improve the predictive characteristics of the screening strategy. The importance of understanding the natural history of immune mediated pre‐diabetes lies in the development of prevention strategies. Several randomized clinical intervention trials have been concluded and the next generation of such trials will rely upon improved and simplified identification of individuals who are at high risk of progression to T1D. This is essential to ensure that trials have sufficient statistical power to detect a given effect of the intervention within the time available for the study. Such understanding is also needed to avoid exposing those who will not develop T1D to the risk of adverse effects of the intervention.
FIG 2.2 Strategies to preserve β‐cell mass in T1D. Modified from Reimann M, Bonifacio E, Solimena M et al. An update on preventive and regenerative therapies in diabetes mellitus. Pharmacol Ther 121(3): 317–331, 2009.
Prevention of T1D: Current Status
Although the process by which pancreatic β‐cells are destroyed is not well understood, several risk factors and immune‐ related markers are known to accurately identify first‐degree relatives of patients with T1D who may develop the disease. Since we now can predict the development of T1D, investigators have begun to explore the use of intervention therapy to halt or even prevent β‐cell destruction in such individuals. The autoimmune pathogenesis of T1D determines the efforts to prevent it. Susceptible individuals are identified by searching for evidence of autoimmune activity directed against β‐cells. While direct evaluation of T‐cell activity might be preferable, antibody determinations are generally used for screening because these assays are more robust. Antibody titers are often used in combination with an assessment of the genetic susceptibility, primarily evaluated by HLA typing. In the near future, testing for oxPTM‐INS‐Ab may help to identify children progressing to overt diabetes.
Interventions are generally designed to delay or prevent T1D by impacting some phases of the immune pathogenesis of the disease. As discussed below, current trials are attempting to modify the course of disease progress at many points along the presumed pathogenic pathway. Most prevention trials include only relatives of T1D patients, a group in which risk prediction strategies are most established. Trials in genetically at‐risk infants evaluate whether avoiding one of the putative environmental triggers for T1D can delay or prevent its onset.
Primary Prevention
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