influence the development of autoantibodies, whereas INS, UBASH3A and IFIH1 impact upon the progression to symptomatic diabetes.
Table 6.2 Main non‐ HLA polymorphisms that have been used in predictive modelling, and their possible role in type 1 diabetes. PTNP22 polymorphisms are shared with other autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease.
| Genetic polymorphism | Possible impact |
|---|---|
| Insulin gene (INS) | Affects amount of insulin mRNA in thymus and influences immune tolerance |
| Protein tyrosine phosphatase non‐receptor type 22 (PTPN22) | Promotes survival of auroreactive T cells in thymus and functional effects on circulating effector and regulator T cells and B cells |
| Cytotoxic T lymphocyte associated protein (CTLA‐4) | Negative regulator of cytotoxic T cells Target for Abatacept therapy |
| Interleukin‐2 receptor subunit α (IL2RA) | Affects sensititvity to IL2 |
| Protein tyrosine phosphatase non‐receptor type 2 (PTPN2) | β cell apoptosis after interaction with interferon |
| Interferon induced helicase (IFIH1) | Binds to virus RNA and moderates interferon mediated viral response |
| Basic leucine zipper transcription factor 2 (BACH2) | Regulates apoptotic pathways in β cells in conjunction with PTNP2 |
| Ubiquitin associated and SH3 domain‐containing protein A (UBASH3A) | Downregulates Nfκβ signaling pathway in response to T cell stimulation decreasing IL‐2 gene expression |
| erb‐b2 receptor tyrosine kinase 3 (ERBB3) | Uncertain role in diabetes. Encodes a member of the epidermal growth factor receptor family receptor tyrosine kinase |
Intriguingly, there seems to be cross‐talk with the type 2 diabetes susceptibility gene transcription factor 7 like‐2 (TCF7L2). People with type 1 diabetes and only a single autoantibody, or who do not have HLA susceptibility haplotypes, are more likely to have the genetic variant TCF7L2 associated with type 2 diabetes, even though its overall frequency in people with type 1 diabetes is not increased.
The genetics of type 1 diabetes are obviously complex and polygenic. The interaction with environmental factors (see below) which results in an orchestrated T cell mediated and B cell facilitated autoimmune destruction of β cells is likely mediated by a range of different mechanisms, some of which will be more prominent in different individuals, and some of which will operate in sequence or together at different stages in the evolution of type 1 diabetes. It is also worth noting that the majority of those who carry genetic polymorphisms that predispose them to developing type 1 diabetes never do so.
Environmental and maternal factors
Although genetic factors are undoubtedly important, the rapidly increasing incidence rates for type 1 diabetes at a younger age strongly suggest that external or environmental factors are playing a part. Much of the evidence that links environmental factors with the aetiology of type 1 diabetes is circumstantial and associative, based upon epidemiology and animal research. The factors most often implicated are viruses, and diet and toxins, but a number of other influences, such as early feeding with cow’s milk have been investigated (Table 6.3). These associations remain unexplained but may add support to the hygiene and accelerator hypotheses (see below).
Viruses
The viruses that have been implicated in the development of human diabetes have been deduced from temporal and geographical associations with a known infection. For example, mumps can cause pancreatitis and occasionally precedes the development of type 1 diabetes in children. Intrauterine rubella infection induces diabetes in up to 20% of affected children. However, the strongest associations have been with enteroviruses. A meta‐analysis of 26 studies found an OR of 3.7 (95% CI 2.1, 6.8) for enterovirus serological positivity in patients with islet cell autoantibodies and symptomatic type 1 diabetes, and the virus most commonly identified is coxsackie B. There was, however, a significant heterogeneity in these studies. In prospective cohort studies, patients with positive enterovirus antibodies had accelerated progression to symptomatic diabetes, but they did not seem to initiate islet autoimmunity.
Table 6.3 Associated foetal, maternal, dietary and environmental factors with the strength of the relationship (where known) on the development of type 1 diabetes (T1DM).
| Associated factor | Strength of relationship |
|---|---|
| Shorter gestation | RR 1.18 (95%CI 1.09, 1.28) for gestational age 33–36 weeks and 1.12 (95% CI 1.07, 1.17) for 37 & 38 weeks |
| Birth weight | SGA RR 0.83 (95% CI 0.75, 0.93) LGA RR 1.14 (95% CI 1.04, 1.24) Severe SGA reduced risk for T1DM |
| Greater linear growth | Children diagnosed aged 5–10 years taller than peers but growth may be slowed with T1DM onset around puberty |
| Maternal age | 5–10% increase odds per 5 year increase in maternal age |
| ABO blood group incompatability | Frequency of HLA DR3 similar in children with ABO incompatability and those with T1DM. OR 2.7 compared to controls |
| Birth order | Weak evidence that 2nd or later child are less likely to develop T1DM < 5 yrs of age |
| Delivery by caesarean section | Adjusted OR 1.19 (95% CI 1.04, 1.36) |
| Breast feeding (bf) | OR 0.75 (95% CI 0.64, 0.88) for 2 weeks bf; weaker for 3 months. No benefit of non‐exclusive bf beyond 2 weeks |
| Dietary cereals | Later exposure (>7 months) to gluten HR for T1DM 3.33(95% CI 1.54, 7.18). Early exposure (<3 months) increases risk of coeliac disease. |
| Vitamin D supplements | OR 0.71 (95% CI 0.60, 0.84) but marked heterogeneity in studies |
| Omega 3 fatty acids | Lower intake associated with higher rates in Norway. Clinical trials underway |
| Atopy | OR 0.82 (95% CI 0.68, 0.99) for asthma in children with T1DM, but not eczema or rhinitis (see hygiene hypothesis) |
| Child day care | Inconclusive data but some association between attending day care and lower T1DM risk |
OR = odds ratio; RR = relative risk; HR = hazard ratio; CI = confidence interval; SGA = small for gestational age; LGA = large for gestational age.
In a few cases, coxsackie viral antigens have been isolated in islets postmortem, and viruses isolated from the pancreas have been shown to induce diabetes in susceptible mouse strains. Electron