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Animal evidence for the transgenerational development of diabetes mellitus

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Abstract

The mammalian fetus develops inside the uterus of its mother and is completely dependent on the nutrients supplied by its mother. Disturbances in the maternal metabolism that alter this nutrient supply from mother to fetus can induce structural and functional adaptations during fetal development, with lasting consequences for growth and metabolism of the offspring throughout life. This effect has been investigated, by several research groups, in different experimental models where the maternal metabolism during pregnancy was experimentally manipulated (maternal diabetes and maternal malnutrition) and the effect on the offspring was investigated. The altered maternal/fetal metabolism appears to be associated with a diabetogenic effect in the adult offspring, including gestational diabetes. This diabetic pregnancy in the offspring again induces a diabetogenic effect into the next generation, via adaptations during fetal development. These experimental data in laboratory animals are confirmed by epidemiological studies on infants of mothers suffering from diabetes or malnutrition during pregnancy.

It can be concluded that fetal development in an abnormal intra-uterine milieu can induce alterations in the fetal metabolism, with lasting consequences for the glucose tolerance of the offspring in adult life. The most marked effect is the development of gestational diabetes, thereby transmitting the diabetogenic tendency to the next generation again. The concept of fetal origin of adult diabetes therefore is of major significance for public health in the immediate and the far future.

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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