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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 microscopy of the pancreas in some subjects who died shortly after the onset of type 1 diabetes identified retrovirus‐like particles within the β cells, associated with insulitis. There have also been case reports of multiple family members developing type 1 diabetes after contracting enteroviral infection.

Viruses may target the β cells and destroy them directly through a cytolytic effect or by triggering an autoimmune attack (Figure 6.7). Autoimmune mechanisms may include ‘molecular mimicry’; that is, immune responses against a viral antigen that cross‐react with a β cell antigen (e.g. a coxsackie B4 protein (P2–C) has sequence homology with GAD, an established autoantigen in the β cell). Also, anti‐insulin antibodies from patients with type 1 diabetes cross‐react with the retroviral p73 antigen in about 75% of cases. Alternatively, viral damage may release sequestered islet antigens and thus restimulate resting autoreactive T cells, previously sensitised against β cell antigens (‘bystander activation’). Persistent viral infection could also stimulate interferon‐α synthesis and hyperexpression of HLA class I antigens, and the secretion of chemokines that recruit activated macrophages and cytotoxic T cells.