Developmental origins of type 2 diabetes: Focus on epigenetics

Traditionally, genetics and lifestyle are considered as main determinants of aging-associated pathological conditions. Accumulating evidence, however, suggests that risk of many age-related diseases is not only determined by genetic and adult lifestyle factors but also by factors acting during early development. Type 2 diabetes (T2D), an age-related disease generally manifested after the age of 40, is among such disorders. Since several age-related conditions, such as pro-inflammatory states, are characteristic of both T2D and aging, this disease is conceptualized by many authors as a kind of premature or accelerated aging. There is substantial evidence that intrauterine growth restriction (IUGR), induced by poor or unbalanced nutrient intake, exposure to xenobiotics, maternal substance abuse etc., may impair fetal development, thereby causing the fetal adipose tissue and pancreatic beta cell dysfunction. Consequently, persisting adaptive changes may occur in the glucose-insulin metabolism, including reduced capacity for insulin secretion and insulin resistance. These changes can lead to an improved ability to store fat, thus predisposing to T2D development in later life. The modulation of epigenetic regulation of gene expression likely plays a central role in linking the adverse environmental conditions early in life to the risk of T2D in adulthood. In animal models of IUGR, long-term persistent changes in both DNA methylation and expression of genes implicated in metabolic processes have been repeatedly reported. Findings from human studies confirming the role of epigenetic mechanisms in linking early-life adverse experiences to the risk for T2D in adult life are scarce compared to data from animal studies, mainly because of limited access to suitable biological samples. It is, however, convincing evidence that these mechanisms may also operate in human beings. In this review, theoretical models and research findings evidencing the role of developmental epigenetic variation in the pathogenesis of T2D are summarized and discussed.