consequences of fetal exposure to maternal diabetes in offspring

REVIEW: Consequences of Fetal Exposure to MaternalDiabetes in Offspring

Lila-Sabrina Fetita, Eugene Sobngwi, Patricia Serradas, Fabien Calvo, and Jean-Francois Gautier

Assistance Publique-Hopitaux de Paris (L.-S.F., E.S., J.-F.G.), Department of Endocrinology and Diabetes, Saint-LouisHospital, University Paris 7, 75475 Paris Cedex 10, France; Institut National de la Sante et de la Recherche Medicale Unite671 (E.S., J.-F.G.), Cordelier Institute of Biomedical Research, 75270 Paris Cedex 06, France; Institut National de la Santeet de la Recherche Medicale CIC9504 (L.-S.F., E.S., F.C., J.-F.G.), University Paris 7, Assistance Publique-Hopitaux deParis, Saint-Louis Hospital, 75475 Paris Cedex 10, France; Centre National de la Recherche Scientifique Unite Mixte deRecherche 7059 (P.S.), Laboratory of Nutrition Physiopathology, University Paris 7, 75005 Paris, France; and School ofPopulation and Health Sciences (E.S.), Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne NE1 7RU,United Kingdom

Context: Type 2 diabetes is the result of both genetic and environ-mental factors. Fetal exposure to maternal diabetes is associated witha higher risk of abnormal glucose homeostasis in offspring beyondthat attributable to genetic factors, and therefore, may participate inthe excess of maternal transmission of type 2 diabetes.

Evidence acquisition: A MEDLINE search covered the period from1960–2005.

Evidence synthesis: Human studies performed in children and ad-olescents suggest that offspring who had been exposed to maternaldiabetes during fetal life exhibit higher prevalence of impaired glu-cose tolerance and markers of insulin resistance. Recent studies thatdirectly measured insulin sensitivity and insulin secretion haveshown an insulin secretory defect even in the absence of impairedglucose tolerance in adult offspring. In animal models, exposure to a

hyperglycemic intrauterine environment also led to the impairmentof glucose tolerance in the adult offspring. These metabolic abnor-malities were transmitted to the next generations, suggesting that inutero exposure to maternal diabetes has an epigenetic impact. At thecellular level, some findings suggest an impaired pancreatic �-cellmass and function. Several mechanisms such as defects in pancreaticangiogenesis and innervation, or modification of parental imprinting,may be implicated, acting either independently or in combination.

Conclusion: Thus, fetal exposure to maternal diabetes may contrib-ute to the worldwide diabetes epidemic. Public health interventionstargeting high-risk populations should focus on long-term follow-upof subjects who have been exposed in utero to a diabetic environmentand on a better glycemic control during pregnancy. (J Clin Endo-crinol Metab 91: 3718–3724, 2006)

TYPE 2 DIABETES (T2D) is increasing in epidemic pro-portions worldwide, resulting from the combination of

genetic and environmental factors. The aging population,postnatal environmental factors, and prenatal environmentalfactors are possible causes of this epidemic. The role of anabnormal fetal environment in the development of T2D inadult life is suggested by an excess of maternal transmissionof T2D (reviewed in Ref. 1). Data from human epidemio-logical studies and animal models suggest that perinatalnutrition affects predisposition to adult obesity, cardiovas-cular disease, hypertension, and T2D (reviewed in Ref. 2),and there are strong arguments showing that diabetes duringpregnancy predisposes offspring to develop obesity and ab-normal glucose tolerance later in life independently fromgenetic transmission. Moreover, these alterations can betransmitted from one generation to another as observed inanimals (3, 4), therefore initiating a vicious cycle (5), whichmay thus contribute to the dramatic increase in T2D.

We will review epidemiological studies that addressed the

association between fetal exposure to diabetes and alteredglucose homeostasis in offspring. Then, we will discuss themetabolic defects that would underlie this association, andfocus on their possible cellular and molecular mechanisms.

Epidemiological Studies

The role of maternal inheritance in T2D was first suggestedby epidemiological studies. Adults with T2D had a higherprevalence of T2D on the maternal side compared with thepaternal side (6, 7). In patients with gestational diabetes, ahigher frequency of diabetes history was also reported in themothers than in the fathers (8, 9). The maternal influence inthe development of T2D was later reported in a majority ofstudies (reviewed in Ref. 1). Although some studies did notfind a maternal effect, none reported a higher paternal trans-mission (10–14).

Most of these studies are retrospective and rely on ques-tionnaires. For example, Alcolado and Alcolado (15) in theUnited Kingdom and Thomas et al. (16) in France showedthat individuals with T2D have approximately twice as manymothers as fathers with diabetes. The prospective Framing-ham Offspring Study, in which all offspring and parentswere formally tested for diabetes, demonstrated that the riskof impaired glucose tolerance (IGT) or T2D was greater inoffspring of mothers with early diabetes onset (�50 yr) (oddsratio �9), suggesting the role of fetal environment (17).

First Published Online July 18, 2006Abbreviations: BMI, Body mass index; GK, Goto Kakizaki; IGT, im-

paired glucose tolerance; T2D, type 2 diabetes; VEGF, vascular endo-thelial growth factor.JCEM is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the en-docrine community.

0021-972X/06/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 91(10):3718–3724Printed in U.S.A. Copyright © 2006 by The Endocrine Society

doi: 10.1210/jc.2006-0624

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The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 26 June 2014. at 05:17 For personal use only. No other uses without permission. . All rights reserved.

Fetal exposure to T2D, as an environmental factor contrib-uting to the maternal transmission of T2D, was first demon-strated in Pima Indians, a population with the highest world-wide prevalence of T2D (18, 19). Offspring of type 2 diabeticmothers had a greater frequency of diabetes compared withthose of type 2 diabetic fathers (5, 20). At age 20–24 yr, 45% ofindividuals whose mothers were diabetic during pregnancydeveloped diabetes compared with 9% of subjects for whom themothers became diabetic after pregnancy (5). At the age of25–34 yr, the prevalence of diabetes reached 70% in offspringwith prenatal exposure to diabetes compared with less than15% in offspring of nondiabetic mothers (21). Third trimester2-h glucose during oral glucose tolerance test was associatedwith risk of T2D in offspring, even for normal glucose-tolerantmothers (22), suggesting that a greater risk of T2D is alreadypresent in offspring exposed to mildly increased blood glucoselevels.

The prevalence of obesity was also higher in offspringexposed in utero to maternal diabetes. At 15–19 yr of age, 58%of the offspring of diabetic mothers weighed 140% or moreof their desirable weight, as compared with 17% of the off-spring of nondiabetic women (23).

The effects of fetal exposure to diabetes may be con-founded by genetic factors. Mothers who had T2D before orduring pregnancy have, by definition, early onset diabetes.Therefore, they may carry more or major T2D susceptibilitygenes, which are transmitted to their offspring. To determinethe role of the intrauterine diabetic environment per se, theprevalence of diabetes was compared in Pima nuclear fam-ilies in which at least one sibling was born before and afterthe mother was diagnosed with T2D. Offspring born aftertheir mother displayed diabetes had a 3.7-fold higher risk ofdiabetes and a higher body mass index (BMI) than their fullsiblings born before their mother developed diabetes (24).These findings indicate that intrauterine exposure to a dia-betic environment increases risk of obesity and T2D beyondthat attributable to genetic factors, at least in Pima Indians.

In Caucasians, offspring whose mothers had pregestationaldiabetes (type 1 or 2) or gestational diabetes had a higher fre-quency of IGT. The prevalence of IGT rose from 9.4% at 1–4 yrto 17.4% at 5–9 yr in offspring of pregestational diabetic moth-ers, and rose from 11.1% to 20.0% in offspring of mothers whodeveloped diabetes during pregnancy (25). In a cohort of olderchildren (10–16 yr) from heterogeneous ethnic groups, off-spring of diabetic mothers with pregestational diabetes (mostlywith type 1 diabetes) or gestational diabetes had a 36% prev-alence of IGT (26, 27). They had higher BMI than offspring ofnondiabetic mothers. IGT offspring were even heavier. Becausethe genetic impact of different phenotypes of diabetes was notaccounted for, it is difficult to distinguish what is attributableto intrauterine environment.

More recently, based on BMI and plasma concentrations ofglucose and insulin during oral glucose tolerance test, Weiss etal. (28) estimated the relative risk of developing T2D in offspringof Caucasian type 1 diabetic mothers to be 3.2. However, to thebest of our knowledge, there are no data on the prevalence ofT2D in adult offspring of type 1 diabetic mothers.

Altogether, these findings suggest that fetal exposure tomaternal diabetes is associated with abnormal glucose ho-

meostasis in offspring and may participate in the excess ofmaternal transmission in T2D.

Metabolic Defects Associated with Fetal Exposure toMaternal Diabetes

Insulin resistance and insulin secretion, the metabolic pre-dictors of further development of T2D (29), have been in-vestigated in offspring of diabetic mothers in humans and inanimal models using various methods.

Human studies

Two studies in Caucasian populations reported that theoccurrence of IGT in offspring exposed to intrauterine dia-betic environment results from decreased insulin actionbased on a high insulin-to-glucose ratio at fasting and afterthe oral glucose challenge (25, 26).

However, fetal exposure to maternal type 1 diabetes was notassociated with reduced insulin sensitivity in offspring aged5–10 yr when using frequently sampled iv glucose tolerance test(minimal model) (30). Offspring of type 2 diabetic motherstended to have decreased insulin action, but they were heaviercompared with offspring of healthy mothers (30).

In adult Pima Indians with normal glucose tolerance, whohad been exposed to an intrauterine diabetic environment,acute insulin response to iv glucose was reduced in offspringof mothers who were diabetic before pregnancy comparedwith offspring whose mothers developed diabetes after preg-nancy (31). Body fat (absorptiometry) and insulin sensitivitymeasured by the gold standard euglycemic hyperinsuline-mic clamp were similar in the two groups of subjects (31).However, in another experiment, acute insulin response wasreduced in offspring of parents (mother or father) with earlyage of onset (�35 yr) of T2D (31), suggesting that a genelinked to early onset diabetes is associated with reducedinsulin secretory response to glucose (32).

Therefore, a pregnant type 2 diabetic mother can transmiteither genes linked to early onset T2D or acquired abnormalitiesresulting from fetal exposure to diabetes. To circumvent theconfounding effect of genetic factors related to T2D, we recentlystudied the effect of fetal exposure to type 1 diabetes in adultoffspring (mean age 24 yr) free from immunological markers oftype 1 diabetes. We observed a 33% prevalence of IGT in off-spring of diabetic mothers compared with none in offspring offathers (control group) (33). Offspring of diabetic mothers hadreduced insulin secretion, more pronounced in IGT subjects,but similar fat mass and insulin action compared with offspringof type 1 diabetic fathers (33).

In conclusion, human studies suggest that insulin secre-tion defect participates in the abnormal glucose toleranceobserved in adult offspring exposed to maternal diabetesduring fetal life. Insulin secretion may be reduced even innormal glucose-tolerant offspring. Nevertheless, in childrenand adolescent offspring, insulin resistance involvement wassuggested and may be attributable, at least in part, to theirhigher body weight.

Animal studies

Animal models of hyperglycemia during gestation. Single iv in-jection of streptozotocin at the beginning of gestation and

Fetita et al. • Fetal Exposure to Maternal Diabetes J Clin Endocrinol Metab, October 2006, 91(10):3718–3724 3719


continuous glucose infusion during the last week of preg-nancy are the main approaches used to generate mild orsevere hyperglycemia during gestation. Adult offspring de-velop IGT or mild gestational diabetes (3, 4, 34–39) withmetabolic abnormalities that differ according to the level ofhyperglycemia during gestation and the period of lifestudied.

Mildly hyperglycemic mothers. Mean blood glucose levelswere between 6.5 and 9.8 mmol/liter to mimic the levels ofwomen with gestational diabetes. Fetuses presented islethyperplasia and increased pancreatic and plasma insulinconcentrations (37, 40). In vivo and in vitro glucose-stimulatedinsulin release was increased (40). The resulting enhancedfetal anabolism explains why fetuses are macrosomic. Inadulthood, total mass of �-cells was normal in young animals(34). However, in vivo and in vitro glucose-stimulated insulinsecretion was deficient (38, 41) and decreased over time (35).Thus, adult youngsters displayed mild glucose intolerancethat worsened with time (35).

Severely hyperglycemic mothers. They were markedly hy-perglycemic (�20 mmol/liter). The offspring fetuses andnewborns were growth retarded (microsomic). Their isletmass was enhanced (3) related to hyperplasia with degranu-lated �-cells, suggesting an overstimulation. Therefore, anearly exhaustion of their secretory capacity was a probablecause of the low pancreatic insulin content and low plasmainsulin levels at the end of gestation (40, 42). In vitro and invivo insulin response to glucose was suppressed (37, 40).Immediately after birth, islet mass decreased with a normal-ization of the granula content, suggesting a restoration oftheir secretory capacity (3). At adult age, the size of endocrinepancreas was enlarged, and �-cell mass increased (34). Invitro insulin response to glucose was enhanced (41). Theseanimals had decreased insulin action (3) confirmed by eu-glycemic hyperinsulinemic clamp (43, 44).

Second and third generation offspring of mild and severelydiabetic mothers. Offspring of severely and mildly hypergly-cemic mothers (second generation) developed gestationaldiabetes (4, 34, 39, 43). Their offspring, the third generation,displayed the same disorders as offspring of mildly hyper-glycemic mothers: 1) fetuses were macrosomic, hyperinsu-linemic with islet hyperplasia; and 2) adults had abnormalglucose tolerance (3, 4) associated with an insulin secretiondefect (4). Of note, the male offspring also displayed a dis-turbed glucose tolerance but did not transmit it to theiroffspring (3).

Goto Kakizaki (GK) rats. The GK rat is a rodent model ofnonobese T2D that was produced by selective breeding ofindividuals with mild glucose intolerance from a nondiabeticWistar rat colony (45, 46). Offspring of female GK are ex-posed in utero to mild diabetes throughout gestation. Fetuseshave a reduced �-cell mass associated with a lack of pan-creatic reactivity to glucose (47). Thus, maternal mild hy-perglycemia may contribute to endocrine pancreas defects inthe first offspring generation (46). Offspring of GK femalescrossed with Wistar males had a more marked hyperglyce-mia than offspring of Wistar females crossed with GK males,

suggesting a higher maternal inheritance (48). However, thisconclusion was not confirmed in other studies (49, 50). Re-cently, Gill-Randall et al. (51) developed an embryo transfersystem to examine the relative contribution of genetic factorsand intrauterine environment to the later development ofdiabetes. Offspring from Wistar oocytes reared in hypergly-cemic GK mothers were more hyperglycemic at adulthoodthan offspring from Wistar oocytes transferred back intoeuglycemic Wistar mothers (51). Thus, in Wistar rats with alow genetic risk of diabetes, exposure to hyperglycemia inutero increases the risk of hyperglycemia in offspring at adultage (51).

Another model. Simmons’ group (52) generated microsomicnewborn rats that developed diabetes at middle age (5–6months), with a phenotype similar to that observed in humanT2D consisting of progressive insulin secretion and insulinaction dysfunction. Pregnancy prematurely precipitated thedevelopment of diabetes in these rats. The pancreatic isletsof their offspring exposed to an in utero diabetic environmentwere normal or enlarged at birth, probably in response to thehigh glycemic stimulus, but showed either no further sig-nificant increase or a subsequent reduction in �-cell massover time (53). They were insulin resistant early in life, andglucose homeostasis was progressively impaired over time.Defective insulin secretion was detectable as early as 5 wk ofage and was glucose-specific because arginine-stimulatedinsulin release was preserved (53).

In summary, animal models have shown convincingly thatdiabetes may be transmitted by intrauterine exposure tomaternal hyperglycemia. Intrauterine exposure to mild hy-perglycemia is associated with normal weight or macrosomicnewborns and IGT at adult age, related to a deficient insulinsecretion. In contrast, newborn offspring of severely hyper-glycemic mothers are microsomic and display, at adult age,a decreased insulin action. In addition, long-term and per-sistent effects of gestational diabetes on glucose homeostasisin the offspring may be transmitted through generations.

Potential Cellular and Molecular AbnormalitiesAssociated with Fetal Exposure to Maternal DiabetesAbnormal organ development in offspring exposed to adiabetic intrauterine environment

Twenty-five years ago, Freinkel (54) introduced the con-cept of the fuel-mediated teratogenesis, postulating that fuelof maternal origin might influence fetus development withsubsequent long-term effect later in life.

Congenital malformations are more frequent in offspringof diabetic mothers (55). The nature and severity of fetalcomplications depend on cell differentiation stage at the timethe mother develops diabetes (56). At the beginning of ges-tation, organogenesis may be affected, inducing diabetic em-bryopathy (open neural tube defect, transposition of greatvessels, cardiac, renal, and gastrointestinal malformations)as observed in offspring of pregestational poorly controlleddiabetic mothers.

Impaired gene expression in the embryo, resulting fromoxidative stress, and consequent apoptosis or disturbed or-ganogenesis, may be a general mechanism to explain diabetic

3720 J Clin Endocrinol Metab, October 2006, 91(10):3718–3724 Fetita et al. • Fetal Exposure to Maternal Diabetes


embryopathy (reviewed in Refs. 57 and 58). In fact, maternalhyperglycemia leads to high glucose delivery to embryos. In-creased glucose metabolism in embryo cells increases oxidativestress through hexosamine biosynthetic pathway (59) or hyp-oxia (60). For example, the expression of Pax3 gene, a tran-scription factor required during neural tube development isinhibited by oxidative stress, leading to neural tube defects.

In contrast to preexisting diabetes, the development ofgestational diabetes has not been associated with an in-creased risk for teratogenesis (55, 61), unless preexisting butundiagnosed T2D is suspected (55, 62).

Reduced organ mass. The first pancreatic endocrine cells aredetected around 7–8 wk of human development (63). Isletformation begins at 12 wk and becomes vascularized fromthe 16th week. Innervation starts around half-gestation, andindividual cell types differentiate to synthesize a single pan-creatic hormone. Mature islets are achieved by early thirdtrimester and account for about 4% of the total pancreas inthe normal human infant at birth. Insulin and glucagon con-centrations rise between mid and late gestation and thenremain stable until near term. During late gestation, the fetal�-cells respond readily to changes in the glucose and aminoacid levels (reviewed in Ref. 64). Therefore, neuronal and�-cell defects may be expected for an event occurring duringthe second half of pregnancy, because this period is criticalfor the nervous system development, and proliferation/dif-ferentiation of endocrine pancreas (reviewed in Ref. 65). InGK rats exposed to hyperglycemia during gestation, Serra-das et al. (66) showed reduced IGF-II expression in �-cells andIGF-II levels in the fetus with decreased �-cell mass.

Looking at other organs, in contrast with pancreas devel-opment, nephrogenesis occurs only during fetal life andstops after birth in humans (67). In animal models, in uteroexposure to hyperglycemia was associated with a reductionof the number of nephrons in offspring (68) and alterationsof IGF expression and their receptors in fetal kidney (69).

In Pima Indians, diabetic adult offspring of mothers whohad diabetes during pregnancy were at increased risk ofelevated urinary albumin excretion (70). This suggests thatthey could have a nephron deficit acquired in utero becausenephron deficit acquired in utero may influence the rate ofprogression of renal disease in adults (71) and may favor thedevelopment of hypertension later in life (72, 73).

Altered angiogenesis. Pancreatic development and its angio-genesis are tightly linked. Blood vessel endothelium is es-sential for cell differentiation and pancreatic morphogenesisthrough signaling molecules, and endothelial cells induceislet formation (74, 75). Newly formed islets express highlevels of vascular endothelial growth factors (VEGFs).Through a paracrine signaling, VEGF seems to regulate pro-liferation and differentiation of vascular endothelium toform blood vessels of pancreatic islets (76). Therefore, en-dothelial and endocrine cells may codevelop as a result ofmutual signaling events between them. Therefore, a reducedangiogenesis linked to hyperglycemia may be a mechanismof reduced pancreatic growth, because the vascular systemis critical for normal organogenesis.

In chicken chorioallantoic membrane, a model of active

neoangiogenesis, hyperglycemia induced defects of angio-genesis through a direct decreased proliferation and in-creased apoptosis of endothelial cells (77). In mice, embryosfrom a diabetic mother or embryos cultured in a diabeticmilieu showed impaired angiogenesis (78, 79). The majorvascular growth factor VEGF is regulated by glucose. How-ever, a direct effect of hyperglycemia on VEGF expressionremains unproved. In experimental models of impaired an-giogenesis, VEGF expression was decreased (79) or not af-fected (77) by hyperglycemia.

Fetal hyperinsulinism. Increased amniotic-fluid insulin levelswere associated with the risk of IGT and overweight in off-spring exposed to maternal diabetes during pregnancy (26,28). Animal studies also showed high insulin levels in fetusesand newborns exposed in utero to maternal diabetes (seeAnimal studies).

By inducing abnormal hypothalamic development, fetalhyperinsulinism may explain obesity and hyperinsulinism ofsubjects exposed in utero to maternal diabetes. Dysplasia ofthe ventromedial hypothalamic nucleus, an area known toinhibit food intake and insulin secretion via sympathetictone, was observed in offspring of gestational diabetic ratsand is suggested to be induced by fetal hyperinsulinemia inthe perinatal period (80). This abnormality persists in adult-hood and can be prevented by normalization of maternalglycemia with islet transplantation before the last third ofgestation (81, 82). Newborn rats that were rendered hyper-insulinemic by sc insulin injection or that received insulindirectly in the ventromedial hypothalamic area displayed atadult age hyperphagia, obesity, abnormal glucose tolerance,and persistent hyperinsulinemia (review in Ref. 83).

The chronically hyperinsulinemic fetal rhesus monkeymodel has been used to dissociate fetal hyperinsulinemiafrom maternal hyperglycemia. Insulin was directly injectedin fetal sc tissue during the last 18 d of gestation in normo-glycemic females using an implantable minipump (84, 85).Offspring exhibited reduced insulin secretion in the neonatalperiod and during the first 5 months of life, which was notobserved at 3 yr of age.

These experimental data strongly support that fetal hy-perinsulinism induces long-term metabolic effects, whichseems however different among species.

The concept of metabolic programming

Alteration of intrauterine and postnatal environment pre-disposes to the development of disorders and diseases laterin life that may result from “programming”, whereby a stim-ulus or an insult at a critical and sensitive period of early lifepermanently alters the organism’s physiology and metabo-lism. Programming may be induced by nutritional, meta-bolic, and hormonal events (83) and is designated as nutri-tional programming (86), fetal programming (87), ormetabolic imprinting (2). Earlier, Dorner et al. (6) suggestedthe possibility of an epigenetic mode of diabetes transmissionmediated by the mother. The potential mechanisms de-scribed above, such as reduced organ mass, angiogenesisdefect, and hyperinsulinism, may reflect how the fetus ex-posed to maternal diabetes is “programmed” to display ab-normal glucose tolerance later in life.



Direct evidence for the molecular mechanism responsiblefor programming abnormal glucose tolerance in offspring ofdiabetic mothers is not available. Epigenetic mechanismssuch as genomic imprinting may contribute to programming.Although most genes are expressed from both parental locisimultaneously, some only expressed from either the mater-nal or the paternal allele are called parental imprinting genes.Most imprinted genes act during fetal development, makingthem plausible candidates for fetal programming (88). Epi-genetic modifications are induced by environmental factorsand affect DNA structure/function rather than sequence.The preferential activation of genes inherited from either themother or father could be influenced by intrauterine envi-ronment (88).

Fetal growth is largely controlled by the complex insulin/IGF system which involves several imprinted genes in ro-dents and humans. For example, IGF-II gene is paternallyexpressed (i.e. maternally imprinted) (89) and is under thecontrol of the neighboring maternally expressed (i.e. pater-nally imprinted) H19 gene (90). Insulin gene, which has a rolein the early fetal growth, is also under imprinting regulationin humans (91). In rodents, IGF-II receptor gene is maternallyexpressed and may control fetal growth either directly or bymodifications of the bioavailability of IGF-II protein (92).Whether these imprinted genes are affected by intrauterineexposure to maternal diabetes needs to be investigated.

An example of disorder of two maternally imprinted genesin a locus localized on chromosome 6 with methylation de-fect, ZAC (zinc finger protein that regulates apoptosis andcell cycle arrest) and HYMAI (hydatiform mole-associatedand imprinted transcript), has been suggested in humans (93,94) and the transgenic mice model (95) with transient neo-natal diabetes. In the mice model there was a marked de-crease in �-cell number (95). Affected adult animals (95) andhuman teenagers (93) developed T2D with insulin secretorydysfunction. Therefore, one can postulate that modificationsof DNA methylation in specific cells are transmitted todaughter cells by replication.

Changes in gene expression by epigenetic process are notrestricted to imprinted genes (88), and we cannot excludethat transcriptional factors involved in pancreas develop-

ment, e.g. HNF1� (96) or insulin-secretion-related genes suchas Kir6.2 (97) or glucokinase (98) genes may be affected.

Conclusion and Clinical Implications

The data summarized in this review clearly demonstrate thatintrauterine exposure to diabetes is associated with increasedrisk of abnormal glucose homeostasis in offspring beyond thatattributable to genetic factors, and may participate in the excessof maternal transmission for T2D. In humans, this environ-mental factor involves mechanisms that lead to insulin secre-tory defects in adult offspring, although markers of insulinresistance were reported in children. At the cellular level, somefindings suggest a defect in pancreas morphology and function.Decreased �-cell mass, defects of angiogenesis, hyperinsulin-ism, and modification of parental imprinting may be impli-cated, acting independently or in combination.

Although intrauterine exposure to T2D is associated witha higher prevalence of T2D in adult offspring, this has notbeen demonstrated for exposure to type 1 diabetes. However,considering the high prevalence of IGT in offspring of type1 diabetic mothers, an increased prevalence of T2D can beanticipated. This has never been reported, probably due tothe fact that 40 yr ago, type 1 diabetic women had very fewchildren (99). Therefore, large-scale epidemiological studiesare needed in offspring of type 1 diabetic mothers.

The predisposing effect of intrauterine exposure to a di-abetic environment has major public health implications inthe present context of the growing diabetes epidemic alongwith the tendency to develop diabetes at younger ages, byinducing a vicious circle (Fig. 1).

Because organogenesis may be affected by hyperglycemia,a tight glycemic control should be attained before conceptionin patient with preexisting diabetes (100). These goals aresimilar in women with T2D. The intensive glucose controlmaintained throughout pregnancy may contribute to a de-crease in the prevalence of T2D in later life. Other strategiesto prevent T2D or IGT might include early diagnosis ofgestational diabetes, with special attention to women whosemothers had diabetes during pregnancy (101). Thus, an in-tensive glycemic control before conception and throughout

FIG. 1. Potential role of fetal exposureto maternal diabetes in the worldwideT2D epidemic: a vicious circle. The com-bination of insulin resistance with�-cell dysfunction leads to IGT and, con-sequently, to T2D. Offspring exposed inutero to maternal diabetes develop ac-quired �-cell dysfunction, conveying agreater risk to develop IGT and T2Dbeyond that attributable to genetic fac-tors, and therefore, inducing a real vi-cious circle.



pregnancy would break this vicious cycle and decrease theprevalence of T2D in future generations.

Because subjects exposed to a hyperglycemic intrauterineenvironment display impaired insulin secretion, it is of im-portance to prevent them from developing insulin resistance.More than another population, they would benefit from pre-vention of obesity. It also seems worthwhile to set up long-term follow-up of subjects exposed to a diabetic environmentin utero with the aim to detect glucose intolerance early.

Acknowledgments

We warmly thank Prof. Bernard Portha, Prof. Eric Ravussin, Prof.Pascal Ferre, and Dr. Delphine Jaquet for their comments on this review.

Received March 21, 2006. Accepted July 11, 2006.Address all correspondence and requests for reprints to: Jean-Fran-

cois Gautier, Department of Endocrinology and Diabetes, Saint-LouisHospital, 1, Avenue Claude Vellefaux, 75475 Paris Cedex 10, France.E-mail: [email protected].

This work has been supported by the Assistance Publique-Hopitauxde Paris, Association de Langue Francaise pour l’Etude du Diabete et desMaladies Metaboliques, and Association Francaise des Diabetiques.

Disclosure statement: The authors have nothing to disclose.

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