The International Journal of Biochemistry & Cell Biology
ReviewAnimal evidence for the transgenerational development of diabetes mellitus
Introduction
Health condition throughout lifetime results from a combination of genetic predisposition and environmental influences. While the genotype is determined at conception, the phenotype is permanently modulated by external factors. This impact starts already prenatally, as the characteristics of the intra-uterine milieu influence the development of embryo and fetus. Structural and functional development of specific tissues or organs can be stimulated or inhibited by the maternal condition, and may result in deficiencies and diseases in later life. The intra-uterine milieu in which the fetus develops, therefore programs to a certain extent the health of an individual throughout life. This effect has been called “fetal origin of adult disease” (FOAD) or, more generally, “developmental origin of health and disease” (DOHaD).
Adult type-2 diabetes for instance can be induced during fetal development, even in the absence of a genetic predisposition. For its growth and development, the fetus is completely dependent on the nutrients supplied by its mother. Abnormalities in maternal metabolism, like maternal diabetes or maternal malnutrition, will alter the supply of fuels and building blocks and may induce adaptations in fetal development that can have lasting consequences for the glucose tolerance of the adult offspring, even in subsequent generations.
This impact of the maternal metabolism on fetal development, resulting in a diabetogenic tendency in later life, has been studied in several animal models where the maternal metabolism was experimentally manipulated in a standardized way. In human populations, where genetic background as well as environmental influences are heterogeneous, the precise impact of maternal metabolism on fetal development is more difficult to recognize. However, numerous epidemiological studies demonstrate a similar fetal origin of adult diabetes.
Section snippets
Maternal diabetes during pregnancy (Fig. 1)
Maternal diabetes during pregnancy confronts the fetus with an abundant supply of glucose. Adaptations will be induced during fetal development that may have lasting consequences for the metabolism of the offspring throughout life. The mechanisms of this transgeneration effect have been studied in several animal models and can be related to observations in human offspring of diabetic mothers.
Malnutrition during pregnancy (Fig. 2)
Fetal malnutrition, whether resulting from maternal malnutrition or from a maternal, placental and/or fetal pathology, also confronts the fetus with an abnormal intra-uterine milieu. Alterations in fetal development might again have lasting consequences for glucose tolerance in the offspring.
Fetal origin of adult diabetes
Experimental studies on laboratory animals and epidemiological studies on human populations both clearly demonstrate that fetal development in an unfavorable intra-uterine milieu can induce persisting alterations in the metabolism of the offspring throughout life. Maternal diabetes or maternal/fetal malnutrition, whether quantitative or qualitative, can induce a diabetogenic tendency in the offspring, which is not obvious in basal conditions, but only appears in situations stressing glucose
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