/ Unlabelled / International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #9: Epidemiology and Risk Factors for Type 1 Diabetes … – Diabetes In Control

Saturday, February 6, 2016

International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #9: Epidemiology and Risk Factors for Type 1 Diabetes … – Diabetes In Control

Date - 

DeFronzoCoverIslet autoantibodies

The first large-scale studies of the prediction of T1DM relied upon the detection of cytoplasmic islet cell autoantibodies (ICA) assays based on indirect immunofluorescence. High titer cytoplasmic ICA is most often associated with the presence of multiple islet autoantibodies and therefore a high risk of progression to diabetes [47]. Screening for risk of T1DM now utilizes “biochemical” autoantibody assays for specific islet autoantigens. These include autoantibodies to insulin (IAA), glutamic acid decarboxylase (GAD), IA-2 (ICA512) and most recently ZnT8 [48]. Individuals having a single positive autoantibody (insulin, GAD, IA-2, or ZnT8 autoantibodies) are at low risk for progression to T1DM. Single positive autoantibodies can be a non-reproducible false positive result (e.g. switched sample), transient, or represent the presence of an autoantibody reacting with the specific autoantigen that does not confer increased risk of diabetes (e.g. low affinity insulin autoantibodies) [49]. Individuals expressing two or more positive autoantibodies, especially on multiple tests over time, are at very high risk of progressing to diabetes. This high risk may result from autoimmunity spreading to other autoantigens whose targeting increases destruction or from the high statistical specificity of expression of multiple autoantibodies. The Diabetes Autoantibody Standardization Program (DASP) workshop aims to improve and standardize measurement of autoantibodies associated with T1DM across laboratories [50].

Different islet autoantibodies have been associated with different risks of progression, with IA-2 autoantibodies most often associated with expression of other biochemical autoantibodies and high risk [51]. Of note, insulin autoantibodies are extremely high at the onset of diabetes in young children while usually negative in individuals first presenting with diabetes after age 12. There is a log-linear inverse relationship between the levels of insulin autoantibodies and the age of onset of diabetes [52]. In DAISY, 89% of children who progressed to diabetes expressed ≥2 autoantibodies with cumulative incidence of 74% by age 10 for those expressing three autoantibodies (Figure 2.3). In children expressing >2 autoantibodies, there is no significant difference in progression to diabetes between relatives and general population subjects.

Autoantibody screening among relatives

The initial large screening studies found approximately 3% of first-degree relatives to be positive for ICA.With analysis of biochemical autoantibodies, it has become evident that the presence of ICA in the absence of GAD65 or ICA512 autoantibodies is associated with a low risk of progression to diabetes [26,53]. The cumulative risk of developing diabetes within 15 years is only 2.8% for individuals with ICA but without GAD or ICA512 (IA-2) autoantibodies versus 66% for those with ICA and either or both GAD or ICA512 autoantibodies. As in numerous studies, in the DAISY study, the incidence of islet autoantibodies is much higher in first-degree relatives,

compared to the general population. The risk by age 10 is particularly high in the HLA-DR3/4,DQB1*0302 positive siblings (43%) and offspring (34%) and moderate-risk siblings (19%) [54]. In the DAISY children without a first-degree relative with T1DM, the incidence of persistent islet autoantibodies by the age of 9 years is 10.6%, 5.5% and 3.4% in, respectively, high-,moderate- and average-HLA risk groups. The HLA genotype and having a diabetic relative, but not gender or ethnicity, predict development of islet autoantibodies.

Islet autoantibodies appear early in life. The BABYDIAB, DIPP, and DAISY studies have demonstrated that a significant proportion of first-degree relatives progressing to T1DM before age 15 develop islet autoantibodies before their 2nd birthday [31,55,56]. Even though IAA usually appear first, a significant percentage of children followed from birth initially express GAD65 autoantibodies, while IA-2 and ZnT8 autoantibodies usually develop later.

Autoantibody screening in the general population

Islet autoantibody screening studies have included mainly first-degree relatives; however, 90% of T1DM cases occur in individuals with no family history of T1DM. Several ongoing studies have followed children from birth for the development of islet autoantibodies.The two studies with the longest follow-up are the DAISY study from Denver Colorado and the DIPP study in Finland [57]. More recently, the multicenter international TEDDY study (The Environmental Determinants of Diabetes in  the Young) [58] has enrolled over 8600 high-risk general population children identified by newborn screening into a prospective follow-up for islet autoantibody measurements from birth.

While the risk of developing islet autoantibodies is 3–4 times higher in relatives than in the general population with the same HLA-DR/DQ genotypes, the persistent presence of islet autoantibodies portends similar high risk of progression to diabetes for both relatives and the general population [52,59]. Higher titer and higher affinity of the autoantibodies as well as presence of autoantibodies to multiple autoantigens predict higher risk of diabetes [60].

Measurement of autoantibodies in adult-onset diabetes

After the age of about 15 years, measuring the incidence of T1DM is complicated by misclassification of some patients as type 2 diabetics. It has been estimated that at least 37% of T1DM is diagnosed after the age of 19 years and 15% after the age of 30 years [61]. brand-new cases of T1DM presenting in adult life tend to have a longer duration of symptoms before diagnosis and higher C-peptide levels remaining at diagnosis compared with those presenting in childhood, suggesting a slower rate of β-cell destruction. However, C-peptide levels in islet autoantibody positive adult diabetic patients are still significantly lower than in those with type 2 diabetes. Assays for GAD65 autoantibodies have been the most useful in identifying latent autoimmune diabetes in adults (LADA).

Between 5 and 10% of patients with a diagnosis of gestational diabetes have positive islet autoantibodies and the great majority progress to T1DM [62]. Among adults diagnosed with type 2 diabetes and participating in the UKPDS, the proportion of patients with ICA and GAD65 decreased with increasing age at diagnosis: from 21% in patients aged 25–34 to 4% in those aged 55–65 for ICA and from 34% to 7% for GAD65 [63] Most (94%) of patients with ICA and 84% of those with GAD65 required insulin therapy by 6 years, compared with 14% of those without the antibodies.

Measurement of beta-cell function

Direct measurement of the functional mass of islet cells is currently not possible. The first-phase insulin response (FPIR) to intravenous glucose can help predict progression to diabetes among individuals with positive islet autoantibodies [64,65]. The FPIR is usually calculated as the sum of the 1- and 3-min insulin levels measured after glucose is administered intravenously at 0.5 g per kg body weight. Low FPIR has been defined as below the 1st, 5th or 10th percentile of the distribution in nonobese healthy subjects. Subjects from the Joslin family study with FPIR below the first percentile on the first test had a 3-year diabetes-free survival rate of 13% compared with 78% for the group with higher FPIR [66]. The FPIR is severely depressed at the time of detection of islet autoantibodies in numerous young children. In the DPT-1 study, loss of the FPIR  was strongly associated with diabetes [64]; the average time from the fall of FPIR below the 1st percentile to the onset of diabetes was 1.8 years. A recent study from the Belgian registry reported similar results relative to first-phase insulin secretion with hyperglycemic clamps amongst individuals with IA-2 autoantibodies [67].

The oral glucose tolerance test (OGTT), performed in clinical trials of T1DM prevention largely to formalize the diagnosis of clinical diabetes, has long been known to have some value in predicting progression to T1DM among subjects with islet autoantibodies [68]. DPT-1 reported that a risk score based on age, BMI, and OGTT indexes (glucose and C-peptide values), without use of IVGTTs or additional autoantibodies, accurately predicted T1DM in ICA-positive relatives [69].The likelihood of progression to diabetes increased with mild fasting or post oral glucose-load dysglycemia.

In 1993, Leech and coworkers reported that HbA1c measured by high-performance liquid chromatography may be slightly but significantly higher in nondiabetic ICA-positive teenagers compared to ICA negative controls [70]. More recently, the DAISY study has demonstrated that Hb1Ac steadily increases within the normal range over a few years preceding diabetes onset and may therefore be useful in early detection of T1DM[71]. Among children who have persistent islet autoimmunity, increase in HbA1c predicted increased risk of progression to T1DM, with a hazard ratio of 4.8 for each 0.4% (SD) increase in HbA1c, independent of random glucose and number of autoantibodies.

Recently, increased HbA1c level has been added by the joint American Diabetes Association (ADA), International Diabetes Federation, and European Association for the Study of Diabetes International Expert Committee (IEC) as a diagnostic tool for diabetes with a recommended threshold of 6.5% for diagnosis of diabetes on two tests [72]. This threshold was established based on research conducted in adults with type 2 diabetes. However, studies in adolescents at high risk for T1DM suggest that HbA1c>6.5% is a specific but not sensitive early indicator for T1DM [73].

Through the Diabetes Complications and Control Trial (DCCT), it has been shown that patients who have sustained production of C-peptide have lower rates of severe hypoglycemia, microalbuminuria, and retinopathy [74,75]. In the Diabetes Prevention Trial-Type 1 (DPT-1), post challenge C-peptide levels begin to decrease appreciably in the 6 months before diagnosis and continue to decrease within 3 months after diagnosis [76]. Recent data from the TrialNet study show a biphasic decline in C-peptide during the first 2 years post diagnosis, with a higher rate of fall during the first year [77].

References:

  1. Mayer-Davis E: Increase in prevalence of type 1 diabetes from the SEARCH for Diabetes in Youth Study: 2001 to 2009, 2012. [Abstract]
  2. Lawrence JM: Trends in incidence of type 1 diabetes among non-Hispanic white youth in the US, 2002–2009, 2012. [Abstract]
  3. Rewers A, Klingensmith G, Davis C, et al.: Presence of diabetic ketoacidosis at diagnosis of diabetes mellitus in youth: the Search for Diabetes in Youth Study. Journal of Pediatrics 2008;121(5):e1258–e1266.
  4. Patterson CC, Gyurus E, Rosenbauer J, 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 2012;55(8):2142–2147.
  5. Fourlanos S, Varney MD, Tait BD, et al.: The rising incidence of type 1 diabetes is accounted for by cases with lower-risk human leukocyte antigen genotypes. Diabetes Care 2008;31(8):1546–1549.
  6. Liese AD, D’Agostino RB, Jr., Hamman RF, et al.: The burden of diabetes mellitus among US youth: prevalence estimates from the SEARCH for Diabetes in Youth Study. Pediatrics 2006; 118(4):1510–1518.
  7. The Environmental Determinants of Diabetes in the Young (TEDDY) Study: Annals of the N Y Academy of Sciences 2008; 1150:1–13.
  8. Harjutsalo V, Sjoberg L, Tuomilehto J: Time trends in the incidence of type 1 diabetes in Finnish children: a cohort study. Lancet 2008;371(9626):1777–1782.
  9. Haynes A, Bulsara MK, Bower C, et al.: Cyclical variation in the incidence of childhood type 1 diabetes in Western Australia (1985–2010). Diabetes Care 2012; 35(11):2300–2302.
  10. Borchers AT, Uibo R, Gershwin ME:The geoepidemiology of type 1 diabetes. Autoimmunity Reviews 2010;9(5):A355–A365.
  11. The DiaMond Project Group: Incidence and trends of childhood type 1 diabetes worldwide 1990–1999. Diabetic Medicine 2006;23(8):857–866.
  12. GreenA, Patterson CC: Trends in the incidence of childhood-onset diabetes in Europe 1989–1998. Diabetologia 2001;44(Suppl 3): B3–B8.
  13. Karvonen M, Viik-Kajander M, Moltchanova E, et al.: Incidence of childhood type 1 diabetes worldwide. Diabetes Mondiale (Dia-Mond) Project Group. Diabetes Care 2000;23(10):1516–1526.
  14. Zhang H, Xia W, Yu Q, et al. Increasing incidence of type 1 diabetes in children aged 0–14 years in Harbin, China (1990–2000). Primary Care Diabetes 2008;2(3):121–126.
  15. Dabelea D, Bell RA, D’Agostino RB, Jr,., et al.: Incidence of diabetes in youth in the United States. JAMA 2007;297(24):2716–2724.
  16. Kostraba JN, Gay EC, Cai Y, et al.: Incidence of insulin-dependent diabetes mellitus in Colorado. Epidemiology 1992;3:232–238.
  17. Gujral JS, McNally PG, Botha JL, Burden AC: Childhood-onset diabetes in the white and South Asian population in Leicestershire, UK. Diabetic Medicine 1994;11(6):570–572.
  18. Dahlquist GG, Nystrom L, Patterson CC: Incidence of type 1 diabetes in Sweden among individuals aged 0–34 years, 1983–2007: an analysis of time trends. Diabetes Care 2011;34(8):1754–1759.
  19. Bruno G,Merletti F, Biggeri A, et al.: Increasing trend of type I diabetes in children and young adults in the province of Turin (Italy). Analysis of age, period and birth cohort effects from 1984 to 1996. Diabetologia 2001;44(1):22–25.
  20. Gale EA, Gillespie KM: Diabetes and gender. Diabetologia 2001; 44(1):3–15.
  21. Serban V, Timar R, Dabelea D, et al.: The epidemiology of childhood-onset type 1 diabetes mellitus in Romania. ONROCAD Study Group. National Romanian Organisation for the Care of Diabetic Children and Adolescents. Journal of Pediatric Endocrinology and Metabolism 2001;14(5):535–541.
  22. Diabetes Epidemiology Research International Group: Secular trends in incidence of childhood IDDM in 10 countries. Diabetes 1990;39:858–864.
  23. EURODIAB ACE Study Group: Variation and trends in incidence of childhood diabetes in Europe. Lancet 2000;355(9207):873–876.
  24. Rosenbauer J, Herzig P, von Kries R, et al.: Temporal, seasonal, and geographical incidence patterns of type I diabetes mellitus in children under 5 years of age in Germany. Diabetologia 1999; 42(9):1055–1059.
  25. Schoenle EJ, Lang-Muritano M, Gschwend S, et al.: Epidemiology of type I diabetes mellitus in Switzerland: steep rise in incidence in under 5 year old children in the past decade. Diabetologia 2001;44(3):286–289.
  26. Verge CF, Gianani R, Kawasaki E, et al.: Prediction of type I diabetes in first-degree relatives using a combination of insulin, GAD, and ICA512bdc/IA-2 autoantibodies. Diabetes 1996;45(7):926–933.
  27. Williams AJ, Bingley PJ, Bonifacio E, et al.: A novel micro-assay for insulin autoantibodies. Journal of Autoimmunity 1997;10(5): 473–478.
  28. Robles DT, Eisenbarth GS,Wang T, et al.: Identification of children with early onset and high incidence of anti-islet autoantibodies. Clinical Immunology 2002;102(3):217–224.
  29. Kupila A, Keskinen P, Simell T, et al. Genetic risk determines the emergence of diabetes-associated autoantibodies in young children. Diabetes 2002;51(3):646–651.
  30. Orban T, Sosenko JM,Cuthbertson D, et al. Pancreatic islet autoantibodies as predictors of type 1 diabetes in the Diabetes Prevention Trial-Type 1. Diabetes Care 2009;32(12):2269–2274.
  31. Siljander HT, Simell S, Hekkala A, et al.: Predictive characteristics of diabetes-associated autoantibodies among children with HLA-conferred disease susceptibility in the general population. Diabetes 2009;58(12):2835–2842.
  32. Redondo MJ, Jeffrey J, Fain PR, et al.: Concordance for islet autoimmunity among monozygotic twins. brand-new England Journal of Medicine 2008;359(26):2849–2850.
  33. Harjutsalo V, Reunanen A, Tuomilehto J: Differential transmission of type 1 diabetes from diabetic fathers and mothers to their offspring. Diabetes 2006; 55(5):1517–1524.
  34. Koczwara K, Bonifacio E, Ziegler AG: Transmission of maternal islet antibodies and risk of autoimmune diabetes in offspring of mothers with type 1 diabetes. Diabetes 2004;53(1):1–4.
  35. Rewers M, Bugawan TL, Norris JM, et al.: Newborn screening for HLA markers associated with IDDM: Diabetes Autoimmunity Study in the Young (DAISY). Diabetologia 1996;39:807–812.
  36. Deschamps I, Khalil I. The role of DQ alpha-beta heterodimers in genetic susceptibilty to insulin-dependent diabetes. Diabetes/Metabolism Reviews 1993;9:71–92.
  37. Valdes AM, Erlich HA, Noble JA: Human leukocyte antigen class I B and C loci contribute to Type 1 Diabetes (T1D) susceptibility and age at T1D onset. Human Immunology 2005;66(3): 301–313.
  38. Nejentsev S, Howson JM, Walker NM, et al.: Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A. Nature 2007;450(7171):887–892.
  39. Aly TA, Ide A, Jahromi MM, et al.: Extreme genetic risk for type 1A diabetes. PNAS 2006;103(38):14074–14079.
  40. Baschal EE, Aly TA, Babu SR, et al.: HLA-DPB1*0402 protects versus type 1A diabetes autoimmunity in the highest risk DR3-DQB1*0201/DR4-DQB1*0302 DAISY population. Diabetes 2007;56(9):2405–2409.
  41. Steck AK, Armstrong TK, Babu SR, Eisenbarth GS: Stepwise or linear decrease in penetrance of type 1 diabetes with lower-risk HLA genotypes over the past 40 years. Diabetes 2011;60(3):1045–1049.
  42. Erlich H, Valdes AM, Noble J, et al.: HLA DR-DQ haplotypes and genotypes and type 1 diabetes risk: analysis of the type 1 diabetes genetics consortium families. Diabetes 2008;57(4):1084–1092.
  43. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007;447(7145): 661–678.
  44. Steck AK,Wong R,Wagner B, et al.: Effects of non-HLA gene polymorphisms on development of islet autoimmunity and type 1 diabetes in a population with high-risk HLA-DR,DQ genotypes. Diabetes 2012;61(3):753–758.
  45. Vang T, Congia M, Macis MD, et al.: Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Nature Genetics 2005;37(12):1317–1319.
  46. Rieck M, Arechiga A, Onengut-Gumuscu S, et al.: Genetic variation in PTPN22 corresponds to altered function of T and B lymphocytes. Journal of Immunology 2007;179(7):4704–4710.
  47. Yu L, Cuthbertson DD, Maclaren N, et al.: Expression of GAD65 and islet cell antibody (ICA512) autoantibodies among cytoplasmic ICA+ relatives is associated with eligibility for the Diabetes Prevention Trial-Type 1. Diabetes 2001;50(8):1735–1740.
  48. Wenzlau JM, Moua O, Sarkar SA, et al.: SlC30A8 is a major target of humoral autoimmunity in type 1 diabetes and a predictive marker in prediabetes. Annals of the N Y Academy of Sciences 2008; 1150:256–259.
  49. Achenbach P, Schlosser M, Williams AJ, et al.: Combined testing of antibody titer and affinity improves insulin autoantibody measurement: Diabetes Antibody Standardization Program. Clinical Immunology 2007;122(1):85–90.
  50. Torn C, Mueller PW, Schlosser M, et al.: Diabetes Antibody Standardization Program: evaluation of assays for autoantibodies to glutamic acid decarboxylase and islet antigen-2. Diabetologia 2008;51(5):846–852.
  51. Achenbach P, Bonifacio E,Williams AJ, et al.: Autoantibodies to IA-2beta improve diabetes risk assessment in high-risk relatives. Diabetologia 2008;51(3):488–492.
  52. Steck AK, Johnson K, Barriga KJ, et al.: Age of islet autoantibody appearance and mean levels of insulin, but not GAD or IA-2 autoantibodies, predict age of diagnosis of type 1 diabetes: Diabetes Autoimmunity Study in the Young. Diabetes Care 2011; 34(6):1397–1399.
  53. Bingley PJ, Gale EA: Progression to type 1 diabetes in islet cell antibody-positive relatives in the European Nicotinamide Diabetes Intervention Trial: the role of additional immune, genetic and metabolic markers of risk. Diabetologia 2006;49(5):881–890.
  54. Ekoé J-M, Rewers M,Williams R, Zimmet P (eds.): The Epidemiology of Diabetes Mellitus Textbook. JohnWiley & Sons, Ltd., 2008.
  55. Ziegler A-G, Hillebrand B, Rabl W, et al.: On the appearance of islet associated autoimmunity in offspring of diabetic mothers: a prospective study from birth. Diabetologia 1993;36:402–408.
  56. Barker JM, Barriga KJ, Yu L, et al.: Prediction of autoantibody positivity and progression to type 1 diabetes: Diabetes Autoimmunity Study in the Young (DAISY). Journal of Clinical Endocrinology & Metabolism 2004;89(8):3896–3902.
  57. Kimpimaki T, Knip M: Disease-associated autoantibodies as predictive markers of type 1 diabetes mellitus in siblings of affected children. Journal of Pediatric Endocrinology and Metabolism 2001;14(Suppl 1):575–587.
  58. The Environmental Determinants of Diabetes in the Young (TEDDY) study: study design. Pediatric Diabetes 2007;8(5): 286–298.
  59. Siljander HT, Veijola R, Reunanen A, et al.: Prediction of type 1 diabetes among siblings of affected children and in the general population. Diabetologia 2007;50(11):2272–2275.
  60. Achenbach P, Koczwara K, Knopff A, et al.: Mature high-affinity immune responses to (pro) insulin anticipate the autoimmune cascade that leads to type 1 diabetes. Journal of Clinical Investigation 2004;114(4):589–97.
  61. Laakso M, Pyorala K: Age at onset and type of diabetes. Diabetes Care 1985;8:114–117.
  62. Fuchtenbusch M, Ferber K, Standl E, Ziegler AG: Prediction of type 1 diabetes postpartumin patients with gestational diabetes mellitus by combined islet cell autoantibody screening: a prospective multicenter study. Diabetes 1997;46(9):1459–1467.
  63. Turner R, Stratton I,Horton V, 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 1997;350(9087):1288–1293.
  64. Chase HP, Dolan LM, Krischer JP, et al.: First phase insulin release (FPIR) during the intravenous glucose tolerance test (IV-GTT) as a risk factor for type 1 diabetes. Journal of Pediatrics 2001; 138(2):244–249.
  65. Keskinen P, Korhonen S, Kupila A, et al.: First-phase insulin response in young healthy children at genetic and immunological risk for Type I diabetes. Diabetologia 2002;45(12):1639–1648.
  66. Eisenbarth GS, Verge CF, Allen H, Rewers MJ: The design of trials for prevention of IDDM. Diabetes 1993;42(7):941–947.
  67. Keymeulen B, Walter M, Mathieu C, et al.: Four-year metabolic outcome of a randomised controlled CD3-antibody trial in recent-onset type 1 diabetic patients depends on their age and baseline residual beta cell mass. Diabetologia 2010;53(4):614–623.
  68. Sosenko JM, Palmer JP, Greenbaum CJ, et al.: Increasing the accuracy of oral glucose tolerance testing and extending its application to individuals with normal glucose tolerance for the prediction of type 1 diabetes: the Diabetes PreventionTrial -Type 1. Diabetes Care 2007;30(1):38–42.
  69. Sosenko JM, Krischer JP, Palmer JP, et al.: A risk score for type 1 diabetes derived from autoantibody-positive participants in the Diabetes Prevention Trial-Type 1. Diabetes Care 2008;31(3): 528–533.
  70. Leech NJ, Rowe RE, Bucksa J, McCulloch DK: HbA1c may be an early indicator of islet cell dysfunction. Autoimmunity 1993;15(Suppl):75. [Abstract]
  71. Stene LC, Barriga K, Hoffman M, et al.: Normal but increasing hemoglobin A1c levels predict progression from islet autoimmunity to overt type 1 diabetes: Diabetes Autoimmunity Study in the Young (DAISY). Pediatric Diabetes 2006;7(5):247–253.
  72. International Expert Committee report on the role of the A1c assay in the diagnosis of diabetes. Diabetes Care 2009;32(7):1327–1334.
  73. Vehik K,Cuthbertson D, Boulware D, et al.: Performance of HbA1c as an early diagnostic indicator of type 1 diabetes in children and youth. Diabetes Care 2012; 35(9):1821–1825.
  74. The Diabetes Control and Complications Trial Research Group: Effects of age, duration and treatment of insulin-dependent diabetes mellitus on residual B-cell function: observations during eligibility testing for the diabetes control and complications trial. Journal of Clinical Endocrinology & Metabolism 1987;65:30–36.
  75. The Diabetes Control and Complications Trial Research Group: Effect of intensive therapy on residual beta-cell function in patients with type 1 diabetes in the diabetes control and complications trial. A randomized, controlled trial. Annals of Internal Medicine 1998;128(7):517–523.
  76. Sosenko JM, Palmer JP, Rafkin-Mervis L, et al.: Glucose and C-peptide changes in the perionset period of type 1 diabetes in the Diabetes Prevention Trial-Type 1. Diabetes Care 2008; 31(11):2188–2192.
  77. Greenbaum CJ, Beam CA, Boulware D, et al.: Fall in C-peptide during first 2 years from diagnosis: evidence of at least two distinct phases from Composite Type 1 Diabetes TrialNet Data. Diabetes 2012;61(8):2066–2073.
  78. Kaprio J, Tuomilehto J, Koskenvuo M, et al.: Concordance for type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus in a population-based cohort of twins in Finland. Diabetologia 1992;35(11):1060–1067.
  79. Conrad B, Weidmann E, Trucco G, et al.: Evidence for superantigen involvement in insulin-dependent diabetes mellitus aetiology. Nature 1994;371(6495):351–355.
  80. Honeyman MC, Coulson BS, Stone NL, et al.: Association between rotavirus infection and pancreatic islet autoimmunity in children at risk of developing type 1 diabetes. Diabetes 2000;49(8):1319–1324.
  81. Coppieters KT, Boettler T, von Herrat M: Virus infections in type 1 diabetes. Cold Spring Harbor Perspectives in Medicine 2012; 2(1):a007682.
  82. Stene LC, Oikarinen S, Hyoty H, et al.: Enterovirus infection and progression from islet autoimmunity to type 1 diabetes: the Diabetes and Autoimmunity Study in the Young (DAISY). Diabetes 2010;59(12):3174–3180.
  83. Oikarinen S, Martiskainen M, Tauriainen S, et al.: Enterovirus RNA in blood is linked to the development of type 1 diabetes. Diabetes 2011;60(1):276–279.
  84. Stene LC, Rewers M: Immunology in the clinic review series; focus on type 1 diabetes and viruses: the enterovirus link to type 1 diabetes: critical review of human studies. Clinical & Experimental Immunology 2012;168(1):12–23.
  85. McKinney PA, Okasha M, Parslow RC, et al.: Early social mixing and childhood Type 1 diabetes mellitus: a case-control study in Yorkshire, UK. Diabetic Medicine 2000;17(3):236–242.
  86. Infections and vaccinations as risk factors for childhood type I (insulin-dependent) diabetes mellitus: a multicentre case-control investigation. EURODIAB Substudy 2 Study Group. Diabetologia 2000;43(1):47–53.
  87. Kaila B, Taback SP: The effect of day care exposure on the risk of developing type 1 diabetes: ameta-analysis of case-control studies. Diabetes Care 2001;24(8):1353–1358.
  88. Zinkernagel RM: Maternal antibodies, childhood infections, and autoimmune diseases. brand-new England Journal of Medicine 2001; 345(18):1331–1335.
  89. Graves PM, Barriga KJ, Norris JM, et al.: Lack of association between early childhood immunizations and beta-cell autoimmunity. Diabetes Care 1999;22(10):1694–1697.
  90. Hummel M, Fuchtenbusch M, Schenker M, Ziegler AG: No major association of breast-feeding, vaccinations, and childhood viral diseases with early islet autoimmunity in the German BABYDIAB Study. Diabetes Care 2000;23(7):969–974.
  91. Hyoty H, Hiltunen M, Reunanen A, et al.: Decline of mumps antibodies in type 1 (insulin-dependent) diabetic children and a plateau in the rising incidence of type 1 diabetes after introduction of the mumps-measles-rubella vaccine in Finland. Childhood Diabetes in Finland Study Group. Diabetologia 1993;36(12):1303– 1308.
  92. Bingley PJ, Douek IF, Rogers CA, Gale EA: Influence of maternal age at delivery and birth order on risk of type 1 diabetes in childhood: prospective population based family study. Bart’s-Oxford Family Study Group. BMJ 2000;321(7258):420–424.
  93. Stene LC, Magnus P, Lie RT, et al.: Maternal and paternal age at delivery, birth order, and risk of childhood onset type 1 diabetes: population based cohort study. BMJ 2001;323(7309):369.
  94. Stene LC, Magnus P, Lie RT, et al.: Birth weight and childhood onset type 1 diabetes: population based cohort study. BMJ 2001;322(7291):889–892.
  95. Dahlquist GG, Patterson C, Soltesz G: Perinatal risk factors for childhood type 1 diabetes in Europe.The EURODIAB Substudy 2 Study Group. Diabetes Care 1999;22(10):1698–1702.
  96. Kyvik KO, Bache I, Green A, et al.: No association between birth weight and Type 1 diabetes mellitus: a twin-control study. Diabetic Medicine 2000;17(2):158–162.
  97. Lamb MM, Yin X, Zerbe GO, et al.: Height growth velocity, islet autoimmunity and type 1 diabetes development: the Diabetes Autoimmunity Study in the Young. Diabetologia 2009;52(10): 2064–2071.
  98. Martin JM, Trink B, Daneman D, et al.: Milk proteins in the etiology of insulin-dependent diabetes mellitus (IDDM). Annals of Medicine 1991;23:447–452.
  99. Gerstein HC: Cow’s milk exposure and type I diabetes mellitus—a critical overview of the clinical literature. Diabetes Care 1994;17: 13–19.
  100. Norris JM, Scott FW: A meta-analysis of infant diet and insulin-dependent diabetes mellitus: do biases play a role? Epidemiology 1996;7:87–92.
  101. Norris JM, Beaty B, Klingensmith G, et al.: Lack of association between early exposure to cow’s milk protein and beta-cell autoimmunity. Diabetes Autoimmunity Study in the Young (DAISY). JAMA 1996;276(8):609–614.
  102. Virtanen SM, Hypponen E, Laara E, et al.: Cow’s milk consumption, disease-associated autoantibodies and type 1 diabetes mellitus: a follow-up study in siblings of diabetic children. Childhood Diabetes in Finland Study Group. Diabetic Medicine 1998;15(9): 730–738.
  103. Knip M, Virtanen SM, Becker D, et al.: Early feeding and risk of type 1 diabetes: experiences from the Trial to Reduce Insulin-dependent diabetes mellitus in the Genetically at Risk (TRIGR). American Journal of Clinical Nutrition 2011;94(6 Suppl): 1814S–1820S.
  104. Norris JM, Barriga K, Klingensmith G, et al.: Timing of initial cereal exposure in infancy and risk of islet autoimmunity. JAMA 2003;290(13):1713–1720.
  105. Ziegler AG, Schmid S, Huber D, et al.: Early infant feeding and risk of developing type 1 diabetes-associated autoantibodies. JAMA 2003;290(13):1721–1728.
  106. Hummel S, Pfluger M, Hummel M, et al.: Primary dietary intervention study to reduce the risk of islet autoimmunity in children at increased risk for type 1 diabetes: the BABYDIET study. Diabetes Care 2011;34(6):1301–1305.
  107. Mathieu C, Laureys J, Sobis H, et al.: 1,25-dihydroxyvitamin D3 prevents insulitis in NOD mice. Diabetes 1992;41:1491–1495.
  108. Hypponen E, Laara E, Reunanen A, et al.: Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 2001;358(9292):1500–1503.
  109. Stene LC, Ulriksen J, Magnus P, Joner G: Use of cod liver oil during pregnancy associated with lower risk of Type I diabetes in the offspring. Diabetologia 2000;43(9):1093–1098.
  110. Simpson M, Brady H, Yin X, et al.: No association of vitamin D intake or 25-hydroxyvitamin D levels in childhood with risk of islet autoimmunity and type 1 diabetes: the Diabetes Autoimmunity Study in the Young (DAISY). Diabetologia 2011; 54(11):2779–2788.
  111. Fronczak CM, Baron AE, Hunt HP, et al.: In utero dietary exposures and risk of islet autoimmunity in children. Diabetes Care 2003;26(12):3237–3242.
  112. Marjamaki L, Niinisto S, Kenward MG, et al.: Maternal intake of vitamin D during pregnancy and risk of advanced beta cell autoimmunity and type 1 diabetes in offspring. Diabetologia 2010; 53(8):1599–1607.
  113. Norris JM, Yin X, Lamb MM, et al.: Omega-3 polyunsaturated fatty acid intake and islet autoimmunity in children at increased risk for type 1 diabetes. JAMA 2007;298(12):1420–1428.
  114. Miller MR, Yin X, Seifert J, et al.: Erythrocyte membrane omega-3 fatty acid levels and omega-3 fatty acid intake are not associated with conversion to type 1 diabetes in children with islet autoimmunity: the Diabetes Autoimmunity Study in the Young (DAISY). Pediatric Diabetes 2011;12(8):669–675.
  115. Skyler JS: Update on worldwide efforts to prevent type 1 diabetes. Annals of the N Y Academy of Sciences 2008;1150:190–196.
  116. Rewers M, Atkinson M: The possible role of enteroviruses in diabetes mellitus. In: Rotbart HA (ed.) Human Enterovirus Infections. Washington, DC: ASM, 1996, pp. 353–385.
  117. Virtanen SM, Laara E, Hypponen E, et al.: Cow’s milk consumption, HLA-DQB1 genotype, and type 1 diabetes: a nested case-control study of siblings of children with diabetes. Childhood Diabetes in Finland Study Group [in process citation]. Diabetes 2000;49(6):912–917.
  118. Pinkey JH, Bingley PJ, Sawtell PA, et al.: Presentation and progress of childhood diabetes mellitus: a prospective population based study. The Bart’s-Oxford Study Group. Diabetologia 1994; 37(1):70–74.
  119. Foulis AK, Liddle CN, Farquharson MA, et al.: The histopathology of the pancreas in type I diabetes (insulin dependent) mellitus: a 25-year review of deaths in patients under 20 years of age in the United Kingdom. Diabetologia 1986;29(5):267–274.
  120. Childhood Diabetes Research Committee–Ministry of Health and Welfare–Japan; Polish Diabetes Research Group–Poznan; The Netherlands Institute for Preventive Health Care–Leiden; Diabetes Research Center of Pittsburgh–Pennsylvania: How frequently do children die at the onset of insulin-dependent diabetes? Analyses of registry data from Japan, Poland, the Netherlands, and Allegheny County, Pennsylvania. Diabetes, Nutrition & Metabolism 1990;3:57–62.
  121. Sabbah E, Savola K, Kulmala P, et al.: Diabetes-associated autoantibodies in relation to clinical characteristics and natural course in children with newly diagnosed type 1 diabetes.The Childhood Diabetes in Finland Study Group. Journal of Clinical Endocrinology & Metabolism 1999;84(5):1534–1539.
  122. Ortqvist E, Falorni A, Scheynius A, et al.: Age governs gender-dependent islet cell autoreactivity and predicts the clinical course in childhood IDDM. Acta Paediatrica 1997; 86(11):1166–1171.
  123. Pipeleers D, Ling Z: Pancreatic beta cells in insulin-dependent diabetes. Diabetes/Metabolism Reviews 1992;8(3):209–227.
  124. Rewers A, Hunt HP, Mackenzie T, et al.: Predictors of acute complications in children with type 1 diabetes. JAMA 2002;287(19):2511–2518.
  125. Secrest AM, Becker DJ, Kelsey SF, et al.: All-cause mortality trends in a large population-based cohort with long-standing childhood-onset type 1 diabetes: the Allegheny County type 1 diabetes registry. Diabetes Care 2010;33(12):2573–2579.
  126. Miller RG, Secrest AM, Sharma RK, et al.: Improvements in the life expectancy of type 1 diabetes: the Pittsburgh Epidemiology of Diabetes Complications Study cohort. Diabetes 2012; 61(11):2987–2992.
  127. Orchard TJ, Secrest AM, Miller RG, Costacou T: In the absence of renal disease, 20 year mortality risk in type 1 diabetes is comparable to that of the general population: a report from the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetologia 2010;53(11):2312–2319.

Share this