The heterogeneous pathogenesis of type 1 diabetes mellitus

Abstract

Type 1 diabetes mellitus (T1DM) results from the destruction of pancreatic β-cells that is mediated by the immune system. Multiple genetic and environmental factors found in variable combinations in individual patients are involved in the development of T1DM. Genetic risk is defined by the presence of particular allele combinations, which in the major susceptibility locus (the HLA region) affect T cell recognition and tolerance to foreign and autologous molecules. Multiple other loci also regulate and affect features of specific immune responses and modify the vulnerability of β-cells to inflammatory mediators. Compared with the genetic factors, environmental factors that affect the development of T1DM are less well characterized but contact with particular microorganisms is emerging as an important factor. Certain infections might affect immune regulation, and the role of commensal microorganisms, such as the gut microbiota, are important in the education of the developing immune system. Some evidence also suggests that nutritional factors are important. Multiple islet-specific autoantibodies are found in the circulation from a few weeks to up to 20 years before the onset of clinical disease and this prediabetic phase provides a potential opportunity to manipulate the islet-specific immune response to prevent or postpone β-cell loss. The latest developments in understanding the heterogeneity of T1DM and characterization of major disease subtypes might help in the development of preventive treatments. Although β-cell targeted autoimmune processes and β-cell dysfunction are known to occur in type 1 diabetes mellitus, the precise aetiology and pathological mechanisms are still largely unclear. This Review explores the current knowledge on the pathogenesis of type 1 diabetes mellitus and describes expected developments in the near future. The incidence of type 1 diabetes mellitus in childhood has increased, and the age at diagnosis has decreased due to environmental changes during the last half of the twentieth century. Inherited defects in central and peripheral immune tolerance allow the generation of autoimmune responses directed against pancreatic islets. Environmental factors that modify the immune system, such as microbiota composition, microbial infections and nutrition, affect the development and course of the autoimmune response. Type 1 diabetes mellitus is a heterogeneous disease with multiple different features, but two major pathways can be discerned with either insulin autoantibodies or glutamic acid decarboxylase autoantibodies as the first autoantibody indicating initiation of the autoimmune process. Multiple trials aiming to prevent development of the disease in different phases of the autoimmune process are ongoing or being planned. The incidence of type 1 diabetes mellitus in childhood has increased, and the age at diagnosis has decreased due to environmental changes during the last half of the twentieth century. Inherited defects in central and peripheral immune tolerance allow the generation of autoimmune responses directed against pancreatic islets. Environmental factors that modify the immune system, such as microbiota composition, microbial infections and nutrition, affect the development and course of the autoimmune response. Type 1 diabetes mellitus is a heterogeneous disease with multiple different features, but two major pathways can be discerned with either insulin autoantibodies or glutamic acid decarboxylase autoantibodies as the first autoantibody indicating initiation of the autoimmune process. Multiple trials aiming to prevent development of the disease in different phases of the autoimmune process are ongoing or being planned.