The environment and the origins of islet autoimmunity and Type 1 diabetes

Abstract

Type 1 diabetes involves the specific destruction of the pancreatic islet β-cells, eventually resulting in a complete dependency of exogenous insulin. The clinical onset of diabetes is preceded by the appearance of autoantibodies against β-cell antigens. The human leukocyte antigen (HLA) region is the single most important genetic determinant of Type 1 diabetes susceptibility, yet variability in the HLA region has been estimated to explain only approximately 60% of the genetic influence of the disease. Over 50 identified non-HLA genetic polymorphisms support the notion that genetics alone cannot explain Type 1 diabetes. Several lines of evidence indicate that environmental triggers may be integral in inducing the onset of islet autoimmunity in genetically susceptible individuals. The association between environmental factors and the clinical onset is complicated by observation that the rate of progression to clinical onset may be affected by environmental determinants. Hence, the environment may be aetiological as well as pathogenic. Putative inductive mechanisms include viral, microbial, diet-related, anthropometric and psychosocial factors. Ongoing observational cohort studies such as The Environmental Determinants of Diabetes in the Young (TEDDY) study aim to ascertain environmental determinants that may trigger islet autoimmunity and either speed up or slow down the progression to clinical onset in subjects with persistent islet autoimmunity.

Figure 1

Type 1 diabetes is viewed as a two-step disease. Children may be born with increased genetic risk for Type 1 diabetes. Environmental factors during pregnancy or during neonatal and infancy are thought to induce step one: islet or β-cell autoimmunity marked by the appearance of autoantibodies against insulin (IAA), glutamic acid decarboxylase 65 (GADA), insulinoma antigen-2 (IA-2A), ZnT8 transporter (ZnT8A), alone or in combination. Persistent islet autoantibodies also mark step two, progression to clinical onset of Type 1 diabetes.