risk of T1D compared to those of children in whom the disease develops later.
FIG 2.1 Pathogenesis and natural history of Type 1 diabetes. Atkinson MA and Eisenbarth GS Type 1 diabetes: new perspectives on disease pathogenesis and treatment. Lancet 2001;358(9277):221–229.
Candidate gene studies also identified the insulin gene on chromosome 11 as another important genetic susceptibility factor, contributing 10% of the genetic susceptibility to T1D [6]. Similarly, an allele of the gene acting as a negative regulator of T‐cell activation, cytotoxic T lymphocyte antigen 4 (CTLA‐4), found on chromosome 2q33, is considered to be another susceptibility gene for T1D [7]. A variant of PTPN22, the gene encoding Lymphoid Phosphatase (LYP), which is a suppressor of T‐cell activation, has been deemed as another susceptibility gene [8]. Similarly, variation in IL2RA which encodes the α‐chain of the IL‐2 receptor is also associated with T1D [9]. The observation that these susceptibility genes for T1D all play important roles in antigen presentation to T‐cells, emphasizes the potential importance of current therapeutic strategies targeting this interaction [10].
Genetic studies have highlighted the importance of large, well‐characterized populations in the identification of susceptibility genes for T1D. Recruitment of increasingly large populations of patients with T1D and their families is required to provide statistically powerful cohorts in which to identify other disease‐associated genes. Some genes have a relatively minor individual impact on susceptibility to disease but could nevertheless provide more clues to future preventive therapies.
The presence of autoantibodies to β‐cells is the hallmark of T1D (Figure 2.1). Abnormal activation of the T‐cell‐mediated immune system in susceptible individuals leads to an inflammatory response within the islets as well as to a humoral response with production of antibodies to β‐cell antigens. Islet‐cell antibodies (ICA) were the first ones described, followed by more specific autoantibodies to insulin (IAA), glutamic acid decarboxylase (GAD), the protein tyrosine phosphatase (IA‐2), and most recently Zinc Transporter 8 (ZnT8A), all of which can be easily detected by sensitive radioimmunoassay to identify subjects at risk of developing T1D [11]. These autoantibodies are common in both childhood and adult onset T1D, with many subjects being positive for multiple autoantibodies. The type of immune response is age‐dependent, but seroconversion to multiple autoantibody positivity usually occurs tightly clustered in time and is associated with genetic risk.
The presence of one or more type of antibodies can precede the clinical onset of T1D by years or even decades. These autoantibodies are usually persistent, although a small group of individuals may revert to being seronegative without progressing to clinical diabetes. The presence and persistence of positivity to multiple antibodies increases the likelihood of progression to clinical disease.
On that note, recent evidence shows that antibodies specific to oxidative post‐translationally modified insulin (oxPTM‐INS) are present in the majority of newly diagnosed individuals with T1D being significantly more abundant than autoantibodies to native insulin (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
