(NT‐INS) [12]. Furthermore, subsequent analysis found that oxPTM‐INS auto‐reactivity is present before diabetes diagnosis in over 90% of individuals, suggesting a potential role for oxPTM‐INS‐Ab as a predictive biomarker of T1D [13].
The progressive reduction of insulin‐secretory reserve leads primarily to the loss of the first phase insulin secretion in response to an intravenous glucose tolerance test, and therefore to a state of absolute insulin deficiency.
Regarding the role of environmental factors, it should be underlined that the increase in incidence of T1D is too rapid to be caused by alterations in the genetic background and is likely to be the result of environmental changes.
What Are the Environmental Factors Triggering Type 1 Diabetes?
Certain viral infections may play a role in the pathogenesis of human T1D. Congenital rubella is the classical example of virus‐induced diabetes in human beings, but effective immunization programs have eliminated congenital rubella in most Western countries. Currently, the main candidate for a viral trigger of human diabetes is members of the group of Enterovirus [14]. They are small non‐enveloped RNA viruses, which belong to the Picornavirus family. They consist of more than 60 different serotypes, with the Polioviruses being their best‐known representatives. Enterovirus infections are frequent among children and adolescents causing aseptic meningitis, myocarditis, rash, hand‐food‐and‐mouth disease, paralysis, respiratory infections, and severe systemic infections in newborn infants. Most infections, however, are subclinical or manifest with mild respiratory symptoms. The primary replication of the virus occurs in the lymphoid tissues of the pharynx and small intestine, and during the following viremic phase the virus can spread to various organs including the β‐cells.
Theoretically, Enterovirus could cause β‐cell damage by two main mechanisms. They may infect β‐cells and destroy them directly or they may induce an autoimmune response against β‐cells. Direct virus‐induced damage has been supported by studies showing that Enterovirus are present in β‐cells in patients who have died from severe systemic Enterovirus infection and that the islet‐cells of these patients are damaged. Enterovirus can also infect and damage β‐cells in vitro and induce the expression of interferon‐alpha and HLA‐class I molecules in β‐cells thus mimicking the situation observed in the pancreas of patients affected by T1D. The first reports connecting Enterovirus infections to T1D were published more than 30 years ago, showing that the seasonal variation in the onset of T1D follows that of Enterovirus infections. At the same time antibodies against Coxsackievirus B serotypes were found to be more frequent in patients with newly diagnosed T1D than in control subjects [14]. Enterovirus have also been isolated from patients with newly diagnosed T1D. In one case report Coxsackievirus B4 was isolated from the pancreas of a child who had died from diabetic ketoacidosis, and this virus caused diabetes when transferred to a susceptible mouse strain. The β‐cells of diabetic patients also express interferon‐alpha, a cytokine that is induced during viral infections, suggesting the presence of some virus in the β‐cells. Prospective studies are particularly valuable in the evaluation of viral triggers because they cover all stages of the β‐cell damaging process.
Enterovirus are not the only viruses that have been connected to the pathogenesis of T1D. Mumps, measles, cytomegalovirus, and retroviruses also have been found to be associated with T1D, but the evidence is less convincing than that for Enterovirus.
The Role of Cow's Milk
There is evidence that cow's milk proteins can act as triggers for the autoimmune process of β‐cell destruction based on studies indicating bottle feeding as a triggering factor for an autoimmune response to β‐cell [15].
There are several arguments for the milk hypothesis in T1D, including the following:
Epidemiological studies show increased risk for T1D if the breast‐feeding period is short and cow's milk is introduced before 3–4 months of age.
Skim milk powder can be "diabetogenic" in diabetes‐prone BB rats.
Patients with T1D have increased levels of antibodies against cow's milk constituents.
Milk albumin and β‐casein have some structural similarity to the islet autoantigen ICA69 and GLUT‐2, respectively.
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