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Original Article:
Gynecology
&
Obstetrics,
Alexandria University, Alexandria, Egypt.
3Department
Clinical Pathology
University, Alexandria, Egypt.
Alexandria
*Corresponding Author:
Fahmy Amara
Emeritus Professor of Internal Medicine, Unit of
Diabetes & Metabolism, Department of Internal
Medicine, Alexandria University, Alexandria,
Egypt.
E-mail: fahmyamara@hotmail.com
(Page number not for citation purposes)
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the secretory granules. Insulin and C-peptide are
stored in equimolar amounts; under normal
conditions, 95% of the biosynthetic products are
secreted as insulin and less than 5% as
unconverted proinsulin (14).
The aim of the present study was to study the
levels of serum proinsulin or proinsulin/insulin ratio
(PIR) in women suffering from gestational
diabetes mellitus (GDM) as an additional factor
to their insulin resistance during pregnancy, and
to evaluate any change or reversibility of serum
proinsulin or PIR during the postpartum period.
Methodology
The study included 40 age matched women
divided into 4 groups as follow:
Group I: included 10 non diabetic pregnant
women as a control group.
Group II: included 10 obese GDM women.
Group III: included 10 lean GDM women.
Group
IV:
included
10
non
pregnant
normoglycemic women as a reference group.
The women included in this study were selected
from the outpatient clinic of the Gynecology and
Obstetric Department and admitted to the
Diabetes and Metabolism Unit, Alexandria Main
University Hospital. Medical history of each
woman enrolled in the study was recorded and
clinical evaluation performed. Body weight (Kg)
and height (m) were determined for all women
and body mass index (BMI) was calculated
according to the Quetelet equation. The study
was approved by the hospital ethics committee,
and written informed consent was obtained from
all subjects.
During pregnancy, OGTT (1) was performed in
the morning after an overnight fast of at least 8
hours; the recommendations are for 8-10 hours
fasting and after at least 3 days of unrestricted
diet and physical activity. The test was done by
using 100 gm glucose orally. Blood samples were
withdrawn at 0, 30, 60, 120, 180 minutes for blood
glucose measurements. After delivery, the
subjects were scheduled for a 2-hour 75 gm OGTT
a t 4-8 weeks, post partum. Blood samples were
withdrawn at 0, 30, 60, 120 minutes. peripheral
blood samples were taken by venipuncture of
antecubital vein and the serum was used to
measure blood glucose levels using the standard
techniques for oxidase method. The remaining
serum was stored at -20c for insulin assay.
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insulin
Statistical Analysis
Data were represented as mean SD. For
intergroup comparisons, measured variables
were analyzed by one way ANOVA test. The
level of significance was determined at P less
than 0.05. Correlation coefficient was used to
study
correlation
between
measured
parameters.
Results
All women were age matched. The mean values
of their age were 28.91.37 years, 28.72.67 years,
29.31.83 years and 28.23.01 years in controls,
obese women with GDM, lean women with GDM
and non pregnant women respectively (p>0.05).
The BMI ranged from 23-30 Kg/m in control
group with a mean value of (26.62.52 Kg/m). In
obese GDM women BMI mean value (31.82.72
Kg/m) was significantly higher than that of other
3 groups (p<0.05). In lean GDM women BMI
mean value (22.81.38 Kg/m) was significantly
lower than that of control group, obese GDM
women and non pregnant women (p<0.05). In
non pregnant women (reference group) BMI
mean value (27.42.5Kg/m) was significantly
lower than that of obese GDM and significantly
higher than lean GDM women (p<0.05) (Table I)
During pregnancy, the mean plasma glucose
levels during 100gm OGTT were significantly
higher in women with gestational diabetes (both
obese and lean) compared with normal glucose
tolerant pregnant women at the fasting state
and at 30, 60, 120 and 180 minutes (p<0.05).
Futhermore; at 30 minutes the mean plasma
glucose level was significantly higher in lean than
obese GDM women (P<0.05), while at 60 minutes,
the mean plasma glucose level was significantly
higher in obese than lean GDM women (P<0.05).
After delivery, the mean plasma glucose levels
during 75 gm OGTT were significantly higher at 30
and 60 minutes in GDM women (both obese and
lean) than in the non diabetic pregnant women
(group I) and the non pregnant non diabetic
women (group IV) (P<0.05).
At 120 minutes, the mean plasma glucose levels
were significantly higher in GDM women (both
obese and lean) than in group I and in obese
GDM women than in group IV (P<0.05).
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Table I: Comparison between the four studied groups as regards age and BMI
Age (years)
Range
Mean SD
BMI (Kg/m)
Range
Mean SD
Group I
non diabetic
pregnant
women
Group II
obese GDM
women
Group III
lean GDM
women
Group IV
non pregnant
non diabetic
women
27-31
28.91.37
25-33
28.72.67
27-32
29.31.83
22-33
28.23.01
P=0.736
23-30
26.62.52
28.5-37
31.82.72*
20.9-24.6
22.81.38*#
23-31.7
27.42.5#
P=0.0001
ANOVA
test
Table II: Comparison between the four studied groups as regards proinsulin, proinsulin/insulin ratio and
C-peptide during pregnancy
Proinsulin (Pmol/l)
Range
Mean SD
Proinsulin/insulin
ratio
Range
Mean SD
C-peptide (ng/ml)
Range
Mean SD
Group I
non diabetic
pregnant
women
Group II
obese GDM
women
Group III
lean GDM
women
Group IV
non pregnant
non diabetic
women
5.30-6.60
5.600.77
13.5-15.8
14.620.75*
14-17.8
16.041.30*#
2.4-4.2
3.010.62*#
P=0.000001
0.29-0.59
0.3960.09
0.34-0.51
0.4350.05*
0.49-0.51
0.5800.08*#
0.27-0.56
0.3670.09#
P=0.00001
0.5-0.8
0.5990.08
0.58-1.0
0.7940.12*
0.66-0.92
0.7380.08*
0.50-0.55
0.5250.02#
P=0.002
ANOVA
test
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Table III: Comparison between the four studied groups as regards proinsulin, proinsulin/insulin ratio and
C-peptide after delivery
Group I
normoglycemic
pregnant
women
Group II
obese GDM
women
Group III
lean GDM
women
Group IV
non pregnant
non diabetic
women
1.90-4.00
2.870.64
9.8-12
10.830.67*
9.8-12.7
11.370.89*#
2.4-4.2
3.010.62#
P=0.00001
0.19-0.44
0.3100.08
0.58-1.44
0.9300.24*
0.64-1.15
0.9890.14*
0.27-0.56
0.3670.09#
P=0.0001
0.53-0.71
0.5840.05
0.51-0.67
0.5830.04
0.50-0.63
0.5610.04
0.50-0.55
0.5250.02*#
P=0.010
Proinsulin (Pmol/l)
Range
Mean SD
Proinsulin/insulin
ratio
Range
Mean SD
C-peptide (ng/ml)
Range
Mean SD
ANOVA
test
P is significant if <0.05
* : significant versus group I
# : significant versus obese GDM women (group II)
: significant versus lean GDM women (group III)
Table IV: Comparison between the levels of proinsulin, proinsulin/insulin ratio and C-peptide during
pregnancy and after delivery in the three pregnant studied groups
Proinsulin
During pregnancy
After delivery
Paired t-test
Proinsulin/insulin
ratio
During pregnancy
After delivery
Paired t-test
C-peptide
During pregnancy
After delivery
Paired t-test
Group I
normoglycemic
pregnant women
Group II
obese GDM women
Group III
lean GDM women
7.600.97
2.870.64
t=12.99*, P=0.0001
14.620.75
10.830.67
t= 11.660*, P=0.0001
16.041.30
11.730.89
t= 7.467*, P=0.0001
0.3960.09
0.3100.08
t= 3.151*, P=0.001
0.4350.05
0.9300.24
t=7.294*, P=0.0001
0.5800.08
0.9890.14
t=8.331*, P=0.0001
0.5990.08
0.5840.05
t=0.853, P=0.416
0.7940.12
0.5380.04
t= 6.640*, P=0.001
0.7380.08
0.5610.04
t=9.132*, P=0.0001
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Table V: Comparison between the three pregnant studied groups as regards insulin sensitivity index
and relative resistance for insulin during pregnancy
Group I
normoglycemic
pregnant
women
Group II
obese GDM
women
Group III
lean GDM
women
4.51-7.54
6.030.92
1.36-3.70
2.440.67*
1.53-3.78
2.820.61*
P=0.00001
2.1-2.89
2.520.25
3.09-6.00
4.121.00*
3.06-6.07
3.880.84*
P=0.0001
ANOVA test
Table VI: Comparison between the four studied groups as regards insulin sensitivity index and relative
resistance for insulin after delivery
Group I
normoglycemic
pregnant
women
Group II
obese GDM
women
Group III
lean
GDM
women
Group IV
non pregnant
non diabetic
women
7.66-19.64
12.13.29
4.43-11.75
7.362.32*
6.8913.57
9.411.96
6.51-13.57
13.223.90 #
P=0.00001
1.91-2.99
2.390.34
2.21-4.29
3.150.68*
1.81-2.33
2.950.15
2.03-3.67
2.460.56 #
P=0.00001
for
ANOVA
test
P is significant if <0.05
* : significant versus group I
# : significant versus obese GDM women (group II)
: significant versus lean GDM women (group III)
Table VII: Comparison between the levels of insulin sensitivity index and relative resistance for insulin
during pregnancy and after delivery in the three pregnant studied groups
Group I
normoglycemic pregnant
women
Group II
obese GDM
women
Group III
lean GDM women
6.030.92
12.063.29
t=6.352*, P=0.001
2.440.67
7.362.32
t=6.714*, P=0.001
2.820.61
9.411.96
t=11.368*, P=0.0001
2.520.25
2.390.34
t=1.047, P=0.322
4.121.00
3.150.68
t=2.757*, P=0.022
3.880.84
2.150.15
t=6.368*, P=0.001
* : significant
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Table VIII: Correlation between proinsulin, proinsulin/insulin ratio and the sensitivity index in the
three pregnant studied groups.
Pro-insulin
Pro-insulin/insulin
ratio
r = correlation coefficient
SI= sensitivity index
Group I
normoglycemic
pregnant women
SI
r = 0.034
P= 0.975
r = -0.767*
P= 0.036
Group III
lean GDM women
SI
r = 0.048
P= 0.942
r = -0.725*
P= 0.039
SI
r = 0.253
P=0.715
r = -0.772*
P= 0.028
P is significant if <0.05
Discussion
It is widely accepted now that insulin resistance
and hyperinsulinemia are characteristic features
of late pregnancy and that gestational diabetes
is associated with a failure in insulin secretory
capacity to compensate for insulin resistance.
Gestational diabetes mellitus is one of the most
common complications of pregnancy (2) and
frequently predictive of later maternal impaired
glucose tolerance or type 2 diabetes mellitus
(18). Pathophysiological abnormalities detected
in women who develop gestational diabetes
may provide clues to the etiology of type 2
diabetes mellitus (2,18).
The important feature in the results of this study is
that the mean levels of proinsulin were
significantly higher during pregnancy than after
delivery in groups I (normoglycemic women), II
(obese GDM women) and III (lean GDM women).
During pregnancy the mean values of proinsulin
were significantly higher in both group II (obese
GDM women) and group III (lean GDM women)
compared with group I (normoglycemic
pregnant women) and group IV (non-pregnant
non-diabetic women). Moreover, the mean
values of proinsulin after delivery were
significantly higher in group II and group III,
compared with group I and group II (Tables III &
IV).
Another important observation is the mean
values of proinsulin/insulin ratio during pregnancy
and after delivery. This ratio was significantly
higher in gestational diabetic women (both
obese and lean) than the control and reference
groups (P= 0.00001). After delivery, the
proinsulin/insulin ratio showed similar profile i.e.
was also significantly higher in groups II and III,
compared with groups I and IV (P=0.0001).
Group II
obese GDM women
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It is known, and was further confirmed in this
study, that women with GDM are known to be
insulin resistant, hyperinsulinemic and have a high
risk of developing type 2 diabetes later in the life.
Such insulin resistance that develops during
gestation and extends into the postpartum
period was not explained on the basis of age or
body mass index. It is likely to have both genetic
and environmental components that are
analogous to the resistance reported in other
groups at risk of having type 2 diabetes (25-31).
Several studies suggest that women with a history
of GDM often have -cell defect compared with
women without such history. Thus, the women
had a marked defect in first phase -cell function
at a time when they had normal glucose
tolerance.(32) Also, increased proinsulin-to- insulin
ratio was found in GDM women when compared
with control subjects, suggesting a -cell defect
which was not simply the result of chronic
hyperglycemia (32,33). This was confirmed in our
study, when significant negative correlations of
the proinsulin-to-insulin ratio with the sensitivity
index in the GDM women (both obese and lean)
were found.
These data are consistent with the data of Ryan
et al (34), but differ from the data of Fisher et al
(35) and Buchanan et al (36) who showed no
significant difference in insulin sensitivity between
women with gestational diabetes mellitus and a
control group. The difference in results of insulin
sensitivity may be explained in part by the
methods used to estimate insulin sensitivity and
by the evaluation of subjects only in late
gestation, when differences in insulin sensitivity
between groups are less pronounced.
In this study, the mean values of C-peptide were
significantly higher in both group II and group III
as compared to the control and reference
groups during pregnancy (P = 0.002). After
delivery these C-peptide levels were significantly
higher in group II (obese GDM women) versus the
group IV (non pregnant reference group)
(P=0.010). Comparing the mean values of Cpeptide, it was found that these mean values
were significantly lower after delivery than during
pregnancy, in the three pregnant study groups.
Kautzky et al (19) showed that fasting C-peptide
was found to be higher in GDM than in nondiabetic
non-pregnant
women
and
normoglycemic pregnant women, meanwhile
markedly lower than in obese insulin-resistant
non-pregnant women. Prager et al (37) studied
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In the present study, the pregnant women
presented with a metabolic pattern suggestive of
enhanced insulin resistance, namely increased
fasting and post load insulin levels. This was
demonstrated as the mean values of plasma
insulin during pregnancy which was significantly
higher in GDM women (both obese and lean)
compared with the control group, measured by
oral glucose tolerance test. Also these mean
values were significantly higher in obese GDM
compared with lean GDM women at the
different points of the test. After delivery, no
significant differences were found, regarding the
plasma insulin, between the obese and lean
GDM women. However, the mean values of
plasma insulin were still significantly higher in
GDM women (both obese and lean) compared
with the controls (normal glucose tolerant
pregnant women) and the reference group (non
pregnant healthy women).
Homko et al (5) studied the insulin secretion
during late gestation (third trimester) and
postpartum. They found that during late
gestation, women with GDM were more insulin
resistant than non diabetic controls and had
significantly lower insulin secretion rates (ISRS) in
response to hyperglycemia. Postpartum, insulin
resistance, ISRS and plasma insulin levels
improved in both groups, and ISRS were no
longer significantly different in patients with GDM
and controls. Insulin resistance, however,
remained higher in women with GDM. They
concluded that the women with GDM had a
major beta-cell defect that made it impossible
for them to compensate for their increased level
of insulin resistance, which occurred during late
pregnancy.
Catalano et al (42) studied the longitudinal
changes
in
glucose
metabolism,
during
pregnancy, in obese women with normal
glucose tolerance and gestational diabetes. The
results showed increase in first-phase and
second-phase
insulin
response
that
was
significantly greater in the gestational diabetes
mellitus group than in the control group. They
concluded that obese women in whom
gestational diabetes develops have a significant
increase in insulin response but decrease in insulin
sensitivity with advancing gestation with respect
to a matched control group.
From the current study, we can conclude that
gestational diabetes mellitus is characterized by
elevated serum proinsulin concentrations and an
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