Aetiology and pathogenesis of type 1 diabetes mellitus

As described in Chapter 13.2.3, type 1 diabetes results from the destruction of the glucose-responsive, insulin-secreting β cells of the pancreatic islets. Its principal clinical features reflect significant insulin deficiency. In general, the β cell damage is immune mediated and other clinical features occur related to other autoimmune processes. Although typically considered to have a short prodrome, in research studies biochemical evidence of impaired glucose metabolism has been detected years before diagnosis, in the form of mild elevation of blood glucose. It is likely that the clinical symptoms only manifest when 90% or more of the β cells are lost. The effects of insulin deficiency are enhanced at times of insulin resistance, which explains the apparent link between clinical onset of type 1 diabetes and acute stress, such as an intercurrent infection or other illness, or physiological changes in insulin resistance, such as during puberty.

The rate of β cell loss is highly variable. It is probable that type 1 diabetes presenting in prepubertal childhood may reflect a more aggressive destructive process, while, at the other extreme, type 1 diabetes may present in adult life with a slow evolution to an absolute need for insulin replacement. The latter is called ‘latent adult onset diabetes’ (LADA), and confounds the clinical definition of type 1 diabetes—often used in recruiting type 1 patients to trials—of requirement for insulin replacement within a year of diagnosis. The diagnosis of type 1A diabetes, i.e. type 1 diabetes of proven autoimmune pathogenesis, may be made by finding evidence of the autoimmune process against β cell antigens, with the presence of anti-islet cell antibodies—or, more accurately, anti-glutamic acid decarboxylase (GAD) or anti-islet-associated protein 2 (IA-2) antibodies—in the blood. Absence of such antibodies does not mean the diagnosis is not type 1, as the antibodies tend to disappear over time, perhaps with loss of the β cell antigens to stimulate them, but their presence is usual in type 1 diabetes when there is at least some residual insulin-secretory capacity, which is usually the case when the question of diagnosis arises.