Metabolic Programming, Epigenetics, and Gestational Diabetes Mellitus

Abstract

The link between an adverse intrauterine environment and the development of disease later in life has been observed in offspring of pregnancies complicated by obesity and diabetes, but the molecular mechanisms underlying this phenomenon are unknown. In this review, we highlight recent publications exploring the role of gestational diabetes mellitus in the programming of disease in the offspring. We also review recent publications aiming to identify mechanisms responsible for the "programming effect" that results from exposure to diabetes in utero. Finally, we highlight research on the role of epigenetic regulation of gene expression in an animal model of uteroplacental insufficiency where the offspring develop diabetes as a model by which an exposure to the mother can alter epigenetic modifications that affect expression of key genes and ultimately lead to the development of diabetes in the offspring.

Folic acid uptake by the human syncytiotrophoblast is affected by gestational diabetes, hyperleptinemia, and TNF-α

“…However, the exact molecular mechanisms underlying this programming effect are still unknown. One speculative explanation is that the intrauterine environment during GDM, perturbed by conditions such as hyperglycemia, hyperinsulinemia or even hyperleptinemia, and increased inflammatory environment, may induce epigenetic changes that will ultimately influence fetoplacental physiology and developmental programming (29). Given that folates are obligatory cofactors for the provision of methyl groups for epigenetic regulation of gene expression and that little is known about the influence of GDM on fetoplacental folate homeostasis, the aims of this work were to investigate whether GDM affects FA placental transport and to identify specific GDM molecular hallmarks that may interfere with this process.…”

Endocrine Disruptors and Fetal Programming

“…These processes are very sensitive to changes in the intrauterine environment [13]. Epidemiological studies and animals models support the concept that there is a critical period of developmental programming in which exposures to adverse intrauterine environments or neonatal events may make an individual more susceptible to the development of adult illnesses such as obesity and DM [14] [15]. James Neel proposed the "economic genotype" hypothesis to explain the pathophysiological association between adverse events in early life and chronic diseases in adulthood [16].…”

“…Many risk factors have been studied, however, prenatal exposure to a diabetic intrauterine environment appears to be the major contributory factor to the development of the disease in its future life [15] [22]. The link between the exposure to an adverse intrauterine environment and the development of diseases in adult life has been observed in pregnancy complicated by obesity and DM, however, the molecular mechanisms behind this phenomenon are still not well understood.…”

“…The link between the exposure to an adverse intrauterine environment and the development of diseases in adult life has been observed in pregnancy complicated by obesity and DM, however, the molecular mechanisms behind this phenomenon are still not well understood. Thus, exposure to an adverse intrauterine environment, namely an environment characterized by hyperglycemia and hyperinsulinemia, may influence epigenetics and the structural and functional adaptive responses responsible for developmental programming [15]. The increased risk of obesity is related to the degree of fetal hyperinsulinism [24].…”

“…GDM may thus result in both macrosomic offspring and intrauterine growth restriction [13] [24], depending on the degree of hyperglycemia presented [15] [21]. There is growing epidemiological evidence that excesso nutritional intake to the fetus can produce phenotypes similar to those of malnutrition in offspring [8].…”