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Evidence for autoimmunity in the pathogenesis of type 1 diabetes originally came from postmortem studies in patients who have died shortly after presentation, and pancreatic biopsies from living patients. They have revealed a chronic inflammatory mononuclear cell infiltrate (‘insulitis’) (Figure 6.4) associated with the residual β cells in the islets of recently diagnosed type 1 diabetic patients. The infiltrate consists of T cell lymphocytes and macrophages. Later in the disease, there is complete loss of β cells, while the other islet cell types (α, δ and PP cells) all survive. The discovery of islet cell antibodies confirmed the autoimmune basis of the inflammation (Figure 6.5).

Since these original observations, four circulating autoantibodies have been found in people with newly diagnosed type 1 diabetes. They are antibodies to the insulin molecule (IAAs), tyrosine phosphatase (insulinoma antigen‐2 protein IA–2), zinc transporter 8 (ZnT8) and glutamic acid decarboxylase 65 (GAD 65). However, less than 10% of individuals with a single autoantibody go on to develop type 1 diabetes, although the proportion increases dramatically in those with two or more autoantibodies (Figure 6.6). The sequence of appearance of autoantibodies differs, the first to appear is IAA (sometimes GAD65) at a median age of 15 (range 6–24) months in prospective studies in high risk children. The second antibody is usually detected within the next 2–4 years, following which the likelihood of developing multiple autoantibodies appears to decline. In first degree relatives of probands with type 1 diabetes, 75% of seroconversions occur before 13 years of age.

The lifetime risk of type 1 diabetes approaches 100% in genetically at‐risk children with two or more autoantibodies. The rate of progression to symptomatic disease in these children depends upon the number of autoantibodies (more = faster), the age of seroconversion (earlier = faster), and the type of antibody (IAA and IA–2 = earlier onset; IA–2 and ZnT8 = faster). In first degree relatives, 78% of those developing symptomatic type 1 diabetes have IA–2 and ZnT8 autoantibodies.

Figure 6.3 Seasonal variation of type 1 diabetes among Finnish children (a) 0–9 years of age, (b) 10–14 years of age during 1983–92. (The observed monthly variation in incidence is the solid line with dots.) The inner interval is the 95% confidence interval (CI) for the observed seasonal variation and the outer interval is the 95% CI for the estimated seasonal variation.

Data from Padaiga et al. Diabetic Med 1999; 16: 1–8.

Figure 6.4 Insulitis. There is a chronic inflammatory cell infiltrate centred on this islet. Haematoxylin–eosin stain, original magnification ×300.

Figure 6.5 ICA demonstrated by indirect immunofluorescence in a frozen section of human pancreas.

The detection of ICAs and GAD antibodies in older persons with type 2 diabetes in Finland and the UKPDS, who were shown subsequently to be more likely to require insulin therapy, has led to the concept of latent autoimmune diabetes of adults (LADA). Although GAD positivity had a specificity of 94.6% for early insulin use in the UKPDS, its sensitivity was only 37.9%. Moreover, the positive predictive value for GAD‐positive antibodies was only 50.8% (i.e. only half of those positive went on to need insulin). Nonetheless, it is now accepted that LADA represents a distinct entity on the spectrum of autoimmune diabetes. It is now thought that LADA may represent 4–14% of people diagnosed as type 2 diabetes, which would make it more prevalent than childhood type 1 diabetes in Europe, and it is the most common cause of autoimmune diabetes in China. GAD65 autoantibodies are positive in 7–14%, IA–2 and ZnT8 are less common. It shares genetic features of both type 1 and 2 diabetes but is phenotypically closer to type 2. However, LADA is characterised by a lower age of onset, lower BMI, greater need for insulin within 6 months of diagnosis, and a tendency for worse glycaemic control. Thyroid peroxidase antibodies were positive in 27% of patients in one Italian study. There may be value in screening people who are thought to have LADA for autoantibodies as early insulin therapy is indicated, although there are no trials of specific therapeutic strategies to guide treatment.

The autoimmune basis for type 1 diabetes is underlined by its association with other diseases such as hypothyroidism, Graves’ disease, pernicious anaemia, coeliac disease and Addison’s disease which are all associated with organ‐specific autoantibodies (Box 6.1). Up to 30% of people with type 1 diabetes have autoimmune thyroid disease. NICE guidance recommends screening all newly diagnosed children with type 1 diabetes for coeliac disease.

Figure 6.6 Progression to symptomatic Type 1 Diabetes in 585 children with two or more antibodies enrolled into three prospective studies in Finland (DIPP), USA (DAISY) and Germany (BABYDIAB & BABYDIET). Symptomatic diabetes developed in 43.5% at 5 years, 69.7% at 10 years and 84.2% at 15 years follow‐up.

Reproduced from Insel RA et al. Diabetes Care 2015; 38: 1964–74.