Early-Life Nutritional Programming of Type 2 Diabetes: Experimental and Quasi-Experimental Evidence

Abstract

Consistent evidence from both experimental and human studies suggest that inadequate nutrition in early life can contribute to risk of developing metabolic disorders including type 2 diabetes (T2D) in adult life. In human populations, most findings supporting a causative relationship between early-life malnutrition and subsequent risk of T2D were obtained from quasi-experimental studies (‘natural experiments’). Prenatal and/or early postnatal exposures to famine were demonstrated to be associated with higher risk of T2D in many cohorts around the world. Recent studies have highlighted the importance of epigenetic regulation of gene expression as a possible major contributor to the link between the early-life famine exposure and T2D in adulthood. Findings from these studies suggest that prenatal exposure to the famine may result in induction of persistent epigenetic changes that have adaptive significance in postnatal development but can predispose to metabolic disorders including T2D at the late stages of life. In this review, quasi-experimental data on the developmental programming of T2D are summarized and recent research findings on changes in DNA methylation that mediate these effects are discussed.

Nutriepigenomics Advances into Personalized Nutrition

“…Exposure to adverse environmental factors such as inadequate or unbalanced nutrient supply during in utero development may 'program' for the long term appetite regulation, feeding behavior, as well as adipose tissue and pancreatic beta cell dysfunction in the developing fetus. As a result of these processes, the fetus may be adapted to adverse nutritional conditions by reducing its ability to produce insulin and by occurrence of insulin resistance [1,5,11].…”

“…Additionally, under malnourished conditions when the fetus exhibits poor growth in utero, commonly referred to as intrauterine growth restriction (IUGR), the fetal adaptation to under nutrition is realized by a variety of mechanisms responsible for the energy and glucose metabolism, such as enhanced peripheral insulin sensitivity for glucose utilization, increased hepatic glucose production, lowered insulin sensitivity for protein synthesis in muscle, and impaired pancreatic development [11].…”

“…The specific DNA methylation markers have been repeatedly identified in peripheral blood and pancreatic islets of the T2D patients. A schematic representation of hypothetical regulatory pathways responsible for developmental nutritional programming of T2D is presented in (Figure 3) [11]. …”

“…The prenatal exposure to the Dutch famine has been repeatedly shown to be related to the impaired metabolic phenotypes such as elevated levels of plasma lipids and body mass index (BMI), as well as enhanced risks of obesity and cardiovascular disease (CVD) later in life. Severe malnourishment during late gestation was also related to impaired glucose tolerance of the offspring into adult life [6,[11][12][13][14].…”

“…The methylation levels of the imprinted gene encoding an insulin-like growth factor 2(IGF2), known to play a crucial role in human growth and development. The IGF2 gene was selected for analysis because its methylation marks are stable up to adult age, making IGF2 gene a good candidate for such a study [11].…”