British Medical Bulletin

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British Medical Bulletin 60:173-182 (2001)
© 2001 Oxford University Press

Long-term consequences for offspring of diabetes during pregnancy

Frans A Van Assche, Kathleen Holemans and Leona Aerts

Department of Obstetrics and Gynaecology, University Hospital Gasthuisberg, Leuven, Belgium

	Abstract

Top Footnotes Abstract Introduction Fetal development and fetal... Animal models Conclusions References

 
There is evidence that the diabetic intra-uterine environment has consequences for later life. Maternal diabetes mainly results in asymmetric macrosomia. This macrosomia is associated with an increased insulin secretion and overstimulation of the insulin producing B-cells during fetal life. In later life, a reduced insulin secretion is found. Intra-uterine growth restriction is present in severe maternal diabetes associated with vasculopathy. Intra-uterine growth restriction is associated with low insulin secretion and reduced development of the insulin receptors. In later life, these alterations can induce insulin resistance. The long-term consequences of an abnormal intra-uterine environment are of primary importance world-wide. Concentrated efforts are needed to explore how these long-term effects can be prevented.

	Introduction

Top Footnotes Abstract Introduction Fetal development and fetal... Animal models Conclusions References

 
Fetal growth and development are partly determined by the fetal genome, but the genetic regulation of fetal growth is influenced by different factors, which can exert a stimulatory or an inhibitory effect. Fetal growth is dependent on the capacity of the mother to supply nutrients and also on the capacity of the placenta to transfer these nutrients to the fetus. But the fetus has its own growth factors which influence growth and differentiation. Normal fetal growth depends on an equilibrium in the interaction between these different compartments and between stimulatory and inhibitory factors. When this equilibrium is disturbed, intra-uterine growth restriction (microsomia) or fetal overgrowth (macrosomia) can be the consequence¹. Both abnormalities in fetal growth are related to an abnormal intra-uterine environment.

In the human, fetal macrosomia is the most important finding in maternal diabetes, since there is increased supply of glucose and other nutrients^2,3. However, in severe maternal diabetes complicated by vasculopathy and nephropathy, intra-uterine growth restriction can be present⁴.

The present review will first concentrate on human fetal development and fetal growth in a diabetic intra-uterine environment and discuss the consequences for these offspring in later life. Second, we will briefly explore the working mechanisms in an experimental design in animal studies on diabetes and pregnancy.

	Fetal development and fetal growth in a diabetic intra-uterine environment and the consequences for later life in the human

Top Footnotes Abstract Introduction Fetal development and fetal... Animal models Conclusions References

 
Maternal diabetes is characterised by an increased placental transport of glucose and other nutrients from the mother to the fetus, resulting in macrosomia^2,3. In the endocrine pancreas islet hypertrophy and hyperplasia of the insulin producing B-cells have been recognised for many years as typical features in fetuses and newborn babies of diabetic mothers^5–11. The features of B-cell stimulation are observed as early as l9 weeks of gestation¹². An increased insulin secretion coincides with an increased amount of insulin producing B-cells (see Fowden & Hill, this issue). Simultaneously, levels of insulin-like growth factors (IGF) also increase. Both insulin and IGFs are related to birth weight¹³.

Macrosomia can be divided into a symmetric and asymmetric type. Symmetric fetal overgrowth may be due to genetic factors, whereas asymmetric fetal overgrowth is induced in a diabetic intra-uterine environment with an increased maternal–fetal nutrient transfer. This macrosomia is characterised by an enlarged thoracic and abdominal circumference, which is relatively larger than the head circumference.

We have recently shown that features of B-cell hyperplasia and of hyperinsulinism are only present in macrosomic fetuses of the asymmetric type and not in macrosomic fetuses of the symmetric type¹⁴. Infiltration by eosinophilic polymorphs in and around the fetal islets is only present in type I diabetes¹⁵.

Insulin is stored in typical granules in B-cells. In situations of excessive stimulation of the B-cells, the stores are used for secretion. Degranulation of the B-cells is, therefore, seen as an expression of overstimulation. In a newborn of a badly controlled diabetic mother (blood glucose >16.7 mmol/l), we found degranulated B-cells with swollen mitochondria, extended rough endoplasmic recticulum and very few granules, as described in fetuses of severely diabetic rats¹⁶.

The study of anencephalics also provides interesting data. The basal development of the fetal endocrine pancreas is normal; however, B-cell hyperplasia and increased insulin secretion is only present in anencephalics with a functional hypothalamic-hypophyseal (HH) system born to diabetic mothers. Furthermore, only these anencephalics are macrosomic¹¹. A summary of the morphometric data is presented in Table 1.

View this table: [in this window] [in a new window]   Table 1 Morphometric data of the human fetal endocrine pancreas (mean ± SD)

 
In severe maternal diabetes associated with vasculopathy and reduced renal function, intra-uterine growth restriction may be present; we have shown that insulin secretion and the number of B-cells are reduced¹⁷. It may be stressed that fetal development in a diabetic environment is characterised by an increased insulin secretion, due to overstimulation and possibly resulting in exhaustion of the fetal pancreatic B-cells. These alterations in fetal life may explain the consequences in later life. Degranulation of the fetal insulin producing B-cells can be found when extremely high glucose levels in the mother are present¹⁶.

The risk for diabetes is significantly higher when the mother rather than the father had non-insulin dependent diabetes¹⁸. Furthermore, 35% of patients with gestational diabetes are offspring of diabetic mothers compared with only 5% of normoglycaemic mothers, and gestational diabetes occurs more frequently in the offspring of diabetic mothers (35%) than in offspring of diabetic fathers (7%)¹⁹. Most convincing are the studies on Pima Indians which have shown that, besides a genetic transmission of diabetes, the diabetic intra-uterine milieu can also induce a diabetogenic tendency in the offspring. Impaired glucose tolerance is more frequent in children of mothers who had diabetes during pregnancy than in children of mothers who developed diabetes after pregnancy (33% versus 14% at age 15–19 years)²⁰.

However, there is at this time no clear-cut explanation why children of diabetic fathers have a greater risk for type I diabetes than children of pregestational diabetic mothers²¹. The eosinophilic infiltration in islets of newborn babies from diabetic mothers could be a protective mechanism for the development of diabetes, since this infiltration is only seen in infants of type l diabetic mothers and not of mothers with gestational diabetes²².

An extensive study over several generations demonstrated a predominance of type II diabetes in great-grandmothers of infantile onset diabetes on the maternal side compared with the paternal side. In addition, a predominance of familial diabetes aggregation in first- and second-degree relatives was found on the maternal side compared with the paternal side. Systematic prevention of hyperglycaemia and impaired glucose tolerance in pregnant women has significantly decreased the prevalence of diabetes mellitus in their children^23,24.

As indicated before, asymmetric macrosomia is associated with increased fetal insulin and IGF levels. IGF and insulin have mitogenic effects on the fetal breast tissue. This may explain the increased incidence of breast carcinoma in women who where macrosomic at birth²⁵.

Intra-uterine growth restriction can be present in severe maternal diabetes complicated by vasculopathy. The perinatal mortality in these growth retarded newborn babies of diabetic mothers has been high, and little information is available on the long-term consequences.

	Animal models

Top Footnotes Abstract Introduction Fetal development and fetal... Animal models Conclusions References

 
Mild maternal diabetes

When the mother has mild diabetes (glycaemia increased by ± 20%) during pregnancy, induced by destroying part of the B-cells^26,27 or by continuous glucose infusion²⁸, increased amounts of glucose reach the fetus by facilitated transfer through the placenta. In order to deal with this abundant glucose supply, adaptations occur in fetal insulin production and insulin action. The development of the fetal islets of Langerhans is enhanced, resulting in hypertrophy of the endocrine pancreas and hyperplasia of the B-cells. Not only the number of fetal B-cells is increased, but also the biosynthetic activity of the individual insulin producing cell is enhanced²⁶. The insulin response to glucose stimulation, both in vivo and in vitro, is clearly increased in the fetuses of mildly diabetic mothers as compared to controls²⁷.

After withdrawal of the hyperglycaemic maternal stimulus at birth, the lactation period appears to represent a poor stimulus for the further development of the endocrine pancreas, which ends up hypoplastic by the time of weaning²⁶. However, at adulthood, the offspring of mildly diabetic mothers display a normal mass of endocrine pancreas, with a normal contribution of the different islet-cell types²⁹. Glycaemia and insulinaemia are normal, at least in basal conditions. On glucose stimulation, however, in vivo and in vitro insulin response is deficient. In this and other experiments with perinatal hyperinsulinaemia^{25,28,30–32}, glucose tolerance in the adult animal is impaired.

Severe maternal diabetes

When maternal rats are made severely diabetic (by destroying the majority of their B-cells), the fetuses are confronted with very high glucose concentrations. The severe fetal hyperglycaemia induces islet hypertrophy and B-cell hyperactivity, and may result in early hyperinsulinaemia. This adaptation, however, appears to be limited, B-cells are overstimulated and the secretion of insulin is faster than its biosynthesis. B-cells become depleted of insulin and often appear disorganized and almost depleted of insulin granules²⁶. These degranulated cells are incapable of insulin secretion in vivo and in vitro²⁷ and B-cell exhaustion results in fetal hypoinsulinaemia. Hypoinsulinaemia and a reduced number of insulin receptors on target cells³² lead to a reduction in fetal glucose uptake³³. The growth of fetal protein mass is suppressed and fetal protein synthesis is consistently lower than in controls³⁴. Circulating amino acid levels in the fetuses of severely diabetic mothers are lower than in the controls; the fetal levels parallel the low maternal levels and the feto-maternal ratio is normal³⁵. Taurine levels, however, are exceptionally low in mothers and fetuses.

Postnatal development of the microsomic pups born to severely diabetic mothers is retarded, and the animals remain small up to adulthood²⁶. At adult age, the endocrine pancreatic mass in these animals exceeds control values, and this excess of islet mass is due to a high number of very small islets of Langerhans²⁹, suggesting an increased contribution of B-cell neogenesis, rather than cell replication.

Plasma amino acid concentrations are normal in the adult offspring of severely diabetic mothers, including the levels for the neurotransmitters taurine, GABA and carnosine³⁵. In vivo and in vitro stimulation of B-cells exerts an increased secretion of insulin²⁶.

Furthermore, these offspring are markedly resistant to the action of insulin as revealed by the euglycaemic hyperinsulinaemic clamp^36,37. The decreased sensitivity to insulin is observed in the liver as well as the extrahepatic tissues³⁶ and peripheral glucose uptake is specifically reduced in skeletal muscles³⁷. The insulin resistance can partly, but not completely, be restored by normalizing maternal glycaemia with islet transplantation in the course of, or even before, pregnancy^38,39. Insulin sensitivity in any tissue is dependent not only on the ability of insulin to stimulate cellular glucose uptake, but is also influenced by the arteriovenous glucose gradient and, potentially, blood flow^40,41. Therefore, we determined cardiovascular function, i.e. blood pressure, heart rate and vascular function, in the offspring of severely diabetic rats⁴². Exposure to severe maternal diabetes during fetal and neonatal life has profound consequences for cardiovascular function in the offspring. Despite normal systolic and diastolic blood pressure, there is evidence of pronounced bradycardia. The offspring of severely diabetic rats also show abnormalities of vascular function in vitro. Mesenteric arteries isolated from adult offspring of diabetic rats show a reduced relaxation to endothelium-dependent dilators and enhanced constriction to noradrenaline. The enhanced sensitivity, but similar maximal response, to noradrenaline is indicative of abnormal receptor-mediated tension development.

The reduction in relaxation to acetylcholine and bradykinin is suggestive of impaired synthesis of endothelium-derived vasodilators. The defect in sensitivity and maximal relaxation to acetylcholine is not observed in the presence of cyclooxygenase, nitric oxide synthase and guanylate synthase blockade, suggesting that prostacyclin/nitric oxide-induced relaxation is responsible for the defect in endothelium-dependent relaxation in offspring of severely diabetic rats, and not an endothelium derived hyperpolarizing factor⁴². The normal sensitivity to sodium nitroprusside also suggests that the defect does not arise from reduced sensitivity of the smooth muscle to nitric oxide, but from reduced nitric oxide synthesis.

Endothelial dysfunction, similar to that we reported in offspring of diabetic rats, is not only observed in adult diabetic subjects⁴³ and animals⁴⁴, but in other conditions with high cardiovascular risk, particularly hypercholesterolaemia^45,46. It is possible, therefore, that the intra-uterine diabetic milieu has conferred upon the offspring of diabetic rats a predisposition to severe cardiovascular disorders in later life.

Offspring during pregnancy

In the experimental model, it was also possible to obtain information on the transmission of the diabetogenic effect to the next generation. Female offspring of mildly diabetic mothers have increased glucose levels when pregnant. This ‘gestational diabetes’ induces typical features in their fetuses: macrosomia, islet hypertrophy and hyperinsulinism. When the offspring become adult, they display an impaired glucose tolerance with the same characteristics as offspring of mildly diabetic mothers^26,28,31. When pregnant, the offspring of severely diabetic rats develop signs of glucose intolerance, they have higher glucose and lower insulin levels than normal pregnant rats. These pregnant offspring do not show the normal pregnancy-induced insulin resistance in the second half of pregnancy⁴⁷. Furthermore, vascular dysfunction shows only a slight deterioration during pregnancy⁴⁸. Interestingly, the plasma concentration of the lipid peroxide 8-epi prostaglandin F₂ in pregnant offspring of diabetic rats was also raised above that of the pregnant offspring of control rats⁴⁸. Previously, we have shown that these pregnant offspring of severely diabetic rats develop mild hyperglycaemia⁴⁷, which could contribute directly to enhanced free radical synthesis and lipid peroxidation⁴⁹. Pregnancy seems to confer additional ‘stress’ and so unmask an already compromised balance between free radical synthesis and antioxidant status. We suggest that oxidative stress in the diabetic pregnant rat and her pregnant offspring could potentially play a role in fetal ‘programming’ and the transmission of a diabetogenic tendency to the next generation through permanent alteration of DNA and tissue damage in the developing fetus.

	Conclusions

Top Footnotes Abstract Introduction Fetal development and fetal... Animal models Conclusions References

 
In 1979, we published the first report on the long-term consequences of an abnormal intra-uterine environment under the title: Is gestational diabetes an acquired condition⁵⁰. At that time, we were aware of major scepticism that an abnormal intra-uterine environment could induce consequences in later life. However, 43 cycles of cell division occur between fertilisation and birth, but only 5 occur after birth. This may explain the crucial role of fetal life.

The consequences are mostly seen at older age, since the vitality of the organism is reduced and can no longer compensate for these alterations. Alterations can also be seen at periods in life when increased stimulation is present, such as puberty and pregnancy.

It is clear that epidemiological data are important to demonstrate the importance of the long-term effects in the human situation^51,52; experimental data can be a guide to explain the working mechanisms.

The maternally-derived changes in fetal plasma composition (glucose, amino acids, fatty acids) certainly influence the development and function of the fetal endocrine pancreas, but they may affect other organs and functions as well, in a direct or an indirect way. High glucose concentrations are know to promote B-cell replication, but the typical B-cell hyperplasia in fetuses of diabetic mothers only occurs if the fetus has a functioning hypothalamo-hypophyseal system¹¹, stressing the involvement of the derived hormones. Moreover, fetal hyperglycaemia induces fetal hyperinsulinaemia, which is known to damage the ventromedial part of the hypothalamus, controlling insulin secretion by modulating the tone on the nervus vagus³²; other body functions might be affected as well by similar mechanisms.

Fetal hypoinsulinaemia, resulting from B-cell exhaustion (severe diabetes) or from malnutrition, might have an opposite effect: moreover, it presents a lack of stimulus for the development of the insulin receptor system and this effect may differ between the different insulin-sensitive organs. Fetal responses depend on the metabolic condition of the mother: severe diabetes is associated with hyperglycaemia whereas malnutrition is associated with hypoglycaemia. The metabolic condition of the mother also influences the maturation of the fetal gastrointestinal tract and the extension of the vascularisation, not only in the endocrine pancreas but in several other organs, including the brain⁵³.

In conclusion, the development of the organs and functions associated with fetal glucose metabolism are determined by the intra-uterine metabolic environment, and the nature of this influence is complex, involving many different aspects and interactions.

The next step in our research needs to explore the prevention of these long-term consequences. Optimal diabetic control, good antenatal and perinatal care for all women in all parts of the world and adequate lactation and nutrition after birth are priorities.

In animal research, it is necessary to develop a stable model of maternal diabetes comparable with the human situation. In human studies, we need to explore gene–early environmental interactions⁵⁴. Studies of the offspring of diabetic mothers have provided unequivocal evidence that alterations in the nutritional environment in utero lead to chronic disease in the offspring.

	Footnotes

Top Footnotes Abstract Introduction Fetal development and fetal... Animal models Conclusions References

 
Correspondence to: Prof. Dr F A Van Assche, Department of Obstetrics and Gynaecology, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium

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Top Footnotes Abstract Introduction Fetal development and fetal... Animal models Conclusions References

 

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