Epigenetics and Developmental Origins of Diabetes: Correlation or Causation?

The incidence of metabolic disorders like type 2 diabetes (T2D) and obesity continue to increase. While it is evident that the increasing incidence of diabetes confers a global societal and economic burden, the mechanisms responsible for the increased incidence of T2D are not well understood. Extensive efforts to understand the association of early life perturbations with later onset of metabolic diseases, the founding principle of DOHaD, have been crucial in determining the mechanisms that may be driving the pathogenesis of T2D. As the programming of the epigenome occurs during critical periods of development, it has emerged as a potential molecular mechanism that could occur early in life and impact metabolic health decades later. In this review, we critically evaluate human and animal studies that illustrated an association of epigenetic processes with development of T2D, as well as intervention strategies that have been employed to reverse the perturbed epigenetic modification, or reprogram the naturally occurring epigenetic marks to favor improved metabolic outcome. We highlight that although our understanding of epigenetics and its contribution towards developmental origins of T2D continues to grow, whether epigenetics is a cause, consequence, or merely a correlation remains debatable due to the many limitations/challenges of the existing epigenetic studies. Finally, we discuss the potential of establishing collaborative research efforts between different disciplines including physiology, epigenetics, and bioinformatics to help advance the developmental origins field with great potential for understanding the pathogenesis of T2D, and developing preventive strategies for T2D.