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.

Keywords: Autoimmunity; Beta cells, diabetes mellitus; Glutamic acid decarboxylase autoantibodies; HLA; Insulin autoantibodies; Insulin secretion; Insulinoma-associated antingen-2 autoantibodies; Next-generation sequencing; Review; Type 1 diabetes; ZnT8 autoantibodies.

Fig. 1

Proposed staging of type 1 diabetes. The aetiology is represented by a variable genetic and environmental risk. The pathogenesis is represented by three stages. In stage 1, beta cell autoantibodies are persistent, normoglycaemia prevails and there are no symptoms. During stage 2, the number of beta cell autoantibodies may affect the pathogenesis to induce dysglycaemia but there are still no diabetes symptoms. In stage 3, beta cell autoantibodies are still prevalent (some of them may have been lost) and there are symptoms of diabetes. The staging of type 1 diabetes pathogenesis was proposed by Insel et al [1] and the figure is adapted with permission from Insel et al [1]. © 2015 The American Diabetes Association

Fig. 2

Map of the HLA DR-DQ-DP complex region on human chromosome 6, with the class II region shown in greater detail below