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Pathogenesis of type 1 diabetes mellitus

Massimo Pietropaolo, MD
Section Editor
Irl B Hirsch, MD
Deputy Editor
Jean E Mulder, MD


Type 1A diabetes mellitus results from autoimmune destruction of the insulin-producing beta cells in the islets of Langerhans [1]. This process occurs in genetically susceptible subjects, is probably triggered by one or more environmental agents, and usually progresses over many months or years during which the subject is asymptomatic and euglycemic. Thus, genetic markers for type 1A diabetes are present from birth, immune markers are detectable after the onset of the autoimmune process, and metabolic markers can be detected with sensitive tests once enough beta cell damage has occurred, but before the onset of symptomatic hyperglycemia [2]. This long latent period is a reflection of the large number of functioning beta cells that must be lost before hyperglycemia occurs (figure 1). Type 1B diabetes mellitus refers to nonautoimmune islet destruction (Type 1B diabetes). (See "Classification of diabetes mellitus and genetic diabetic syndromes".)

The pathogenesis of type 1A diabetes is quite different from that of type 2 diabetes mellitus, in which both decreased insulin release (not on an autoimmune basis) and insulin resistance play an important role. Genome-wide association studies indicate that type 1 and type 2 diabetes' genetic loci do not overlap, although inflammation (eg, interleukin-1 mediated) may play a role in islet beta cell loss in both types [3]. (See "Pathogenesis of type 2 diabetes mellitus".)

The pathogenesis of type 1 diabetes mellitus will be reviewed here. The diagnosis and management of type 1 diabetes are discussed separately. (See "Epidemiology, presentation, and diagnosis of type 1 diabetes mellitus in children and adolescents" and "Prevention of type 1 diabetes mellitus" and "Management of type 1 diabetes mellitus in children and adolescents" and "Associated autoimmune diseases in children and adolescents with type 1 diabetes mellitus".)


Polymorphisms of multiple genes are reported to influence the risk of type 1A diabetes (including, HLA-DQalpha, HLA-DQbeta, HLA-DR, preproinsulin, the PTPN22 gene, CTLA-4, interferon-induced helicase, IL2 receptor (CD25), a lectin-like gene (KIA0035), ERBB3e, and undefined gene at 12q) [4-10]. A meta-analysis of data from genome-wide association studies confirmed the above associations and identified four additional risk loci (BACH2, PRKCQ, CTSH, C1QTNF6) associated with an increased risk of type 1 diabetes [11].

In addition, some loci conferring shared risk for celiac disease (RGS1, IL18RAP, CCR5, TAGAP, SH2B3, PTPN2) have been identified [12]. Most loci have small effects, and the variants studied are common. The CCR5 association is of interest in that a 32-base pair insertion deletion in a chemokine receptor, CCR5, results in a loss of function and, when homozygous, a twofold decrease in risk of type 1 diabetes. (See 'MHC genes' below and 'Non-MHC genes' below and 'Association with other autoimmune diseases' below.)


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Literature review current through: Sep 2016. | This topic last updated: Oct 11, 2016.
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