Diagnostic approach for assessment of beta cell function during

pregnancy and after delivery

Clinical significance and interpretation

Mariana P. Genova, Katia Todorova, Bisera Atanasova

Mariana P. Genova, MD, PhD, Senior Professor-Assistant, Department of

Clinical laboratory and Clinical Immunology, Medical University, Sofia.
Key words: gestational diabetes mellitus, body mass index, insulin
resistance, -cell dysfunction, disposition index, leptin, diabetes and
pregnancy, HOMA model, proinsulin , PIR-ratio

I am deeply grateful to Professor Kamen Tzatchev, MD, PhD, DSc,

President of Bulgarian Society of Clinical Laboratory,
for his strong support and invaluable help during many years.

Content
1. Abreviations4
2. Abstract...5
3. Change in the levels of HOMA-IR, HOMA-B and DI during pregnancy
and after delivery....

4. Measurement of insulin secretion by tree methods 15

5. Levels of PI and PIR in healthy pregnant, pregnant with GDM and post
partum

17

6. Impact of BMI on insulin sensitivity, assessing by QUICKI and HOMAS% indices.23

7. HOMA-IR method for assessing of the insulin resistance during
pregnancy and after delivery.34
8. Leptin and pregnancy. Relationship between leptin, BMI, insulin
resistance and insulin sensitivity (QUICKI index)

36

9. References.45

Abbreviations
ADA American Diabetes Association
BMI body mass index
CI confidence interval
DI disposition index
FG fasting blood glucose concentration
FPI fasting insulin concentration
GDM gestational diabetes mellitus
HAPO study of Hyperglycemia and Adverse Pregnancy Outcome
HOMA-B homeostasis model assessment value for insulin secretion
HOMA-IR homeostasis model assessment value for insulin resistance
HOMA-S homeostasis model assessment value for insulin sensitivity
IADPSG International Association Diabetes in Pregnancy Study Group
IR insulin resistance
IS insulin sensitivity
NGT normal glucose tolerance
OGTT oral glucose tolerance test
OR odds ratio
PI pro-insulin
PI/I pro-insulin/insulin
PIR pro-insulin-insulin ratio
QUICKI quantitative insulin sensitivity check index
ROC receiver operating characteristic
SD standard deviation
T2DM type 2 diabetes mellitus

Abstract
The field of diabetes and pregnancy has existed for a long time.
Historically diabetes during pregnancy has subdivided in gestational diabetes
and pre-gestational diabetes or diabetes during pregnancy since the 1960s.
Gestational diabetes mellitus (GDM) is defined as any degree of glucose
intolerance with onset or first recognition during the current pregnancy or
impaired carbohydrate tolerance with varying intensity, which is diagnosed
during pregnancy and that can either be resolved or not after birth. This
definition includes women with pre-existing but unrecognized before pregnancy
diabetes, in particular type 2 diabetes (T2DM) / abnormal carbohydrate
tolerance, whose expression is during pregnancy and have not put a question
whether or there is a need for insulin treatment, or whether or not it exists after
delivery.
Pregnancy is a physiological state of insulin resistance (IR), while
pancreatic -cells normally increase their insulin secretion to compensate the
occurrence of physiological IR. GDM is an islet -cell failure condition for
compensation of insulin resistance. GDM appears to be a result of a wide
spectrum of physiological and genetic dysfunctions, with synergistic action of
some endogenous and exogenous factors. It identifies pregnant women with a
high risk of perinatal mortality, prolonged overweight and impaired glucose
tolerance after birth. Women with GDM have high risk for developing T2DM
outside pregnancy.
Diabetes mellitus is a chronic social disease, which has become a
worldwide epidemic. This increased frequency of T2DM is closely related to
prevalence of obesity. The frequency of GDM also increases in parallel with that
of T2DM and obesity. This fact does not cause a surprise because of the same
basic pathogenetic mechanisms underlying GDM and T2DM. In essence, they
are different phases of one illness for mother.

There are several factors which can trigger GDM, but only some of them
are well studied. Obesity, heredity and limited exercise activity are the main
exogenous factors and abnormally high insulin resistance and altered -cell
function are the main key endogenous factors in the pathogenesis of GDM. The
pathogenetic mechanisms, associated with impaired placental function, insulin
resistance and -cell dysfunction in pregnant women with GDM, are not well
studied.
The increasing frequency of GDM, related consecutive complications for
newborns and mothers and not sufficient investigation of this medical problem
provoke an interest in studying of pathogenetic mechanisms and diagnostic
opportunities for risk assessment and early diagnosis of the condition
gestational diabetes mellitus.

Pregnancy is a normal physiological state of insulin resistance (IR) with

both maternal adiposity and the insulin-desensitizing effects of placental
hormones lead to it. In this case, insulin resistance presents a physiological
stress model of pancreatic -cells (1, 2). In normal pregnancy, pancreatic -cells
normally increase their insulin secretion (about 30%) to compensate pregnancyassociated insulin resistance, but insulin sensitivity decreases by 30-60%
compared to healthy non-pregnant women (3). Alterations in glucose levels
during pregnancy are very small in difference to the large changes in insulin
sensitivity. Great plasticity of -cell function in the face of progressive insulin
resistance is the hallmark of normal glucose regulation during pregnancy (4).
In gestational diabetes, insulin resistance is not adequately compensated
by insulin hypersecretion because of defective beta-cell function. Insulin
resistance during pregnancy reveals limitations in insulin secretion, on the other
hand, increasing insulin resistance and subsequent insulin hypersecretion maybe
worsen the level of beta-cell failure (3).
The primary mechanisms for the development of GDM are related to cell dysfunction and IR or decreased maternal insulin sensitivity. Ryan et al. are
the first reporting 40% decrease in insulin sensitivity and 67% reduction in
relation to insulin resistance in women with GDM compare to pregnant control
group in late pregnancy using a euglycemic clamp (5).
Pancreatic beta-cell dysfunction is one of the main pathogenetic
mechanisms of GDM (6). During pregnancy with GDM the pancreatic -cell
function is insufficient to meet the bodys insulin needs. Existing evidence
suggests that -cell defect in GDM is a result of the same spectrum of causes
that underlie hyperglycemia (7). Although this defect likely precedes the
pregnancy (8), it is first detected clinically in the form of insufficient -cell
compensation for insulin resistance in late pregnancy. The -cell defect in
women with GDM is still present in the postpartum (9). Evaluation of pancreatic
7

-cell function in human is a challenge because it is a complex interaction of

insulin secretion, insulin sensitivity and hepatic insulin sensitivity.
The pancreatic -cell defect can be quantified by expressing insulin levels
relatively to each individuals degree of insulin resistance, using the hyperbolic
relationship between insulin sensitivity and insulin secretion (10, 11). The
product of these two variables, referred to as disposition index (DI), can be
calculated and has showed the inability of the -cell to compensate for insulin
resistance (12). The strength and limitations of DI are widely discussed in the
literature (13). It is known that the age, weight, distribution of the fat and other
clinical conditions or treatment influence significantly insulin resistance and
insulin secretion (14).
Change in the levels of HOMA-IR, HOMA-B and DI during
pregnancy and after delivery
The easiest and most popular assessment of -cell function is the
homeostatic index HOMA-B. It is widely used because of its simplicity and it
reflects the release of insulin under non-stimulated conditions (15). Although
surrogate marker HOMA-B is less evaluated as an index, it provides high
reliability in the measurement of -cell function (16). HOMA model is
considered as a structural model of the underlying physiological basis for the
feedback loop between the liver and the -cell in fasting (17). The indexes are
derived from mathematical assessment of the balance between hepatic glucose
output and insulin secretion from basal levels of both glucose and insulin (17,
18). HOMA-IR has been observed to have a linear correlation with the glucose
clamp and considered as minimal model for estimations of insulin
sensitivity/resistance in various studies (17, 18). HOMA-IR determines the
relationship between the liver and pancreas. This index reflects more the liver
insulin resistance in comparison to peripheral insulin resistance (19) and it is a
good indicator of overall insulin sensitivity during pregnancy. Both indices,
8

HOMA-B and HOMA-IR submit better overall picture of the essential metabolic
disorder (16).
HOMA-indexes are first developed in 1985 by Matthews et al (20).
Disadvantage of HOMA model is related to the fact that it underlines the lack of
linearity at deepening of insulin resistance (21). This model is a widely used and
well correlates with the insulin sensitivity, as measured by the venous clamp
technique in various studies (17, 18).
Our study comprised 102 pregnant women between 21-28 gestational
weeks (53 with GDM and 49 with normal glucose tolerance) and 22 postpartum
women (8-14 weeks). Selected anthropometric, clinical, and pathophysiological
parameters of all women were assessed. Exclusion criteria for pregnant women
were chronic diseases, acute infection during pregnancy or establishing of
diagnosis, intake of drugs that affect the carbohydrate metabolism or interfere
with

insulin

sensitivity,

multiple

pregnancies,

known

diabetes,

fetal

malformation, or other severe maternal illnesses, age <18 or > 45 years.

Informed consent was obtained in written from all patients.
All the tested pregnant women with no previously diagnosed diabetes
went through screening for gestational diabetes mellitus with a 2 h 75 g oral
glucose tolerance test (OGTT). Diagnosis of GDM was in accordance with the
recommendations of the International Diabetes in Pregnancy Study Group
(IADPSG) -2010 (22) and Standards of Medical Care in Diabetes-2011 (23).
HOMA is a method to quantify IR and beta-cell function. Any
pair of fasting glucose and insulin concentrations can be used to
quantify -cell function and insulin resistance. HOMA index of insulin
resistance (HOMA-IR) is a product of basal glucose and insulin levels divided
by 22.5 (20, 17). HOMA of -cell function (HOMA-B) index, can be used to
quantify -cell function using the following formula: HOMA%B=(20xFPI(IU/L))/(FPG(mmol/L)3.5)(17).To

estimate

insulin

secretion, independent on insulin sensitivity, DI was calculated as

9

the insulinogenic index [(insulin60 - insulin0)/(glucose60-glucose0)] (24)

divided by the insulin resistance index (25). Glucose and insulin at 0, 60 min
were received during the course of 2 h 75g OGTT.
The three groups were compared in the level of the fasting glucose,
glucose at 60 min, fasting insulin, insulin at 60 min, HOMA-IR, HOMA-B and
DI (Tabl. 1).

10

Characteristics of the patients metabolic parameters.

Table 1
Characteristics

Fasting glucose
(mmol/l)

Pregnant with NGT

Pregnant with GDM

After delivery

(n1=49)

(n2=53)

(n3=22)

4.62 0.28*

5.93 1.04*

5.33 0.79

Statistical significance

p<0,0001*
p<0.0001
p< 0.001

Glucose at 60
min

6.95 1.37

7.62 2.36+

+8.49 2.29

p= 0.0004
p= 0.002+

(mmol/l)
11.35 4.98

13.84 8.43

10.6 7.53

Fasting insulin
(IU/l)

p= 0. 02
p<0.01
p<0.01
p<0. 011

Insulin at 60
min

63.89 32.93***

68.47 54.76

76.98 57.47***

p=0. 0048
p=0, 0021

(IU/l)
p<0.0001
HOMA-IR

*1.79 1.08

3.8 3.05

2.5 1.94*

p=0.017
p= 0.004*

126.4 8 57.69

99.94 41.51*

*99.41 41.37

p0.05
p=0.017
NS*

Disposition
index

13.22 21.70

6.47 12.93

10.06 15.50

p<0.0001
p=0.011
p0.04

Stumvoll I
phase

*784.76 67.22**

*673.54 165.151

716.57 131.09**

<0.0001*
<0.00011
=0.005**

Stumvoll
II phase

148.33 32.672

+118.72 61.342

+134.52 66.28

=0.0212
<0.0002+
=0.012

The results were expressed as meanSD.

Reduced insulin secretion evaluated by significant differences for

HOMA-B and DI index at the time of GDM diagnosis and after delivery was
11

observed. GDM women were more insulin resistant (HOMA-IR) and their -cell
function was not able to meet the insulin demands induced by the pregnancy, in
comparison to NGT and postpartum groups (P<0.0001, P=0.017). Finally,
young mothers were more insulin-resistant in comparison to NGT (P=0.004)
(Tabl.1). Similar to our results, Morkrid et al. (2012) have established GDM
pregnant women more insulin resistant compared to GDM women 3 months
post partum, measured by HOMA-IR. They have found -cell function,
measured by HOMA-B, similar in these groups (26), opposite to our results. Our
data pointed HOMA-B statistically lower in GDM pregnancy than that in NGT
group (P=0.017). This trend was also observed in young mothers with a history
of GDM when compared to GDM pregnant (NS).The reduced insulin secretion
in the period after birth was expressed by reliable difference in HOMA-B index
between the NGT group and women post partum (P0.05). No significant
difference for HOMA-B between GDM pregnant women and those after
delivery supports the hypothesis that beta cell defect prolongs during the post
partum period. Consistent with this, our observations for higher fasting glucose
in GDM than in healthy pregnant (P<0,0001) point possible defect in insulin
secretion with failure of compensatory mechanisms and development of
hyperglycemia (Tabl.1).
Endo et al. (2006) have found higher values of HOMA-B in pregnant with
NGT compared to pregnant with GDM (P<0.01) (27). Similar result has been
reported by Das S, Behera et al (2010) (28). Di Cianni et al. (2007) have
established a progressive decrease in insulin sensitivity and in insulin secretion
(29) with a significant difference of HOMA-B between healthy pregnant women
and those with GDM (P < 0.01).
A cross-sectional study of pregnant Japanese women has demonstrated
lower basal insulin sensitivity in GDM compared to normal weight NGT women.
HOMA-B levels in normal weight NGT subjects have been increased during
pregnancy with no increase of HOMA B in GDM during the last trimester (30).
12

HOMA-B is important prognostic factor for GDM development. It is an

indicator for insulin secretion in GDM Korean women according to Sunmin and
Sung-Hoon (2011) (31). Established major pathogenetic mechanisms of GDM
development (marked insulin resistance and -cell dysfunction) were confirmed
by our own study results.
Beta-cell secretory function can be assessed by oral disposition index. GDM
female population exhibit reduced mean disposition index both during and after
pregnancy, when compared with normoglycaemic counterparts (32, 33).
Our study showed that DI decreased progressively from NGT to GDM
(P<0.0001). Women after delivery exhibited higher absolute DI value compared
to GDM pregnant (P=0.011), but it remained significantly lower than the value
in the healthy pregnant women (P0.04) (Tabl. 1)
Prospective studies indicated DI reduced before the increasing of glucose
to values typical for diabetes. Thus, low DI presents an early marker of
inadequate -cell compensation (34, 35).

On the other hand, DI could be

interpreted as the ability of the glucose-regulatory system to compensate insulin

resistance by increasing the level of plasma insulin. Glucose intolerance is often
associated with increased risk of diabetes and -cell dysfunction development,
represent by reduced DI in comparison to healthy individuals thus suggesting
reduced DI also as strong predictor of T2D development (36).
Reducing of DI indicates a worsening of -cell compensation in respect of
insulin sensitivity. Therefore, the limited -cell reserve is a potential etiologic
factor in GDM development (37) with contribution to the development of
impaired glucose tolerance during pregnancy. Determination of DI during
pregnancy may have the potential to predict impaired glucose tolerance also
after birth (38).
Qvigstad et al. (2010) have found lower values for DI in GDM pregnant
compared to NGT women (P<0.0001) (30). Similar results have been obtained by
13

Miyakoshi et al. (2011). They have estimated -cell function in pregnant women
with GDM (according to the criteria of IAPDSG-2010), using DI during the 75 g
OGTT. The authors have observed DI in pregnant with GDM significantly lower
compared to healthy pregnant women (P<0.001). The results suggest that
pregnant women GDM, identified under the new consensus criteria, have a
greater risk of developing diabetes type 2 in the future, and adverse perinatal
outcomes (39). A Double Cohort Study, at the Kuopio University Hospital,
Kuopio, Finland (2014) established significantly decreased of DI in the GDM
subjects (P < 0.001) as compared to the controls (40).
Such differences in HOMA-B and DI between the tree selected groups
have indicated a significant pathophysiological variation in the severity of -cell
dysfunction during the diagnosis of GDM and after birth. The precise
mechanisms of -cell mass expansion during human pregnancy have only
partially been elucidated (41).
Our study on comparison of - between NGT and GDM pregnant
demonstrated that the OR of developing GDM was 0.989 (95% CI, 0.980-0.998,
P=0.013). Comparison of DI between healthy pregnant and GDM showed OR of
developing GDM 0.967 (95% CI, 0.947-0.988, P=0.002). HOMA-B and DI
appear to be protective factors against the risk of GDM development. Increasing
the value of HOMA-B with one unit reduces the risk of developing GDM with
11% and increasing the value of DI with unit would reduce the risk of
developing GDM with 33%.
The function of pancreatic -cell can be estimated by the results obtained
in the course of the OGTT in different ways: the mathematical calculation of the
dynamic performance of -cell function, measuring the relative pro-insulin
secretion and assessment of the insulin secretion in comparison to the insulin
sensitivity (42).

14

Measurement of insulin secretion by tree methods

We used the following three measures of insulin secretion: the
homeostatic model for assessment of -cell (HOMA-B) (described above);
Stumvoll first-phase and Stumvoll secondphase of insulin secretion. Neither
HOMA-B nor Stumvoll indices have been validated in pregnancy (42). Stumvoll
first-phase measure of insulin secretion is defined by the following formula:
1,194+4.724 x Inso 117 x Glu60 + 1.414 x Ins60 . Stumvoll second-phase
measure of insulin secretion is defined as follows: 295 +0.349 x Ins60 -25.72 x
Glu60 + 1.107 x Inso (44). Stumvoll first phase model has been validated using
the hyperglycaemic clamp technique (44).
We calculated the first-and the second-phase insulin secretions and they
both appeared to be progressively reduced going from women with NGT,
pregnant with GDM to women after delivery, but with GDM history. The first
phase comprised NGT compared to GDM pregnant and young mothers
(<0.0001; P=0.005 and comparison between GDM and women after birth
(<0,0001). The results were similar to that of the second phase: statistical
difference between two pregnant groups (=0.021), between NGT and women
after delivery (=0.012) and between GDM and after birth (0,0002) (Tabl.1)
The comparison of the average value for Stumvoll first phase (78467,22)
in pregnant women with NGT to the average value in GDM (673,54165,15)
showed very well manifested difference in the secretory ability of pancreatic cell between both groups of pregnant (P<0.0001) (Tabl.1). This result correlated
with the lower value of HOMA-B (99.94 41.51) in the group pregnant with
GDM, compared to HOMAB in NGT (126.4 8 57.69). We hypotheses that the
statistical difference between GDM pregnant and after birth could be related to
the first phase of insulin response: although impaired in young mothers, it is able
to maintain glucose within the normal range. It is important to note the
significant difference between GDM pregnant and post-GDM for Stumvoll first
phase (P<0.0001).
15

Statistically significant difference between healthy pregnant and after

birth (P= 0.005 and P=0.012 for Stumvoll first and second phase) in respect of
insulin secretion is normally found because of reduced after birth requirements
for higher insulin response, with no complete elimination of insulin resistance
and possibly the presence of -cell defect. We assume that these reduced
requirements are the base for a very distinctive difference in insulin secretion
between GDM pregnant and after birth for Stumvoll second-phase (P<0.0002).
Women in the group after birth showd some increase in insulin secretion,
probably due to better insulin sensitivity.
Di Cianni et al. (2007) have found a statistically significant difference
(P<0.001) between NGT and GDM pregnant for Stumvoll first and second
phases (P<0.001). According to them, in going from one condition of glucose
tolerance to another, both insulin sensitivity and -cell function progressively
decline (29). Retnakaran et al. (2005) have obtained similar results between both
groups (NGT and GDM) in regard to Stumvoll first phase (P=0.0154) and
borderline difference for the second phase (P= 0.0590). But their HOMA-B has
been no significantly different between the two groups in opposite to our results.
Insulin secretory capability, determined by HOMA-B index and by Stumvoll
first-and second-phase indexes, reflects dynamic insulin response. Both
approaches quite clearly point tendency for deterioration of insulin secretion
with worsening of glucose tolerance (43). Some surveys assess insulin secretion
by Stumvoll first and second phase in the relation with certain indices of insulin
sensitivity as ISOGTT (43). We studied the correlation between both indices of
insulin secretion HOMA-B and Stumvoll first and second phase and
established higher correlation between GDM pregnancy (r=0,768; r=0,462) and
group after birth (r=0,764; r=0,353) with significant difference <0.001;
=0.018 for first and second phase, respectively); significant correlation
between NGT group (r=0.558 for the first phase) and the group after delivery
with statistical difference (P<0.0001). Surprisingly, there was no difference
16

between two pregnant groups. We suggest, that in this case, certain

physiological and specific to pregnancy mechanisms might influence.
It is not clear why pregnant with GDM are with higher or lower insulin
response in comparison to healthy pregnant. According to some researchers
obese pregnant with GDM have higher values for the second phase insulin
response compared to pregnant women with NGT (45).
The deterioration of -cell function in women with GDM precedes
disturbance in glucose levels with a possible progression to T2DM. It could be
suggested that -cell function in pregnant GDM women is reduced despite
impaired glucose balance only between three and 12 months after birth.
Chronically developing of -cell dysfunction is probably the dominant
pathophysiological defect progressing to T2DM in women with a history of
GDM (46). Lapolla (2008) has suggested careful monitoring of women with a
history of GDM, because compensation could be expressed during pregnancy
but -cell defect probably increases the risk of developing T2DM (47).
Buchanan hypotheses (2001) that the pancreatic -cell in pregnant with GDM
has another important feature-the ability to adapt the insulin secretion to changes
in insulin sensitivity.
Pancreatic -cell in GDM can reduce or increase the level of insulin for
maintenance of approximately constant compensation for the insulin resistance
at a level which is lower compared to healthy pregnant women (32).
Levels of PI and PIR in healthy pregnant, pregnant with GDM and post
partum
The pancreatic -cell function can be estimated also by the results
obtained in the course of the 2h OGTT measuring the relative secretion of proinsulin (PI). As it is noted upper, GDM appears when the increase of insulin
secretion is not enough to compensate for the increased insulin resistance in
pregnant women (4, 48). During normal pregnancy basal insulin needs may
17

increase almost double (49) and this increase is relevant to its permanent
character. Greater insulin secretion is produced in the postprandial period, which
is completely physiological. In this connection, "functional pancreatic reserve"
will be exceeded in a low percentage of cases (12%) which is equal with the
prevalence of GDM in normal weight population. Increased requirements led to
a stimulation rate of the processes involved in the production of secretory
vesicles. Part of pro-insulin and of pro-amilin remain, resulting in higher level
within the pancreatic -cells, but also in the peripheral circulation (50). Proinsulin levels increase together with insulin concentrations in insulin resistance
(51), but raised pro-insuli/insulin ratio (PIR), due to a disproportionate release of
pro-insulin from -cells, is considered as an early marker of islet dysfunction
(52). It is widely accepted now that insulin resistance and hyper-insulinemia 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 (4) and frequently predictive of later maternal
impaired glucose tolerance or type 2 diabetes mellitus (53).
We established that maternal levels of pro-insulin, but not of pro-insulinto-insulin ratios, significantly higher in GDM group than in NGT group
(P=0.006). After delivery, pro-insulin and PIR were significantly lower in GDM
pregnant compare to women with GDM history after delivery (P=0.022;
P=0.009 for pro-insulin and RIR, respectively). Healthy pregnant showed
difference with post-GDM women for pro-insulin and PIR (P=0.022; <0.02)
(Tabl.2). PIR could be a better marker in assessing the dysfunction of pancreatic
-cells in the early period after birth (54). Similar results for levels of insulin,
pro-insulin, HOMA-R and pro-insulin/insulin ratio in GDM pregnant compared
to NGT have been found by Wang et al. (2013) (55).

18

Lu Xu1 and et al. (2013) have established HOMA-IR and fasting plasma level
of pro-insulin increased in GDM patients compared to NGT women as glucose
tolerance status worsened (P =0.007, P = 0.012, respectively) (56).
According to our data, comparison of fasting pro-insulin in NGT and
GDM pregnant demonstrated that OR of developing GDM was 1.194 (95% CI,
1.072-1.329, P=0.001). Any subsequent increase in pro-insulin at fasting with 10
pmol/l increases the risk for developing of GDM with 19.4%.
Homko and et al. have studied the insulin secretion during late gestation
(third trimester) and postpartum. Insulin resistance remains higher in women
with GDM. They conclude that the women with GDM have a major -cell
defect with impossibility to compensate for their increased level of insulin
resistance, which occurs during late pregnancy (49). Based on data
accumulated during the last years, it can be stated that irrespectively of the type
of diabetes, the primary and probably the main -cell change could be identified
in the increase of the pro-insulin levels and of pro-insulin-to-insulin ratios (57).
It becomes evident that one of the primary -cell defects in the processing
of pro-insulin can be seen evolved in one of two distinct but parallel pathways:
the pro-insulin/insulin defect can explain the increased levels of plasma proinsulin, that is associated automatically with decreased plasma insulin levels as
well as with the mentioned defects of the insulin-secretory pattern. Increased
plasma pro-insulin levels could be seen as a common denominator for all the
diabetes phenotype, including the condition GDM (57).
More recent studies of Amara and et al. have established serum levels of
pro-insulin and the PIR significantly higher in women with GDM than the
control and reference groups during pregnancy and after delivery (P=0.0001)
(58). The increased plasma pro-insulin could be better explained by a
supplementary beta cell load due to the supplementary body fat mass which will
stimulate the production of a higher amount of insulin (55).

19

Previous studies of relative pro-insulin levels in GDM have yielded

conflicting results. Some earlier studies have signaled the presence of increased
pro-insulin and PIR in gestational diabetes compared with the NGT controls.
Kautzky-Willer and et al. have found that both serum pro-insulin and PIR
significantly higher in GDM patients compared to control subjects. They have
also reported that after delivery the PIR remained elevated (59). Increased proinsulin concentrations and a raised PIR are specific for GDM and might thus serve
as its marker and potentially even identify subjects at high risk for the
development of type 2 diabetes (59). In contrast, Hanson and et al. have not
supported the hypothesis for increased fasting PIR as a marker in later
development of type 2 diabetes or impaired glucose tolerance in former GDM
subjects (60). Swinn and et al. have studied the relationship between
abnormalities of glucose metabolism and the 32, 33 split pro-insulin. They have
reported elevated levels of such pro-insulin in GDM patients both fasting and
120-min versus pregnant normoglycemic control subjects (61).
Furthermore, Festa and et al. have investigated the levels of pro-insulin,
specific insulin (SpI) and PI/SpI ratio consecutively in pregnant women with
normal glucose tolerance and with GDM, in comparison to healthy, non-pregnant
women. They have found no significant differences in the levels of PI and the
PI/SpI ratio between pregnant and non pregnant women, and between pregnant
women with GDM and NGT. So, they have suggested that in normoglycemic
pregnancy as well as GDM pregnancy, metabolic alterations with enhanced
insulin resistance and hyperglycemia do not result in increased circulating levels
of specific insulin, as indicated by PIR (62).
Several factors may contribute to the lack of consistent findings in these
studies. These factors include differences among the study populations with
respect to severity of glucose intolerance, body weight, and hepatic insulin
extraction. Finally, description of the basal PIR is useful for characterising the cell status (61).
20

Rentnakaran and et a. (2005) have established that the relative PI secretion

in late pregnancy is primarily associated with insulin resistance, but do not always
reflects -cell function. It looks likely that women with a history of GDM could
develop relative hyperpro-insulinemia for a long time in tandem with progressive
-cell dysfunction thus leading to the development of T2DM (63).
In our study, the pregnant women presented a metabolic pattern
suggestive of enhanced insulin resistance, namely increased fasting insulin
levels and HOMA-IR. It was demonstrated by the mean values of plasma fasting
insulin and HOMA-IR significantly higher in GDM women compared to the
NGT group (P=0.02; P<0.0001) and women after delivery (P<0.01; P=0,017).
Statistically significant difference between healthy pregnant and women after
delivery (P<0.01; P=0.004) was found (Tabl.1).
We established, that the comparison between fasting insulin and fasting
glucose in NGT and GDM pregnant demonstrated the OR of developing GDM
1.117 (95% CI, 1.042-1.197, P=0.002 for insulin and 1.81 (95% CI, 1.011-2.311,
P=0.001) for glucose at fasting. Any subsequent increase in fasting insulin level
with 10 U/ml increases the risk of developing of GDM with 11.7%.
Based on the pronounced insulin resistance in studied individuals, we
established high correlation between pro-insulin in fasting and HOMA-IR
r=0.851 in NGT group; r=0.891in GDM pregnant (without statistical
difference); and r=0.915 in women after delivery (P<0.0005; P<0.0002
compared to healthy pregnancy and GDM, respectively). We hypotheses that
relative pro-insulin secretion in late pregnancy and after delivery is associated
with pronounced insulin resistance, so as the existing beta-cell dysfunction.
After the pregnancy, women with GDM history have a chronic defect in -cell
function in response to the severe insulin resistance of late pregnancy (7, 64) and
an increased risk of developing type 2 diabetes. HOMA-IR assessment results
are predictor of postpartum -cell dysfunction (65).

21

After the pregnancy, women with GDM history have a chronic defect in
-cell function in response to the severe insulin resistance of late pregnancy (7,
64). HOMA-IR assessment results are predictor of postpartum -cell
dysfunction (65). Women with gestational diabetes have a higher risk of
developing type 2 diabetes or altered glucose metabolism after delivery (66-69).
The cumulative incidence of T2D is highest in the first 5 years after pregnancy
and then it decreases, reaching a plateau at ten years postpartum (66). Various
factors influence this process. The majority of women with GDM have -cell
dysfunction that appears on a background of chronic insulin resistance - the
main pathophysiological factors of GDM just as they are for diabetes outside of
pregnancy (70). Xiang and et al. have considered that the elevated blood glucose
levels and reduced -cell function are indicators of the progression from normal
to impaired glucose tolerance and diabetes (34). Similar opinion is expressed
also by other researchers (6, 45, 71). Seghieri and et al. suggest that the -cell
function could be improved over time in women with a history of GDM. This
supposed phenomenon could be proven for years after birth. Secretory
impairment stands out as the dominant pathophysiological feature of gestational
diabetes. Women who maintain insulin resistance into the post-gestational
period are at heightened risk of incident diabetes (72).
Based on the examined indicators glucose, insulin and pro-insulin at fasting,
PIR, Stumvoll first- and second phase, HOMA-B and HOMA-IR we created a
mathematical model assessing beta cell function and risk of developing type 2
diabetes. We found that pregnant women with GDM and beta-cell dysfunction
are at higher risk of developing type 2 diabetes (94.4%), followed by women
with a history of GDM -74.4%. Healthy pregnant women have the lowest risk of
developing diabetes only 0.6% (Fig 1).

22

Beta-cell dysfunction and risk of type 2 diabetes

Fig 1

Impact of BMI on insulin sensitivity, assessing by QUICKI and HOMA-S%

indices
Obesity is one of todays major public health problems in different
countries. It is increasing at an epidemic rate in women of reproductive age.
Estimates suggest that 1835% of pregnant women in the USA are clinically
obese (73). Obesity in pregnancy is strongly associated with the development of
gestational diabetes (74, 75). There are numerous studies in the U.S. reporting
an increased risk of GDM among women who are overweight or obese
compared with normal-weight women (76). Maternal obesity increases the risk
of a number of pregnancy complications, including pre-eclampsia, cesarean
delivery, adverse outcome of pregnancy for mother and child, not only
23

gestational diabetes (77). Pre-pregnancy BMI is increasingly recognized as a

major determinant of pregnancy outcome. Several large cohorts, systematic
reviews and meta-analyses have attempted to provide accurate risk estimates for
specific complications relative to maternal obesity (78-82). Obese pregnant have
a 3-fold higher risk of developing GDM in late pregnancy than pregnant women
with normal body weight (78). Many studies have found association between
weight gain during pregnancy and the risk of GDM (80), and the degree of this
association remains uncertain (78).
Excessive weight gain during pregnancy and postpartum retention of
pregnancy weight are significant risk factors for later obesity and related
disorders in women (83). It has been found that in Finnish obstetric population
the maternal morbidity rises markedly when comparing overweight (BMI 26
to 29 kg/m2) vs. obese (BMI 30 kg/m2) women: the incidence of maternal
diabetes, hypertension, chronic diseases (84).
Our study evaluated the impact of BMI on some laboratory parameters
assessing insulin sensitivity (QUICKI, HOMA-S% indices), insulin resistance
(HOMA-IR) and leptin in pregnant women with NGT, GDM and postpartum
(Tabl 2).

24

Table 2. Characteristics of the patients metabolic parameters-part 2

Table 2.
Characteristics

BMI (kg/m2)

Pregnant with NGT

Pregnant with GDM

After delivery

(n1=49)

(n2=53)

(n3=22)

26.83 5.54

30.54 6.9

27.90 6.27

Statistical
significance
<0.05
=0.011
<0.001
<0.0001

Leptin at fasting
(ng/ml)

8.49 5.38

16.96 11.89

4.83 4.2

=0.002
<0.0001

HOMA-S%

113.24 64.7

81.15 54

115 76

=0.002
<0.0001

QUICKI

0.65 0.1+

++0.5 6 0.11+

++0.63 0.14

=0.001+
0.001++

Pro-insulin at
fasting (pmol/l)

3.94 2.78*

Proinsulin/insulin
ratio at fasting

0.4 1 0.14

7.59 5.27*

4.46 1.14

=0.006*
= 0.022

0.46 0.16

0.14 8 0.031

=0.009
< 0.02

Pregnancy BMI was calculated and categorized according to the World

Health Organization guidelines: underweight (BMI 18.5), normal weight (BMI
18.524.9), overweight (BMI 25.029.9), obese class I (BMI 30.034.9), obese
class II (BMI 35.039.9), and obese class III (BMI 40.0) (85).
We used the self-reported weight in kilograms (kg) and the height
measured during the interview in squared meters (m2) to calculate maternal BMI
(kg/m2). We suspect that overweight and obesity, evaluated through BMI, are
significant risk factors for GDM developing. Obtained results from our patients
are as following: in the GDM group overweight pregnant (BMI 25-30 kg/m)
women are n=26 (49%), obesity pregnant women (BMI 30 kg/m) are n=22
(40.8%). In NGT group women with normal BMI (18.5 24.9 kg/m)
predominated n=20 (40.8%) and with overweight n=17 (34.6%). Postpartum
group is presenting predominantly of overweight and obese women n=17
25

(76.5%). Our observations confirmed that the prevalence of overweight and

obesity before and during pregnancy are important risk factors for GDM
developing. In this connection compared pregnant women with NGT and GDM
(BMI 26.835.54 and 30.566.9, p0.011 respectively) (Tabl.2) demonstrated
that the OR of GDM developing was 1.099 (95% CI, 1.028-1.176, P=0.006).
The increasing of BMI index with 1kg/m2 increased the risk of GDM developing
with 9.9%. Our data confirmed the trend towards overweight and obesity in
women of reproductive age in the Bulgarian population. This trend continued
during pregnancy and after birth - the body weight does not tend to return back
to normal values, but remains higher and these women are defined
predominantly as women overweight and obese.
Similarity results are obtained in two meta-regression analyses that the
odds ratios for developing GDM were 1.972.14 in overweight (BMI 25
kg/m), 3.013.56 in obese (most studies BMI 30 kg/m) and 5.558.56 in
severely obese (BMI 3545 kg/m) women compared with normal weight
women. These results confirm that maternal overweight (BMI 25 kg/m) has
been shown to be the strongest risk factor for GDM (78).
In late gestation, the normal reduction in peripheral insulin sensitivity of
50% (86) is reduced in obese women as determined by the quantitative insulin
sensitivity check index and that insulin sensitivity in women with GDM
worsened as gestation progressed (27). ISOGTT, ISQUICKI, and ISHOMA significantly
correlated with a direct measurement of insulin sensitivity using the euglycemichyperinsulinemic clamp during pregnancy. The ISQUICKI has been validated
against the euglycemic-hyperinsulinemic clamp and was found to have a good
linear correlation (r2 = 0.61) (45).
The quantitative insulin sensitivity check index (QUICKI) an empiricallyderived mathematical transformation of fasting blood glucose and plasma
insulin concentrations (87, 88). QUICKI is a simple, robust, accurate,
reproducible method that appropriately predicts changes in insulin sensitivity
26

after therapeutic interventions as well as the onset of diabetes (89). QUICKI has
been seen to have a significantly better linear correlation with glucose clamp
determinations of insulin sensitivity than minimal-model estimates,
especially in obese and diabetic subjects (90). It is calculated and used to
evaluate of insulin sensitivity (91), including during early and late pregnancy
(19). QUICKI index is defined as follows: QUICKI=1/[(log(Ins0)+log(Glu0)],
where Ins0 is the fasting plasma insulin level (U/ml) and Glu 0 is the fasting
blood glucose level (mmol/l) (91).

The index assumes that the circulating

glucose and insulin are determined by a feedback loop between the liver and
pancreatic -cells (92).
The precise mechanisms regulating insulin sensitivity are uncertain; it
would appear that pre-conceptual fat mass is a major determinant. Lean women
exhibit an inverse correlation between changes in insulin sensitivity and fat mass,
which is not seen in obese women (93). Obese women exhibit a negative
relationship between the decrease in insulin sensitivity and accretion of fat mass
from pre-pregnancy to late gestation (94).
Human pregnancy is characterized by the occurrence of a series of
metabolic changes that contribute to fat accumulation as part of physiologically
increased body weight during pregnancy. The insulin sensitivity during the
pregnancy is related with the amount of maternal energy metabolism and
visceral fat accumulation. Visceral fat volume in human body has important
biological meaning, which is well expressed during the pregnancy. In this
relation the influence of visceral fat, respectfully BMI on the insulin sensitivity
is too important. In this connection, we sought the influence of BMI on insulin
sensitivity, assessing by QUICKI index. We found a statistically significant
difference between GDM and healthy pregnant, between pregnant with
gestational diabetes and women after delivery (P=0.001; P0.001, respectively)
(Tabl.2). No difference was found between healthy pregnant women with
gestational diabetes history because the QUICKI index absolute values were
27

similar in this groups. We assume that the elimination of the placental hormones
with subsequent normalization of hormonal balance and reduced adipokine
levels in this period of 2-3 month after birth contribute to improved insulin
sensitivity.
When we evaluated the BMI effects over insulin sensitivity, we
established a reverse, well expressed correlation between QUICKI-IS and BMI
in the both pregnancy groups (r= -0.458 for NGT and r= - 0.603 for GDM; NS)
and r=-0.729 for women after delivery (P0.0001 compare to GDM pregnant).
Our results were similar to data of other authors. Yilmaz . et all (2010)
have announced diminished insulin sensitivity in pregnant women with GDM
compare to NGT for BMI (P>0.05) with significantly higher body fat percentage,
expressed by connection QUICKI index - BMI (r=0.384, P<0.01) (95). Values
of QUICKI index in overweight women with NGT and in women with GDM
have been significantly (P< 0.01) lower than those in normal-weight women
with NGT, and QUICKI in women with GDM has been decreased significantly
(p < 0.05) during pregnancy, according to Endo S and et all. (27). Furthermore, J.
Hauth and et all. (2011) have reported significant interaction between race and
BMI (under/normal weight, overweight/obese) for glucose, insulin and HOMAIR at or above the 75th percentile and QUICKI less than the 25th percentile in
mid-trimester (96).
It is known that overweight predisposed women to impaired glucose
metabolism during pregnancy. In this connection Vhmiko and et all. (2010)
have detected lower levels of QUICKI index in overweight compared to normalweight women at third trimester of pregnancy (97).
Insulin sensitivity has been modeled by proportionately decreasing the
effect of plasma insulin concentrations at both the liver and the periphery (98).
Other parameter to assess insulin sensitivity is HOMA-S%. The computer model
can be used to determine insulin sensitivity (HOMA-S%) from paired fasting
plasma glucose and insulin concentrations. The data from individual subjects
28

determine unique combinations of insulin sensitivity (HOMA %S) and beta cell
function (HOMA %B) from steady-state conditions (99). HOMA-S% was
calculated using the validated calculator available at www.dtu.ox.ac.uk. HOMA
can be used to track changes in insulin sensitivity and -cell function in
individuals. Also, it can be used in individuals to indicate whether reduced
insulin sensitivity or -cell failure predominates. Determination of HOMA-%S
is used to establish the prevailing normal over a normoglycemic population in
each comparative group (17).
In the present study, we examined else the differences in the insulin
sensitivity index HOMA %S between women with NGT, GDM, postpartum and
the influence of BMI on it. The HOMA-S% values, which used to assess insulin
sensitivity, were progressively lower in GDM pregnancy, compare to NGT and
after GDM delivery (P=0.002; P0.0001) (Tabl.2) without difference between
healthy pregnancy and postpartum. Other studies present similar results for
HOMA-S%, compared GDM to normal pregnant (100, 101)
Our study evaluated insulin sensitivity and secretion 11-14 weeks
postpartum, where fasting glucose levels were in normal range (5.330.79)
mmol/l (Tabl.1). There are a number of studies, including a large number of
women, tested for glucose metabolism abnormalities for year or more with
history of GDM. In our analyses we used HOMA S% and HOMA-B which are
non-invasive, indirect methods, but considered reliable in the medical literature
(102). Presented by us results for women with GDM history showed decrease
insulin secretion (statistically lower levels of HOMA-B, DI0), accompanying
insulin resistance, but without difference between insulin sensitivity indices
(QUICKI and HOMA-S%), compare to NGT. Insulin resistance was associated
with higher BMI and higher adipose tissue. We assume that women with a
history of GDM and state of normoglycemia showed impairment -cell function
on the background of normal insulin sensitivity. Studies in women with previous
GDM determinates different results for HOMA-S% - without statistical
29

difference (103) and significantly lower HOMA %S (P=0.004) compared to

controls (104).
In our study we established expressed negative correlation between
HOMA S% and BMI as following: NGT r=-0.467, GDM r=-0.679 and in group
after GDM r=- 0.697 without statistical difference between two pregnant groups.
Women after delivery showed difference with NGT and GDM pregnant
(P0.0001; P0.0003, respectively).
This results we presented graphically as following: Fig 2, 3, 4.

Correlation between HOMA-S% and BMI in NGT group

Fig 2

Linear Regression

2 00 ,0 0

HOMA %S

1 00 ,0 0

0 ,00

2 0,0 0

3 0,0 0

HOMA %S = 261,30 + -5,52 * BMI

R-Squar e = 0,22

4 0,0 0

BMI

30

Correlation between HOMA-S% and BMI in GDM group

Fig 3

Linear Regression

2 50 ,0 0

2 00 ,0 0

HOMA %S

1 50 ,0 0

1 00 ,0 0

5 0,0 0

2 0,0 0

3 0,0 0

HOMA %S = 217,55 + -4,47 * BMI

R-Squar e = 0,32

4 0,0 0

BMI

31

Correlation between HOMA-S% and BMI in after - GDM group

Fig 4

Linear Regression

2 00 ,0 0

HOMA %S

1 00 ,0 0

0 ,00

2 0,0 0

3 0,0 0

HOMA %S = 354,78 + -8,59 * BMI

R-Squar e = 0,50

4 0,0 0

BMI

According to our opinion, these results could be explained with the

metabolic changes occurring in pregnancy-normal and with gestational diabetes.
Pregnancy is a physiological condition of IR and it is a result of increased
placental hormonal production such as estradiol, progesterone, placental
lactogen, etc. that reduce the insulin sensitivity and contribute to accumulation
of fat mass in the period of early pregnancy (106). Metabolic changes in the
direction of fat accumulation, changes in insulin sensitivity, secretion and
resistance are more pronounced in pregnant women with GDM. A large number
of reports show the role of adipose tissue in the expression of insulin resistance
in pregnant and non-pregnant women. In this regard, adipokines, released from
adipose tissue, are examined as participants in the regulation of metabolism and
maternal gestational IR (107).

32

We assume that the elimination of the placental hormones with

subsequent normalization of hormonal balance and reduced adipokine levels in
this period of 2-3 months after birth contribute to the improvement of insulin
sensitivity.
Changes occurring during pregnancy affect overall the normal physiology
of women with a history of GDM. Insulin levels are lower than those in women
without a history of GDM, and corresponding to the existing degree of IR.
Development of progressive loss of the ability of -cell to compensate for IR
leads to a slow rise in glucose levels. Relatively late in this proces, the glucose
levels begin to rise rapidly to the expressing of hyperglycemia and diabetes, the
most common when -cell compensation decreases with approximate 10% of
the normal response (34).
Pregnancy is characterized by progressive insulin resistance, the degree of
which is further accentuated in women with gestational diabetes mellitus (108).
Obese pregnant women often enter into pregnancy with mild insulin resistance,
which is associated with hyperinsulinemia. The incidence of GDM in obese
mothers is nearly double compared to mothers of normal BMI (109). Recent
estimates indicate that 32% of women in reproductive age (2039 years) are
obese (110). GDM pregnant women have more pronounced insulin resistance
and glucose intolerance than pregnant women with normal BMI (106), but the
underlying mechanisms remain elusive (116).
Multiple studies have linked absolute maternal weight gain to the risk for
GDM, especially pre-pregnancy BMI (111,112, 113) that represents an
important modifiable risk factor. High rates of gestational weight may increase a
womans risk for GDM. Gestational weight gain is a significant risk factor for
GDM with stronger association for obese pregnant (114, 115).

33

HOMA-IR method for assessing of the insulin resistance during

pregnancy and after delivery
For assessment of insulin resistance HOMA-IR was used in our study. In
more than 500 publications, the estimation of IR has been reported at about 20
times more frequently than -cell function (117). Our data pointed HOMA-IR
value higher in women with GDM than in those with NGT during the third
trimester of pregnancy as well as in the postpartum period (P0.0001; P=0.017).
Significant difference between NGT pregnant and women after GDM (P=0.004)
was found. These results are similar to those of other authors (118, 119, 120,
121). There are also reports with no established difference in HOMA-IR levels
between GDM and NGT controls (122,123,124,125).
Our goal was to define the predictive value of HOMA-IR, fasting plasma insulin
and glucose at 60 min in the third trimester, expressed by OGTT results among
NGT and GDM pregnancy as predictive marker for IR development. Sensitivity
and specificity calculations with ROC analysis were in use.
The optimal HOMA value for diagnosis of insulin resistance was
established with Receiver Operating Characteristic (ROC) scatter plot. Each
point on the ROC plot represents a sensitivity/specificity pair corresponding to a
particular decision threshold. Test with perfect discrimination has a ROC plot
that passes through the upper left corner (100% sensitivity and 100% specificity).
The ROC plot for HOMA is close to the upper left corner, indicating greater
overall accuracy of the test (Fig 5). To calculate the sensitivity and specificity of
diagnostic tests, we used this cutoff point.
The present HOMA cut-off point for diagnosis of insulin resistance of 1.8
yielded a sensitivity of 77.4% and a specificity of 40.8%. HOMA-IR score and
insulin resistance levels were higher in GDM women in our population.
In a study from Turkey, a cut-off value of 2.60 for the first trimester
HOMA-IR gave 100% sensitivity and 94% specificity (126). Caudana L et al
reported fasting glycemia to be the best predictor of GDM with an equal
34

predictive value to insulin and HOMA-IR (127). According to the International

Diabetes Federation criteria, the HOMA-IR cut-off point to differentiate
between low and high insulin resistance is 2.38, several previous studies
performed on smaller populations have demonstrated that HOMA-IR index
assessed at diagnosis of GDM is ranged from 1.6 to 25 (128).
ROC curves for indexes of insulin resistance
Fig 5

HOMA-IR has a statistically significant impact on development of the

insulin resistance in NGT compared to pregnant with GDM and demonstrated
OR=0,760 (95% CI, 0,668-0.853, P0.0001). It was found that HOMA-IR is
more reliable as risky factor to development of IR than fasting plasma insulin
OR=0,677 (95% CI, 0,573-0.781, P=0.002, sensitivity 54.7% and specificity
24.5%) and glucose at 60 min (OR = 0,710 (95% CI; 0,609-0.811, P0.0001

35

with sensitivity 73.6% and specificity 49%). This suggests that HOMA-IR is
more appropriate for use in large scale epidemiological studies.
Finally, HOMA-IR was found with statistically significant impact on
developing of GDM - OR = 2,039 (95%, CI, 1.427- 2.914, P0,0001). The
increasing of HOMA-IR index with unit increases the risk of GDM developing
about 2 times.
Based on our dataset, predictive threshold values for developing of IR in
gestational pregnant are HOMA IR >1.8; FPI >12 lU/ml and glucose at 60 min
>6.95 mmol/l.
In our study we established a positive correlation between BMI and
HOMA-IR as following: in NGT group r=0.485; in GDM pregnant r=0.594; in
group after GDM r=0.639 without statistical difference between two pregnant
groups. Women after delivery showed difference between NGT and GDM
pregnant groups (P0.0002; P0.0001, respectively). Our results are similar to
those of others studies (129, 116, 130).
Leptin and pregnancy. Relationship between leptin, BMI, insulin
resistance and insulin sensitivity (QUICKI index)
Gestational diabetes mellitus is more common in pregnancies and
complicated by obesity. However, as might be anticipated from the increased fat
mass, obese pregnant women demonstrate elevated circulating concentrations of
leptin and raised levels of inflammatory mediators (131). Adipose tissue is not
only involved in energy storage but also functions as an endocrine organ that
secretes various bioactive molecules adipokines. They are involved in a wide
range of physiological processes, including haemostasis, lipid metabolism,
atherosclerosis, blood pressure regulation, insulin sensitivity and angiogenesis.
Some of them also influence immunity and inflammation (132). The role of
adipose tissue and circulating adipokines in regulating maternal glucose
homeostasis has been recently recognized as an important component in the
development of glucose intolerance and insulin resistance (116).
36

Leptin is involved in a number of physiological processes, particular it

increases insulin sensitivity by influencing insulin secretion, glucose utilization,
glycogen synthesis and fatty acid metabolism (132). In normal pregnancy
circulating leptin levels reach two- to three-fold higher concentrations as
compared to non-pregnant conditions with a peak occurring around 28 weeks of
gestation and a decrease to pregravid concentrations observed immediately after
delivery (133). There is strong evidence that the placenta, rather than maternal
adipose tissue, contributes a substantial part to the rise in maternal leptin
concentrations during pregnancy (134). In gestational diabetes data on leptin
have been controversial. Changes in leptin levels in pregnant women with GDM
are a subject of interest and focus of numerous studies. Most studies have found
increased leptin concentrations in GDM (135, 136, 137, 138). Higher leptin
level in early pregnancy appears to be predictive factor of an increased risk to
develop GDM later in pregnancy independent of maternal adiposity (139).
Kautzky - Willer et al (2001) have found conection between leptin and
parameters of glucose metabolism in pregnant with GDM. Hyperleptinemia
could be considered as marker for latent metabolic syndrome manifested as
GDM (137). Mokhtari et al (2011) have not found significant differences
between GDM and normal pregnant women regarding leptin levels (140). In fact,
prevailing opinion is that GDM is associated with an increased level of leptin
(141, 142, 143, 136). These discrepancies may be partly attributed to differences
in severity of GDM (145) or to ethnic differences (132).
In our study we established higher leptin level in pregnant with GDM in
comparison to NGT and after GDM (P=0.002; P0.0001); between
normotolerant pregnant and after birth (P0.0001) because a decrease to
pregravid leptin concentration observed immediately after delivery (Tabl.2).
Comparison between leptin level in pregnant women with NGT and GDM
demonstrated that OR of GDM development was 1.115 (95% CI, 1.052-1.181,

37

P0.0001). The increasing of leptin with 10 ng/ml increases the risk of GDM
development with 11.5%.
Qiu et al (2004) have noted linear correlation between increased maternal
plasma leptin and increased risk of GDM with each 10 ng/ml increase in leptin
concentration being associated with a 20% increase in GDM risk (139). Increase
in leptin concentrations before the onset of GDM has been shown by other
authors (144). Strong linear correlation between increased maternal plasma
leptin and increased risk of GDM has been found (144). Some researches have
found correlation between high leptin level and increased risk of GDM in
pregnant women (135, 145,146). Other studies have reported an inverse
relationship (143, 148).
There are several possible explanations why the existing studies are not in
complete agreement, the most likely being differences in study design and the
timing of maternal blood collection (ie, gestational age) may likely account for
some of the variability seen across studies. Distortions from uncontrolled
confounding secondary to whether blood samples were collected before, after, or
during labor; receiving pharmacologic and dietary therapy after diagnosis and
before blood was collected for leptin determination. Variations in population
characteristics and dissimilar distributions of the severity of GDM could also
account for some of the observed differences in study results (144).
Maternal body mass considerably changes during pregnancy. BMI is
related to maternal serum leptin due to the increase in maternal body weight that
occurs with increasing gestational age. In non-pregnant women plasma leptin
relates to BMI and body fat mass. Similar correlation is observed during
pregnancy (149), but Masuzaki et al. (2005) have reported conflicting results
(150). A number of studies have established that pregnancy leptin level
correlates with pregnancy BMI (116, 137, 147,151, 152). Others

have found

that leptin correlates well with pre-pregnancy BMI (137, 139, 153), gestational
weight gain (154) and relates to BMI post partum (137).
38

In our study we found a higher positive correlation between pregnancy

BMI and leptin particularly in pregnant group with GDM r=0.914, in NGT
group r=0.763 without difference (NS), in group after pregnant r=0.629
(statistically different with GDM P0.04). Kautzky-Willer et al. have obtained
correlation coefficient r=0.51 (P<0.0002) between leptin and BMI in GDM
pregnant examined by them at 28 gestational week, but similarity to us after
delivety (r=0.67, P0.00001) (137).
Some studies have found a significant positive correlation between BMI
values and level leptin (155, 142, 144, 146, 156). Jie Xu et al (2008) have found
in their meta-analysis PICOS that plasma leptin concentrations has remained
significantly higher in GDM patients compared to their BMI matched control
subjects and have concluded that maternal weight in GDM seems to have less
important role in modifying cytokine levels (138).
Body fat mass has steadily increased from 15 to 35 weeks of pregnancy
and has gone down rapidly after delivery. At all time points, maternal BMI has
strongly correlated with leptin (157). Schubring C et al (1999) have established
correlation coefficient of 0.81 between maternal leptin serum levels and BMI at
68 weeks of pregnancy (158). This coefficient has gone down to 0.50 at birth
and has gone up to 0.76 six weeks after delivery (157). We assume that the
lower correlation between BMI and leptin et early postpartum are because of a
change in fluid collection and lack of placental production of leptin. It has been
shown that the leptin production per unit fat mass is higher in pregnancy than
after delivery (154). In this connection maternal leptin levels are the sum of
leptin secretion from adipose tissue, which is proportional to maternal fat levels,
and from the placenta, which occurs at an adiposity-independent rate. This
explains why maternal leptin levels do not correlate well with body mass index
(BMI) at low BMI values, but do show a correlation with higher BMIs (159).
Pregnancy is characterized by an increase in weight, body fat mass (160)
and by varying degrees of progressive insulin resistance (70). During normal
39

pregnancy, circulating levels of several adipocytokines, inclusively leptin, rise.

This increase in adipocytokines levels during pregnancy may be implicated in
the development of insulin resistance during pregnancy (161). The role of
adipose tissue and circulating adipokines in regulating maternal glucose
homeostasis has been recognized as an important component in the development
of glucose intolerance and insulin resistance (116). Leptin plays an important
role in glucose metabolism and acts as a metabolic and neuroendocrine hormone
(162).
In our study we found high positive correlation between leptin and
HOMA-IR with higher level in normal pregnancy r=0.780, r=0.629 in GDM
pregnant and r=0.735 in women postpartum. Significant difference between
pregnant with gestational diabetes and group after GDM (P0.00003) and lack
of difference between pregnant groups (NS) were established. The present
results are in agreement with those of Maghbooli et al. (146), Soheilykhah S et
al (142), (163). Higher plasma leptin concentrations are observed in noticeably
insulin-resistant women with GDM both during pregnancy and post-partum
when compared with hyperglycemic pregnant women (137). Eriksson et al. have
established that serum leptin significantly correlated with HOMA-IR before
pregnancy and in gestational weeks 14 and 32, but not postpartum in (164).
Correlation between leptin in serum and insulin resistance has also been found
in a group of pregnant women including women with gestational diabetes (147).
It is intriguing that serum concentrations of leptin correlated with HOMA-IR in
our healthy women, in agreement with previous observations by Eriksson et al.
Leptin concentrations in the NGT and GDM groups have correlated significantly
with HOMAIR (Skvarka at al, 2012) (165). Similarity results have been found
by Lio H et al. (2012) in NGT and GDM groups during late pregnancy (36 - 38
weeks) and 6 weeks post-partum (167). We would like to note that the obtained
correlation coefficients for the relationship between leptin and HOMA-IR were
higher than those obtained in the above-cited studies.
40

Saucedo et al. (2011) have established that women with GDM show
higher insulin resistance, but after pregnancy leptin and insulin resistance
remain elevated and glucose tolerance worsens (167). Yilmaz et al. (2010) have
not found any correlation between leptin levels and insulin resistance (96).
Unfortunately, we did not find enough evidence of the relationship
between leptin and insulin resistance in women with a history of GDM three
months after birth.
Furthermore, recent studies have found that the rise in leptin levels during
pregnancy is correlated with the decline in insulin sensitivity. There is an
inverse correlation between leptin and insulin sensitivity during late pregnancy
(145, 137, 147) and postpartum (147). Yilmaz et al. (2010) have found negative
correlation between leptin levels and insulin sensitivity, using QUICKI index
(96).
Leptin as potential mediator of insulin resistance has correlated inversely
with changes in insulin sensitivity in late pregnancy, but to a far lesser degree
(145). Whereas the placenta appears to be a primary site of maternal leptin
production (168), secretion from the fat cells is also important, and plasma leptin
is positively correlated with level of obesity (169). In this regard, Vhmiko et
al (2010) have found negative association between leptin and QUICKI in late
pregnancy for normal weight women (r=-0.484, P=0.011) and overweight
women (r=- 0.711, P0.001)(98).
Since adipocytokines are secreted from adipose tissue and relate strongly
to adiposity, it is important to match for adiposity to remove it as a confounding
factor, when investigating the possible role in GDM (147).
In our study we found high negative correlation between leptin and
insulin sensitivity, using QUICKI index, with higher level in normal pregnancy
r= -0.740, in GDM pregnant r= -0.78 without difference between groups, and r=
-0.630 in women postpartum with normal glucose tolerance. Significant
difference was established between pregnant with gestational diabetes and group
41

after GDM (P0.003). Our results are consistent with those obtained by other
researchers studied populations of pregnant women with NGT and GDM (96,
146). Our observation of reduced insulin sensitivity in women with GDM
postpartum is in keeping with the findings reported by previous investigators
(170). Leptin functions at the periphery as a paracrine/autocrine factor capable
of modifying insulin sensitivity, tissue metabolism, stress response and
reproductive functions (171).
Most studies have investigated leptin in normal pregnancy and pregnancy
with GDM as factor for insulin resistance. Increased leptin levels have been
implicated in the increased insulin resistance in pregnancy (172). Animal
models characterized by reduced-leptin signaling show hyperphagia, obesity,
and insulin resistance (173), and leptin management improves insulin sensitivity
and glucose metabolism in these models (174).
The normal pregnancy is considered as a state of leptin resistance, which
is associated with impairment of leptin signaling in the hypothalamus (175).
Available hyperinsulinemia may stimulate leptin production. On the other hand
the elevated leptin levels increases inflammation and enhance leptin resistance
(176). Growing body of evidence has been accumulated showing that the
adipose tissuederived hormone leptin directly acts on pancreatic -cells, on
both insulin secretion and insulin biosynthesis. Leptin seems to represent a
signaling molecule from the adipose tissue to the endocrine pancreas to restrict
insulin secretion. This effect establishes an adipo-insular transmission of
signals from the adipocyte to the pancreatic -cell (177). There are a lot of
arguments, indicating that the adipo-insular axis also physiologically regulates
insulin secretion and leptin production in humans (178). The adipo-insular axis
may, however, plays an important role during the development of type 2
diabetes in obese individuals (177).
After birth, women with a history of GDM have a higher risk of
developing T2DM, metabolic syndrome and often found expression of markers,
42

associated with the endothelial dysfunction and a change in the ratio of intimamedia of the carotid arteries (179). It has been suggested different factors which
are considered risk factors for developing of T2DM in women with a history of
gestational diabetes. A number of studies have indicated that previous GDM is
associated with a significant reduction in insulin sensitivity, insulin secretion or
both in women who maintain NGT at follow-up ( 46, 59, 170). Research of
Seghieri et al. (2007) has showed that even in the absence of significant insulin
resistance, beta cell dysfunction can still be detected in normotolerant women
with previous GDM (180). Several risk factors for postpartum diabetes have
been identified, some of which are potentially modifiable whereas others are not
(180, 181).
In the context of the spectrum disorders of glucose homeostasis in GDM
and identifying the risk of developing diabetes in the future, the
pathophysiological changes in the early postpartum period may have appropriate
expression of this risk potential. Usually gestational hyperglycemia is
normalized after birth, but -cell defect in women post- GDM still exists for a
period of time after delivery (46).
Violations in -cell function and reduction of -cell mass have a crucial
role in the progression to type 2 diabetes. There are more evidences that
inflammation plays a key role in the pathogenesis of type 2 diabetes. Evidence
exists for the role of pro-inflammatory mechanisms and in the development of
GDM. Increased markers of oxidative stress and impaired antioxidant protection
have been identified in patients with T2DM and pregnant with GDM (182).
Based on the examined laboratory parameters and indexes such fasting
glucose, insulin and pro-insulin at fasting, HOMA-B and HOMA-IR, pregnancy
BMI and leptin at fasting, we created a mathematical model assessing beta cell
function and risk of developing type 2 diabetes. Pregnant women with GDM,
higher insulin resistance and beta-cell dysfunction are at higher risk of
developing type 2 diabetes (73 %), followed by women with a history of GDM 43

65 %. Healthy pregnant women have the lowest risk of developing diabetes

only 1.7% (Fig 6).
Mathematical model assessing beta cell function and risk of developing of type 2 diabetes.
Fig 6

44

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