A number of hypotheses have been postulated to explain the pathogenic role of cow's milk. One of the most convincing ones is that immature gut mucosa allows the passage of high molecular weight, potentially antigenic proteins which share some molecular mimicry with pancreatic β‐cells. Among diabetogenic proteins in cow's milk, β‐casein, β‐lactoglobulin, and albumin have been implicated as sources of potential antigens.
Casein represents the major protein in cow's milk. Human and bovine β‐casein are approximately 70% homologous and 30% identical. There are several reasons why it is thought that β‐casein is a good candidate to explain the observed association between cow's milk consumption and T1D: (1) it has several structural differences from the homologous human protein; (2) casein is probably the milk fraction promoting diabetes in the NOD mouse, since a protein‐free diet prevents the disease while a diet containing casein as the sole source of protein produces diabetes in the same animals; (3) several sequence homologies exist between bovine β‐casein and β‐cell autoantigens; (4) specific cellular and humoral immune responses toward bovine β‐casein are detectable in most T1D patients at the time of diagnosis, highly suggestive that this protein may participate in the immune events triggering the disease; (5) casein hydrolysate was shown to be non‐diabetogenic in the BB rat and NOD mouse models, therefore it was thought that this dietary intervention might be beneficial in humans as well for disease prevention.
The rationale behind the use of cow's milk hydrolysate for primary prevention of T1D is based on several epidemiological and in vitro studies, indicating that intact cow's milk, if given before three months of age, may induce an immune response towards β‐cells. The TRIGR trial (see section on primary prevention of T1D) investigated whether the administration of a cow's milk hydrolysate could prevent or delay the onset of T1D.
The Role of Vitamin D Deficiency
Several epidemiological studies have described an intriguing correlation between geographical latitude and the incidence of T1D and an inverse correlation between monthly hours of sunshine and the incidence of diabetes. A seasonal pattern of disease onset has also been described for T1D, once again suggesting an inverse correlation between sunlight and the disease [16]. Vitamin D is an obvious candidate as a mediator of this sunshine effect.
Dietary vitamin D supplementation is often recommended in pregnant women and in children to prevent vitamin D deficiency. Cod liver oil taken during the first year of life reportedly reduced the risk of childhood‐onset T1D and a multicenter case‐control study also showed an association between vitamin D supplementation in infancy and a decreased risk of T1D. Two further meta‐analyses of retrospective studies showed that the risk of T1D was lower in children who were supplemented with calcitriol compared with those who were not supplemented [17]. Nonetheless, it remains to be determined whether these observations are the result of supplementation of vitamin D to supraphysiological levels or are simply the result of the prevention of vitamin D deficiency. On that note, other clinical studies reported no effect of vitamin D supplementation on β‐cell function in recent‐onset T1D [18]. In summary, despite continuing interest in vitamin D supplementation as a potential intervention to prevent islet autoimmunity and T1D, there is still little supporting evidence from prospective birth cohort studies.
Prediction of T1D as the Basis for Disease Prevention
There are different approaches for the identification of individuals at risk for T1D. These approaches are based on family history of T1D, genetic disease markers, autoimmune markers, or metabolic markers of T1D (Figure 2.2). These alternatives may also be combined in various ways to 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
