Elsevier

Reproductive Toxicology

Volume 77, April 2018, Pages 1-24
Reproductive Toxicology

Effect of maternal hypoglycaemia during gestation on materno-foetal nutrient transfer and embryo-foetal development: Evidence from experimental studies focused primarily on the rat

https://doi.org/10.1016/j.reprotox.2018.01.007Get rights and content

Highlights

  • Supply of glucose to the developing embryo/foetus is pivotal for normal growth.

  • Regulation of glucose supply during maternal hypoglycaemia is poorly understood.

  • Glucose transport to the foetus is reduced during maternal hypoglycaemia.

  • The regulation seems to involve regulation of placental nutrient transporter levels.

  • The result is intra-uterine growth restriction and foetal skeletal malformations.

Abstract

Glucose is the major energy substrate during embryogenesis and the embryo is dependent on glucose from the maternal circulation to ensure normal metabolism and growth. The placenta plays a key role in this nutrient transfer in mammals, both during embryogenesis and after the development of the chorio-allantoic placental circulation. Maternal hypoglycaemia is accompanied by foetal hypoglycaemia and maternal counter-regulatory measures including a priority to keep nutrients in the maternal circulation by restricting their transfer to the foetus. Concomitantly, the foetus initiates its own counter-regulatory attempt to secure nutrients for its development and survival. Despite these measures, there is a general decrease in nutrient transfer to the foetus, which may have severe consequences for foetal development such as malformations and delayed skeletal development.

Introduction

Supply of glucose to the embryo from the maternal circulation is important for normal metabolism and growth, as glucose constitutes the main energy substrate during embryogenesis [[1], [2], [3], [4], [5]]. The placenta plays a key role in this nutrient transfer in mammals, both during embryogenesis and after the development of the chorio-allantoic circulation [[6], [7], [8]]. In addition to growth retardation, maternal fasting-induced hypoglycaemia in rats and mice causes malformations in foetuses [[9], [10], [11]]. Similarly, maternal insulin-induced hypoglycaemia in rats results in foetal growth retardation and delayed ossification [[12], [13]]. Although maternal nutrient status clearly affects foetal development and growth [14], the mechanisms involved in the regulation of placental nutrient transfer to the foetus during altered maternal nutritional status and especially potential adaptive responses are only partly understood [14].

Two main paradigms explaining the regulation of placental nutrient transfer have been proposed: the placental nutrient sensing model and the foetal demand model [[14], [15]]. The placental nutrient sensing model predicts that foetal growth is adjusted to the level of maternal nutrient supply to the foetus, so that during maternal nutrient restriction, adaptive down-regulation of placental nutrient transfer to the foetus will lead to impaired intrauterine growth [[14], [16], [17], [18]]. The foetal demand model conversely predicts that during nutrient scarceness, the foetus will signal to the placenta to up-regulate nutrient transfer. This represents a mechanism aiming to compensate for decreases in nutrient availability by up-regulating placental nutrient transfer capacity [[14], [16], [19]]. The two models of regulation of placental nutrient transfer are not necessarily mutually exclusive and might predominate at different time-points during gestation (e.g. organogenesis versus foetal period), which has yet to be elucidated [14].

This review discusses the regulation of materno-foetal nutrient transfer and evidence of whether the placental nutrient sensing model or fetal demand model dominates. Furthermore, potential consequential changes to foetal development such as growth restriction and malformations based on the available literature on the effects of maternal hypoglycaemia and general nutrient restriction will be touched upon. Insulin-induced maternal hypoglycaemia will be the main focus, but hypoglycaemia of other causes such as fasting are also considered. Emphasis will be put on evidence from experimental studies in rats, as this species is often used to investigate effects on nutrient-transfer and foetal development during maternal energy-restriction. Furthermore, little data is available from human studies.

Section snippets

Maternal metabolism during gestation

During gestation, two distinct phases in the maternal metabolism occur: an anabolic followed by a catabolic phase [20]. During the first two thirds of gestation, maternal metabolism is in an anabolic phase, increasing maternal fat stores through increased food consumption both in the rat and human [[20], [21], [22], [23], [24], [25], [26]]. Subsequently, maternal metabolism shifts to a catabolic state during the last third of gestation, characterised by increased break-down of fat stores,

The rat placenta

One of the primary functions of the placenta is to ensure materno-foetal nutrient transfer [[51], [52], [53]]. Throughout gestation, two different types of placentas are present in the rat, the yolk sac (also known as the choriovitelline placenta) and the chorioallantoic placenta [[54], [55]]. During early gestation after implantation, the yolk sac is responsible for the absorption and transport of nutrients to the embryo before the allantoic circulation is established [54]. By GD14 (total

Placental glycogen

The rat placenta contains glycogen, which is located in cells in the junctional zone and in trophoblasts of the labyrinth [[62], [215]]. However, on GD21 placental glycogen levels are approximately 1/100 of those in the foetal liver [[78], [216], [217]]. The importance of this relatively small placental glucose reserve during periods of glucose deprivation is unclear, but it has been suggested that it may act as a local rather than systemic energy reserve [218]. While studies investigating the

Foetal metabolism

As discussed above foetal blood glucose status correlates with maternal through regulation of glucose transporter expression, it is therefore not surprising that several studies have shown that foetal hypoglycaemia coincides with maternal hypoglycaemia induced by food-restriction, fasting, or insulin administration in rats and mice [[18], [76], [239], [253]]. On the other hand, the contribution of endogenous sources of glucose in the foetus needs to be considered, especially during periods of

Concluding remarks

An overall summary of effects of maternal hypoglycaemia on placental nutrient transporters as well as foetal metabolism and development is given in Table 9.

Maternal nutrient restriction during gestation seem to reach a balance in the resource allocation between mother and foetus during such a period of sparse nutrient supply. Results from studies in rats and mice indicate that maternal nutrient restriction generally down-regulates placental nutrient transporter expression and activity to keep

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