mentioned above, various nutritional components have been suggested to modulate the risk of T1D. Among them, several epidemiological and in vitro studies indicating that intact cow's milk, if given before 3 months of age, may induce an immune response towards β‐cells.
In a prospective study called DAISY, which followed children at increased T1D risk for IA and T1D development, cow's milk protein intake was associated with increased IA risk in children with low/moderate risk HLA‐DR genotypes [hazard ratio (HR): 1.41, 95% confidence interval (CI): 1.08–1.84], but not in children with high risk HLA‐DR genotypes. Furthermore, cow's milk protein intake was associated with progression to T1D (HR: 1.59, CI: 1.13–2.25) in children with IA [15].
TRIGR is a large international randomized double‐blind intervention study intended to provide information on the incidence of predictive islet‐cell autoantibodies vs the actual occurrence of clinical diabetes in two treatment groups [19]. The aim of this trial was to investigate whether early exposure to complex dietary proteins of cow's milk could increase the risk of T1D in new‐born infants with genetic disease susceptibility (diabetogenic HLA alleles and first‐degree relatives with T1D) and whether the use of a cow's milk hydrolysate could protect from the disease. The recruitment was carried out over a 5‐year period in nine European countries, six major centers in the USA, 12 centers in Canada, and three centers in Australia. Due to statistical considerations, the frequency of the high‐risk HLA genotype, consent and drop‐out rates, the trial required initial access to 8000 pregnancies, which ultimately yielded 5156 infants necessary for randomization. 1081 were randomized to be weaned to the extensively hydrolyzed casein formula and 1078 to a conventional adapted cow's milk formula supplemented with 20% of the casein hydrolysate. The participants were observed for a median of 11.5 years.
TABLE 2.1 Prevention in T1D
| Study | |
|---|---|
| Primary prevention | DAISY: cow's milk intake and IA development |
| TRIGR: Casein hydrolysate vs cow's milk formula | |
| Babydiet: Delayed introduction of dietary gluten | |
| TEDDY: Timed introduction of gluten‐containing cereals | |
| DIPP: Intranasal insulin | |
| Secondary prevention | ENDIT: Nicotinamide |
| DPT‐1: Insulin/oral insulin | |
| DIPP: Intranasal insulin | |
| INIT: Intranasal Insulin Trial | |
| Tertiary prevention | Cyclosporine |
| Nicotinamide | |
| Vitamin D | |
| Insulin | |
| Anti‐CD3 | |
| Anti‐CD20 | |
| Anti TNF alfa | |
| CTLA4‐Ig | |
| GAD‐ Alum | |
| Anti IL‐1 | |
| Anti IL‐6 | |
| Anti IL‐8 | |
| CXCR1/2 inhibitor |
The strength of this trial was the larger number of participants, which provides substantially greater statistical power in a more heterogeneous study population compared with previous studies and, therefore, provides a more definitive answer to whether weaning to an extensively hydrolyzed formula might be protective of diabetes. This trial showed that among infants at risk for T1D, weaning to a hydrolyzed formula compared with a conventional formula did not reduce the cumulative incidence of T1D. Thus, the absolute risk of T1D was 8.4% among participants randomized to the casein hydrolysate vs 7.6% among those randomized to the conventional formula; the hazard ratio for T1D adjusted for HLA risk group, duration of breastfeeding, duration of study formula consumption, sex, and region while treating study center as a random effect was 1.1 (95% CI, 0.8 to 1.5; P = 0.46). The median age at diagnosis of type 1 diabetes was similar in the 2 groups (6.0 years [Q1–Q3, 3.1–8.9] vs 5.8 years [Q1–Q3, 2.6–9.1]) [19].
In conclusion, studies investigating cow's milk as an environmental factor show inconsistent results and do not currently support the need to revise the dietary recommendations for infants at risk for T1D.
Another outstanding question concerns the association between timing of gluten introduction and IA development. The BABYDIET study was an intervention study aimed to determine whether primary intervention through delayed introduction of dietary gluten was feasible and could reduce the incidence of IA in high‐risk first degree relatives of patients with T1D [20]. The study was based on the premise that introduction of foods containing gluten or cereal before the age of 3 months was associated with an increased risk of IA in childhood. New‐born children were eligible if they were younger than 3 months, were offspring or siblings of patients with T1D and had HLA genotypes that confer a high T1D risk. In this study, authors did not find a benefit in delaying gluten exposure with respect to autoimmunity associated with diabetes and celiac disease at 3 years of age.
The follow‐up findings of the BABYDIET study confirm previous results, failing to demonstrate that an intervention based on delayed gluten introduction will reduce the risk of developing autoimmunity related to T1D [21].
Conversely, in The Environmental Determinants of Diabetes in the Young (TEDDY) study, which prospectively followed 8676 children with increased genetic risk of T1D in the U.S., Finland, Germany, and Sweden, authors observed that later introduction of gluten‐containing cereals was associated with increased risk of any IA using Cox regression models [22]. In this study, the HRs for every 1‐month delay in gluten introduction were 1.05 (95% CI 1.01, 1.10; P = 0.02) and 1.08 (95% CI 1.00, 1.16; P = 0.04), respectively. The risk of IA associated with introducing gluten before 4 months of age was lower (HR 0.68; 95% CI 0.47, 0.99), whereas the risk of IA associated with introducing it after 9 months of age was higher (HR 1.57; 95% CI 1.07, 2.31) than introduction between 4 and 9 months of age. Interestingly, another sub‐analysis performed on TEDDY participants shows that administration of probiotics during the first 27 days of life reduced the risk for a first‐appearing β‐cell autoantibody in children with the HLA‐DQ2/8 genotype [23]. However, once again, authors acknowledged the need to confirm these results in further studies before any recommendation of dietary intake or probiotics use is made.
Also noteworthy are some observational studies suggesting a protective role of vitamin D and long‐chain n‐3 fatty acid against T1D by modulating the immune system. Nonetheless, clinical trials have been inconclusive so far [14, 24].
Finally, the Diabetes Prediction and Prevention Project (DIPP Study) (Clinical trial NCT03269084; www.clinicaltrials.gov) was a longitudinal study on T1D prediction and prevention carried out in the university hospitals of Turku, Tampere, and Oulu (Finland). The aim of the study was to investigate longitudinally the dietary factors in relation to the development of diabetic autoantibodies and clinical T1D. The diet of children was followed up by a structured questionnaire and by 3‐day dietary records at various ages. A food frequency questionnaire was applied for studying the dietary intake of pregnant and lactating mothers.
The aims of this project were: (1) to identify infants at increased
