (2013).
Caillat-Zucman, S. et al. Age-dependent HLA genetic heterogeneity of type 1 insulin-dependent diabetes mellitus. J. Clin. Invest. 90, 2242–2250 (1992).
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).
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).
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.
Dahlquist, G. et al. The epidemiology of diabetes in Swedish children 0–14 years — a six-year prospective study. Diabetologia 28, 802–808 (1985).
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).
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).
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).
Cooper, J. D. et al. Confirmation of novel type 1 diabetes risk loci in families. Diabetologia 55, 996–1000 (2012).
Pociot, F. & Lernmark, Å. Genetic risk factors for type 1 diabetes. Lancet 387, 2331–2339 (2016).
Rich, S. S. et al. Overview of the Type I Diabetes Genetics Consortium. Genes Immun. 10, S1–S4 (2009).
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).
Polychronakos, C. & Li, Q. Understanding type 1 diabetes through genetics: advances and prospects. Nat. Rev. Genet. 12, 781–792 (2011).
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).
Beyerlein, A., Donnachie, E., Jergens, S. & Ziegler, A. G. Infections in early life and development of type 1 diabetes. JAMA 315, 1899–1901 (2016).
Ashton, M. P. et al. Incomplete immune response to coxsackie B viruses associates with early autoimmunity against insulin. Sci. Rep. 6, 32899 (2016).
Hyoty, H. Viruses in type 1 diabetes. Pediatr. Diabetes 17 (Suppl. 22), 56–64 (2016).
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).
La Torre, D. et al. Decreased cord-blood phospholipids in young age-at-onset type 1 diabetes. Diabetes 62, 3951–3956 (2013).
Oresic, M. et al. Cord serum lipidome in prediction of islet autoimmunity and type 1 diabetes. Diabetes 62, 3268–3274 (2013).
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).
Resic Lindehammer, S. et al. Seroconversion to islet autoantibodies after enterovirus infection in early pregnancy. Viral Immunol. 25, 254–261 (2012).
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).
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).
Hofer, J. et al. Elevated proportions of recent thymic emigrants in children and adolescents with type 1 diabetes. Rejuvenation Res. 12, 311–320 (2009).
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).
Roep, B. O. & Peakman, M. Antigen targets of type 1 diabetes autoimmunity. Cold Spring Harb. Perspect. Med. 2, a007781 (2012).
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).
van Lummel, M. et al. Post-translational modification of HLA-DQ binding islet-autoantigens in type 1 diabetes. Diabetes 63, 237–247 (2014).
Delong, T. et al. Pathogenic CD4 T cells in type 1 diabetes recognize epitopes formed by peptide fusion. Science 351, 711–714 (2016).
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).
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).
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).
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).
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).
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).
McGinty, J. W. et al. Recognition of posttranslationally modified GAD65 epitopes in subjects with type 1 diabetes. Diabetes 63, 3033–3040 (2014).
Wiberg, A. et al. Characterization of human organ donors testing positive for type 1 diabetes-associated autoantibodies. Clin. Exp. Immunol. 182, 278–288 (2015).
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).
Campbell-Thompson, M. Organ donor specimens: what can they tell us about type 1 diabetes? Pediatr. Diabetes 16, 320–330 (2015).
In't Veld, P. et al. Screening for insulitis in adult autoantibody-positive organ donors. Diabetes 56, 2400–2404 (2007).
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).
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).
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).
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).
Helminen, O. et al. HbA1c predicts time to diagnosis of type 1 diabetes in children at risk. Diabetes 64, 1719–1727 (2015).
Magnuson, A. M. et al. Population dynamics of islet-infiltrating cells in autoimmune diabetes. Proc. Natl Acad. Sci. USA 112, 1511–1516 (2015).
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).
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).
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).
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).
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).
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).
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).
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).
Lernmark, Å. et al. Heterogeneity of islet pathology in two infants with recent onset diabetes mellitus. Virchows Arch. 425, 631–640 (1995).
Bottazzo, G. F. & Lendrum, R. Separate autoantibodies to human pancreatic glucagon and somatostatin cells. Lancet 2, 873–876 (1976).
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).
Akirav, E., Kushner, J. A. & Herold, K. C. β-Cell mass and type 1 diabetes: going, going, gone? Diabetes 57, 2883–2888 (2008).
Bjork, E. et al. Glucose regulation of the autoantigen GAD65 in human pancreatic islets. J. Clin. Endocrinol. Metab. 75, 1574–1576 (1992).
Melendez-Ramirez, L. Y., Richards, R. J. & Cefalu, W. T. Complications of type 1 diabetes. Endocrinol. Metab. Clin. North Am. 39, 625–640 (2010).
Miki, T., Yuda, S., Kouzu, H. & Miura, T. Diabetic cardiomyopathy: pathophysiology and clinical features. Heart Fail. Rev. 18, 149–166 (2013).
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).
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).
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).
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.
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).
Zinman, B. et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N. Engl. J. Med. 373, 2117–2128 (2015).
Wanner, C. et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N. Engl. J. Med. 375, 323–334 (2016).
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).
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).
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).
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).
Giacco, F. & Brownlee, M. Oxidative stress and diabetic complications. Circ. Res. 107, 1058–1070 (2010).
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).
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).
American Diabetes Association. 2. Classification and diagnosis of diabetes. Diabetes Care 39, S13–S22 (2016).
American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 36, S67–S74 (2013).
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).
Flanagan, S. E. et al. Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease. Nat. Genet. 46, 812–814 (2014).
Johnson, M. B., Hattersley, A. T. & Flanagan, S. E. Monogenic autoimmune diseases of the endocrine system. Lancet Diabetes Endocrinol. 4, 862–872 (2016).
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).
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).
Strauss, R. S. & Pollack, H. A. Epidemic increase in childhood overweight, 1986–1998. JAMA 286, 2845–2848 (2001).
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).
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).
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).
Pinhas-Hamiel, O., Dolan, L. M. & Zeitler, P. S. Diabetic ketoacidosis among obese African-American adolescents with NIDDM. Diabetes Care 20, 484–486 (1997).
Sellers, E. A. & Dean, H. J. Diabetic ketoacidosis: a complication of type 2 diabetes in Canadian aboriginal youth. Diabetes Care 23, 1202–1204 (2000).
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).
Libman, I. M. & Becker, D. J. Coexistence of type 1 and type 2 diabetes mellitus: “double” diabetes? Pediatr. Diabetes 4, 110–113 (2003).
Dabelea, D. et al. Etiological approach to characterization of diabetes type: the SEARCH for Diabetes in Youth Study. Diabetes Care 34, 1628–1633 (2011).
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).
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).
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.
Livingstone, S. J. et al. Estimated life expectancy in a Scottish cohort with type 1 diabetes, 2008–2010. JAMA 313, 37–44 (2015).
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).
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).
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).
Yau, J. W. et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care 35, 556–564 (2012).
Frank, R. N. Diabetic retinopathy. N. Engl. J. Med. 350, 48–58 (2004).
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).
Gross, J. L. et al. Diabetic nephropathy: diagnosis, prevention, and treatment. Diabetes Care 28, 164–176 (2005).
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).
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).
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).
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).
Perkins, B. A. et al. Regression of microalbuminuria in type 1 diabetes. N. Engl. J. Med. 348, 2285–2293 (2003).
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).
Gerstein, H. C. Diabetes: dysglycaemia as a cause of cardiovascular outcomes. Nat. Rev. Endocrinol. 11, 508–510 (2015).
Gerstein, H. C. & Werstuck, G. H. Dysglycaemia, vasculopenia, and the chronic consequences of diabetes. Lancet Diabetes Endocrinol. 1, 71–78 (2013).
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).
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).
Jarvisalo, M. J. et al. Carotid artery intima-media thickness in children with type 1 diabetes. Diabetes 51, 493–498 (2002).
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).
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).
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).
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).
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).
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).
Hahl, J., Simell, T., Ilonen, J., Knip, M. & Simell, O. Costs of predicting IDDM. Diabetologia 41, 79–85 (1998).
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).
Larsson, H. E. et al. Diabetes-associated HLA genotypes affect birthweight in the general population. Diabetologia 48, 1484–1491 (2005).
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).
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).
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).
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).
Knip, M. et al. Hydrolyzed infant formula and early β-cell autoimmunity: a randomized clinical trial. JAMA 311, 2279–2287 (2014).
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).
Chase, H. P. et al. Nutritional Intervention to Prevent (NIP) type 1 diabetes a pilot trial. Infant Child Adolesc. Nutr. 1, 98–107 (2009).
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).
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).
American Diabetes Association. 5. Glycemic targets. Diabetes Care 39, S39–S46 (2016).
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).
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).
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).
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).
Lowes, L. & Gregory, J. W. Management of newly diagnosed diabetes: home or hospital? Arch. Dis. Child. 89, 934–937 (2004).
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).
Dhaliwal, R. & Weinstock, R. S. Management of type 1 diabetes in older adults. Diabetes Spectr. 27, 9–20 (2014).
Auer, R. N. Hypoglycemic brain damage. Metab. Brain Dis. 19, 169–175 (2004).
Auer, R. N. Hypoglycemic brain damage. Forensic Sci. Int. 146, 105–110 (2004).
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).
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).
Skyler, J. S. Immune intervention for type 1 diabetes mellitus. Int. J. Clin. Pract. Suppl. 65, 61–70 (2011).
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).
Cook, J. J. et al. Double-blind controlled trial of azathioprine in children with newly diagnosed type I diabetes. Diabetes 38, 779–783 (1989).
Herold, K. C. et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N. Engl. J. Med. 346, 1692–1698 (2002).
Keymeulen, B. et al. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N. Engl. J. Med. 352, 2598–2608 (2005).
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.
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).
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).
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).
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).
Ludvigsson, J. et al. GAD treatment and insulin secretion in recent-onset type 1 diabetes. N. Engl. J. Med. 359, 1909–1920 (2008).
Ludvigsson, J. et al. GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus. N. Engl. J. Med. 366, 433–442 (2012).
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).
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).
Haller, M. J. et al. Autologous umbilical cord blood infusion for type 1 diabetes. Exp. Hematol. 36, 710–715 (2008).
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).
Rubin, R. R. Diabetes and quality of life. Diabetes Spectr. 13, 21–22 (2000).
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).
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).
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).
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).
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).
Delamater, A. M. Psychological care of children and adolescents with diabetes. Pediatr. Diabetes 10 (Suppl. 12), 175–184 (2009).
Lohr, K. N. & Zebrack, B. J. Using patient-reported outcomes in clinical practice: challenges and opportunities. Qual. Life Res. 18, 99–107 (2009).
Lernmark, Å. The streetlight effect — is there light at the end of the tunnel? Diabetes 64, 1105–1107 (2015).
Rolandsson, O. & Palmer, J. P. Latent autoimmune diabetes in adults (LADA) is dead: long live autoimmune diabetes! Diabetologia 53, 1250–1253 (2010).
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).
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).
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).
Little, R. R. & Rohlfing, C. L. The long and winding road to optimal HbA1c measurement. Clin. Chim. Acta 418, 63–71 (2013).
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).
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).
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).