Читать книгу Clinical Dilemmas in Diabetes - Группа авторов - Страница 43

Primary prevention identifies and attempts to protect individuals at risk from developing T1D. It can therefore reduce both the need for diabetes care and the need to treat diabetes‐related complications (Figure 2.2).

T1D is relatively easy to prevent in animal models of the disease and an array of therapies is effective. However, the mechanism of prevention is usually poorly defined, and there is a lack of surrogate assays of the immune response to define which therapies are likely to prevent diabetes in humans. Inability to define surrogate assays probably results from a fine balance of the immune system, so that even with inbred strains of animals, only a subset progress to diabetes, and thus relatively small changes in immune function may prevent disease. These observations have led to the hypothesis that identifying children at a very high genetic risk for diabetes, prior to development of measurable β‐cell autoimmunity, and treating them at that point may be a more effective means of diabetes prevention. Studies for the primary prevention of T1D, i.e., prior to the expression of islet autoantibodies, are currently being designed and implemented. These studies target young children at a very high genetic risk for T1D and propose treatments that are very safe. These studies require large‐scale screening to identify high‐risk subjects and a follow‐up over a long period of time to observe the outcome of anti‐islet autoimmunity as a surrogate marker for the disease and onset of hyperglycemia as the main end point (Table 2.1).

As 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 genetic risk for T1D from the general population at birth; (2) to monitor such children for the appearance of diabetes‐associated autoantibodies, to identify those at high risk to develop clinical disease and to characterize the natural course of T1D; (3) to identify the environmental factors inducing the seroconversion to autoantibody‐positivity in children at increased genetic risk; and (4) to evaluate whether it is possible to delay or prevent progression to clinical T1D by daily administration of intranasal insulin. Whereas points 1–4 have been fulfilled and useful information has been obtained, the trial with intranasal insulin started soon after detection of autoantibodies, and did not show any beneficial effect of this treatment in preventing or delaying the disease [25].

In conclusion, since the failure of ENDIT and DPT1 trials (see secondary prevention) in preventing the onset of T1D in subjects who are β‐cell autoantibody positive, interest has switched to prevention trials starting before islet‐cell autoimmunity has developed. These primary prevention trials of T1D offer an exciting view of how our knowledge of the pathogenesis of this disease can lead to the possibility of intervening at birth. There is still a long way to go; however, the rationale is sound and the prospects seem good.