.

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.

Apoptosis

One model of β cell destruction is via the process of apoptosis or programmed cell death (Figure 6.8). This is effected by the activation of cellular caspases triggered by extrinsic means, including the interaction of cell surface Fas (the death‐signalling molecule) with its ligand FasL, on the surface of infiltrating CD4 and CD8 cells. There is an intrinsic pathway mediated by a balance between anti‐ and pro‐apoptotic mitochondrial pathways and both converge via the caspase activation pathway to cause β cell death. Other factors that induce apoptosis include macrophage derived nitric oxide (NO) and toxic free radicals, and disruption of the cell membrane by perforin and granzyme B produced by cytotoxic T cells. T cell cytokines (e.g. interleukin–1, tumour necrosis factor–α, interferon–γ) have been shown to up‐regulate Fas and FasL and induce NO and toxic free radicals.

Dietary factors

      Wheat gluten is a potent diabetogen in animal models of type 1 diabetes (BB rats and NOD mice; see below), and 5–10% of patients with type 1 diabetes have gluten‐sensitive enteropathy (coeliac disease). Recent studies have demonstrated that patients with type 1 diabetes and coeliac disease share disease‐specific alleles. Wheat may induce subclinical gut inflammation and enhanced gut permeability to lumen antigens in some patients with type 1 diabetes, which may lead to a breakdown in tolerance for dietary proteins. Other possible diabetogenic factors in diet include N–nitroso compounds, speculatively implicated in Icelandic smoked meat, which was a common dietary constituent in winter months.

Toxins

The notion that there may be environmental β cell toxins is supported by the existence of chemicals that cause an insulin‐dependent type of diabetes in animals. Examples are alloxan and streptozocin, both of which damage the β cell at several sites, including membrane disruption, enzyme interaction (e.g. with glucokinase) and DNA fragmentation. The rat poison vacor causes type 1 diabetes in humans, possibly because it has a similar action to streptozocin.

Figure 6.7 Potential mechanisms of viral aetiology of autoimmune and non‐autoimmune type 1 diabetes. IL = Interleukin; IFN = Interferon; TNF = Tumour Necrosis Factor.

      Adapted from Craig ME et al Pediatr Diabetes 2013;14:149–58.

Figure 6.8 Proposed mechanisms of β cell death. β cells die through a process known as apoptosis, characterised by condensation and fragmentation of nuclear chromatin, loss of cytoplasm and expression of surface receptors that signal macrophages to ingest the apoptotic cell. Apoptosis is effected by activation of the caspase pathway.

Animal models

      Spontaneous diabetes that resembles type 1 diabetes in humans occurs in some animals, notably the BioBreeding (BB) rat and the non‐obese diabetic (NOD) mouse. These ‘animal models’ have many of the same characteristics as human autoimmune diabetes, including a genetic predisposition, MHC association, insulitis, circulating islet cell surface and GAD autoantibodies, a long prediabetic period that precedes overt hyperglycaemia and environmental factors that trigger or accelerate the appearance of diabetes, such as wheat and cow’s milk proteins. Many hypotheses of the causes of type 1 diabetes have been developed and tested in these animals.

Hygiene hypothesis

      The increasing incidence of atopy as well as early‐onset type 1 diabetes in Western societies may be a consequence of a lack of exposure to common pathogens such as helminth worms (so called ‘old friends’), or lactobacilli (microflora). Chronic exposure might include a more tolerant T cell response to antigens, while a cleaner, more sterile early environment would result in an exaggerated response in subsequent months or years. Some of the associated factors listed in Table 6.3 would support this hypothesis.

      Pregnancy is thought to have a Th2 lymphocyte orientation whilst early environmental antigen exposure stimulates Th1 responses. The first line immune response in children comprises immature dendritic cells which are primed to respond to specific antigens, and they also carry innate pattern recognition receptors that bind to viral or bacterial cell surfaces. T‐cell receptors are highly cross reactive so an immune response to common allergens or self antigens might be activated by infection. It was originally thought that an imbalance in Th1 and 2 cells would lead to a different balance in cytokine release predisposing to either autoimmunity (Th1 predominance) or allergy (Th2 predominance). However, this construct has not been supported by the observation that helminth (pinworm) exposure actually leads to a more pronounced Th2 response but lower rates of atopy. Thus, the hygiene hypothesis, despite supportive associative data, remains unproven.

Accelerator hypothesis

      The observed increase in non‐autoimmune type 1 diabetes and its links to type 2 diabetes susceptibility genes, as well as the increasing rates of obesity in children, has led to the concept of increasing insulin resistance as a cause of β cell loss. It is generally believed that β cell loss is a feature of ageing, and obesity related insulin resistance could accelerate this loss through apoptosis and be partly responsible for the increasing incidence of both type 1 and type 2 diabetes. Much of the supportive evidence remains cross sectional rather than prospective, however.

      Stages of Diabetes

The increasing understanding of the processes leading to symptomatic type 1 diabetes has resulted in a consensus model in individuals who have a genetic susceptibility and comprises 3 stages (Figure 6.9). Stage 1 individuals have positive autoantibodies but normal glucose tolerance. As mentioned above, increasing numbers of islet autoantibodies and increasing titres represent disease progression. Stage 2 is reached as β cell loss results in glycaemic responses to a glucose challenge becoming abnormal, but there is no universal agreement as to what the glucose stimulus