Epigenetics of gestational diabetes mellitus and offspring health: the time for action is in early stages of life

Abstract

The epidemic increase of type 2 diabetes and obesity in developed countries cannot be explained by overnutrition, physical inactivity and/or genetic factors alone. Epidemiologic evidence suggests that an adverse intrauterine environment, in particular a shortage or excess of nutrients is associated with increased risks for many complex diseases later in life. An impressive example for the 'fetal origins of adult disease' is gestational diabetes mellitus which usually presents in 1% to >10% of third trimester pregnancies. Intrauterine hyperglycemia is not only associated with increased perinatal morbidity and mortality, but also with increased lifelong risks of the exposed offspring for obesity, metabolic, cardiovascular and malignant diseases. Accumulating evidence suggests that fetal overnutrition (and similarly undernutrition) lead to persistent epigenetic changes in developmentally important genes, influencing neuroendocrine functions, energy homeostasis and metabolism. The concept of fetal programming has important implications for reproductive medicine. Because during early development the epigenome is much more vulnerable to environmental cues than later in life, avoiding adverse environmental factors in the periconceptional and intrauterine period may be much more important for the prevention of adult disease than any (i.e. dietetic) measures in infants and adults. A successful pregnancy should not primarily be defined by the outcome at birth but also by the health status in later life.

Keywords: developmental origins hypothesis; fetal overnutrition; fetal programming; gestational diabetes mellitus; metabolic disease.

Figure 1

The cycle of metabolic disease epidemics. Fetal overnutrition due to GDM and/or maternal obesity leads to epigenetic changes in the exposed offspring. As an example, the box plot diagrams on top show the significantly different distribution of placenta MEST methylation values in newborns of mothers with dietetically treated D-GDM and insulin-treated I-GDM, compared with newborns of mothers without GDM. MEST hypomethylation may foreshadow diet-induced obesity. Similarly, epigenetic changes in numerous other genes may increase the lifelong metabolic disease susceptibility and, thus, the likelihood for a new generation of mothers with GDM and/or obesity, feeding the vicious cycle. Consistent with the decreasing plasticity of the epigenome, the effect of possible interventions to break the cycle can be expected to be larger in the periconceptional and prenatal period than after birth, during infancy and in adulthood.