While rare monogenic forms of autoimmune type 1 diabetes are known (see below), in most cases, type 1 diabetes is a complex disorder in which multiple genes and environmental factors interact to cause the disease or confer protection against it. There is a clear familial clustering of type 1 diabetes, with prevalence in siblings approaching 6% while the prevalence in the general population in the USA is only 0.4%. This difference yields a relative risk value of 15 (6/0.4). Risk of diabetes is also increased when a parent has diabetes and this risk differs between the two parents; the risk is 2% if the mother has diabetes, but 7% when the father has diabetes.
At this time, we have no explanation for this difference in risk transmission between fathers and mothers. Twin studies show that the heritability of type 1 diabetes is high (0.72±0.21 in one population-based Danish study43) but is less than unity, indicating that there is also a non-shared environmental component. In monozygotic twins, the concordance rate ranges from 30 to 65%,44 whereas dizygotic twins have a concordance rate of 6–10%. Since the concordance rate of dizygotic twins is higher than the sibling risk, factors other than the shared genotypes (for example, the shared intrauterine environment) may play a role in increasing the risk in dizygotic twins (Table 12.1).
Table 12.1 Genetic susceptibility to type 1 diabetes mellitus
It should be kept in mind that although there is a large genetic component in type 1 diabetes, 85% of newly diagnosed type 1 diabetic patients do not have a family member with type 1 diabetes. Thus, we cannot rely on family history to identify patients who may be at risk for the future development of type 1 diabetes as most cases will develop in individuals with no such family history. Monogenic type 1 diabetes. Classic single-gene defects are an extremely rare cause of type 1 diabetes, but they are not unknown. In two rare syndromes (IPEX and APS-1) the genetic susceptibility that leads to diabetes is due to a classic single-gene defect. The IPEX (immune dysfunction, polyendocrinopathy, enteropathy, X-linked) syndrome is caused by mutations of the FOXP3 gene. These mutations lead to the lack of a major population of regulatory T lymphocytes with resulting overwhelming autoimmunity and development of diabetes (as early as 2 days of age) in approximately 80% of the children with this disorder.
The APS-I syndrome (autoimmune polyendocrinopathy syndrome type 1) is caused by mutations of the AIRE (autoimmune regulator) gene, leading to abnormalities in expression of peripheral antigens within the thymus and/or abnormalities of negative selection in the thymus. This results in widespread autoimmunity. Approximately 18% of children with this syndrome develop type 1a diabetes. Genes altering the risk of autoimmune type 1 diabetes. As noted above, most patients with type 1 diabetes do not have single-gene defects. Instead, their risk of developing type 1 diabetes is modified by the influence of several risk loci. The genomic region with by far the greatest contribution to the risk of type 1 diabetes is the major histocompatibility complex on chromosome 6. One other region which consistently shows up in genetic studies is the promoter region 5 of the insulin gene on chromosome 11. More recent studies have identified several other risk loci, but except for PTPN22, their contribution is relatively small, thus making them less useful for predicting the genetic risk of type 1 diabetes in a given individual.
MHC/HLA encoded susceptibility to type 1 diabetes. The major histocompatibility complex (MHC) is a large genomic region or gene family that is found in most vertebrates and that encodes a variety of genes that are involved in immune recognition and response. In humans, the MHC region is usually referred to as the HLA (human leukocyte antigen) region and it is a superlocus that contains a large number of genes related to immune system function in humans (Fig. 12.3). These genes are further divided into HLA class I, II, III, and IV genes. Class I HLA genes encode antigens that are expressed on all body cells and include three major gene types, HLA A, B, and C. HLA class II genes encode antigens that are only expressed on certain immune cells and include HLA DP, DQ, and DR antigens. Class II genes are the ones most strongly associated with risk of type 1 diabetes, but as genetic studies become more detailed, it is becoming apparent that some of the risk associated with various HLA types is due to variation in genes in HLA classes other than class II. Overall, genetic variation in the HLA region can explain 40–50% of the genetic risk of type 1 diabetes.
Initially, much of the risk associated with diabetes appeared to be linked to DR3 and DR4 alleles, but the genes of the HLA locus display strong linkage disequilibrium and it is now known that some of the earlier identified risk alleles (like DR3/DR4) confer much of their increased risk because of their linkage with other alleles in the DQ region with which they are tightly linked with relatively low recombination rates. The HLA DR3/4-DQ2/8 is a high-risk genotype which is present in 2.3% of all newborns in Colorado, but is seen in more than 30% of children who develop diabetes. Compared to a population prevalence of type 1 diabetes of approximately 1/300, DR3/4-DQ2/8 newborns from the general population have a 1/20 genetic risk. This risk of development of type 1 diabetes is even higher when the high-risk HLA haplotypes are shared with a sibling or parent with type 1 diabetes.
Thus, if one sibling has type 1 diabetes and shares the same high-risk DR3/4-DQ2/8 haplotype with another sibling, then the risk of autoimmunity in the other sibling is 50%. On the other hand, if a subject happens to have the same DR3/4-DQ2/8 haplotype in the general population, he or she has a risk of only 5% (1/20). And this risk approaches 80% when siblings share both HLA haplotypes identical by descent. This is known as the “relative paradox” and points to the existence of other shared genetic risk factors (most likely in the extended HLA haplotype). With advances in genotyping, further discrimination is now possible and we can identify more specific risk ratios for specific haplotypes. For example, the DRB1*0401-DQA1*0301 g-DQB1*0302 haplotype has an odds ratio (OR) of 8.39 while the DRB1*0401-DQA1*0301 g-DQB1*0301 has an OR of 0. Implicating the DQB1*0302 allele as a critical susceptibility allele. Risk of diabetes is influenced by both DRB1*04 variants and DQ alleles on DR4 haplotypes. Thus there is a hierarchy of DRB1*04 haplotypes, even with the same DQA1*0301–DQB1*0302 alleles, with higher risk from DRB1∗0405 (OR = 11.4), DRB1*0401 (OR = 8.4), DRB1*0402 (OR = 3.6), and DRB1*0404 (OR = 1.6), while DRB1*0403 is protective (OR = 0.27). Similarly, for DRB1*0401, variation of DQB1 influences risk, as haplotypes with DQB1*0302 (OR = 8.4) are highly susceptible, while those with DQB1*0301 (OR = 0.35) are modestly protective. There are some dramatically protective DR–DQ haplotypes [e.g., DRB1*1501-DQA1*0102-DQB1*0602 (OR = 0.03), DRB1*1401-DQA1*0101-DQB1*0503 (OR = 0.02), and DRB1*0701-DQA1*0201-DQB1*0303 (OR = 0.02)]. The DR2 haplotype (DRB1*1501-DQA1*0102-DQB1*0602) is dominantly protective and is present in 20% of general population but is seen in only 1% of type 1A diabetes patients (Table 12.2). Role of aspartate at position in DQB1. DQB1*0302 (high risk for diabetes) differs from DQB1*0301 (protective against diabetes) only at position, where it lacks an aspartic acid residue. The DQB1*0201 allele (increased risk for diabetes) also lacks aspartic acid at position, and it has been proposed that this residue may be involved in the molecular mechanism underlying diabetes susceptibility.
It has been proposed that the presence of aspartate at this position alters the protein recognition and protein binding characteristics of this molecule. But while the absence of aspartate at this position appears to be important in most Caucasian studies, it does not have the same role in Korean and Japanese populations. Moreover, certain low-risk DQB1 genotypes also lack aspartic acid at position, including DQB1*0302/DQB1*0201 (DR7) and DQB1*0201 (DR3)/DQB1*0201 (DR7). Thus the presence of aspartate at this position is usually, but not always, protective in Caucasian populations. In other populations, it may even be associated with increased risk in association with particular haplotypes.
Role of HLA class I. While the alleles of class II HLA genes appear to have the strongest associations with diabetes, recent genotyping studies and analyses of pooled data have identified associations with other elements in the HLA complex, especially HLA-A and HLA-B. The most significant association is with HLA-B39, which confers high risk for type 1A diabetes in three different populations, makes up the majority of the signal from HLA-B, and is associated with a lower age of onset of the disease. The above-mentioned HLA-risk haplotypes appear to confer increased risk in all populations, but they are not equally distributed in different populations. Part of the reason for the lower incidence of type 1 diabetes in Asian populations is lower prevalence of the highest risk haplotypes in those populations and the existence of unique haplotypes in which the high-risk alleles are associated with protective alleles. The Insulin Gene Locus, IDDM2.
The second locus found to be associated with risk of type 1 diabetes was labeled IDDM2 and has been localized a region upstream of the insulin gene (5 of the insulin gene). It is estimated that this locus accounts for about 10% of the familial risk of type 1 diabetes. Susceptibility in this region has been primarily mapped to a variable number of tandem repeats (VNTR) about 500 bp upstream of the insulin gene. This highly polymorphic region consists of anywhere from 30 to several hundred repeats of a 14–15 bp unit sequence (ACAGGGGTCTGGGG). The number of repeats tends to cluster into three ranges: class I (short) with 26–63 repeats, class II (intermediate) with an average of 85 repeats, and class III (long) with 140–210 repeats. Caucasians and Asians mostly have class I and class III alleles and class II alleles are relatively rare in these populations, but somewhat more common in Africans (in line with the generally greater diversity of haplotypes in the older African population). Class I (short) alleles are associated with a higher risk of type 1 diabetes, while class III (longer) alleles appear to be protective. Thus, homozygosity for class I alleles is found in 75–85% of diabetic patients, as compared to a frequency of 50–60% in the general population.
It has been hypothesized that this locus alters the risk of type 1 diabetes by altering immune tolerance of insulin and this effect is due to a variation in insulin production in thymic cells, with smaller alleles being associated with lower insulin production. An effect of this locus on IGF-2 transcription was also postulated, but has not been confirmed. PTPN22 (lymphoid tyrosine phosphatase). In 2004, it was reported that a single-nucleotide polymorphism (SNP) in the PTPN22 gene on chromosome 1p13 that encodes lymphoid tyrosine phosphatase (Lyp) correlates strongly with the incidence of type 1 diabetes in two independent populations. Since then, this discovery had been replicated in several populations and the gene has been found to have an association with several other autoimmune diseases. Lyp is an enzyme that has a role in signal transduction downstream of the T-cell receptor and the risk variant may represent a gain of function (increased inhibition of signal transduction), which raises the possibility that an inhibitor of this protein may hold promise as a preventive intervention in type 1 diabetes. CTLA-4.
The cytotoxic T lymphocyte associated-4 (CTLA-4) gene is located on chromosome 2q33 and has been found to be associated with type 1 diabetes risk64 as well as the risk of other autoimmune disorder in several studies. This gene is a negative regulator of T cell activation and therefore is a good biological candidate for type 1 diabetes risk modification. Because of its role in immune regulation, this gene is another candidate for therapeutic intervention and a fusion protein with human immunoglobulin is already being tested by Diabetes Trial Net as a possible preventive treatment. IL2-receptor. SNPs in or near the gene for the interleukin-2 receptor have been found to have an association with type 1 diabetes risk. Since IL2-receptor is an important modulator of immunity, it is another obvious candidate for the development of potential therapeutic interventions. Interferon-induced helicase. Another gene that has recently been identified as having a modest effect on the risk of type 1 diabetes is the interferon-induced helicase (IFIH1) gene. This gene is thought to play a role in protecting the host from viral infections and given the specificity of different helicases for different RNA viruses, it is possible that knowledge of this gene locus will help to narrow down the list of viral pathogens that may have a role in type 1 diabetes. CYP27B1. Cytochrome P450, subfamily, polypeptide 1 gene encodes vitamin D 1alpha hydroxylase.
Because of the known role of vitamin D in immune regulation and because of epidemiologic evidence that vitamin D may play a role in type 1 diabetes, this gene was examined as a candidate gene and two SNPS were found to be associated. Other genes. Several other genes (e.g., PTPN-2) and linkage blocks, including two linkage blocks on chromosome 12 (12q13 and 12q24) and blocks on 16p13, 18p11, and 18q22 have been found to be significant in GWA studies and further fine mapping and functional studies of genes in these regions are pending. In addition, it has been suggested that viral infections (or other environmental factors) may activate dormant retroviruses in the human genome, or may introduce new retroviruses into the genome. A human endogenous retrovirus (IDDMK1) was reported to be expressed in leukocytes from type 1 diabetes patients, but not in controls. This, however, was not confirmed in subsequent studies.At this time, the retroviral hypothesis remains unproven.
Environmental Factors
The fact that 50% or so of monozygotic twins are discordant for type 1 diabetes, the variation seen in urban and rural areas populated by the same ethnic group, the change in incidence that occurs with migration, the increase in incidence that has been seen in almost all populations in the last few decades, and the occurrence of seasonality all provide evidence that environmental factors also play a significant role in the causation of type 1 diabetes. The various factors that have been suggested are discussed below. Viral infections. There are several mechanisms by which viruses may play a role in triggering or accelerating type 1 diabetes. For instance, some viruses are capable of infecting and destroying beta cells directly. In addition, viral antigens may share sequences with beta-cell antigens (molecular mimicry) or may cause the release of sequestered islet antigens (bystander damage). Repeated viral infections may induce immune dysregulation and trigger autoimmunity or aggravate pre-existing autoimmunity.
Evidence for the role of several different viruses in the pathogens of type 1 diabetes is discussed below, but it should be kept in mind that most of the evidence is descriptive or suggestive, not definitive. It is possible that various viruses do play a role in the pathogenesis of type 1 diabetes, but no single virus and no single pathogenic mechanism, stands out in the environmental etiology of type 1 diabetes. Instead, a variety of viruses and mechanisms may contribute to the development of diabetes in genetically susceptible hosts. Viruses implicated in animal models of diabetes. BBDP (BioBreeding Diabetes Prone) rats are prone to insulitis and type 1 diabetes and were discovered in a colony of outbred Wistar rats at the Biobreeding laboratories in Ottawa, Canada, in 1974.74 BBDR (BioBreeding Diabetes Resistant) rats are derived from BBDP rats, but do not develop diabetes spontaneously. It was then discovered that if BBDR rats become infected with Kilham Rat Virus (KRV), a member of the parvovirus family, they develop type 1 diabetes. Another example in which viral infection can cause diabetes is seen in neonatal hamsters, in which rubella infection leads to diabetes. The significance of these examples for humans remains unknown.
Enteroviruses. The viruses most often suspected of playing a role in type 1 diabetes are the small RNA viruses of the picornavirus family. Studies have shown an increase in evidence of enteroviral infection in type 1 diabetics and an increased prevalence of enteroviral RNA in prenatal blood samples from children who subsequently developed type 1 diabetes. In addition, there are case reports of association between enteroviral infection and subsequent type 1 diabetes. Molecular mimicry and bystander damage have also been suggested as mechanisms by which enteroviruses may cause type 1 diabetes. It has been proposed that some of the increase in incidence that is being seen in developed countries is due to the fact that childhood enteroviral infections have become rarer and therefore, mothers do not provide antibodies to the fetus or neonate and make them more susceptible to persistent enterovirus infection. While interesting, these speculations are unproven and the true significance of enteroviral infection in type 1 diabetes remains unknown. Congenital rubella syndrome. The clearest evidence of a role for viral infection in human type 1 diabetes is seen in congenital rubella syndrome (CRS).
Prenatal infection with rubella is associated with beta-cell autoimmunity in up to 70%, with development of type 1 diabetes in up to 40% of infected children. The time lag between infection and development of diabetes may be as high as 20 years. Type 1 diabetes after congenital rubella is more likely in patients that carry the higher risk genotypes. Interestingly, there appears to be no increase in risk of diabetes when rubella infection develops after birth, or when live virus rubella immunization is used. Exactly how rubella infection leads to diabetes and why it is pathogenic only if infection occurs prenatally, remains unknown. Mumps virus. It has been observed that mumps infection leads to the development of beta-cell autoimmunity with high frequency, and to type 1 diabetes in some cases. It has also been noted that there is an uptick in the incidence of type 1 diabetes 2–4 years after an epidemic of mumps infection. But a larger European study did not find any association between mumps infection and subsequent development of diabetes. Mumps vaccination, on the other hand, appears to be protective against type 1 diabetes. But while mumps may play a role in some cases of diabetes, the fact that type 1 diabetes incidence has increased steadily in several countries after universal mumps vaccination was introduced, and that incidence is extremely low in several populations where mumps is still prevalent, indicates that mumps is not an important causal factor in diabetes. Rotavirus.
Rotavirus infection in Non-Obese Diabetic (NOD) mice can involve the pancreas and the rotavirus protein VP7 shows sequence homology with the autoantigens tyrosine phosphatase IA-2 and Glutamic Acid Decarboxylase (GAD).87 But to date, there is no conclusive evidence that rotavirus infections play any role in causing or aggravating beta-cell autoimmunity in humans. Parvoviruses. As noted above, the parvovirus KRV can induce diabetes in the BBDR rat. One case has been reported in which type 1 diabetes, Graves’ disease, and rheumatoid arthritis developed in a woman after acute parvovirus infection, but evidence of any large-scale association with type 1 diabetes in humans is lacking. Cytomegalovirus (CMV). CMV viruses are capable of infecting beta cells and molecular mimicry is a possibility, but there is no evidence that CMV infection plays any significant role in most cases of type 1 diabetes. Role of childhood immunizations. Several large-scale, well-designed studies have conclusively shown that routine childhood immunizations do not increase the risk of type 1 diabetes. On the contrary, immunization against mumps and pertussis may decrease the risk of type 1 diabetes. The hygiene hypothesis: possible protective role of infections. While some viral infections may increase the risk of type 1 diabetes, infectious agents may also play a protective role against diabetes.
The hygiene hypothesis states that lack of exposure to childhood infections may somehow increase an individual’s chances of developing autoimmune diseases, including type 1 diabetes. Epidemiologic patterns suggest that this may indeed be the case. For example, rates of type 1 diabetes and other autoimmune disorders are generally lower in underdeveloped nations with high prevalence of childhood infections, and tend to increase as these countries become more developed. As noted above, the incidence of type 1 diabetes differs almost sixfold between Russian Karelia and Finland even though both are populated by a genetically related population and are located next to each other at the same latitude. The incidence of autoimmunity in the two populations varies inversely with IgE antibody levels and IgE is involved in the response to parasitic infestation. All these observations indicate that decreased exposure to certain parasites and other microbes in early childhood may lead to an increased risk of autoimmunity in later life, including autoimmune diabetes. On the other hand, retrospective case–control studies have been equivocal at best and direct evidence of protection by childhood infections is still lacking.
In animal studies, it has been shown that diabetes can be prevented in the NOD mouse model by infecting the mice with mycobacteria, salmonella or helminthes, or even by exposing them to products of these organisms. But the NOD mouse is not a perfect model of human type 1 diabetes and a very large number of interventions (some of them apparently trivial) can prevent the development of diabetes in this animal, so the significance of these observations for human type 1 diabetes is open to debate. DIET. Breast feeding may lower the risk of type 1 diabetes, either directly or by delaying exposure to cow’s milk protein. Early introduction of cow’s milk protein and early exposure to gluten have both been implicated in the development of autoimmunity and it has been suggested that this is due to the “leakiness” of the immature gut to protein antigens. Antigens that have been implicated include beta lactoglobulin, a major lipocalin protein in bovine milk, which is homologous to the human protein glycodelin (PP14), a T-cell modulator. Other studies have focused on bovine serum albumin as the inciting antigen, but the data are contradictory and not yet conclusive.
Other dietary factors that have been suggested at various times as playing a role in diabetes risk include omega-3 fatty acids, vitamin D, ascorbic acid, zinc, and vitamin E. Vitamin D is biologically plausible (it has a role in immune regulation), deficiency is more common in Northern countries like Finland, and there is some epidemiologic evidence that decreased vitamin D levels in pregnancy or early childhood may be associated with diabetes risk; but the evidence is not yet conclusive and it is hoped that ongoing studies like the TEDDY (the Environmental Determinants of Diabetes in the Young) study will help to resolve some of the uncertainties in this area. Environmental chemicals. Dietary nitrosamines and nitrates can induce beta-cell autoimmunity in animal models and some epidemiologic studies suggested that they may play a role in type 1 diabetes, but other studies contradicted these findings and at least one large prospective study has failed to find any association with chemicals in water supply.
At this time, the role of environmental chemicals in type 1 diabetes awaits clarification. Psychological stress. Several studies show an increased prevalence of stressful psychological situations among children who subsequently developed type 1 diabetes. Whether these stresses only aggravate pre-existing autoimmunity or whether they can actually trigger autoimmunity remains unknown. Role of insulin resistance: the accelerator hypothesis. The accelerator hypothesis proposes that type 1 and type 2 diabetes are the same disorder of insulin resistance, set against different genetic backgrounds. This “strong statement” of the accelerator hypothesis has been criticized as ignoring the abundant genetic and clinical evidence that the two diseases are distinct. Still, the hypothesis has focused attention on the role of insulin resistance and obesity in type 1 diabetes and there is evidence that the incidence of type 1 diabetes is indeed higher in children who exhibit more rapid weight gain. Whether this is simply another factor that stresses the beta cell in the course of a primarily autoimmune disorder, or whether type 1 and type 2 diabetes can really be regarded as the same disease, is still open to question.
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