Early prediction of autoimmune (type 1) diabetes

Abstract

Underlying type 1 diabetes is a genetic aetiology dominated by the influence of specific HLA haplotypes involving primarily the class II DR-DQ region. In genetically predisposed children with the DR4-DQ8 haplotype, exogenous factors, yet to be identified, are thought to trigger an autoimmune reaction against insulin, signalled by insulin autoantibodies as the first autoantibody to appear. In children with the DR3-DQ2 haplotype, the triggering reaction is primarily against GAD signalled by GAD autoantibodies (GADA) as the first-appearing autoantibody. The incidence rate of insulin autoantibodies as the first-appearing autoantibody peaks during the first years of life and declines thereafter. The incidence rate of GADA as the first-appearing autoantibody peaks later but does not decline. The first autoantibody may variably be followed, in an apparently non-HLA-associated pathogenesis, by a second, third or fourth autoantibody. Although not all persons with a single type of autoantibody progress to diabetes, the presence of multiple autoantibodies seems invariably to be followed by loss of functional beta cell mass and eventually by dysglycaemia and symptoms. Infiltration of mononuclear cells in and around the islets appears to be a late phenomenon appearing in the multiple-autoantibody-positive with dysglycaemia. As our understanding of the aetiology and pathogenesis of type 1 diabetes advances, the improved capability for early prediction should guide new strategies for the prevention of type 1 diabetes.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-017-4308-1) contains a slideset of the figures for download, which is available to authorised users.

Intensive multidisciplinary weight management in patients with type 1 diabetes and obesity: A one‐year retrospective matched cohort study

“…Type 1 diabetes (T1D) is characterized by progressive autoimmune destruction of insulin‐producing pancreatic β cells, mandating use of exogenous insulin . Insulin, through its myriad of physiological effects, acts as a double‐edged sword .…”

Type 1 Diabetes: Disease Stratification

“…Risk is higher for identical twins or with sharing of HLA genotype with the proband, is higher in offspring of fathers with T1D compared to offspring of mothers with T1D, and is ∼ 14-fold higher in DR3/DR4-positive siblings if the proband develops symptomatic diabetes before age 10 years [35,36] . As noted above, HLA genotype accounts for half of the genetic risk, and specific HLA alleles are associated with higher risk of disease and have been used to stratify a high versus moderate risk population [35,37] , or protection or resistance from developing disease, such as occurs with HLA class II DRB1 * 1501 and DQA1 * 0102-DQB1 * 0602 [38] . Both HLA genes [25] and non-HLA genotypes can be used to stratify subjects who have a faster rate of progression to stage 3 T1D [39,40] .…”

“…There are differences in age and genetic predisposition for specificity of antibodies -insulin antibodies occur at an earlier peak age incidence (9-24 months) than GAD antibodies ( ∼ 36 months), with IA-2 and ZnT8 tending to occur later and rarely as the first autoantibody. Insulin antibodies have a higher association with HLA-DR4-DQ8 and GAD with HLA-DR3-DQ2 [35,82,83] .…”

“…Only approximately 10-15% of individuals newly diagnosed with T1D have a family history, but family history increases risk of disease ∼ 10-100-fold higher than background population [24,35] . Risk is higher for identical twins or with sharing of HLA genotype with the proband, is higher in offspring of fathers with T1D compared to offspring of mothers with T1D, and is ∼ 14-fold higher in DR3/DR4-positive siblings if the proband develops symptomatic diabetes before age 10 years [35,36] .…”

“…Only approximately 10-15% of individuals newly diagnosed with T1D have a family history, but family history increases risk of disease ∼ 10-100-fold higher than background population [24,35] . Risk is higher for identical twins or with sharing of HLA genotype with the proband, is higher in offspring of fathers with T1D compared to offspring of mothers with T1D, and is ∼ 14-fold higher in DR3/DR4-positive siblings if the proband develops symptomatic diabetes before age 10 years [35,36] . As noted above, HLA genotype accounts for half of the genetic risk, and specific HLA alleles are associated with higher risk of disease and have been used to stratify a high versus moderate risk population [35,37] , or protection or resistance from developing disease, such as occurs with HLA class II DRB1 * 1501 and DQA1 * 0102-DQB1 * 0602 [38] .…”