Metabolism

Gestational Diabetes and Insulin Resistance: Role in Short- and

Long-Term Implications for Mother and Fetus1,2
Patrick M. Catalano,*y3 John P. Kirwan,*** Sylvie Haugel-de Mouzonz and Janet Kingzz
*Department of Reproductive Biology, ySchwartz Center for Metabolism and Nutrition, **Department of
Nutrition, Case Western Reserve University School of Medicine at MetroHealth Medical Center,
Cleveland, OH 44109, zDepartment dEndocrinologie, Institute Cochin de Genetique Moleculaire,
Paris, France 75014 and zzUSDA Western Human Nutrition Research Center, University of California,
Davis, CA 95616

ABSTRACT Gestational diabetes and obesity are the common metabolic abnormalities occurring during
pregnancy. Decreased maternal pregravid insulin sensitivity (insulin resistance) coupled with an inadequate insulin
response are the pathophysiological mechanisms underlying the development of gestational diabetes. Insulin-
regulated carbohydrate, lipid and protein metabolism are all affected to a variable degree. Decreased maternal insulin
sensitivity in women with gestational diabetes may increase nutrient availability to the fetus, possibly accounting for
an increased risk of fetal overgrowth and adiposity. Epidemiological studies from Europe show an increased risk of
the insulin resistance syndrome in adults who were low birth weight at delivery. However, in the United States over
the past 20 y there has been a signicant 33% increase in the incidence of type 2 diabetes, which has been
associated with a parallel increase in obesity. All age groups have been affected but the most dramatic increases
have occurred in adolescents. The relationship between decreased maternal insulin sensitivity and fetal overgrowth
particularly in obese women and women with gestational diabetes may help explain the increased incidence of
adolescent obesity and related glucose intolerance in the offspring of these women. In this review, we address 1) the
pathophysiology of gestational diabetes, 2) the changes in maternal insulin sensitivity during pregnancy that effect
maternal accretion of adipose tissue and energy expenditure, 3) the inuence of maternal metabolic environment on
fetal growth, 4) the life-long effect of being born at either extreme of the birth weight continuum and 5 ) micronutrients
and decreased insulin sensitivity during pregnancy. J. Nutr. 133: 1674S1683S, 2003.

KEY WORDS:  insulin resistance  gestational diabetes

In the United States 135,000 women per year develop
gestational diabetes (1). The prevalence of gestational diabetes
increased in developed countries from 2.9% to 8.8% over 20 y,
particularly in populations immigrating from less-developed
areas (2). Furthermore, there is a significant risk of adolescent
obesity and type 2 diabetes in the offspring of these women
(3,4). Given the tremendous increase in the prevalence of
adolescent obesity and type 2 diabetes in the United States over
the past 10 y, the long-term implications for developing
counties are important. As developing areas strive to meet the
1 sensitivity or increased insulin resistance. We define insulin
Manuscript prepared for the USAID-Wellcome Trust workshop on Nutrition
as a preventive strategy against adverse pregnancy outcomes, held at Merton
College, Oxford, July 1819, 2002. The proceedings of this workshop are
published as a supplement to The Journal of Nutrition. The workshop was
sponsored by the United States Agency for International Development and The
Wellcome Trust, UK. USAIDs support came through the cooperative agreement
managed by the International Life Sciences Institute Research Foundation.
Supplement guest editors were Zulqar A. Bhutta, Aga Khan University, Pakistan,
Alan Jackson (Chair), University of Southampton, England, and Pisake Lumbiga-
non, Khon Kaen University, Thailand.
2
Supported by: National Institutes of Health grant #HD22965, P50DH
11089 and General Clinical Research Center grant #MO1RR080.
3
To whom correspondence should be addressed. E-mail: pcatalano@
metrohealth.org.
nutritional demands of women of reproductive age, there is the
potential that the converse problems of macrosomia leading
to adolescent type 2 diabetes and obesity may emerge. In this
review, we concentrate on the role of insulin resistance in the
pathophysiology of gestational diabetes and the implications for
mother and fetus.
Gestational diabetes is carbohydrate intolerance of varied
severity that begins or is first recognized during pregnancy (5).
Insulin may be used for treatment and the condition may persist
after pregnancy. Unrecognized glucose intolerance may have
antedated the pregnancy. The underlying pathophysiology of
gestational diabetes is a function of decreased maternal insulin
resistance as the inability of a defined concentration of insulin
to effect a predictable biological response of nutrient metab-
olism at the level of the target tissue. Insulin resistance as it
relates to glucose metabolism results in decreased glucose up-
take in skeletal muscle, white adipose tissue and liver as well
as decreased suppression of endogenous (primarily hepatic)
glucose production. The manifestation of these abnormalities of
glucose metabolism become clinically evident when beta cell
response is inadequate. Although we primarily relate insulin
resistance to glucose metabolism, other nutrients are also

0022-3166/03 $3.00 2003 American Society for Nutritional Sciences.

1674S
 GESTATIONAL DIABETES IMPLICATIONS
involved. Insulin resistance results in the inability of insulin to
suppress lipolysis, and increased insulin resistance results in
a decreased ability of insulin to suppress amino acid turnover.
Additionally, in women with gestational diabetes, alterations in
nutrient metabolism existed before gestation.
Pathophysiology of gestational diabetes
Glucose metabolism. The pathophysiology of gestational
diabetes involves abnormalities of insulin-sensitive tissue. Beta
cell sensing of glucose is also abnormal and is manifested as an
inadequate insulin response for a given degree of glycemia.
Earlier studies reported that the incidence of islet cell
antibodies in women with gestational diabetes as measured by
immunofluorescence techniques is between 10% and 35% (6).
Recent studies using specific monoclonal antibodies, however,
have found a lower incidence on the order of 12% (7),
suggesting a low risk of type 1 diabetes in women with ges-
tational diabetes. Postpartum studies of women with gestational
diabetes have demonstrated defects in insulin secretory
response and decreased insulin sensitivity (8), indicating
typical type 2 abnormalities in glucose metabolism. The alter-
ations in insulin secretory response and insulin resistance in
women with a previous history of gestational diabetes as com-
pared with a weight-matched control group may differ depend-
ing on whether the women with previous gestational diabetes
are lean or obese. Thus in women with gestational diabetes, the
metabolic stress of pregnancy may unmask a genetic suscep-
tibility to type 2 diabetes.
Significant alterations in glucose metabolism occur in
women who develop gestational diabetes relative to pregnant
women with normal glucose tolerance. Decreased insulin re-
sponse to a glucose challenge was demonstrated by Xiang et al.
(9) in women with gestational diabetes in late gestation. In
longitudinal studies of both lean and obese women with
gestational diabetes, Catalano et al. (10) showed a progressive
decrease in first-phase insulin response in late gestation in lean
women compared with a weight-matched control group (Fig.
1). In contrast, in obese women developing gestational dia-
betes, first-phase insulin response did not change but second-
phase insulin response significantly increased to an intravenous
glucose challenge compared with a weight-matched control
group (Fig. 2) (11). These differences in insulin response may
be related to the ethnicity of the study groups. The studies by
Xiang et al. focused on Latina women whereas our evaluation
was of a white study group. However, we believe that the pri-
FIGURE 1 Longitudinal increase in A) 1st phase (area under the curve from 0 to 5 min) and B) 2nd phase (area under the curve from 5 to 60 min) and
second phase insulin response to an intravenous glucose challenge in lean women with normal glucose tolerance and gestational diabetes, pregravid,
early pregnancy and late pregnancy. Multiply values by 7.175 to convert to pmol/L. Reprinted with permission from reference 10.
1675S
mary reason for the differences in insulin response is the pre-
sence or absence of obesity in our study groups. Although there
is an increase in the metabolic clearance rate of insulin with
advancing gestation, no evidence exists for a difference in in-
sulin clearance between women with normal glucose tolerance
and gestational diabetes (11).
Basal glucose concentrations decrease with advancing ges-
tation in women developing gestational diabetes. In late gesta-
tion, hepatic glucose production was reported by Xiang et al.
(9) to be increased in women with gestational diabetes in com-
parison with a control group whereas no difference was noted in
either fasting glucose concentration or hepatic glucose pro-
duction in the longitudinal studies of Catalano et al. (10,11).
These differences may be population specific and related to the
degree of glucose intolerance. However, to date all reports
indicate that in late gestation, women with gestational diabetes
have increased fasting insulin concentrations (Fig. 3) and less
suppression of hepatic glucose production during insulin
infusion, thereby indicating decreased hepatic insulin sensitiv-
ity in women with gestational diabetes compared with a weight-
matched control group (911). In the studies of Xiang et al. (9),
there was a significant correlation between fasting free fatty
acids and hepatic glucose production, suggesting that free fatty
acids may further contribute to hepatic insulin resistance.
Women with gestational diabetes have decreased insulin
sensitivity in comparison with weight-matched control groups.
Ryan et al. (13) were the first to report a 40% decrease in
insulin sensitivity in women with gestational diabetes in com-
parison with a pregnant control group in late pregnancy using
a euglycemic clamp. Xiang et al. (9), reported that women with
gestational diabetes, who had normal glucose tolerance within
6 mo of delivery, had significantly decreased insulin sensitivity
as estimated by the glucose clearance rate during a hyper-
insulinemic-euglycemic clamp when compared with a matched
control group in late gestation. Catalano et al. (10,11) using
similar techniques described the longitudinal changes in insulin
sensitivity in both lean and obese women developing
gestational diabetes in comparison with a matched control
group. Women developing gestational diabetes had lower
pregravid insulin sensitivity than did the matched control group
(Fig. 4). The differences in insulin sensitivity between the
groups were greatest before and during early gestation and were
less pronounced but still significant by late gestation. Of note,
in Figure 4, there was an increase in insulin sensitivity from the
time before conception through early pregnancy, particularly in
women with the lowest pregravid insulin sensitivity.
1676S SUPPLEMENT
FIGURE 2 Longitudinal increase in A) 1st phase (area under the curve from 0 to 5 min) and B) 2nd phase (area under the curve from 5 to 60 min)
insulin response in obese women with normal glucose tolerance and gestational diabetes, pregravid, early pregnancy and late pregnancy. Multiply values
by 7.175 to convert to pmol/L. Reprinted with permission from reference 11.
Studies in human skeletal muscle and adipose tissue have
demonstrated that postreceptor defects in the insulin signal-
ing cascade are related to decreased insulin sensitivity in
pregnancy. Garvey et al. (14) were the first to demonstrate that
there were no significant differences in the concentration of the
glucose transporter (GLUT 4) responsible for insulin action in
skeletal muscle of pregnant compared with nonpregnant
women despite reduced insulin-timulated glucose transport.
On the basis of studies by Friedman et al. (15) in pregnant
women with normal glucose tolerance and gestational diabetes
as well as a nonpregnant control group, several defects in the
insulin signaling cascade were characterized in late pregnancy.
Additional abnormalities were observed in women with
gestational diabetes. Pregnant women appeared to have
a decrease in insulin receptor substrate-1 expression; its
down-regulation closely parallels the decreased ability of insulin
to induce additional steps in the insulin signaling cascade. This
results in a decrease in insulin-stimulated 2-deoxyglucose
uptake in vitro. In addition to the above mechanisms, women
with gestational diabetes demonstrate a distinct decrease in the
ability of the insulin receptor beta subunit to undergo tyrosine
FIGURE 3 Longitudinal increase in basal or fasting insulin (mU/ml)
in lean and obese women with normal glucose tolerance and gestational
diabetes, pregravid, early pregnancy and late pregnancy. Multiply values
by 7.175 to convert to pmol/L. Reprinted with permission from reference
12.
phosphorylation. This additional defect in the insulin signaling
cascade results in a 25% lower glucose transport activity in
muscle compared with that in nondiabetic pregnant women.
Amino acid metabolism
In addition to glucose, which is the primary energy source of
fetoplacental tissues, accretion of protein is essential for fetal
growth. Nitrogen retention is increased in pregnancy in both
maternal and fetal compartments. It is estimated that there is
a 500-g increase in protein accretion by about 30 wk (16). A
significant decrease occurs in most fasting maternal amino acid
concentrations in early pregnancy before the accretion of
significant maternal or fetal tissue (17). These anticipatory
changes in fasting amino acid metabolism occur after a shorter
period of fasting in comparison with nonpregnant women.
Maternal amino acid concentrations were significantly de-
creased in mothers of small-for-gestational-age neonates
compared with maternal concentrations in appropriate-size
neonates (18).
Protein turnover (i.e., protein synthesis and degradation), is
measured with stable isotopes techniques using specific amino
FIGURE 4 Longitudinal changes in the insulin sensitivity index
(glucose infusion rate adjusted for residual endogenous glucose pro-
duction and insulin concentrations achieved during the glucose clamp) in
lean and obese women with normal glucose tolerance and gestational
diabetes, pregravid, early gestation and late gestation. Reprinted with
permission from reference 12.
 GESTATIONAL DIABETES IMPLICATIONS
acids. Based on a review of various studies, Duggleby and
Jackson (19) estimated that during pregnancy, protein syn-
thesis is similar to that for nonpregnant women in the first
trimester. However, a 15% increase occurs during the second
trimester and a further increase of about 25% occurs in the
third trimester. Additionally, there are marked interindividual
differences at each time that have a strong relationship with
fetal growth; mothers who had increased protein turnover in
midpregnancy had infants who had increased lean body mass
after adjustment for significant covariables (20).
Amino acids can be used either for protein accrual or
oxidized as an energy source. Urea synthesis has been estimated
with the use of using stable isotopes in a number of studies. In
general, there is a modest shift in oxidation in early pregnancy
with an accrual of amino acids for protein synthesis in late
gestation (20). Kalhan et al. (21) reported that there are
significant pregnancy-related adaptations in maternal protein
metabolism early in gestation before any significant increase in
fetal protein accretion. Preliminary studies by Catalano et al.
(22) reported that decreased insulin sensitivity manifested
by a decreased suppression of leucine turnover occurs during
insulin infusion in late gestation in all pregnant women.
Furthermore, there is evidence for an increase in basal leucine
turnover in women with gestational diabetes compared with
a matched control group. Whether these decreases in amino
acid insulin sensitivity are related to decreased whole-body or
liver protein synthesis or increased breakdown are not known.
Lipid metabolism
Although ample literature exists on the changes in glucose
metabolism during gestation, data on the alterations in lipid
metabolism are meager. Darmady and Postle (23) measured
serum cholesterol and triacylglycerol before, during and after
pregnancy in 34 normal women. Both cholesterol and tri-
acylglycerol decreased at approximately 7 wk gestation and
then increased progressively until term. Serum triacylglycerol
decreased postpartum. The decrease was more rapid in women
who breast-fed than in those who bottle fed their infants.
The increase in maternal free fatty acids in late gestation
has been hypothesized to be a mechanism related to the decrease
in maternal glucose insulin sensitivity in late pregnancy. Free
fatty acids have also been associated with fetal overgrowth
particularly of adipose tissue. There is a significant difference in
the arteriovenous free fatty acid concentration at birth much as
there is with arteriovenous glucose concentration. Knopp et al.
(24) reported that neonatal birth weight was positively
correlated with concentrations of triacylglycerol and free fatty
acid, which readily cross the placenta in late pregnancy. Similar
conclusions were reached by Ogburn et al. (25) who using
a pregnant ewe model showed that increased fetal insulin
concentrations suppress free fatty acid concentrations, inhibit
lipolysis and result in increased fat deposition. Kleigman et al.
(26) reported that infants of obese women not only had
increased birth weight and skinfold measurements but increased
serum free fatty acids compared with infants from lean women.
In women with gestational diabetes, Knopp et al. (27) re-
ported that there is an associated increase in triacylglycerol and
decrease in high-density lipoprotein concentration. However,
Montelongo et al. (28) reported little change in free fatty acid
concentrations through all three trimesters after a 12-h fast.
Recently, Koukkou et al. (29) reported an increase in total
triacylglycerol but a lower low-density lipoprotein cholesterol in
women with gestational diabetes. Hyperinsulinemic-euglyce-
mic clamp studies in pregnant women with normal glucose
tolerance (30) and gestational diabetes (31) showed that there
1677S
was a decreased ability of insulin to suppress free fatty acids with
advancing gestation. Insulins ability to suppress plasma free
fatty acid was less in women with gestational diabetes than in
women with normal glucose tolerance (31).
Taken together these studies demonstrate that insulin sen-
sitivity to nutrients decreases in all women with advancing gesta-
tion. These decreases in insulin sensitivity are further enhanced
by the presence of decreased pregravid maternal insulin sensi-
tivity, which becomes manifest in later pregnancy as gestational
diabetes. The result of the decreases in insulin sensitivity is
greater nutrient availability and higher ambient insulin concen-
trations for the developing fetoplacental unit, which may even-
tually result in fetal overgrowth.
Short- and long-term implications of decreased
insulin sensitivity
Fetal and neonatal implications. At birth the human fetus
has a significantly greater amount of body fat, approximately
12%16%, than do other mammalian species. For example,
mice, rats and lambs, which are commonly used in perinatal
metabolic studies, have about 13% body fat at birth.
Influence of parental anthropometrics. Various demo-
graphic parental anthropometric factors have been correlated
with fetal growth (3233). Many of these variables (e.g., ma-
ternal prepregnancy weight or weight gain during pregnancy)
have commonly been thought to be excellent predictors of birth
weight. Although statistically significant, these factors explain
only approximately 2030% of the variance in birth weight.
Maternal nutrition is obviously an important factor in
determining fetal growth. Based on the data from the Dutch
famine of 19441945 (34), the level of energy intake associated
with nutritional deprivation and impaired fetal growth is
approximately ,1500 kcal/d. Deprivation in early gestation is
associated with a higher rate of prematurity and very low birth
weight whereas deprivation in late gestation is associated with
9% lower fetal weight but not length (34). In contrast, Ravelli
et al. (35) reported in the same population, that neonates
exposed to famine in early pregnancy were heavier and longer
than unexposed children at birth. The size of the head as well
as their placentas, however, were smaller. The infants of
the women exposed to the famine in late pregnancy were on
average lighter, shorter and thinner than infants of women not
exposed to famine. Of interest, mothers exposed to famine in
early pregnancy gained more weight than women not exposed
to the famine. In follow-up studies at age 50 y, female infants
exposed to the famine in early pregnancy had increased body
weight, body mass index and waist circumference (36). We
speculate that the increase in maternal weight gain in preg-
nancy and female infant weight gain into adult life may have
resulted from increased maternal nutrient intake in mid to late
gestation possibly resulting in increased fetal adiposity relative
to a control group not exposed to famine. Nutritional sup-
plementation can improve birth weight. Based on studies in
Guatemala (37), the type of supplementation (i.e., protein or
carbohydrate) may not make a difference in the increase in
birth weight if minimal protein requirements are achieved.
Prentice et al. (38) observed a mean increase in birth weight of
225 6 56 g in women in The Gambia who received a dietary
supplement (430 kcal/d). However, this increase only occurred
when food shortages and increased work load resulted in
a negative energy balance.
Maternal anthropometric variables are important factors
related to fetal growth. Maternal pregravid weight is a strong
predictor of birth weight (39). Maternal height is also asso-
ciated with an increase in birth weight, but when maternal
1678S SUPPLEMENT

height is adjusted for weight, there is no longer a significant TABLE 1

correlation between maternal height and birth weight (40).
Maternal weight gain during gestation is also correlated with Stepwise regression analysis for factors affecting fetal
birth weight: r 5 0.26 in nulliparous women and r 5 0.16 in growth and body composition in 183 women with normal
multiparous women (40). The interaction of maternal pre- glucose tolerance
gravid weight and weight gain was examined by Abrams and
Laros (41). They reported that there was a progressively Dependent and
stronger correlation between maternal weight gain and birth independent variables R2 DR2
weight in women who were moderately overweight, had ideal
Birth weight
body weight and were underweight. In women .135% of ideal Estimated gestational age 0.10
weight for height before conception, there was no correlation Maternal weight gain 0.16 0.06
between weight gain during pregnancy and birth weight. The Maternal pregravid weight 0.21 0.05
mean birth weight of the infants of the very obese women was Neonatal sex 0.25 0.04
the greatest in their study population. Parity was shown to have Parity 0.29 0.04
a positive correlation with birth weight. McKeown and Gibson Fat-free mass
Neonatal sex 0.08
(42) reported that when maternal age was adjusted for parity, Estimated gestational age 0.17 0.09
no consistent correlation was seen between maternal age and Maternal weight gain 0.23 0.06
birth weight. Parity was shown by Thompson et al. (33) to be Maternal pregravid weight 0.27 0.04
associated with a 100150-g increase in birth weight in sub- Paternal height 0.30 0.03
sequent pregnancies. However, the additional effect of parity Fat mass
on birth weight is diminished with increasing parity. Parity 0.08
Estimated gestational age 0.12 0.04
Relative to maternal anthropometric factors, paternal Pregravid weight 0.14 0.02
anthropometric factors have a limited effect on fetal birth Maternal weight gain 0.16 0.02
weight. Morton (43) reported that in half-siblings where the Neonatal sex 0.17 0.01
mother was the common parent, the correlation in birth weight
between the half-siblings was r 5 0.58. In contrast, the Reprinted with permission from reference 47.
correlation of birth weight in half-siblings where the father is
the common parent was only r 5 0.10. Crossbreeding studies
support these findings. In the studies by Walton and Hammond unexplained fetal growth restriction had greater insulin sen-
(44), Shetland ponies and Shire horses were crossbred. The size sitivity than did a control group of women whose infants were of
of the foals was roughly the same size as the maternal pure appropriate weight for gestational age. Therefore, increased
breed. A recent study by Klebanoff et al. (45) reported that maternal insulin sensitivity may decrease nutrient availability
paternal birth weight, adult height and adult weight explained to the fetus, resulting in undergrowth.
about 3% of the variance in infant birth weight versus 9% for Life-long effect of extreme birth weights. From studies by
the corresponding maternal factors. Hales et al. (51), low birth weight may affect the life-long
Influence of metabolic environment: role of insulin development of the organism. Environmental stress in utero,
sensitivity. In an effort to improve our understanding of fac- particularly at critical periods of development, may have long-
tors affecting fetal growth, we conducted a series of studies in term effects on metabolic function. In studies of the Hert-
which we estimated neonatal body composition. As noted by fordshire population, low birth weight was a significant risk
Sparks (46), genetic factors may have a stronger relationship
with fat-free body mass whereas in utero environment may
correlate better with fetal fat mass. In a series of metabolic
studies we used anthropometric methods to estimate body TABLE 2
composition in 183 neonates (47). Fat-free mass, which Stepwise regression analysis of factors including maternal
comprised 86% of mean birth weight, accounted for 83% of insulin sensitivity affecting fetal growth and body composition
the variance in birth weight; fat mass, which comprised only
14% of birth weight, accounted for 46% of the variance in in 16 lean women with normal glucose tolerance and
birth weight. Male infants also had significantly greater fat-free gestational diabetes
mass but not fat mass than did female infants (48). Using
independent variables such as maternal height, pregravid Dependent and
independent variables R2 DR2
weight, weight gain during pregnancy, parity, paternal height
and weight, neonatal sex and gestational age, we accounted for Birth weight
29% of the variance in birth weight, 30% of the variance in fat- Insulin sensitivity index (late pregnancy) 0.28
free mass and 17% of the variance in fat mass (Table 1) (48). Maternal weight gain 0.48 0.20
Including estimates of maternal insulin sensitivity in 16 lean Fat-free mass
subjects, increased our ability to explain approximately 50% of Insulin sensitivity index (late pregnancy) 0.33
Maternal weight gain 0.53 0.20
the variance in body composition (Table 2) (49). The strong- Fat mass
est correlation with fetal fat accretion was pregravid mater- Insulin sensitivity (pre gravid) 0.15
nal insulin sensitivity (R2 5 0.15). We speculate that because Parity 0.29 0.14
obese women are in general less insulin sensitive than a normal- Neonatal sex 0.39 0.10
weight population, they have the greatest risk of having a large Insulin sensitivity index (late pregnancy) 0.46 0.07
baby. Kleigman et al. (26) reported that maternal obesity was Placental weight
Insulin sensitivity index (late pregnancy) 0.28
a twofold (15% vs. 8%) greater risk in a woman having a large Neonatal sex 0.50 0.22
infant than in women with diabetes. Studies by Caruso et al. Maternal weight gain 0.58 0.08
(50) corroborated these findings by looking at the opposite end
of the birth-weight spectrum. They reported that women with Reprinted with permission from reference 48.
 GESTATIONAL DIABETES IMPLICATIONS
factor for the development of glucose intolerance at age 64.
The proportion of men with either diabetes or impaired glucose
tolerance fell inversely with increasing birth weight and weight
at age 1. Obesity was not a hallmark of their population al-
though it was an independent risk factor. The authors hypo-
thesized that beta cell development and function may be
impaired because of the nutritional deprivation in utero and
through age 1 y that resulted in adverse stimuli. An increased
risk of the features associated with metabolic syndrome (e.g.
hypertension and hyperlipidemia in their low-birth-weight
cohort) was also noted.
From 1990 to 1998 in the United States, the prevalence of
type 2 diabetes increased 33%, including in children (52). The
prevalence was strongly correlated with obesity. Eightyfive
percent of children diagnosed with type 2 diabetes are obese
(53). Additionally, in a recent study by Sinha et al. (54),
impaired glucose tolerance was diagnosed in 25% of obese
children (ages 410 y) and 21% of obese adolescents (ages 11
18 y). In this study impaired glucose tolerance was associated
with insulin resistance whereas beta cell function was relatively
preserved.
Infants of women with gestational diabetes have increased
body fat compared with weight-matched infants of control
women (55). The increased birth weight of these infants then
tends to normalize by age 1 y before increasing again during early
childhood. Silverman et al. (3) reported a strong correlation
between amniotic fluid insulin levels and increased body mass
index in adolescents aged 1417 y, indicating an association
between islet cell activation in utero and the development of
childhood obesity. This obesity present in childhood then
predisposes to obesity in the adult. Pettitt et al. (4) showed that
infants born to Pima Indian women with impaired glucose
tolerance were more obese as children than infants of women
with normal glucose tolerance even when they developed
diabetes in later life. Additionally, maternal family history was
shown to have an increased relative risk of 2.51 (95% con-
fidence interval: 1.554.17) compared with a nonsignificant
paternal family history relative risk of 1.41 (95% confidence
interval 0.553.05) (56). These risks were adjusted for glucose
disappearance rate from an intravenous glucose tolerance test,
fasting glucose, obesity, physical fitness, triacylglycerol con-
centrations and age. The data suggest that both in utero ma-
ternal metabolic factors as well genetic factors participate in the
subsequent development of type 2 diabetes and obesity.
In summary, from available data we are only able to explain
a relatively small amount of the variance in fetal growth using
parental demographic and anthropometric factors. However,
when we incorporate measures of maternal insulin sensitivity,
we are able to explain approximately twice the variance in fetal
growth, in particular accretion of adipose tissue. Decreased
maternal insulin sensitivity before conception was found to
have the strongest correlation with fetal fat mass at term. These
data support the observation that decreased maternal insulin
sensitivity, as observed in obese women and women with
gestational diabetes, is associated with fetal overgrowth, in
particular of adipose tissue, which may be a long-term risk
factor for obesity and glucose intolerance in these children.
Maternal implications
Estimates of the energy cost of pregnancy range from a cost
of 80,000 kcal to a net savings of 10,000 kcal (57). As a result,
the recommendations for nutritional intake in pregnancy are
diverse and depend on the population being evaluated.
Furthermore, on the basis of more recent data, recommen-
dations for individuals within a population may be more diverse
1679S
than previously believed, making general guidelines for nutriti-
onal intake difficult (58).
The theoretical energy cost of pregnancy was estimated by
Hytten and Leitch (15). The additional energy cost of preg-
nancy consisted of the additional maternal and fetoplacental
tissue accrued during pregnancy and the additional running cost
of pregnancy, for example, increased cardiac output. In Hytten
and Leitchs model the greatest increases in maternal energy
expenditure occur between 10 and 30 wk gestation, primarily
because of maternal accretion of adipose tissue. However, the
mean increases in maternal adipose tissue vary considerably
among various ethnic groups. Forsum et al. (59) reported a mean
increase of .5 kg of adipose tissue in Swedish women whereas
Lawrence et al. (60) found no increase in adipose tissue stores in
women from The Gambia with their usual nutritional intake.
Basal metabolic rate accounts for 6070% of total energy
expenditure in individuals not engaged in competitive physical
activity and correlates well with total energy expenditure. As
with the changes in maternal accretion of adipose tissue, there
are wide variations in the change in maternal basal metab-
olic rate during gestation. The cumulative changes in basal
metabolic rate range from a high of 52,000 kcal in Swedish
women (61) to a net savings of 10,700 kcal in women from The
Gambia (60) without nutritional supplementation. The mean
increase in basal metabolic rate in Western women averages
approximately 20% (62). However, the coefficient of variation
in basal metabolic rate in these populations during gestation
ranges from 93% in women from the United Kingdom (58) to
.200% in Swedish women (61). When assessing energy intake
in relation to energy expenditure, however, estimated energy
intake remains significantly lower than the estimates of total
energy expenditure. These discrepancies have usually been
explained by factors such as increased metabolic efficiency
during gestation, decreased maternal activity and unreliable
assessment of food intake (63,64).
Data in nonpregnant subjects may help explain some of the
wide variations in metabolic variables measured during human
gestation. Swinburn et al. (65) reported that Pima Indians with
decreased insulin sensitivity gained less weight than did insulin-
sensitive subjects (3.1 vs. 7.6 kg) over 4 y. Furthermore, the
percent weight change per year was highly correlated with
glucose disposal. Catalano et al. (66) conducted a study of the
changes in maternal body fat and energy expenditure in women
with normal glucose tolerance and gestational diabetes in
relation to insulin sensitivity in early pregnancy. Women with
gestational diabetes had decreased glucose insulin sensitivity
before conception and had significantly smaller increases in
body fat and energy expenditure than did women with normal
glucose tolerance. A significant inverse correlation occurred
between the changes in fat accretion and insulin sensitivity:
women with decreased pregravid insulin sensitivity (i.e., obesity
and gestational diabetes) had less accretion of body fat than did
women with increased pregravid insulin sensitivity. These
results are consistent with a previous report showing that
weight gain in lean women with gestational diabetes was 2.5 kg
less than in a matched control group (67).
Similarly, an inverse relationship was noted between the
changes in total energy expenditure and insulin sensitivity (66).
Women with decreased pregravid insulin sensitivity had little
or no increase in energy expenditure and in some cases
a decrease in energy expenditure compared with pregravid
measurements. In contrast, women who were more insulin
sensitive had greater increases in energy expenditure in early
pregnancy.
To place these data in perspective, a closer look at the data
of Lawrence et al. (60) in The Gambia is necessary. In this study
1680S SUPPLEMENT
some women had their basic 1500-kcal diet supplemented by
400 kcal/d. In women whose diets were not supplemented,
maternal body fat did not increase and basal metabolic rate
actually decreased during the first 30 wk gestation. However,
women whose diets were supplemented gained a mean of 2 kg
fat, and although basal metabolic rate decreased in early
pregnancy, it returned to pregravid levels by 20 wk gestation.
As a result of the changes in basal metabolic rate and body
composition, there was a saving of 11,700 kcal in the group not
supplemented and a cost of 27,500 kcal in the supplemented
group. Hence, if we presume that women in The Gambia were
genetically insulin resistant, then the energy supplementation
may have resulted in a change from net savings of energy to net
cost of energy. Additionally, there was a mean increase of 225
6 56 g in the offspring of the women whose diets were
supplemented. However, the increase in birth weight only
occurred during the wet season when the women were in
negative energy balance because of food shortages and an
increased work load (38). We speculate that the increased fetal
growth may have resulted primarily in accretion of adipose
tissue.
Women with gestational diabetes are at an increased risk of
developing type 2 diabetes. The original studies of OSullivan
(68) show that the 15-y prevalence of type 2 diabetes in women
with a history of gestational diabetes was approximately 60% in
obese women during pregnancy and 30% in lean women at the
time of diagnosis. Subsequent studies supported these original
findings. The greatest risk factor for early-onset type 2 diabetes
after pregnancy was early gestational age at the time of
diagnosis and elevated fasting glucose (69). The greatest long-
term risk factor was maternal obesity (70).
In summary, the results of these studies show that there
is a relationship between the changes in maternal insulin
sensitivity and changes in accretion of adipose tissue and energy
expenditure in early gestation. The ability of women with
decreased pregravid insulin sensitivity to conserve energy
expenditure and accretion of body fat and make available
sufficient nutrients to produce a healthy fetus is a reproductive
advantage when availability of food is marginal. These data
support the thrifty gene hypothesis that decreased maternal
insulin sensitivity may have a reproductive metabolic advan-
tage in times of nutritional dearth. In contrast, decreased ma-
ternal insulin sensitivity before conception in an environment
where food is plentiful and a sedentary life style is more
common may manifest itself as gestational diabetes during
pregnancy. This may then increase the long-term risk for both
diabetes and obesity in the woman and her offspring.
Micronutrients and decreased insulin sensitivity
during pregnancy
If decreased maternal insulin sensitivity during gestation
potentially results in adverse maternal and fetal consequences,
can any dietary micronutrient interventions improve maternal
insulin sensitivity? The metabolism of zinc, magnesium and
chromium may be altered in women with gestational diabetes.
Increases in urinary excretion and lower circulating levels of
these nutrients have been reported in diabetic women. It is
unclear, however, whether these shifts affect fetal growth or
maternal health.
Zinc. Studies of zinc depletion in experimental animals
show that zinc is required for normal glucose metabolism. The
incorporation of [14C]glucose into fatty acids in epididymal fat
pads is reduced in zinc-deficient rats. Recent research by Tang
and Shay (71) provides a mechanism for this observation. A
correlation had been shown between zinc and the degree of
glycosuria and serum hemoglobin A1c concentrations (72).
Serum zinc concentrations may have an insulin-like effect on
glucose transport into adipocytes. Zinc potentiates insulin-
induced glucose transport into cells by influencing the insulin
signaling pathway. This may explain why glucose use is reduced
and lipolysis is enhanced in zinc deficiency (71). Experimental
zinc depletion confirms that zinc depletion also alters glucose
metabolism in humans. Men with zinc depletion exhibited a rise
in plasma glucose concentrations and a decline in respiratory
quotient (73). Because pregnancy creates a state of insulin
resistance and hyperglycemia, mothers in a marginal state of
zinc nutrition may be at risk for developing gestational diabetes.
Diabetes per se also appears to alter zinc metabolism. Urinary
zinc excretion is elevated in diabetic patients compared with
control subjects (74,75). This increase is associated with uri-
nary protein losses. Urinary zinc was not associated with the
excretion of any amino acid, urea or ammonia. Possibly, gly-
cosylated amino acids or peptides chelated with zinc contrib-
uted to the increased urinary zinc losses. A decline in serum zinc
may also be related to diabetic control (76). Zinc originating
from bone loss and exogenous insulin accounted for a small part
of the hyperzincemia. Other homeostatic adjustments must
have occurred. Rats made diabetic by the administration of
streptozotocin did not have an increase in zinc absorption but
the amount of zinc excreted into the intestine was reduced (77).
This decreased endogenous loss of zinc into the intestine may be
a homeostatic response to the increased urinary excretion of
endogenous zinc in diabetic patients.
The role of zinc in gestational diabetes is not well
established. Studies in diabetic pregnant rats suggest that zinc
transport to the fetus is reduced either because of a decrease in
placental transport or altered maternal or fetal zinc-binding
ligands (78). In humans no differences in serum zinc were
observed between insulin-requiring diabetic women and con-
trol pregnant women if the diabetic women were maintaining
careful control (79). Further research is needed to establish the
effects of marginal zinc status on glucose homeostasis in women
during pregnancy.
Magnesium. Type 1 diabetes is associated with increased
urinary losses of magnesium (80). Serum magnesium levels also
were lower in women with type 1 diabetes compared with
control women (80). Serum magnesium concentrations are
inversely related to glycosylated hemoglobin concentrations
and glucosuria. The increased urinary losses may be related
to hyperfiltration in combination with impaired tubular
reabsorption. A reduction in serum magnesium may reflect
depressed tissue magnesium levels. Lower levels of striated
muscle magnesium were measured in patients with diabetes
requiring insulin (81).
Decreases in serum magnesium and increased urinary losses
of magnesium were reported in type 1 diabetes and gestational
diabetes (79). These lower levels persisted after good glycemic
control was achieved. The fall in serum magnesium during
pregnancy in both healthy and diabetic women is probably due
partly to the decline in serum albumin concentrations because
about one-third of serum magnesium is transported by albumin.
Magnesium depends on insulin for entry into cells. More
intensive treatment with insulin during pregnancy in women
with gestational diabetes may lead to a further decline in
circulating magnesium. No functional consequences of this
lower level of magnesium during gestation in diabetic women
have been reported.
Chromium. Chromium is thought to play a role in the
function of insulin. Chromium was identified as an essential
nutrient because it restored glucose tolerance in rats fed low-
chromium diets (82). However, a specific function for chro-
 GESTATIONAL DIABETES IMPLICATIONS
mium in glucose tolerance has not been identified, and it is
unclear whether chromium plays a role in the pathogenesis of
diabetes in humans. Several investigators have reported that
hair chromium concentrations decline during pregnancy
(82,83) and the concentration of hair chromium was markedly
reduced in women who had repeated pregnancies within 4 y
(84). To test the effect of chromium supplementation on
glucose tolerance in pregnancy, Jovanovic-Peterson and
Peterson (82) randomly assigned 24 women with gestational
diabetes to a chromium supplementation (4 mg/[kg
d]21) or
placebo group. Subjects given supplemental chromium had
lower fasting and peak blood glucose levels. However,
supplemental chromium did not lower blood glucose con-
centrations in women with severe glucose intolerance enough
to eliminate the need to give insulin. Presently, chromium is
not an accepted treatment for gestational diabetes nor is there
sufficient evidence that poor chromium status increases the risk
for gestational diabetes.
Pregestational diabetes: maternal and fetal risks
Before the increases in type 2 diabetes in the United States
over the past 1020 y, most women with pregestational
diabetes had type 1 rather than type 2 diabetes. Women with
pregestational diabetes, whether type 1 or type 2, undergo
changes in glucose metabolism that are similar when compared
with women with normal glucose metabolism or gestational
diabetes. In women with well-controlled type 1 diabetes, there
may be a 1015% decrease in insulin requirements from 10 to
17 wk gestation and a 50% increase from 17 wk until term
compared with pregravid requirements (85).
Women with pregestational diabetes, whether type 1 or type
2, are at increased risk for having offspring with major organ
structural anomalies (86). The risk of congenital anomalies is
related to the degree of glucose control during organogenesis
(i.e., the first 68 wk gestation). In contrast, women with
normal pregravid glucose tolerance who develop gestational
diabetes in late gestation have no increased risk of fetal
congenital anomalies beyond the population risk for women
with normal glucose metabolism.
Relative to fetal growth, women with pregestational diabetes
may have an increased risk of fetal growth restriction as
compared with women with normal glucose tolerance or
gestational diabetes. The risk of fetal growth restriction may
be related to the increased incidence of comorbidities in these
women such as chronic hypertension or diabetic nephropathy.
These comorbidities may also increase the risk of preterm
delivery relative to a control group of women with gestational
diabetes because of the increased incidence of preeclampsia
in these women (87). The long-term risks of obesity and risk
of type 2 diabetes in the offspring of these women have been
less well examined, although we speculate that they may mirror
the findings in the population of women with gestational
diabetes.
Summary
The development of insulin resistance in late gestation is
a process common to all human pregnancies. The development
of maternal insulin resistance is associated with accretion of
maternal adipose tissue in early pregnancy and increased
fetoplacental nutrient availability in late gestation, when 70%
of fetal growth occurs. In women who develop gestational
diabetes, insulin resistance is increased before conception,
often in association with maternal obesity and increased risk of
fetal macrosomia or overgrowth. The macrosomic infants of
1681S
these women have an increased risk for the development of
adolescent obesity and type 2 diabetes. Efforts are urgently
needed to reverse these trends in the developed areas of the
world, in particular the United States, and prevent the problem
in the developing world. Increased maternal insulin resistance
may have a reproductive advantage when there is a dearth of
food and excessive maternal work but may develop with the
incorporation of Western diets and decreased physical activity.
To date, the primary means to prevent the development of
insulin resistance are lifestyle measures of diet, activity and
avoidance of obesity. The potential role of micronutrients to
improve insulin resistance in women of reproductive age is
a potential avenue to explore but needs further evaluation. In
the interim, it appears prudent to stress the importance of
lifestyle measures in order to prevent the potential long-term
implications of altered fetal growth.
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