Epigenetics and developmental origins of diabetes: correlation or causation?

Abstract

The incidence of metabolic disorders like type 2 diabetes (T2D) and obesity continue to increase. Although 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 developmental origins of health and disease, 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 toward 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.

Epigenetic responses and the developmental origins of health and disease

“…Moreover, studies have demonstrated that perinatal stressors such as protein deprivation can also alter histone acetylation (Sun et al 2015). Similarly, high-fat diet is also known to alter histone acetylation as well as methylation which may lead to changes in gene expression in adipose tissue, liver, skeletal muscle and other fetal tissues (Masuyama & Hiramatsu 2012, Suter et al 2014, Bansal & Simmons 2018. In contrast, a recent study showed that providing better environmental conditions during gestation reduced risk of Alzheimer's disease in the offspring by histone hyperacetylation (Liu et al 2019).…”

Dietary antioxidants remodel DNA methylation patterns in chronic disease

“…It is also well documented that stress exposure in utero is associated with developmental origins of T2D in accordance with the Barker hypothesis of the developmental origins of disease (Barker et al, 1993) and this link is mediated through changes in DNA methylation patterns in the fetus (Bansal & Simmons, 2018). For instance, the link between epigenetic silencing of a gene encoding for leptin in placental tissues of the offspring exposed to gestational diabetes and higher risk for T2D in adulthood has been described (Bansal & Simmons, 2018). Furthermore, low or high birth weight as a result of malnutrition during pregnancy has been strongly associated with later-life risk of T2D (U-shaped relation; Barker et al, 1993).…”

Epigenetics and Type 2 Diabetes Risk

“…A strong case for the involvement of epigenetic factors in T2D is made by studies on the effect of maternal and intrauterine nutrition and growth retardation on diabetes development in multiple species [15]. Studies on the Dutch Hunger Winter famine have shown that intrauterine malnutrition and low birth weight leads to an increased likelihood for developing diabetes in subsequent generations [16].…”