OBJECTIVE -In a prospective birth cohort study, we followed infants who had a firstdegree relative with type 1 diabetes to investigate the relationship between early growth and infant feeding and the risk of islet autoimmunity.RESEARCH DESIGN AND METHODS -Infants with a first-degree relative with type 1 diabetes were identified during their mother's pregnancy. Dietary intake was recorded prospectively to determine duration of breast-feeding and age at introduction of cow's milk protein, cereals, meat, fruit, and vegetables. At 6-month reviews, length (or height) and weight, antibodies to insulin, GAD65, the tyrosine phosphatase-like insulinoma antigen, and tissue transglutaminase were measured. Islet autoimmunity was defined as persistent elevation of one or more islet antibodies at consecutive 6-month intervals, including the most recent measure, and was the primary outcome measure.RESULTS -Follow-up of 548 subjects for 5.7 Ϯ 3.2 years identified 46 children with islet autoimmunity. Weight z score and BMI z score were continuous predictors of risk of islet autoimmunity (adjusted hazard ratios 1.43 [95% CI 1.10 -1.84], P ϭ 0.007, and 1.29 [1.01-1.67], P ϭ 0.04, respectively). The risk of islet autoimmunity was greater in subjects with weight z score Ͼ0 than in those with weight z score Յ0 over time (2.61 [1.26 -5.44], P ϭ 0.01). Weight z score and BMI z score at 2 years and change in weight z score between birth and 2 years, but not dietary intake, also predicted risk of islet autoimmunity.CONCLUSIONS -Weight gain in early life predicts risk of islet autoimmunity in children with a first-degree relative with type 1 diabetes. Diabetes Care 32:94-99, 2009

The hypothesis that early exposure to cow's milk or lack of breast-feeding predisposes to type 1 diabetes remains controversial. We aimed to determine prospectively the relationship of, first, duration of exclusive breast-feeding and total duration of breast-feeding, and second, introduction of cow's milk protein as infant formula, cow's milk, or dairy products, to the development of islet antibodies in early life. Some 317 children with a first-degree relative with type 1 diabetes were followed prospectively from birth for 29 months (4-73). Mothers kept a home diary and answered infant feeding questionnaires at 6-month intervals. No systematic feeding advice was given. Insulin autoantibodies (normal range <5.5%), anti-GAD antibodies (<5.0 U), and anti-IA2 antibodies (<3.0 U) were measured at 6-month intervals. Cox proportional hazards model of survival analysis detected no significant difference between children who did not develop islet antibodies (225 of 317 [71%]), children with one islet antibody raised once (52 of 317 [16.4%]), children with one antibody raised repeatedly (18 of 317 [5.7%]), or children with two or more antibodies raised (22 of 317 [6.9%]), in terms of duration of exclusive breast-feeding, total duration of breast-feeding, or introduction of cow's milk-based infant formulas, cow's milk, or dairy products (relative risk: 0.91-1.09). Four of the children with two or more islet antibodies developed type 1 diabetes. We conclude that there is no prospective association between duration of breast-feeding or introduction of cow's milk and the development of islet autoimmunity in high-risk children.

Type I (insulin-dependent) diabetes mellitus is caused by immune-mediated destruction of the insulin-secreting beta cells in the islets of the pancreas [1]. Studies in first-degree relatives of patients with Type I diabetes [2±4] have shown conclusively that autoantibodies to islet antigens precede the onset and can be used to predict clinical disease. Initially, islet cell antibodies (ICA) and insulin autoantibodies (IAA) were used to identify relatives at high risk. Recently, several studies have concluded that antibodies to glutamic acid decarboxylase (GADAb) and to the putative tyrosine phosphatase IA2 (IA2Ab) in combination are as disease specific and sensitive as ICA, simpler to analyse and thus more suitable for preclinical screening [5±8].Many questions remain to be answered regarding the natural history of development of islet autoimmunity that are central to furthering our understanding of pathogenesis and developing screening and prevention strategies. These include the timing and se- Diabetologia (2000) Abstract Aims/hypothesis. To determine the sequence of development of islet autoantibodies and their relation to HLA genes in infants at risk for Type I diabetes followed from birth. Methods. We followed 357 (189 male, 168 female) infants, with a first degree relative with Type I diabetes for a mean of 3 years from birth. Human leukocyte antigen typing and assays for insulin autoantibodies (IAA), glutamic acid decarboxylase antibodies (GADAb) and tyrosine phosphatase IA2 (IA2Ab) antibodies were done on cord blood, and venous blood was sampled every 6 months for IAA, GADAb and IA2Ab. Results. We did not find any antibodies in 263 (73 %) infants; 50 (14 %) were positive for a single antibody once, 19 (5 %) for a single antibody more than once and 25 (7 %) for two or more antibodies. Of the latter, 10 (2.8 % overall) were persistently positive; they had higher frequencies of HLA DR4 (p < 0.01) and HLA DR3, 4 (p < 0.05). Of the group persistently positive for two or more antibodies four infants developed diabetes. Insulin autoantibodies were the first ones to develop in 64 % of infants with two or more antibodies. Conclusion/interpretation. Infants with high risk HLA-DR alleles and multiple antibodies at high risk for diabetes were identified. A much larger group of infants had transient low level increases usually of a single antibody. Whereas transient low level positivity could be attributed to difficulties with assay technique and cut off levels for normality, the results overall support the phenomenon of transient`self limited' islet autoimmunity in at risk infants. [Diabetologia (2000) 43: 203±209]