Article

endocrinology

The Diabetogenic State of

Maternal Metabolism in
Pregnancy
Patrick Catalano, MD*

Objectives

After completing this article, readers should be able to:

1. Explain why normal pregnancy has been characterized as a diabetogenic state and
early gestation can be viewed as an anabolic condition.
2. Compare and contrast the general differences between women who have type 2 or
gestational diabetes and women who have type 1 diabetes mellitus or normal glucose
tolerance.
3. Describe insulin abnormalities seen in women who have gestational diabetes mellitus.
4. Characterize the relationship between neonatal birthweight and triglyceride and free
fatty acid concentrations.

Introduction
There are significant alterations in maternal metabolism during pregnancy, which provide
for adequate nutritional stores in early gestation to meet the increased maternal and fetal
demands of late gestation and lactation. Although diabetes mellitus is thought of as a
disorder exclusively of maternal glucose metabolism, it affects all aspects of maternal
nutrient metabolism. Herein we consider maternal glucose metabolism as it relates to
pancreatic beta cell production of insulin and insulin clearance, endogenous hepatic
glucose production and suppression with insulin, and peripheral glucose insulin sensitivity.
We also address maternal protein and lipid insulin metabolism. Lastly, we examine the
impact of these alterations on maternal metabolism related to fetal growth.

Glucose Metabolism
Normal pregnancy has been characterized as a diabetogenic state because of the
progressive increase in postprandial glucose and insulin response in late gestation. However, early gestation can be viewed as an anabolic condition because of the increase in
maternal fat stores and decrease in free fatty acid concentration. Longitudinal studies in
women who have normal glucose tolerance have shown significant progressive alterations
in all aspects of glucose metabolism as early as the end of the first trimester. (1)
Insulin secretion progressively increases in response to an intravenous glucose challenge
with advancing gestation (Fig. 1). The increases in insulin concentration are more
pronounced in lean than in obese women, most probably due to the greater decreases in
insulin sensitivity in lean women. Data regarding insulin clearance in pregnancy are scant.
Among other investigators, Catalano et al (2), using the euglycemic-clamp model,
reported a 20% increase in insulin clearance among lean women and a 30% increase among
obese women by late pregnancy. Although the placenta is rich in insulinase, the exact
mechanism for the increased insulin clearance in pregnancy remains speculative.
The progressive decrease in fasting glucose with advancing gestation most probably
results from the increase in plasma volume in early gestation and increase in fetoplacental
glucose utilization in late gestation. Kalhan and associates (3) and Cowett and colleagues
(4), using various stable isotope methodologies in cross-sectional study designs, were the
first to describe increased fasting hepatic glucose production in late pregnancy. Catalano et
al (5), using a stable isotope of glucose in a prospective longitudinal study design, reported
a 30% increase in maternal fasting hepatic glucose production with advancing gestation
(Fig. 2), which remained significant even when adjusted for maternal weight gain. The
*Professor of Reproductive Biology, Case Western Reserve University, and Chairman, Department of Obstetrics and Gynecology,
MetroHealth Medical Center, Cleveland, Ohio.
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endocrinology diabetes

increase in fasting maternal hepatic glucose production

occurred despite a significant increase in fasting insulin
concentration, thereby indicating a decrease in maternal
hepatic glucose sensitivity in women who have normal
glucose tolerance.
Peripheral insulin sensitivity in pregnancy has been
estimated via the measurement of insulin response to a
fixed oral or intravenous glucose challenge or the ratio of
insulin to glucose under a variety of experimental conditions. Among obese women in early gestation, Catalano
et al (6) reported a 10% increase in maternal peripheral
insulin sensitivity using the euglycemic-hyperinsulinemic
clamp (Fig. 3). Hence, the decrease in insulin requirements in early gestation observed in some women who
require insulin may be a consequence of a relative increase in insulin sensitivity, particularly among women
who have decreased insulin sensitivity prior to conception. In contrast to the metabolic alterations in early
pregnancy, there is a uniform decrease in peripheral
insulin sensitivity in late gestation. Spellacy and associates
(7) were among the first investigators to report an increase in insulin response to a glucose challenge in late
gestation. Later research from a number of laboratories
has demonstrated a decrease in insulin sensitivity ranging
from 33% to 78%. It should be noted, however, that all of
these quantitative estimates of insulin sensitivity are very
likely overestimates because of noninsulin-mediated glucose disposal by the fetus and placenta. Approximately
one third of maternal glucose utilization in the pregnant
ewe model was accounted for by uterine, placental, and
fetal tissue in one study. (8) Human fetal blood sampling
revealed fetal glucose concentration to be a function of
fetal size and gestational age as well as maternal glucose
concentration. (9)

Diabetes Mellitus
Diabetes mellitus is a chronic metabolic disorder characterized by either absolute or relative insulin deficiency
that results in increased glucose concentration. Although
glucose intolerance is the common outcome of diabetes
mellitus, the pathophysiology remains heterogeneous.
The two major classifications of diabetes mellitus are type
1, formerly referred to as insulin-dependent diabetes or
juvenile onset diabetes, and type 2, formerly referred to
as noninsulin-dependent or adult onset diabetes. During
pregnancy, classification of women who had diabetes
often relied on the White classification (10), first proposed in the 1940s. This classification is based on factors
such as the age of onset of diabetes, disease duration, and
end-organ involvement, primarily retinal and renal.

Type 1 Diabetes
Type 1 diabetes usually is characterized by an abrupt
onset at a young age and absolute insulinopenia, with
lifelong requirements for insulin replacement. Depending on the population, the onset of type 1 diabetes may
occur in individuals in their third or fourth decade. These
patients may have a genetic predisposition for antibodies
directed against their pancreatic islet cells. The degree of
concordance for the development of type 1 diabetes in
monozygotic twins is 33%, suggesting that the events
subsequent to the development of autoantibodies and
appearance of glucose intolerance also are related to
environmental factors. Because of their complete dependence on exogenous insulin, pregnant women who have
type 1 diabetes are at increased risk for the development
of diabetic ketoacidosis when pregnant. Additionally,
because intensive insulin therapy is used in women who
have type 1 diabetes to decrease the risk of spontaneous
abortion and congenital anomalies in early gestation,
these women are at increased risk of hypoglycemic reactions.
The alterations in glucose metabolism in women who
have type 1 diabetes are not well characterized. Because
of maternal insulinopenia, insulin response during gestation can only be estimated relative to pregravid requirements. Estimates of the changes in insulin requirements
are complicated by the degree of preconceptual glucose
control and the frequent presence of insulin antibodies.
Schmitz and associates (11) evaluated longitudinal
changes in insulin sensitivity in women who had type 1
diabetes in early and late pregnancy as well as postpartum
and compared them with changes in nonpregnant
women who had type 1 diabetes. Among the pregnant
women, a 50% decrease in insulin sensitivity was seen
only in late gestation. There was no significant difference
in insulin sensitivity in early pregnancy or within 1 week
of delivery compared with nonpregnant women. Available data suggest that women who have type 1 diabetes
appear to have similar decreases in the magnitude of
insulin sensitivity as women who have normal glucose
tolerance.

Type 2 Diabetes/Gestational Diabetes

The pathophysiology of type 2 diabetes involves abnormalities of both insulin-sensitive tissues; that is, both a
decrease in skeletal muscle and hepatic sensitivity to
insulin and beta cell response, as manifested by an inadequate insulin response for a given degree of glycemia.
Initially in the course of developing type 2 diabetes, the
insulin response to a glucose challenge may be increased
relative to that of individuals who have normal glucose

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endocrinology diabetes

tolerance, but it is inadequate to maintain normoglycemia. Whether decreased insulin sensitivity (increased insulin resistance) precedes beta cell dysfunction in the
development of type 2 diabetes continues to be debated.
Despite the limitations of any classification system,
certain generalizations can be made regarding women
who have type 2 or gestational diabetes. They are typically older and more often heavier than women who have
type 1 diabetes or normal glucose tolerance. The onset of
the disorder is usually insidious, with few patients complaining of the classical triad of polydipsia, polyphagia,
and polyuria. Individuals who have type 2 diabetes often
initially are advised to lose weight, increase their activity,
and follow a diet that is low in fats and high in complex
carbohydrates. Individuals who have type 2 diabetes
eventually may require insulin therapy to maintain euglycemia, but they are not at risk for diabetic ketoacidosis. Data from monozygotic twin studies have reported a
lifetime risk of both twins developing type 2 diabetes that
ranges from 58% to almost 100%, suggesting that the
disorder has a strong genetic component.
Women who have type 2 diabetes usually are classified
as having class B diabetes according the White classification system. Women developing gestational diabetes (ie,
glucose intolerance first recognized during pregnancy)
share many of the metabolic characteristics of women
who have type 2 diabetes. Although earlier studies reported the incidence of islet cell antibodies in women
who had gestational diabetes, as measured by immunofluorescence techniques, as 10% to 35% (12)(13), more
recent data using specific monoclonal antibodies have
documented a much lower incidence of 1% to 2% (14),
suggesting a low risk of type 1 diabetes in women who
have gestational diabetes. Furthermore, postpartum
studies of women who have gestational diabetes have
demonstrated defects in insulin secretory response (15)
and decreased insulin sensitivity (16), indicating that
typical type 2 abnormalities in glucose metabolism are
present in women who have gestational diabetes. Of
interest, the alterations in insulin secretory response and
insulin resistance among women who have a previous
history of gestational diabetes compared with a weightmatched control group may differ, depending on
whether the woman who has previous gestational diabetes is lean or obese. (17) Thus, in women who have
gestational diabetes, the hormonal events of pregnancy
may represent an unmasking of a genetic susceptibility to
type 2 diabetes.
Fasting glucose concentration decreases significantly
with advancing gestation among women developing gestational diabetes. To date, all reports indicate that in late

gestation, women who have gestational diabetes have

increased fasting insulin concentrations (Fig. 4) and less
suppression of hepatic glucose production during insulin
infusion, which indicates decreased hepatic glucose insulin sensitivity compared with a weight-matched control
group. (6)(18)(19) The studies of Xiang and associates
(19) documented a significant correlation between fasting free fatty acid concentrations and hepatic glucose
production, suggesting that insulin resistance in fat cells
may contribute to hepatic insulin resistance.
Women who have gestational diabetes have decreased
insulin sensitivity compared with weight-matched control groups. Ryan and colleagues (20) were the first
to report a 40% decrease in insulin sensitivity among
women who had gestational diabetes compared with a
pregnant control group in late pregnancy, using a
hyperinsulinemic-euglycemic clamp. Catalano et al
(6)(18), using similar techniques, described the longitudinal changes in insulin sensitivity in both lean and obese
women who were developing gestational diabetes compared with a matched control group. Women developing
gestational diabetes had decreased insulin sensitivity
compared with the matched control group (Fig. 5). The
differences in insulin sensitivity were greatest before and
during early gestation; by late gestation, the differences
were less pronounced but still significant. Of interest,
insulin sensitivity increased from the time prior to conception through early pregnancy (12 to 14 weeks), particularly among women who had the greatest decreases
in insulin sensitivity prior to conception. The changes in
insulin sensitivity from the time prior to conception
through early pregnancy were significantly correlated
with changes in maternal weight gain and energy expenditure. (21) The relationship between alterations in maternal glucose insulin sensitivity and weight gain and
energy expenditure may help to explain the decreases in
maternal weight gain and insulin requirements in women
who have diabetes during early gestation. (22)
Studies in human skeletal muscle and adipose tissue
have demonstrated that postreceptor defects in the insulin signaling cascade are related to decreased insulin
sensitivity in pregnancy. Garvey and associates (23) initially demonstrated no significant differences in the glucose transporter (GLUT 4) responsible for insulin action
and skeletal muscle in pregnant compared with nonpregnant women. The studies of Friedman et al (24) in both
pregnant women who had normal glucose tolerance and
gestational diabetes and weight-matched nonpregnant
controls suggested defects in the insulin signaling cascade relating to pregnancy as well as what may be additional abnormalities in women who have gestational
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endocrinology diabetes

diabetes. All pregnant women appeared to have a decrease in insulin receptor substrate-1 (IRS-1) expression.
The downregulation of the IRS-1 protein closely parallels the decreased ability of insulin to induce additional
steps in the insulin signaling cascade that result in movement of the GLUT 4 to the cell surface membrane to
facilitate glucose transport into the cell. In addition,
there is a distinct decrease in the ability of the insulin
receptor beta (that component of the insulin receptor
not on the cell surface) to undergo tyrosine phosphorylation that is not found in either pregnant or nonpregnant women who have normal glucose tolerance. The
additional defect in the insulin signaling cascade results
in a 25% lower glucose transport activity.

Amino Acid Metabolism

Although glucose is the primary source of energy for the
fetus and placenta, there are not appreciable amounts of
glucose stored as glycogen in the fetus or placenta.
Because accretion of protein is essential for growth of
fetoplacental tissue, nitrogen retention is increased in
pregnancy in both maternal and fetal compartments. For
example, it is estimated that there is approximately 0.9 kg
accretion of maternal fat-free mass by 27 weeks gestation, (25) and most fasting maternal amino acid concentrations decrease significantly in early pregnancy prior to
accretion of significant maternal or fetal tissue. (26)
These anticipatory changes in fasting amino acid metabolism occur after a shorter period of fasting compared
with nonpregnant women and may be another example
of the accelerated starvation of pregnancy. (27) Furthermore, concentrations of amino acids such as serine
correlate significantly with fetal growth in both early and
late gestation. (28) Maternal amino acid concentrations
have been shown to be significantly decreased in mothers
of small-for-gestational age neonates compared with maternal concentrations in appropriately grown neonates.
(29)
There is also a significant conservation of nitrogen/
protein in late gestation, with a decrease in maternal
plasma urea nitrogen concentrations and urea nitrogen
synthesis and excretion. (30) Estimates of amino acid
turnover using stable isotopes of leucine, for example, are
useful for evaluating the balance between protein breakdown and resynthesis. Studies by Denne and Kalhan (31)
have shown that the rates of basal or fasting proteolysis or
protein turnover are similar in pregnant and nonpregnant women, indicating that there may be no change in
fasting amino acid insulin sensitivity during pregnancy.
No published studies have evaluated the effect of infused
insulin on amino acid turnover during pregnancy in

women who have either normal or abnormal glucose

tolerance. Studies of whole body protein turnover in late
gestation suggest that there may be a slight decrease in
the rate of protein breakdown during fasting (32) and a
small increase in protein turnover during the day. (33)
Amino acids are transported actively across a concentration gradient from mother to fetus through the placenta via energy-requiring amino acid transporters.
Amino acid transporters are highly stereospecific, but
they have low substrate specificity. Additionally, they
may vary with location between the microvillus and basal
membranes. (34) Decreased amino acid concentrations
have been reported in growth-restricted neonates compared with appropriately grown neonates, with decreased
amino acid transporter activity implicated as a possible
mechanism. However, the potential role, if any, of placental amino acid transporters in macrosomic infants of
women who have diabetes is currently unknown. (35)

Lipid Metabolism
Although there is ample literature regarding the changes
in glucose metabolism during gestation, data regarding
alterations in lipid metabolism are meager. Knopp et al
(36) have reported a two- to four-fold increase in total
triglyceride concentration and a 25% to 50% increase in
total cholesterol concentration during gestation. Additionally, there is a 50% increase in low-density lipoprotein
(LDL)-cholesterol and a 30% increase in high-density
lipoprotein (HDL)-cholesterol by midgestation that decreases slightly in the third trimester. Maternal triglyceride and very low-density lipoprotein (VLDL) triglyceride
levels in late gestation are positively correlated with maternal estriol and insulin concentrations.
The increase in maternal lipid concentration, especially free fatty acids, in late gestation has been hypothesized as a possible mechanism relating to the decrease in
maternal glucose insulin sensitivity in late pregnancy.
(37) Free fatty acids have been associated with fetal
overgrowth, particularly of fetal 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 and colleagues
(38)(39) reported that neonatal birthweight was positively correlated with concentrations of triglycerides and
free fatty acids, which readily cross the placenta in late
pregnancy. Also, Kleigman and associates (40) reported
that infants of obese women not only had increased
birthweight and skinfold measurements, but also increased free fatty acids compared with infants of lean
women.
Lipid metabolism in women who have diabetes mel-

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litus is influenced by the type of diabetes, a difference that

also applies when these women become pregnant.
Among women who had type 2 diabetes and gestational
diabetes, Knopp et al (41) reported an increase in triglyceride and decrease in HDL-cholesterol concentrations.
In contrast, Montelongo and colleagues (42) reported
little change in free fatty acid concentrations through all
three trimesters after a 12-hour fast. Recently, Koukkou
and associates (43) reported an increase in total triglycerides, but a lower LDL-cholesterol level in women who
had gestational diabetes. In women who had type 1
diabetes, there was no change in total triglycerides, but a
lower cholesterol concentration, which was due to a
decrease in HDL-cholesterol. This is of interest because
HDL-cholesterol acts as plasma antioxidant, and oxidative stress has been implicated as a potential factor in the
increased incidence of congenital anomalies among infants born to women who have type 1 diabetes.

Fetal Macrosomia
Macrosomia has been variously defined as a birthweight
greater than 4,000 to 4,500 g and as an infant who is
large for gestational age in whom the birthweight is
above the 90th percentile for population and genderspecific growth curves. Fetal macrosomia complicates as
many as 50% of pregnancies in women who have gestational diabetes and 40% of pregnancies in women who
have type 1 diabetes, including some women treated with
intensive glycemic control. Delivery of an infant weighing greater than 4,500 g occurs 10 times more often in
women who have diabetes than in women who have
normal glucose tolerance. (44)
According to the Pedersen hypothesis, maternal hyperglycemia results in fetal hyperglycemia and hyperinsulinemia, which causes excessive fetal growth. Increased
fetal beta cell mass may be identified as early as the
second trimester. (45) Evidence supporting the Pedersen
hypothesis has come from studies of amniotic fluid and
cord blood insulin and C-peptide concentrations. Both
are increased in the amniotic fluid of insulin-treated
women who have diabetes at term (46) and correlate
with neonatal fat mass. (47) Lipids and amino acids,
which are elevated in pregnancies complicated by gestational diabetes, also may play a role in excessive fetal
growth by stimulating insulin and other growth factors
from the fetal pancreatic beta cells and placenta. Infants
of mothers who have gestational diabetes have an increase primarily of fat mass rather than fat-free mass. (48)
Additionally, the growth is disproportionate, with chest/
head and shoulder/head ratios larger than those of infants of women who have normal glucose tolerance,

which may contribute to the higher rate of shoulder

dystocia and birth trauma observed in these infants. (49)
The results of several clinical series have validated the
Pedersen hypothesis inasmuch as tight maternal glycemic
control has been associated with a decline in the incidence of macrosomia. In one series of 260 insulindependent women achieving fasting plasma glucose concentrations between 109 and 140 mg/dL (6 to
7.7 mmol/L), there were 58 (22%) macrosomic infants.
(50) Other investigators reported that only 11% of 134
women achieving fasting glucose concentrations between 105 and 121 mg/dL (5.8 to 6.7 mmol/L) were
delivered of infants whose birthweights were in excess of
4,000 g. (51) A more dramatic reduction in the rate of
macrosomia has been reported when more physiologic
control has been achieved. With a program of maximally tolerated insulin administration, macrosomia was observed in only 6% of cases in one study, (52) and other
researchers eliminated macrosomia in 52 women who
achieved mean glucose levels of 80 to 87 mg/dL (4.4 to
4.8 mmol/L) throughout gestation. (53) A 9% rate of
macrosomia was reported among insulin-dependent
women whose mean values were less than 110 mg/dL
(6.1 mmol/L) using daily capillary glucose values obtained during the second and third trimester compared
with a 34% rate when less optimal control was achieved.
(54) It has been suggested that 1-hour postprandial
glucose measurements correlate best with the frequency
of macrosomia. (55) After controlling for other factors,
investigators noted that the strongest predictor for birthweight was third trimester nonfasting glucose measurements.
In a series of metabolic studies, Catalano and associates (56) estimated body composition in 186 neonates
using anthropometry. Fat-free mass, which comprised
86% of mean birthweight, accounted for 83% of the
variance in birthweight, and fat mass, which comprised
only 14% of birthweight, accounted for 46% of the
variance. There was also significantly greater fat-free mass
in male than in female infants. Using independent variables, such as maternal height, pregravid weight, weight
gain during pregnancy, parity, paternal height and
weight, neonatal gender, and gestational age, the investigators accounted for 29% of the variance in birthweight, 30% of the variance in fat-free mass, and 17% of
the variance in fat mass. (57) Including estimates of
maternal insulin sensitivity in 16 additional subjects, they
were able to explain 48% of the variance in birthweight,
53% of the variance in fat-free mass, and 46% of the
variance in fat mass. (58) Other studies have corroborated these findings with reports that women who had
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unexplained fetal growth restriction had greater insulin

sensitivity compared with a control group of women
whose infants were of appropriate weight for gestational
age. (59) There was a positive correlation between
weight gain in women who had normal glucose tolerance, but a negative correlation in women who had
gestational diabetes. In women who had normal glucose
tolerance, the correlation was strongest in women who
were lean before conception and became progressively
weaker as pregravid weight for height increased. (60)
Among women who had gestational diabetes, there were
no significant correlations between maternal weight gain
and birthweight, irrespective of pregravid weight for
height. These studies emphasized the role of maternal
metabolic environment and fetal growth.
In addition to the perinatal risk associated with fetal
macrosomia in the infants of women who have abnormal
glucose tolerance, there are significant long-term risks.
The increase in birthweight of these infants tends to
normalize by 1 year of age, but it increases again at early
childhood. (61) There is an increase in the risk of obesity
in these children at ages 1 to 9 years and 14 to 16 years.
Silverman et al (61) reported a strong correlation between amniotic fluid insulin concentrations and increased body mass index (weight/height) (2) in 14-to
17-year-olds, indicating an association between islet cell
activation in utero and development of childhood obesity. This childhood obesity predisposes to adult obesity.
Infants born to Pima Indian women who had impaired
glucose tolerance were more obese as children than
infants of women who had normal glucose tolerance,
even when they developed diabetes later. (62) These data
suggest that there is both an in utero maternal metabolic
factor as well genetic factors in the later development of
type 2 diabetes and obesity.

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endocrinology diabetes

NeoReviews Quiz
1. Fetal macrosomia is a frequent manifestation of a pregnancy complicated by diabetes mellitus. Of the
following, the factor most predictive of fetal macrosomia in a diabetic pregnancy is:
A.
B.
C.
D.
E.

Ethnicity.
Glycosylated hemoglobin.
Nonfasting glucose concentration.
Plasma lipid profile.
Response to glucagon.

2. The pathophysiology of type 2 or gestational diabetes mellitus primarily involves abnormalities of insulin
sensitivity of the peripheral tissues. In contrast, type 1 diabetes mellitus largely results from the loss of
pancreatic islet cells and consequent lack of insulin production. Of the following, the most accurate
statement regarding type 2 or gestational diabetes mellitus is that:
A.
B.
C.
D.
E.

Characteristic symptoms include polydipsia and polyuria.

Diabetic ketoacidosis is a frequent complication.
Leaner women are at an increased risk.
The onset of disease is insidious.
Younger women are at an increased risk.

e172 NeoReviews Vol.3 No.9 September 2002

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The Diabetogenic State of Maternal Metabolism in Pregnancy

Patrick Catalano
NeoReviews 2002;3;e165
DOI: 10.1542/neo.3-9-e165

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The Diabetogenic State of Maternal Metabolism in Pregnancy

Patrick Catalano
NeoReviews 2002;3;e165
DOI: 10.1542/neo.3-9-e165

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