Type 1 diabetes (T1D) is a chronic T-cell mediated disease that leads to the destruction of the insulin-secreting islet β-cells (Figure 1) resulting in absolute insulin deficiency and hyperglycaemia.
Type 1 diabetes accounts for about 5-10% of all patients with diabetes and the worldwide incidence is increasing by 3% every year. There is considerable geographical variation in the incidence of the disease; it occurs more frequently in Europeans and less so in Asians, with the highest incidence noted in Finland.
The clinical presentation of T1D is preceded by an asymptomatic period lasting from months to years which is characterised by autoantibodies against islet β-cell components. Insulin autoantibodies are amongst the first to appear, followed by autoantibodies to glutamic acid decarboxylase (GAD) and then spreading to IA-2 (insulinoma-associated tyrosine phosphatase protein) and ZnT8 (zinc-transporter 8). It is generally thought that these autoantibodies serve as a diagnostic marker and have no etiological role in the development of T1D.
The destruction of the islet β-cell in T1D is the result of a complex interplay between multiple players of both the innate and adaptive immune system; immunohistochemical analysis of islet inflammation from pancreata of patients with T1D obtained at autopsy indicate a mononuclear cell infiltrate in islets (termed insulitis) consisting mainly of macrophages, B cells and T cells. Both CD4+ and CD8+ T cells are required for disease development, by destroying the insulin-producing β cells through the effector functions of Th1 cells and direct killing by cytotoxic T lymphocytes (CTLs). CTLs initiate killing by various mechanisms including the production of inflammatory cytokines such as TNF-a and IFN-g, which act synergistically with IL-1 produced by macrophages in targeting the β-cells; they also directly kill β-cells through the secretion of perforin or by apoptosis by the activation of the Fas-Fas-L pathway.
Figure 1. Healthy islet (a) and an islet in a patient with chronic type 1 diabetes (b) stained with anti-insulin antibody.
Type 1 diabetes is polygenic disease with a strong genetic component. The major susceptibility locus for T1D maps to the HLA region on chromosome 6p21 and this accounts for 30-50% of the genetic risk; specifically these are the loci HLA-DRB1 and HLA-DQB1. The highest risk DR/DQ haplotypes for T1D are DR3-DQA1*0501-DQB1*0201 (DR3) and DR4-DQA1*0301-DQB1*0302 (DR4). In addition, more than 40 non-HLA, loci have been confirmed which impart a smaller effect on disease risk − these include the insulin gene, CTLA-4, PTNP22, IL-2RA and IF1H1.
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