Age-Dependent Influences on the Origins of Autoimmune Diabetes

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Abstract
A decade ago we proposed that environmental factors operating in early life lead to type 1 diabetes, outlining the evidence and the implications if the hypothesis was true (1). Today we can be confident that environmental factors can indeed operate in childhood to cause type 1 diabetes, but we now review evidence that this is unlikely to be true in the generality of cases of type 1 diabetes. Indeed, type 1 diabetes presenting in adult life is remarkably distinct from diabetes presenting in children in terms of its genetic, immune, metabolic, and clinical features. If the mechanism and timing of disease induction is also distinct in adult-onset, compared with childhood-onset, type 1 diabetes, then these differences would have implications for our understanding of the disease pathogenesis, prediction, and prevention. The aim of this article is to explore the different influences of genetic and nongenetic factors on type 1 diabetes according to the age of clinical disease onset and the potential consequences of such differences. Type 1 diabetes is caused by the destruction of insulin-secreting islet cells by an immune-mediated process. This adverse immune response is induced and promoted by the interaction of genetic and environmental factors and is one of a group of autoimmune diseases that affect ∼10% of the population in the developed world (2–5). Type 1 diabetes is genetically determined as shown by family, twin, and genetic studies. The frequency of type 1 diabetes is higher in siblings of diabetic patients (e.g., 6% by age 30 years in the U.K.) than in the general population (0.4% by age 30 years) (6). Familial clustering could be caused by shared genetic or environmental factors, and to distinguish between them, twin studies have been used. Higher concordance rates for autoimmune diseases in identical compared with nonidentical twins is …