Carotid intimal-medial thickness is not increased in women with previous gestational diabetes mellitus.

Abstract

Gestational diabetes mellitus (GDM) is known to increase the risk of cardiovascular diseases. Measuring the carotid artery intimal-medial thickness (CIMT) is a non-invasive technique used to evaluate early atherosclerosis and to predict future cardiovascular diseases. We examined the association between CIMT and cardiovascular risk factors in young Korean women with previous GDM.
One hundred one women with previous GDM and 19 women who had normal pregnancies (NP) were recruited between 1999 and 2002. At one year postpartum, CIMT was measured using high-resolution B-mode ultrasonography, and oral glucose tolerance tests were performed. Fasting glucose, glycated hemoglobin A1c (HbA1c), insulin levels and lipid profiles were also measured. CIMTs in the GDM and NP groups were compared, and the associations between CIMT and cardiovascular risk factors were analyzed in the GDM group.
CIMT results of the GDM group were not significantly different from those of the NP group (GDM, 0.435±0.054 mm; NP, 0.460±0.046 mm; P=0.069). In the GDM group, a higher HbA1c was associated with an increase in CIMT after age adjustment (P=0.011). CIMT results in the group with HbA1c >6.0% were higher than those of the normal HbA1c (HbA1c ≤6.0%) (P=0.010). Nine of the patients who are type 2 diabetes mellitus converters within one year postpartum but showed no significant difference in CIMT results compared to NP group.
Higher HbA1c is associated with an increase in CIMT in women with previous GDM. However, CIMT at one year postpartum was not increased in these women compared to that in NP women.

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D I A B E T E S & M E T A B O L I S M J O U R N A L
This is an Open Access article distributed under the terms of the Creative Commons At-
tribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/)
which permits unrestricted non-commercial use, distribution, and reproduction in any
medium, provided the original work is properly cited.
Copyright © 2011 Korean Diabetes Association http://e-dmj.org
Diabetes Metab J 2011;35:497-503
http://dx.doi.org/10.4093/dmj.2011.35.5.497
pISSN 2233-6079 · eISSN 2233-6087
Carotid Intimal-Medial Thickness Is Not Increased in
Women with Previous Gestational Diabetes Mellitus
Yun Hyi Ku1, Sung Hee Choi1,2, Soo Lim1,2, Young Min Cho1, Young Joo Park1,2, Kyong Soo Park1,
Seong Yeon Kim1, Hak Chul Jang1,2
1Department of Internal Medicine, Seoul National University College of Medicine, Seoul,
2Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
Background: Gestational diabetes mellitus (GDM) is known to increase the risk of cardiovascular diseases. Measuring the ca-
rotid artery intimal-medial thickness (CIMT) is a non-invasive technique used to evaluate early atherosclerosis and to predict
future cardiovascular diseases. We examined the association between CIMT and cardiovascular risk factors in young Korean
women with previous GDM.
Methods: One hundred one women with previous GDM and 19 women who had normal pregnancies (NP) were recruited be-
tween 1999 and 2002. At one year postpartum, CIMT was measured using high-resolution B-mode ultrasonography, and oral
glucose tolerance tests were performed. Fasting glucose, glycated hemoglobin A1c (HbA1c), insulin levels and lipid profiles were
also measured. CIMTs in the GDM and NP groups were compared, and the associations between CIMT and cardiovascular risk
factors were analyzed in the GDM group.
Results: CIMT results of the GDM group were not significantly different from those of the NP group (GDM, 0.435±0.054 mm;
NP, 0.460±0.046 mm; P=0.069). In the GDM group, a higher HbA1c was associated with an increase in CIMT after age adjust-
ment (P=0.011). CIMT results in the group with HbA1c >6.0% were higher than those of the normal HbA1c (HbA1c ≤6.0%)
(P=0.010). Nine of the patients who are type 2 diabetes mellitus converters within one year postpartum but showed no signifi-
cant difference in CIMT results compared to NP group.
Conclusion: Higher HbA1c is associated with an increase in CIMT in women with previous GDM. However, CIMT at one year
postpartum was not increased in these women compared to that in NP women.
Keywords: Cardiovascular diseases; Carotid atherosclerosis; Diabetes, gestational; Diabetes mellitus, type 2
Corresponding author: Sung Hee Choi
Department of Internal Medicine, Seoul National University Bundang
Hospital, 300 Gumi-dong, Bundang-gu, Seongnam 463-707, Korea
E-mail: shchoimd@gmail.com
Received: Dec. 20, 2010; Accepted: Mar. 30, 2011
INTRODUCTION
Gestational diabetes mellitus (GDM) is a subtype of diabetes
that occurs during pregnancy, and its prevalence in females
who have been pregnant is 3% to 8% worldwide. A Korean
survey showed that the prevalence of GDM is 2.2% [1]. Given
that the number of obese and older pregnant women is increas-
ing, the number of cases of gestational diabetes is continuously
increasing as well [2]. Women who have been diagnosed with
gestational diabetes have a high probability of developing type
2 diabetes after giving birth, and the incidences of atheroscle-
rosis and cardiovascular disease risk factors are also higher
than those in normal women [3,4].
Recently, a study to predict or diagnose cardiovascular dis-
ease was performed by measuring carotid intimal-medial thick-
ness (CIMT). Studies have shown that CIMT tends to increase
with age, and that CIMT values of smokers and patients with
dyslipidemia, hypertension, and type 2 diabetes are increased
compared with those of control groups [5-10]. In addition, in
individuals with thicker CIMTs, the risk of stroke and coro-
nary artery disease is known to be higher [11-13].
The association between GDM and CIMT has not yet been
Original Article

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Ku YH, et al.
Diabetes Metab J 2011;35:497-503http://e-dmj.org
clearly established. However, females who have a history of
GDM have been reported to have increased CIMTs compared
to those of females with normal pregnancies [14,15]. On the
other hand, in a comparison of carotid and femoral artery in-
timal-medial thickness (IMT) in females who had insulin re-
sistance associated with pre-eclampsia, Blaauw et al. [16] re-
ported increased femoral artery IMTs in these females com-
pared to those of the normal pregnancy group, and that there
was no significant difference between the two groups in CIMT
value.
In this study, the CIMTs of Korean women with a history of
gestational diabetes were measured using a high-resolution B-
mode ultrasound. Results were examined to determine if there
was a difference between the CIMT of women with a history
of GDM and that of women who had normal pregnancies and
if there is a connection among CIMT, cardiovascular risk fac-
tors and glucose intolerance in women with history of GDM.
METHODS
Target group
This study was performed between January 1999 and Decem-
ber 2002 with females who were diagnosed with gestational
diabetes between the 24th and 28th week of pregnancy at the
Department of Endocrinology and Metabolism Internal Med-
icine, Cheil General Hospital. Among the diagnosed patients,
101 agreed to participate in this study. The gestational diabetes
diagnostic criteria used in this study are those recommended
at the Third International Workshop-Conference on GDM
[17]. The control group (normal pregnancy, NP) was com-
prised of women who had a negative result on gestational dia-
betes screening tests performed during a previous pregnancy.
A total of 19 females were enrolled who had no family history
of diabetes. There were no statistical differences in age or body
mass index (BMI) between the two study groups.
This study was approved by the Institutional Review Board
of Seoul National University Hospital. The study participants
received a summary of the study purpose and method and
submitted written consent prior to participation in the study.
Study method
One year after women with a history of GDM gave birth, and
one to two years after women in the control group gave birth,
CIMT and cardiovascular risk indicators were measured. Body
measurements, including height, weight and waist and hip cir-
cumference, were collected from all subjects. The area of ab-
dominal fat was measured using a CT scan (Somatom Sensa-
tion 16; Siemens, Erlangen, Germany), an image was taken at
the navel with 10 mm thickness and the areas between -250 to
-50 Hounsfield units were measured. The images were edited
to maintain only the portion containing the innermost abdom-
inal muscles, while the rest was deleted, and the internal fat
was used for measurements.
A 75 g oral glucose tolerance test was performed after an
eight hour fast, and fasting plasma glucose, insulin, glycated
hemoglobin and plasma lipid concentrations were measured.
The plasma glucose levels were measured using the oxidase
method YSI 2300 STAT (Yellow Springs Instrument Co., Yel-
low Springs, OH, USA), glycated hemoglobin was measured
using the principles of a variant of ion-exchange high perfor-
mance liquid chromatography (Bio-Rad Laboratories, Hercu-
les, CA, USA) and plasma insulin concentration was measured
using a human-specific radioimmunoassay kit (Linco Research,
St. Charles, MO, USA). Total cholesterol, triglycerides, and
high density lipoprotein/low density lipoprotein cholesterol
(HDL-C/LDL-C) levels were measured using a Hitachi 747
autoanalyzer (Hitachi Ltd., Tokyo, Japan), and lipoprotein
concentration was calculated using the Friedewald formula:
([total cholesterol–HDL-C–triglyceride]/5) [18]. The homeo-
stasis model assessment of insulin resistance (HOMA-IR) was
used as an indicator of insulin resistance and was calculated
using the following formula: fasting plasma glucose (mmol/
L)×fasting plasma insulin (mU/L)/22.5 [19].
Carotid IMT measurement
One technician measured CIMTs of all subjects using a high-
resolution B-mode ultrasound on each side of the carotid ar-
tery. Starting 1 cm from the proximal end of the left and right
carotid arteries, the CIMT was measured at ten 1 mm inter-
vals, for a total of 20 locations on the distal walls, using a Dig-
matic calipus (CD-15B; Mitutoyo, Tokyo, Japan) caliper, and
the mean value was calculated (coefficient of variation value,
9%).
Data analysis
The statistical analysis of the data was conducted using SPSS
version 12.0 (SPSS Inc., Chicago, IL, USA). Data that followed
a normal distribution are expressed as mean±standard devia-
tion, and variables that did not follow a normal distribution
were logarithmically transformed prior to statistical analysis.

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Carotid atherosclerosis in gestational diabetes
Diabetes Metab J 2011;35:497-503http://e-dmj.org
Results are presented as medians (interquartile range). The
characteristics of the GDM group and the NP control group
were compared using an independent t-test. A linear regres-
sion analysis was used for women with a history of GDM in
order to analyze the associations between CIMT and cardio-
vascular risk factors, and the association between CIMT and
glucose intolerance was verified using ANOVA.
RESULTS
Clinical characteristics of women with a history of GDM
versus those of the NP control group
In this study, according to the physical measurements taken
one year after delivery, the waist circumference of the females
with a history of gestational diabetes group was thicker than
that of the control group, but there was no difference in BMI
or internal fat mass. In the results of the 75 g oral glucose tol-
erance test, the fasting plasma glucose levels were 100.2±15.1
mg/dL in the GDM group vs. 91.0±8.1 mg/dL in the NP con-
trol group (P=0.011). Two hours after the glucose tolerance
test, blood glucose levels were 136.2±39.9 mg/dL in the GDM
group vs. 105.7±14.0 mg/dL in the NP group (P<0.001). The
results from the GDM group were statistically and significant-
ly higher. The glycated hemoglobin levels were higher in the
GDM group (6.3±1.1% in GDM vs. 5.9±0.5% in NP, P=0.096),
but this difference was not statistically significant. The fasting
plasma insulin concentration was 9.9 (6.8 to 15.3) μU/mL in
the GDM group vs. 8.2 (6.8 to 8.8) μU/mL in the NP group
(P=0.007), and the HOMA-IR results in women with a history
of GDM appeared to be significantly higher: 2.25 (1.61 to 3.79)
in the GDM group vs. 1.91 (1.41 to 2.00) in the NP group (P=
0.001). Total cholesterol, triglycerides, HDL-C and LDL-C
concentrations were similar in both groups. When CIMT re-
sults from the GDM group were compared with those of the
NP group, there did not appear to be a statistically significant
difference: 0.435±0.054 mm in GDM vs. 0.460±0.046 mm in
NP, respectively (P=0.069) (Table 1).
Cardiovascular risk factors that affect the CIMT of females
with a history of gestational diabetes
In order to determine the factors affecting CIMT in women
with a history of GDM, a linear regression analysis that adjust-
ed for age was performed. Waist circumference, blood pressure,
fasting glucose, fasting insulin, and lipids did not affect CIMT.
However, as glycated hemoglobin increased, CIMT increased
as well (P=0.011) (Table 2). When the glycated hemoglobin
group was separated into two groups, a control group (glycat-
ed hemoglobin ≤6.0%) and a high glycated hemoglobin group
(glycated hemoglobin >6.0%), and compared, the CIMT of
the high glycated hemoglobin group was significantly thicker:
0.420±0.047 mm vs. 0.448±0.057 mm, respectively (P=0.011)
(Fig. 1).
Differences in CIMT based on glucose tolerance
Among the 101 females who had histories of GDM, 94 re-
ceived a 75 g oral glucose tolerance test six weeks and again
Table 1. Comparison of clinical characteristics between those
with previous GDM and the control group
Characteristic
Age, yr
BMI, kg/m2
Body weight, kg
Waist circumfer-
ence, cm
Visceral fat, cm2
Subcutaneous fat,
cm2
SBP, mm Hg
DBP, mm Hg
FPG, mg/dL
2-hr glucose of 75 g
OGTT, mg/dL
HbA1c, %
Fasting insulin,
μU/mL
Total cholesterol,
mg/dL
Triglyceride, mg/dL 107.0 (79.5-137.5)
HDL-C, mg/dL
LDL-C, mg/dL
HOMA-IR
Carotid IMT, mm
GDM (n=101)
32.2±4.1
22.3 (20.4-24.2)
53.8±15.2
80.3±7.7
Control (n=19)
32.6±4.6
20.4 (19.5-23.1)
53.6±7.1
74.5±7.7
P value
0.746
0.082
0.954
0.003
96.1±46.6
228.7±94.5
82.0±38.3
218.2±68.5
0.237
0.660
110.2±16.5
66.5±10.3
100.2±15.1
136.2±39.9
106.6±7.7
65.8±6.4
91.0±8.1
105.7±14.0
0.352
0.776
0.011
<0.001
6.3±1.1
9.9 (6.8-15.3)
5.9±0.5
8.2 (6.8-8.8)
0.096
0.007
184.6±28.0 189.8±35.10.625
73.5 (62.0-102.0)
49.0 (46.0-65.3)
117.9±28.9
1.91 (1.41-2.00)
0.460±0.046
0.059
0.392
0.315
0.001
0.069
49.5 (43.3-60.0)
107.4±28.0
2.25 (1.61-3.79)
0.435±0.054
Data characterized by normal distribution are expressed as mean±
standard deviation. Parameters not normally distributed are expressed
as median (interquartile range).
GDM, gestational diabetes mellitus; BMI, body mass index; SBP, sys-
tolic blood pressure; DBP, diastolic blood pressure; FPG, fasting plas-
ma glucose; OGTT, oral glucose tolerance test; HDL-C, high density
lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol;
HOMA-IR, homeostatic model assessment–insulin resistance; IMT,
intimal-medial thickness.

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one year after delivery. When the glucose tolerance state was
judged based on the test results after six weeks, 49 patients
(52.1%) had normal glucose tolerance (NGT), 11 patients
(11.7%) had impaired fasting glucose (IFG), 14 patients (14.9%)
had impaired glucose tolerance (IGT), 16 patients (17.0%) had
both impaired fasting glucose and impaired glucose tolerance
(IFG/IGT) and four patients (4.3%) were diagnosed with dia-
betes (DM). After one year had passed, 31 patients (33.0%)
had NGT, 16 patients (17.0%) had IFG, 16 patients (17.0%)
had IGT, 22 patients (23.4%) had IFG/IGT and nine patients
(9.6%) were diagnosed with DM.
No statistically significant difference was seen at six weeks or
one year when the differences in IMT were compared among
all five groups (Table 3). In addition, the results were the same
whether the IFG group, IGT group, and the IFG/IGT group
were analyzed together or separated into three groups (Table
4). There was also no difference observed when the NGT and
DM groups were compared (data not shown).
DISCUSSION
Placental growth hormone and placental lactogen are hor-
mones produced by the placenta during pregnancy. During
the late stages of pregnancy, the concentrations of insulin an-
tagonizing hormones, such as prolactin, cortisol and glucagon,
and cytokines such as tumor necrosis factor-alpha (TNF-α)
increase, and insulin resistance is lower [20-22]. During nor-
mal pregnancies, the compensatory insulin secretion from the
pancreas increases. However, when adequate amounts of insu-
lin are not secreted to overcome the compensatory insulin re-
sistance, gestational diabetes occurs [23]. Compared with nor-
mal pregnancies, women who previously had GDM have a
higher risk for developing type 2 diabetes, and as a result, fu-
ture risk of cardiovascular complications have been known to
increase [24,25].
In this study, the clinical characteristics of females who had
gestational diabetes and of females with a normal pregnancy
were compared. The results showed that, compared to normal
pregnancies, women who had gestational diabetes had higher
concentrations of insulin and had higher insulin resistance. As
mentioned earlier, during pregnancy, the effects of several
physiological hormones increase insulin resistance. Particu-
Table 2. Associations between CIMT and cardiovascular risk
factors in women with a history of GDM
Variable
BMI, kg/m2
Body weight, kg
Waist circumference, cm
Visceral fat, cm2
Subcutaneous fat, cm2
SBP, mm Hg
DBP, mm Hg
FPG, mg/dL
2-hr glucose of 75 g OGTT, mg/dL
HbA1c, %
Fasting insulin, μU/mL
Total cholesterol, mg/dL
Triglyceride, mg/dL
HDL-C, mg/dL
LDL-C, mg/dL
HOMA-IR
r2
P value
0.594
0.327
0.425
0.574
0.912
0.186
0.199
0.216
0.449
0.011
0.752
0.128
0.079
0.299
0.314
0.649
0.020
0.027
0.026
0.017
0.013
0.025
0.024
0.017
0.023
0.077
0.008
0.029
0.037
0.015
0.014
0.018
Variables that were not normally distributed were logarithmically
transformed before statistical analysis. Linear regression analysis was
used to calculate r2 and corresponding P values after controlling for
age.
GDM, gestational diabetes mellitus; BMI, body mass index; SBP, sys-
tolic blood pressure; DBP, diastolic blood pressure; FPG, fasting plas-
ma glucose; OGTT, oral glucose tolerance test; HDL-C, high density
lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol;
HOMA-IR, homeostatic model assessment–insulin resistance.
≤6.0 >6.0
HbA1c (%)
0.5
0.4
0.3
0.2
0.1
CIMT (mm)
P=0.010
Fig. 1. Difference in carotid artery intimal-medial thickness
(CIMT) between normal and increased HbA1c groups in
women with a history of gestational diabetes mellitus. In the
women with a history of gestational diabetes mellitus, the CIMT
of those in the high HbA1c group (HbA1c >6.0%) was higher
than that of those women who had a normal HbA1c (HbA1c
≤6.0%) (0.448±0.057 mm vs. 0.420±0.047 mm, P=0.010).

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larly in patients with gestational diabetes who suffer from
chronic insulin resistance, as physiological insulin resistance
increases, they develop a higher level of insulin resistance
compared to that in women with normal pregnancy [26-28],
as was shown in the present study.
Considering that the patients with a history of gestational
diabetes are at future risk for cardiovascular disease, we mea-
sured the CIMT in such patients, and the resulting correla-
tions with cardiovascular risk factors were analyzed. When a
multiple linear regression analysis was performed, none of
waist circumference, blood pressure, internal fat, HDL- and
LDL-C or triglycerides showed a significant correlation with
CIMT. However, as glycated hemoglobin increased, the CIMT
significantly increased as well. In previous studies performed
on people with impaired glucose tolerance, CIMT was report-
ed to increase as glycated hemoglobin increased [29], and stud-
ies targeting type 2 diabetes patients reported that there was a
positive correlation between CIMT and glycated hemoglobin
levels [30,31]. In the present study, a statistical significance in
the increase in glycated hemoglobin levels and CIMT was ob-
served in women with a history of GDM.
In this study, we observed no difference in CIMT between
the two study groups. When CIMT results of the GDM and
control groups in Western countries were analyzed in a previ-
ous study, the results showed that women with histories of
GDM were reported to have thicker CIMT measurements com-
pared to those of normal healthy females [14]. In that study, the
group that had a history of gestational diabetes had a mean
CIMT of 0.582±0.066 mm, while that of the control group
was 0.543±0.049 mm, showing that the group with a history
of GDM had significantly thicker CIMT [14]. However, in our
study, the mean CIMT of women with history of GDM was
0.435±0.054 mm, and the mean CIMT of the control group
was 0.460±0.046 mm, which was significantly lower than those
in the Western cases. Ethnic background and culturally-based
obesity have been suggested as causes to explain this difference.
One major factor that influences CIMT is obesity [32]. How-
ever, compared to Western populations, obesity is much less
common in Koreans, in whom the average overall BMI is also
much lower. The BMI of the GDM group and the NP group in
this study fell within the normal range. By way of comparison,
in the Western study [14], the mean BMI of the GDM group
was 28.65±4.75 kg/m2, and that of the control group was
27.17±2.90 kg/m2, which both fall in the overweight range.
The differences in the weight ranges are believed to influence
the CIMT measurements. In addition, the average BMI of the
women who had a history of GDM in our study was low com-
pared to the average BMIs of study groups in other countries.
Therefore, the inclusion of a high number of very lean GDM
patients is considered to be a limitation which may have af-
fected the study results.
In addition, one thing that must be considered when inter-
preting the results for CIMT measurements is the age of our
study population. The mean CIMTs of Korean females in their
30s and 40s are 0.57±0.10 mm and 0.60±0.10 mm, respec-
tively, which seems to increase gradually with age [33]. Howev-
er, in the present study, the mean CIMT values of patients in
their 30s were significantly lower than those of patients in
Table 3. Carotid IMT according to glucose tolerance status in women with a history of GDM (I)
NGT
49
IFG
11
IGT
14
IFG/IGT
16
0.446±0.051
22
0.425±0.048
DM
4
P value
0.5066wa
No.
IMT, mm
No.
IMT, mm
0.433±0.054
31
0.427±0.053
0.444±0.060
16
0.461±0.055
0.432±0.049
16
0.442±0.053
0.432±0.071
9
0.442±0.059
1yb
0.218
IMT, intimal-medial thickness; GDM, gestational diabetes mellitus; NGT, normal glucose tolerance; IFG, impaired fasting glucose; IGT, im-
paired glucose tolerance; DM, diabetes.
aAt post-partum six weeks, bAt post-partum one year.
Table 4. Carotid IMT according to glucose tolerance status in
women with a history of GDM (II)
NGT
49
IFG or IGT
41
DM
4
P value
0.7906waNo.
IMT, mm0.433±0.054 0.441±0.052 0.432±0.071
31 54
0.427±0.053 0.441±0.053 0.442±0.059
1ybNo.9 0.506
IMT, mm
IMT, intimal-medial thickness; GDM, gestational diabetes mellitus;
NGT, normal glucose tolerance; IFG, impaired fasting glucose; IGT,
impaired glucose tolerance; DM, diabetes.
aAt post-partum six weeks, bAt post-partum one year.