The primary objective of this multicenter, multinational, epidemiological study is the identification of infectious agents, dietary factors, or other environmental exposures that are associated with increased risk of autoimmunity and type 1 diabetes mellitus (T1DM). Factors affecting specific phenotypic manifestations such as early age of onset or rate of progression or with protection from the development of T1DM will also be identified. The Environmental Determinants of Diabetes in the Young (TEDDY) is an observational cohort study in which newborns who are younger than 4 months and have high-risk human leukocyte antigen alleles in the general population or are first-degree relatives (FDRs) of patients affected with T1DM will be enrolled. Six clinical centers in the USA and Europe will screen 361 588 newborns, of which it is anticipated that 17 804 will be eligible for enrollment with just over 7800 followed. Recruitment will occur over 5 yr, with children being followed to the age of 15 yr. Identification of such factors will lead to a better understanding of disease pathogenesis and result in new strategies to prevent, delay, or reverse T1DM.

The environmental determinants of diabetes in the young (TEDDY) study: Study design

The incidence rate of insulin-dependent (Type I) diabetes mellitus is bimodal: one peak occurs close to puberty, and the other in the fifth decade. To evaluate possible differences in these forms of the disease, we examined the clinical, biochemical, autoimmune, and genetic features of 82 children and adolescents (1.3 to 18.2 years old) and 44 adults (20.0 to 55.8 years old) when they presented with Type I diabetes. The mean (+/- SEM) duration of symptoms before diagnosis was longer in the adults (7.5 +/- 1.0 vs. 3.9 +/- 0.4 weeks; P less than 0.001), and their serum C-peptide concentrations at diagnosis were higher (0.29 +/- 0.03 vs. 0.17 +/- 0.01 nmol per liter; P less than 0.001), suggesting that they had more residual beta-cell function. There were no significant differences between the two groups in sex ratio, blood glucose levels, hemoglobin A1 values, degree of metabolic decompensation, or frequency of Type I diabetes in first-degree relatives. Thirty-four of 80 children tested (42.5 percent) were positive for insulin autoantibodies, as compared with only 1 of 26 adults (3.8 percent; P less than 0.001). However, the frequencies of islet-cell autoantibodies were similar in the adults and children (conventional autoantibodies, both 81 percent; complement-fixing autoantibodies, 46.2 percent and 60 percent). More children than adults were heterozygous for both HLA-Dw3/4 antigens (26.6 percent vs. 9.8 percent; P less than 0.05) and HLA-DR3/4 antigens (36.6 percent vs. 12.5 percent; P less than 0.05). We conclude that Type I diabetes that begins in adulthood is characterized by a longer symptomatic period before diagnosis, better preservation of residual beta-cell function, and lower frequencies of insulin autoantibodies and HLA-D3/D4 heterozygosity than Type I diabetes that begins in childhood or adolescence.

A Comparison of Childhood and Adult Type I Diabetes Mellitus

Little is known about the timing of the etiological events and the preclinical process of type 1 diabetes during the first years of life in the general population. In this population-based prospective birth cohort study, the appearance of diabetes-associated autoantibodies as a sign of beta-cell autoimmunity and the development of type 1 diabetes were monitored from birth. Of 25,983 newborn infants, 2,448 genetically susceptible children were monitored for islet cell antibodies (ICA) at 3- to 6-month intervals. If an infant seroconverted to ICA positivity, all his/her samples were also analyzed for insulin autoantibodies (IAA), antibodies to the 65-kDa isoform of glutamic acid decarboxylase, and antibodies to the protein tyrosine phosphatase-related IA-2 molecule. Fifteen children of those who carried the high-risk genotype (2.7%) and 23 of those who carried the moderate-risk genotype (1.2%; P = 0.019) tested positive for ICA at least once. Among those who showed positivity for at least 2 antibodies during the observation period (25 of 38), IAA appeared as the first or among the first antibodies in 22 children (88%) and emerged earlier than the other antibodies (P < 0.019 or less). The first autoantibodies appeared in the majority of the children in the fall and winter (30 of 38 vs. 8 of 38 in the spring and summer, P < 0.001). These observations suggest that young children in the general population with a strong human-leukocyte-antigen-DQ-defined genetic risk of type 1 diabetes show signs of beta-cell autoimmunity proportionally more often than those with a moderate genetic risk. IAA emerge as the first detectable antibody more commonly than any other antibody specificity, implying that insulin may be the primary antigen in most cases of human type 1 diabetes associated with the DR4-DQB1*0302 haplotype. The seasonal variation in the emergence of the first signs of beta-cell autoimmunity suggests that infectious agents may play a role in the induction of such autoimmunity.

The First Signs of β-Cell Autoimmunity Appear in Infancy in Genetically Susceptible Children from the General Population: The Finnish Type 1 Diabetes Prediction and Prevention Study

A quantitative fluid-phase radioassay for autoantibodies reacting with insulin (competitive insulin autoantibody assay, CIAA) was developed. The assay's features include 1) use of a physiologic amount of 125I-labeled insulin, 2) parallel incubations with supraphysiologic cold insulin (competitive), and 3) an incubation time of 7 days and a single-step multiple-wash polyethylene glycol separation. Mean +/- SE CIAA levels in 50 controls were 8 +/- 1.4 nU/ml (range -16-33.3). In 36 cytoplasmic islet cell antibody (ICA)-positive nondiabetic first-degree relatives of type I (insulin-dependent) patients less than 30 yr of age, CIAA levels exceeded the normal range in 20 (55.6%) of 36 (mean 86.8 +/- 17.1 nU/ml). In 26 ICA-positive relatives greater than 30 yr of age, only 5 (19.2%) of 26 exceeded the normal range (mean 26.1 +/- 9.4 nU/ml); P less than .001 compared with younger ICA-positive relatives). Six ICA-negative HLA-identical siblings of type I diabetic patients had normal CIAA levels (mean 3.6 +/- 5.8 nU/ml), and only 2 of 13 ICA-negative identical twins discordant for diabetes (mean 15.4 +/- 6.6 nU/ml) exceeded the normal range. Nine (50%) of 18 ICA-positive schoolchildren exceeded the normal range (mean 105.3 +/- 36.7 nU/ml). Genetically susceptible subjects negative for CIAA (with only 3 exceptions) remained negative for CIAA on multiple determinations (3 conversions observed), and CIAA levels of positive subjects were relatively stable. Linear regression of the first CIAA level versus last (interval between sampling 1 mo to 10 yr) in genetically susceptible individuals showed a highly significant correlation (r = .95, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Competitive Insulin Autoantibody Assay: Prospective Evaluation of Subjects at High Risk for Development of Type I Diabetes Mellitus

Revue sur les nombreuses anomalies immunologiques rencontrees dans la diabete de type I: certaines sont transitoires, la plupart pourraient etre liees a l'insuffisance en insuline ou a sa regulation defectueuse. Discussion sur la chronologie des evenements (role des cellules effectrices ou des cellules cibles)

/pdf/multiple-immunological-abnormalities-in-patients-with-type-1-20jffgrr9z.pdf

Multiple immunological abnormalities in patients with type 1 (insulin-dependent) diabetes mellitus.

The case for elimination of cow's milk in early infancy in the prevention of type 1 diabetes: the Finnish experience.

SUMMARY To test the hypothesis that insulin-binding antibodies (IBAs) appearing in the circulation before insulin treatment are markers of p-cell damage, we studied the prevalence of IBAs and both conventional (IF-ICAs)and complement (CF-ICAs)-fixing cytoplasmic islet cell antibodies in 60 newly diagnosed diabetic children with a mean age of 9.5 yr. Seventeen (28.3%) had an insulin binding exceeding the upper range (2.8%) of that observed in 68 age-matched controls. The IBA-positive subjects were characterized by a younger age of onset [6.2 ± 4.0 (SD) vs. 10.8 ± 3.2 yr; P < 0.001], lower glycosylated hemoglobin A, levels (14.1 ± 3.1 vs. 16.0 ± 3.0%; P < 0.05), lower serum C-peptide concentrations (0.12 ± 0.07 vs. 0.20 ± 0.17 nmol/L; P < 0.05), and an increased frequency of HLA-Dw4 (9/13 vs. 11/37; P < 0.05). There was no significant relation between IBAs and serum C-peptide concentrations after age adjustment by multiple regression analysis. Forty-three children (75%) were positive for IF-ICA and 38 (63.3%) for CF-ICA. Twelve IBA-positive diabetics (70.6%) had IFICA as well as CF-ICA in their serum. No association could be observed between IBA and either IF-ICA or CF-ICA, however. The results suggest that IBAs developing before diagnosis serve as an indicator of clinical and genetic heterogeneity within IDDM rather than as a marker of autoimmune p-cell destruction. DIABETES 1986; 35:620-22.

Rapid Publication Relation Between Insulin Antibody and Complement-Fixing Islet Cell Antibody at Clinical Diagnosis of IDDM

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The case for elimination of cow's milk in early infancy in the prevention of type 1 diabetes: the Finnish experience.

Rapid Publication Relation Between Insulin Antibody and Complement-Fixing Islet Cell Antibody at Clinical Diagnosis of IDDM