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Assistance Publique-Hopitaux de Paris (L.-S.F., E.S., J.-F.G.), Department of Endocrinology and Diabetes, Saint-Louis Hospital, University Paris 7, 75475 Paris Cedex 10, France; Institut National de la Santé et de la Recherche Médicale Unité 671 (E.S., J.-F.G.), Cordelier Institute of Biomedical Research, 75270 Paris Cedex 06, France; Institut National de la Santé et de la Recherche Médicale CIC9504 (L.-S.F., E.S., F.C., J.-F.G.), University Paris 7, Assistance Publique-Hopitaux de Paris, Saint-Louis Hospital, 75475 Paris Cedex 10, France; Centre National de la Recherche Scientifique Unité Mixte de Recherche 7059 (P.S.), Laboratory of Nutrition Physiopathology, University Paris 7, 75005 Paris, France; and School of Population and Health Sciences (E.S.), Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne NE1 7RU, United Kingdom
Address all correspondence and requests for reprints to: Jean-François Gautier, Department of Endocrinology and Diabetes, Saint-Louis Hospital, 1, Avenue Claude Vellefaux, 75475 Paris Cedex 10, France. E-mail: jean-francois.gautier{at}sls.aphp.fr.
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Abstract |
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Evidence acquisition: A MEDLINE search covered the period from 1960–2005.
Evidence synthesis: Human studies performed in children and adolescents suggest that offspring who had been exposed to maternal diabetes during fetal life exhibit higher prevalence of impaired glucose tolerance and markers of insulin resistance. Recent studies that directly measured insulin sensitivity and insulin secretion have shown an insulin secretory defect even in the absence of impaired glucose tolerance in adult offspring. In animal models, exposure to a hyperglycemic intrauterine environment also led to the impairment of glucose tolerance in the adult offspring. These metabolic abnormalities were transmitted to the next generations, suggesting that in utero exposure to maternal diabetes has an epigenetic impact. At the cellular level, some findings suggest an impaired pancreatic ß-cell mass and function. Several mechanisms such as defects in pancreatic angiogenesis and innervation, or modification of parental imprinting, may be implicated, acting either independently or in combination.
Conclusion: Thus, fetal exposure to maternal diabetes may contribute to the worldwide diabetes epidemic. Public health interventions targeting high-risk populations should focus on long-term follow-up of subjects who have been exposed in utero to a diabetic environment and on a better glycemic control during pregnancy.
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Introduction |
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TopAbstractIntroductionEpidemiological StudiesMetabolic Defects Associated...Potential Cellular and Molecular...Conclusion and Clinical...References |
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We will review epidemiological studies that addressed the association between fetal exposure to diabetes and altered glucose homeostasis in offspring. Then, we will discuss the metabolic defects that would underlie this association, and focus on their possible cellular and molecular mechanisms.
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Epidemiological Studies |
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Most of these studies are retrospective and rely on questionnaires. For example, Alcolado and Alcolado (15) in the United Kingdom and Thomas et al. (16) in France showed that individuals with T2D have approximately twice as many mothers as fathers with diabetes. The prospective Framingham Offspring Study, in which all offspring and parents were formally tested for diabetes, demonstrated that the risk of impaired glucose tolerance (IGT) or T2D was greater in offspring of mothers with early diabetes onset (<50 yr) (odds ratio 
9), suggesting the role of fetal environment (17).
Fetal exposure to T2D, as an environmental factor contributing to the maternal transmission of T2D, was first demonstrated in Pima Indians, a population with the highest worldwide prevalence of T2D (18, 19). Offspring of type 2 diabetic mothers had a greater frequency of diabetes compared with those of type 2 diabetic fathers (5, 20). At age 20–24 yr, 45% of individuals whose mothers were diabetic during pregnancy developed diabetes compared with 9% of subjects for whom the mothers became diabetic after pregnancy (5). At the age of 25–34 yr, the prevalence of diabetes reached 70% in offspring with prenatal exposure to diabetes compared with less than 15% in offspring of nondiabetic mothers (21). Third trimester 2-h glucose during oral glucose tolerance test was associated with risk of T2D in offspring, even for normal glucose-tolerant mothers (22), suggesting that a greater risk of T2D is already present in offspring exposed to mildly increased blood glucose levels.
The prevalence of obesity was also higher in offspring exposed in utero to maternal diabetes. At 15–19 yr of age, 58% of the offspring of diabetic mothers weighed 140% or more of their desirable weight, as compared with 17% of the offspring of nondiabetic women (23).
The effects of fetal exposure to diabetes may be confounded by genetic factors. Mothers who had T2D before or during pregnancy have, by definition, early onset diabetes. Therefore, they may carry more or major T2D susceptibility genes, which are transmitted to their offspring. To determine the role of the intrauterine diabetic environment per se, the prevalence of diabetes was compared in Pima nuclear families in which at least one sibling was born before and after the mother was diagnosed with T2D. Offspring born after their mother displayed diabetes had a 3.7-fold higher risk of diabetes and a higher body mass index (BMI) than their full siblings born before their mother developed diabetes (24). These findings indicate that intrauterine exposure to a diabetic environment increases risk of obesity and T2D beyond that attributable to genetic factors, at least in Pima Indians.
In Caucasians, offspring whose mothers had pregestational diabetes (type 1 or 2) or gestational diabetes had a higher frequency of IGT. The prevalence of IGT rose from 9.4% at 1–4 yr to 17.4% at 5–9 yr in offspring of pregestational diabetic mothers, and rose from 11.1% to 20.0% in offspring of mothers who developed diabetes during pregnancy (25). In a cohort of older children (10–16 yr) from heterogeneous ethnic groups, offspring of diabetic mothers with pregestational diabetes (mostly with type 1 diabetes) or gestational diabetes had a 36% prevalence of IGT (26, 27). They had higher BMI than offspring of nondiabetic mothers. IGT offspring were even heavier. Because the genetic impact of different phenotypes of diabetes was not accounted for, it is difficult to distinguish what is attributable to intrauterine environment.
More recently, based on BMI and plasma concentrations of glucose and insulin during oral glucose tolerance test, Weiss et al. (28) estimated the relative risk of developing T2D in offspring of Caucasian type 1 diabetic mothers to be 3.2. However, to the best of our knowledge, there are no data on the prevalence of T2D in adult offspring of type 1 diabetic mothers.
Altogether, these findings suggest that fetal exposure to maternal diabetes is associated with abnormal glucose homeostasis in offspring and may participate in the excess of maternal transmission in T2D.
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Metabolic Defects Associated with Fetal Exposure to Maternal Diabetes |
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Human studies
Two studies in Caucasian populations reported that the occurrence of IGT in offspring exposed to intrauterine diabetic environment results from decreased insulin action based on a high insulin-to-glucose ratio at fasting and after the oral glucose challenge (25, 26).
However, fetal exposure to maternal type 1 diabetes was not associated with reduced insulin sensitivity in offspring aged 5–10 yr when using frequently sampled iv glucose tolerance test (minimal model) (30). Offspring of type 2 diabetic mothers tended to have decreased insulin action, but they were heavier compared with offspring of healthy mothers (30).
In adult Pima Indians with normal glucose tolerance, who had been exposed to an intrauterine diabetic environment, acute insulin response to iv glucose was reduced in offspring of mothers who were diabetic before pregnancy compared with offspring whose mothers developed diabetes after pregnancy (31). Body fat (absorptiometry) and insulin sensitivity measured by the gold standard euglycemic hyperinsulinemic clamp were similar in the two groups of subjects (31). However, in another experiment, acute insulin response was reduced in offspring of parents (mother or father) with early age of onset (<35 yr) of T2D (31), suggesting that a gene linked to early onset diabetes is associated with reduced insulin secretory response to glucose (32).
Therefore, a pregnant type 2 diabetic mother can transmit either genes linked to early onset T2D or acquired abnormalities resulting from fetal exposure to diabetes. To circumvent the confounding effect of genetic factors related to T2D, we recently studied the effect of fetal exposure to type 1 diabetes in adult offspring (mean age 24 yr) free from immunological markers of type 1 diabetes. We observed a 33% prevalence of IGT in offspring of diabetic mothers compared with none in offspring of fathers (control group) (33). Offspring of diabetic mothers had reduced insulin secretion, more pronounced in IGT subjects, but similar fat mass and insulin action compared with offspring of type 1 diabetic fathers (33).
In conclusion, human studies suggest that insulin secretion defect participates in the abnormal glucose tolerance observed in adult offspring exposed to maternal diabetes during fetal life. Insulin secretion may be reduced even in normal glucose-tolerant offspring. Nevertheless, in children and adolescent offspring, insulin resistance involvement was suggested and may be attributable, at least in part, to their higher body weight.
Animal studies
Animal models of hyperglycemia during gestation. Single iv injection of streptozotocin at the beginning of gestation and continuous glucose infusion during the last week of pregnancy are the main approaches used to generate mild or severe hyperglycemia during gestation. Adult offspring develop IGT or mild gestational diabetes (3, 4, 34, 35, 36, 37, 38, 39) with metabolic abnormalities that differ according to the level of hyperglycemia during gestation and the period of life studied.
Mildly hyperglycemic mothers. Mean blood glucose levels were between 6.5 and 9.8 mmol/liter to mimic the levels of women with gestational diabetes. Fetuses presented islet hyperplasia and increased pancreatic and plasma insulin concentrations (37, 40). In vivo and in vitro glucose-stimulated insulin release was increased (40). The resulting enhanced fetal anabolism explains why fetuses are macrosomic. In adulthood, total mass of ß-cells was normal in young animals (34). However, in vivo and in vitro glucose-stimulated insulin secretion was deficient (38, 41) and decreased over time (35). Thus, adult youngsters displayed mild glucose intolerance that worsened with time (35).
Severely hyperglycemic mothers. They were markedly hyperglycemic (>20 mmol/liter). The offspring fetuses and newborns were growth retarded (microsomic). Their islet mass was enhanced (3) related to hyperplasia with degranulated ß-cells, suggesting an overstimulation. Therefore, an early exhaustion of their secretory capacity was a probable cause of the low pancreatic insulin content and low plasma insulin levels at the end of gestation (40, 42). In vitro and in vivo insulin response to glucose was suppressed (37, 40). Immediately after birth, islet mass decreased with a normalization of the granula content, suggesting a restoration of their secretory capacity (3). At adult age, the size of endocrine pancreas was enlarged, and ß-cell mass increased (34). In vitro insulin response to glucose was enhanced (41). These animals had decreased insulin action (3) confirmed by euglycemic hyperinsulinemic clamp (43, 44).
Second and third generation offspring of mild and severely diabetic mothers. Offspring of severely and mildly hyperglycemic mothers (second generation) developed gestational diabetes (4, 34, 39, 43). Their offspring, the third generation, displayed the same disorders as offspring of mildly hyperglycemic mothers: 1) fetuses were macrosomic, hyperinsulinemic with islet hyperplasia; and 2) adults had abnormal glucose tolerance (3, 4) associated with an insulin secretion defect (4). Of note, the male offspring also displayed a disturbed glucose tolerance but did not transmit it to their offspring (3).
Goto Kakizaki (GK) rats. The GK rat is a rodent model of nonobese T2D that was produced by selective breeding of individuals with mild glucose intolerance from a nondiabetic Wistar rat colony (45, 46). Offspring of female GK are exposed in utero to mild diabetes throughout gestation. Fetuses have a reduced ß-cell mass associated with a lack of pancreatic reactivity to glucose (47). Thus, maternal mild hyperglycemia may contribute to endocrine pancreas defects in the first offspring generation (46). Offspring of GK females crossed with Wistar males had a more marked hyperglycemia than offspring of Wistar females crossed with GK males, suggesting a higher maternal inheritance (48). However, this conclusion was not confirmed in other studies (49, 50). Recently, Gill-Randall et al. (51) developed an embryo transfer system to examine the relative contribution of genetic factors and intrauterine environment to the later development of diabetes. Offspring from Wistar oocytes reared in hyperglycemic GK mothers were more hyperglycemic at adulthood than offspring from Wistar oocytes transferred back into euglycemic Wistar mothers (51). Thus, in Wistar rats with a low genetic risk of diabetes, exposure to hyperglycemia in utero increases the risk of hyperglycemia in offspring at adult age (51).
Another model. Simmons’ group (52) generated microsomic newborn rats that developed diabetes at middle age (5–6 months), with a phenotype similar to that observed in human T2D consisting of progressive insulin secretion and insulin action dysfunction. Pregnancy prematurely precipitated the development of diabetes in these rats. The pancreatic islets of their offspring exposed to an in utero diabetic environment were normal or enlarged at birth, probably in response to the high glycemic stimulus, but showed either no further significant increase or a subsequent reduction in ß-cell mass over time (53). They were insulin resistant early in life, and glucose homeostasis was progressively impaired over time. Defective insulin secretion was detectable as early as 5 wk of age and was glucose-specific because arginine-stimulated insulin release was preserved (53).
In summary, animal models have shown convincingly that diabetes may be transmitted by intrauterine exposure to maternal hyperglycemia. Intrauterine exposure to mild hyperglycemia is associated with normal weight or macrosomic newborns and IGT at adult age, related to a deficient insulin secretion. In contrast, newborn offspring of severely hyperglycemic mothers are microsomic and display, at adult age, a decreased insulin action. In addition, long-term and persistent effects of gestational diabetes on glucose homeostasis in the offspring may be transmitted through generations.
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Potential Cellular and Molecular Abnormalities Associated with Fetal Exposure to Maternal Diabetes |
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Twenty-five years ago, Freinkel (54) introduced the concept of the fuel-mediated teratogenesis, postulating that fuel of maternal origin might influence fetus development with subsequent long-term effect later in life.
Congenital malformations are more frequent in offspring of diabetic mothers (55). The nature and severity of fetal complications depend on cell differentiation stage at the time the mother develops diabetes (56). At the beginning of gestation, organogenesis may be affected, inducing diabetic embryopathy (open neural tube defect, transposition of great vessels, cardiac, renal, and gastrointestinal malformations) as observed in offspring of pregestational poorly controlled diabetic mothers.
Impaired gene expression in the embryo, resulting from oxidative stress, and consequent apoptosis or disturbed organogenesis, may be a general mechanism to explain diabetic embryopathy (reviewed in Refs. 57 and 58). In fact, maternal hyperglycemia leads to high glucose delivery to embryos. Increased glucose metabolism in embryo cells increases oxidative stress through hexosamine biosynthetic pathway (59) or hypoxia (60). For example, the expression of Pax3 gene, a transcription factor required during neural tube development is inhibited by oxidative stress, leading to neural tube defects.
In contrast to preexisting diabetes, the development of gestational diabetes has not been associated with an increased risk for teratogenesis (55, 61), unless preexisting but undiagnosed T2D is suspected (55, 62).
Reduced organ mass. The first pancreatic endocrine cells are detected around 7–8 wk of human development (63). Islet formation begins at 12 wk and becomes vascularized from the 16th week. Innervation starts around half-gestation, and individual cell types differentiate to synthesize a single pancreatic hormone. Mature islets are achieved by early third trimester and account for about 4% of the total pancreas in the normal human infant at birth. Insulin and glucagon concentrations rise between mid and late gestation and then remain stable until near term. During late gestation, the fetal ß-cells respond readily to changes in the glucose and amino acid levels (reviewed in Ref. 64). Therefore, neuronal and ß-cell defects may be expected for an event occurring during the second half of pregnancy, because this period is critical for the nervous system development, and proliferation/differentiation of endocrine pancreas (reviewed in Ref. 65). In GK rats exposed to hyperglycemia during gestation, Serradas et al. (66) showed reduced IGF-II expression in ß-cells and IGF-II levels in the fetus with decreased ß-cell mass.
Looking at other organs, in contrast with pancreas development, nephrogenesis occurs only during fetal life and stops after birth in humans (67). In animal models, in utero exposure to hyperglycemia was associated with a reduction of the number of nephrons in offspring (68) and alterations of IGF expression and their receptors in fetal kidney (69).
In Pima Indians, diabetic adult offspring of mothers who had diabetes during pregnancy were at increased risk of elevated urinary albumin excretion (70). This suggests that they could have a nephron deficit acquired in utero because nephron deficit acquired in utero may influence the rate of progression of renal disease in adults (71) and may favor the development of hypertension later in life (72, 73).
Altered angiogenesis. Pancreatic development and its angiogenesis are tightly linked. Blood vessel endothelium is essential for cell differentiation and pancreatic morphogenesis through signaling molecules, and endothelial cells induce islet formation (74, 75). Newly formed islets express high levels of vascular endothelial growth factors (VEGFs). Through a paracrine signaling, VEGF seems to regulate proliferation and differentiation of vascular endothelium to form blood vessels of pancreatic islets (76). Therefore, endothelial and endocrine cells may codevelop as a result of mutual signaling events between them. Therefore, a reduced angiogenesis linked to hyperglycemia may be a mechanism of reduced pancreatic growth, because the vascular system is critical for normal organogenesis.
In chicken chorioallantoic membrane, a model of active neoangiogenesis, hyperglycemia induced defects of angiogenesis through a direct decreased proliferation and increased apoptosis of endothelial cells (77). In mice, embryos from a diabetic mother or embryos cultured in a diabetic milieu showed impaired angiogenesis (78, 79). The major vascular growth factor VEGF is regulated by glucose. However, a direct effect of hyperglycemia on VEGF expression remains unproved. In experimental models of impaired angiogenesis, VEGF expression was decreased (79) or not affected (77) by hyperglycemia.
Fetal hyperinsulinism. Increased amniotic-fluid insulin levels were associated with the risk of IGT and overweight in offspring exposed to maternal diabetes during pregnancy (26, 28). Animal studies also showed high insulin levels in fetuses and newborns exposed in utero to maternal diabetes (see Animal studies).
By inducing abnormal hypothalamic development, fetal hyperinsulinism may explain obesity and hyperinsulinism of subjects exposed in utero to maternal diabetes. Dysplasia of the ventromedial hypothalamic nucleus, an area known to inhibit food intake and insulin secretion via sympathetic tone, was observed in offspring of gestational diabetic rats and is suggested to be induced by fetal hyperinsulinemia in the perinatal period (80). This abnormality persists in adulthood and can be prevented by normalization of maternal glycemia with islet transplantation before the last third of gestation (81, 82). Newborn rats that were rendered hyperinsulinemic by sc insulin injection or that received insulin directly in the ventromedial hypothalamic area displayed at adult age hyperphagia, obesity, abnormal glucose tolerance, and persistent hyperinsulinemia (review in Ref. 83).
The chronically hyperinsulinemic fetal rhesus monkey model has been used to dissociate fetal hyperinsulinemia from maternal hyperglycemia. Insulin was directly injected in fetal sc tissue during the last 18 d of gestation in normoglycemic females using an implantable minipump (84, 85). Offspring exhibited reduced insulin secretion in the neonatal period and during the first 5 months of life, which was not observed at 3 yr of age.
These experimental data strongly support that fetal hyperinsulinism induces long-term metabolic effects, which seems however different among species.
The concept of metabolic programming
Alteration of intrauterine and postnatal environment predisposes to the development of disorders and diseases later in life that may result from "programming", whereby a stimulus or an insult at a critical and sensitive period of early life permanently alters the organism’s physiology and metabolism. Programming may be induced by nutritional, metabolic, and hormonal events (83) and is designated as nutritional programming (86), fetal programming (87), or metabolic imprinting (2). Earlier, Dörner et al. (6) suggested the possibility of an epigenetic mode of diabetes transmission mediated by the mother. The potential mechanisms described above, such as reduced organ mass, angiogenesis defect, and hyperinsulinism, may reflect how the fetus exposed to maternal diabetes is "programmed" to display abnormal glucose tolerance later in life.
Direct evidence for the molecular mechanism responsible for programming abnormal glucose tolerance in offspring of diabetic mothers is not available. Epigenetic mechanisms such as genomic imprinting may contribute to programming. Although most genes are expressed from both parental loci simultaneously, some only expressed from either the maternal or the paternal allele are called parental imprinting genes. Most imprinted genes act during fetal development, making them plausible candidates for fetal programming (88). Epigenetic modifications are induced by environmental factors and affect DNA structure/function rather than sequence. The preferential activation of genes inherited from either the mother or father could be influenced by intrauterine environment (88).
Fetal growth is largely controlled by the complex insulin/IGF system which involves several imprinted genes in rodents and humans. For example, IGF-II gene is paternally expressed (i.e. maternally imprinted) (89) and is under the control of the neighboring maternally expressed (i.e. paternally imprinted) H19 gene (90). Insulin gene, which has a role in the early fetal growth, is also under imprinting regulation in humans (91). In rodents, IGF-II receptor gene is maternally expressed and may control fetal growth either directly or by modifications of the bioavailability of IGF-II protein (92). Whether these imprinted genes are affected by intrauterine exposure to maternal diabetes needs to be investigated.
An example of disorder of two maternally imprinted genes in a locus localized on chromosome 6 with methylation defect, ZAC (zinc finger protein that regulates apoptosis and cell cycle arrest) and HYMAI (hydatiform mole-associated and imprinted transcript), has been suggested in humans (93, 94) and the transgenic mice model (95) with transient neonatal diabetes. In the mice model there was a marked decrease in ß-cell number (95). Affected adult animals (95) and human teenagers (93) developed T2D with insulin secretory dysfunction. Therefore, one can postulate that modifications of DNA methylation in specific cells are transmitted to daughter cells by replication.
Changes in gene expression by epigenetic process are not restricted to imprinted genes (88), and we cannot exclude that transcriptional factors involved in pancreas development, e.g. HNF1
(96) or insulin-secretion-related genes such as Kir6.2 (97) or glucokinase (98) genes may be affected.
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Conclusion and Clinical Implications |
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TopAbstractIntroductionEpidemiological StudiesMetabolic Defects Associated...Potential Cellular and Molecular...Conclusion and Clinical...References |
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Although intrauterine exposure to T2D is associated with a higher prevalence of T2D in adult offspring, this has not been demonstrated for exposure to type 1 diabetes. However, considering the high prevalence of IGT in offspring of type 1 diabetic mothers, an increased prevalence of T2D can be anticipated. This has never been reported, probably due to the fact that 40 yr ago, type 1 diabetic women had very few children (99). Therefore, large-scale epidemiological studies are needed in offspring of type 1 diabetic mothers.
The predisposing effect of intrauterine exposure to a diabetic environment has major public health implications in the present context of the growing diabetes epidemic along with the tendency to develop diabetes at younger ages, by inducing a vicious circle (Fig. 1
).
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Because subjects exposed to a hyperglycemic intrauterine environment display impaired insulin secretion, it is of importance to prevent them from developing insulin resistance. More than another population, they would benefit from prevention of obesity. It also seems worthwhile to set up long-term follow-up of subjects exposed to a diabetic environment in utero with the aim to detect glucose intolerance early.
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Acknowledgments |
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Footnotes |
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Disclosure statement: The authors have nothing to disclose.
First Published Online July 18, 2006
Abbreviations: BMI, Body mass index; GK, Goto Kakizaki; IGT, impaired glucose tolerance; T2D, type 2 diabetes; VEGF, vascular endothelial growth factor.
Received March 21, 2006.
Accepted July 11, 2006.
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References |
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