These authors contributed equally to this work.
Intrauterine insulin resistance in fetuses of overweight mothers
Article first published online: 13 JUN 2012
© 2012 The Authors. Journal of Obstetrics and Gynaecology Research © 2012 Japan Society of Obstetrics and Gynecology
Journal of Obstetrics and Gynaecology Research
Volume 39, Issue 1, pages 132–138, January 2013
How to Cite
Liu, B., Xu, Y., Liang, J.-m., Voss, C., Xiao, H.-y., Sheng, W.-y., Sun, Y.-h. and Wang, Z.-l. (2013), Intrauterine insulin resistance in fetuses of overweight mothers. Journal of Obstetrics and Gynaecology Research, 39: 132–138. doi: 10.1111/j.1447-0756.2012.01919.x
These authors contributed equally to this work.
- Issue published online: 7 JAN 2013
- Article first published online: 13 JUN 2012
- Received: September 12 2011.; Accepted: March 21 2012.
- development origins of health and disease;
- gestational diabetes mellitus;
- insulin resistance;
- sex hormone binding globulin
Aim: To investigate the relationship between maternal overweight and fetal insulin resistance.
Material and Methods: Nineteen overweight and 30 lean pregnant women were recruited in the present study. Maternal and fetal insulin resistance were determined by measuring sex hormone binding globulin (SHBG) concentrations in maternal venous or umbilical cord serum, respectively. Maternal age, gestational age, height, pre-gravidity weight, pre-partum weight, as well as fetal gender, birth weight, birth height, and head circumference were collected as clinical data.
Results: Fetuses of overweight mothers had larger birth weight (3.58 ± 0.55 kg vs 3.32 ± 0.42, adjusted P = 0.006) and lower SHBG concentrations (26.64 ± 3.65 vs 34.36 ± 7.84, adjusted P = 0.007) than those of lean mothers after values were adjusted for potential cofactors. Fetal SHBG level was negatively correlated with pre-gravidity body mass index (R = −0.392, adjusted P = 0.025) and weight gain during pregnancy (R = −0.332, adjusted P = 0.026) even with adjustment for potential cofactors. Among the 29 pregnant women with gestational diabetes mellitus, the overweight mothers had higher H1AC levels than their lean counterparts (6.47 ± 0.44 vs 5.74 ± 0.52, adjusted P = 0.004).
Conclusion: Intrauterine insulin resistance is more prominent in fetuses of overweight mothers, an effect that is decreased by weight gain control during pregnancy.
The intrauterine environment has a substantial influence on the health and disease state of a fetus in both the short- and long-term.1–3 The long-term effects of the intrauterine environment on the offspring have been generalized in the ‘developmental origins of health and disease (DOHaD)’ theory.4,5 Maternal obesity6,7 and gestational diabetes mellitus (GDM)8 are both common pregnancy complications which are associated with various diseases of the offspring that may emerge during childhood or even adulthood.9
Recently, Catalano et al.10 reported that fetuses of obese mothers were more likely to develop insulin resistance (IR) in the uterus. In the study, 53 lean (body mass index [BMI] <25 kg/m2) and 68 obese (BMI>30 kg/m2) healthy women were recruited, and umbilical cord glucose and insulin concentrations were measured. Then, homeostasis model assessment (HOMA-IR) was used to compare between lean and obese groups. Results from their study showed that HOMA-IR was positively correlated with maternal pregravid BMI, and was consequently greater in the obese group.
Catalano's study10 was the initial investigation focusing on the relationship between maternal body mass and fetal insulin resistance. Discovery of this relationship is of great significance for both clinic and public health. Therefore, in the present study, we intend to extend this research in two aspects.
First, as mentioned above, fetuses of obese mothers are more prone to insulin resistance, compared with those of lean mothers. However, it remains unclear whether fetuses of overweight (in global population: 25–30 kg/m2; in the Asian population: 23–30 kg/m2) mothers also suffer from increased insulin resistance in the uterus. Although not as severe as obesity, being overweight is twice as common in the general population.11 If overweight expecting mothers also have increased occurrence of fetal insulin resistance, the standard for clinical control of body weight should be stricter. Therefore, the primary purpose of the present study is to investigate the influence of maternal BMI on fetal insulin resistance, specifically the difference between overweight and lean mothers.
Second, along with lipid metabolic disorders, glucose metabolic disorders are also associated with insulin resistance. Maternal overweight and gestational diabetes mellitus (GDM) are both IR-related disorders that often present concurrently in the clinic. Therefore, in the present study, we also aim to investigate the influence of maternal hyperglycemia on fetal insulin resistance.
Patients and diagnosis
The study population was randomly chosen from term (37–42 weeks) singleton pregnant women with or without gestational diabetes mellitus (GDM) who received prenatal care and caesarean section in our center. Mothers or fetuses complicated with severe diseases (i.e. preeclampsia, prenatal infection, hyperthyreosis, and fetal anomaly) were excluded.
Recruited patients were divided into two groups, according to World Health Organization (WHO) criteria on BMI for the Asian population.12 In detail, pregnant women whose pre-gravidity BMI was over 23 kg/m2 were enrolled in the overweight group, while those with a pre-gravidity BMI in the range of 18.5–23 kg/m2 were placed in the lean group. The diagnosis of GDM was determined according to the oral glucose tolerance test (OGTT) result performed within 24–28 weeks of pregnancy following American Diabetes Association (ADA) criteria (two-step approach).
The study was approved by the research ethical committee of The First Affiliated Hospital of Sun Yat-sen University and informed consent was provided by all volunteers.
Clinical data, including maternal age, gestational age, height, pre-gravidity weight, pre-partum weight, as well as fetal gender, birth weight, birth height, and head circumference were obtained from subjects or measured by researchers.
Blood sample collection
Maternal venous blood samples were collected within 37–38 weeks of gestation and umbilical cord venous blood samples were collected immediately after placenta delivery. The samples were collected in two sterile vacuum blood collection tubes, one with anticoagulant and the other without. Samples in the anticoagulative tubes for measuring H1Ac (in total blood) and glucose (in plasma) were sent to the clinical laboratory within 1 h following collection. The other samples were placed at room temperature (25°C) for 1 h to allow the blood to clot. After blood coagulation, sera were separated by centrifugation at 720 g for 15 min at 4°C, frozen in aliquots of 100µL, and stored at −80°C until analysis.
Sex hormone binding globulin (SHBG) from maternal and fetal sera was detected using an Architect SHBG detection kit (Abbott Laboratory, Princeton, NJ, USA) using an i2000 immunoanalysis array machine (Abbott Laboratory). For the GDM group only, the fasting plasma glucose level was determined using a GOD-PAP kit (Human, Wiesbaden, Germany); the fasting insulin level was examined using a chemiluminescent microparticle immunoassay (CMIA) kit (Abbott Laboratory); the plasma C-peptide was tested by an ARCHITECT C-Peptide Reagent kit (Abbott Laboratory, Princeton, NJ, USA); the cholesterol and triglyceride (TG) levels were measured using the enzymatic colorimetric test kit (Human, Wiesbaden, Germany), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) were determined by homogeneous assay using Chestiest N HDL kits (Human, Wiesbaden, Germany); the H1Ac were tested by Bio-Rad Variant II H1Ac kit (Bio-Rad Laboratories, Hercules, CA, USA).
Data were shown as mean ± SD and statistical analyses were performed using SPSS version 13.0 software. Maternal and fetal SHBG, clinical data, and laboratory data were compared between overweight and lean groups. Differences were adjusted for potential cofactors by ANCOVA. Correlations between SHBG and other test indexes were analyzed and positive findings were adjusted for potential cofactors by partial correlation.
Among the 49 pregnant women, 19 were diagnosed as overweight according to the WHO criteria of BMI for the Asian population,12 while the remaining 30 mothers were placed in the control (lean) group. Clinical data including age, gestational age, height, pre-gravidity and pre-partum weight, weight gain during pregnancy, pre-gravidity and pre-partum BMI, morbidity of gestational diabetes mellitus (GDM) were compared between overweight and lean mothers (Table 1). Gender, birth weight, height, and head circumference were compared between fetuses of overweight and lean mothers (Table 1). As shown in Table 1, after adjusting for maternal age, gestational age, fetal gender and morbidity of GDM, the overweight group had higher maternal weight and BMI both before and late in pregnancy, while no differences in height, weight gain during pregnancy, and blood glucose levels (as measured by the OGTT test) were observed between groups. Fetuses of overweight mothers were heavier at birth (after adjusted by the morbidity of GDM, maternal age, gestational age, and fetal gender) and had a shorter gestational age than those of lean mothers.
|Age (years)||30.89 ± 3.14||30.73 ± 3.57||0.873|
|Gestational age (days)||269.97 ± 5.8||273.78 ± 4.7||0.021|
|Height (m)||1.58 ± 0.04||1.60 ± 0.04||0.471||0.188|
|Pre-gravidity weight (kg)||62.23 ± 7.94||51.85 ± 4.19||0.000||0.000|
|Pre-partum weight (kg)||77.47 ± 6.85||65.28 ± 5.13||0.000||0.000|
|Weight gain during pregnancy (kg)||15.24 ± 4.05||13.43 ± 3.98||0.131||0.595|
|Pre-gravidity BMI (kg/m2)||24.38 ± 1.51||20.55 ± 1.38||0.000||0.000|
|Pre-partum BMI (kg/m2)||30.34 ± 1.82||25.88 ± 1.88||0.000||0.000|
|Complicated with GDM|
|OGTT-fast (mmol/L)||4.92 ± 0.97||4.52 ± 0.57||0.091||0.082|
|OGTT-1h (mmol/L)||10.40 ± 2.65||9.51 ± 1.77||0.184||0.086|
|OGTT-2h (mmol/L)||9.02 ± 2.68||8.12 ± 1.88||0.201||0.236|
|OGTT-3h (mmol/L)||6.19 ± 1.22||5.94 ± 1.42||0.560||0.594|
|Birth weight (kg)||3.58 ± 0.55||3.32 ± 0.42||0.106||0.006|
|Birth height (cm)||50.00 ± 2.22||49.70 ± 2.09||0.676||0.503|
|Head circumference (cm)||34.39 ± 1.69||34.50 ± 1.63||0.845||0.316|
Insulin resistance in overweight mothers and fetuses
To investigate the insulin resistance status of mothers and fetuses, serum SHBG levels were detected and compared between groups, after adjusting for potential cofactors including maternal age, gestational age, fetal gender and morbidity of GDM. As shown in Figure 1, there was no statistically significant difference in SHBG levels between overweight and lean women (542.58 ± 110.46 nmol/L vs 565.51 ± 123.77 nmol/L, P = 0.514, adjusted P = 0.188) during late pregnancy (Figure 1A). On the contrary, fetuses of overweight mothers had lower SHBG levels than those of lean mothers even after adjusting for potential cofactors (26.64 ± 3.65 nmol/L vs 34.36 ± 7.84 nmol/L, P < 0.001, adjusted P = 0.007), indicating that they were more likely to develop insulin resistance in the uterus (Figure 1B).
To analyze the relationship between maternal pre-gravidity BMI and insulin resistance in both mothers and fetuses, we further investigated the correlation between pre-gravidity BMI and SHBG levels, adjusting for the potential cofactors mentioned above. As shown in Figure 1, pre-gravidity BMI has a negative correlation with fetal SHBG levels (R = −0.392, P = 0.005, adjusted P = 0.025) but not with maternal SHBG levels (R = −0.113, P = 0.440, adjusted P = 0.537). As SHBG levels are negatively correlated with fetal insulin resistant status, this result indicates that offspring of mothers with higher pre-gravidity BMI have increased insulin resistance.
Maternal weight gain control during pregnancy improves fetal insulin resistance
As higher pre-gravidity BMI is associated with increased fetal insulin resistance, it would be interesting to examine whether weight gain control of pregnant women will improve fetal insulin resistance. We first studied the correlation between maternal weight gain and fetal SHBG, and found they had a negative correlation (R = −0.327, P = 0.022). Next, we performed a partial correlation analysis on maternal weight gain and fetal SHBG, taking GDM morbidity, fetal gender, maternal age, and pre-gravidity BMI as control factors. Results showed that after adjusting for the cofactors mentioned above, maternal weight gain still had a negative correlation (R = −0.332, adjusted P = 0.026) with fetal SHBG. This result suggests that weight gain control during pregnancy will improve fetal insulin resistance.
Gestational diabetes mellitus, overweight and fetal insulin resistance
Gestational diabetes mellitus is a common complication during pregnancy. As they can both be a result of insulin resistance, GDM and obesity are likely to complicate with each other. Several studies have shown that the offspring of GDM mothers developed insulin resistance either before or after birth. Therefore, we studied the influence of GDM on fetal insulin resistance, either as an independent factor or as a cofactor of overweight. Results showed that fetal SHBG levels were not different between GDM and control groups (31.53 ± 7.86 nmol/L vs 31.12 ± 7.20 nmol/L, P = 0.852). Then, to investigate the coeffect of overweight and GDM on fetal IR, we performed a two-way ANOVA on the total population. Results demonstrated that these two IR-related disorders did not have a coeffect on fetal IR development (F = 0.385, P = 0.538). Taken together, these results indicate that GDM has little relation with fetal insulin resistance in the present cohort, no matter as an independent factor or as a cofactor of being overweight.
In addition, we analyzed the potential influence of overweight on GDM pregnancy. As shown in Table 2, compared with lean GDM mothers, overweight GDM mothers had higher hemoglobin 1Ac (H1Ac) levels, indicating that higher pre-gravidity weight is related to decreased glucose control in GDM mothers. Other laboratory characteristics, including fasting insulin, C-peptide, cholesterol, triglyceride, HDL, and LDL were not different between overweight and lean GDM mothers.
|Fast insulin (µU/mL)||14.78 ± 6.84||11.18 ± 3.97||0.134||0.967|
|HOMA-IR||3.26 ± 1.26||2.02 ± 0.68||0.009||0.399|
|C-peptide (pmol/L)||1.28 ± 0.47||0.94 ± 0.34||0.060||0.438|
|Total cholesterol (pmol/L)||5.93 ± 1.13||5.96 ± 1.00||0.951||0.983|
|Triglyceride (mmol/L)||6.41 ± 7.15||3.23 ± 0.95||0.125||0.751|
|High-density lipoprotein (mmol/L)||1.31 ± 0.40||1.54 ± 0.40||0.174||0.995|
|Low-density lipoprotein (mmol/L)||2.59 ± 0.77||3.13 ± 0.78||0.126||0.972|
|HbA1c (%)||6.47 ± 0.44||5.74 ± 0.52||0.000||0.004|
More than one billion adults from all over the world are either obese or overweight,11 including a large number of reproductive-age women. Maternal obesity has already been identified as a risk factor for fetal insulin resistance.10,13 Being overweight, a condition between obesity and normal-range BMI, is twice as common as obesity.11 Therefore, in the present study, we mainly focus on whether being overweight could also be associated with fetal insulin resistance. Our results indicate that, compared to a fetus from a lean mother, insulin resistance is more likely to develop in the fetus of an overweight mother, an effect that could be reduced by weight gain control during pregnancy.
Sex hormone binding globulin level is negatively correlated with insulin resistance and has been taken as a biomarker for IR.14–17 Our findings show that maternal pre-gravidity BMI is negatively associated with maternal and fetal SHBG, although no statistically significant difference was observed for maternal SHBG. This indicates that higher pre-gravidity BMI is associated with increased fetal IR. Next, maternal and fetal SHBG levels were compared between overweight and lean pregnancies. As expected, overweight mothers and their offspring had lower SHBG levels than lean mothers, although no statistical significance was found between mothers in the two weight groups. These results indicate that the influence of overweight on IR is more remarkable in the developing fetus than in the mother. The relationship between maternal pre-gravid BMI and fetal SHBG found in our study (R = −0.392) for overweight and lean mothers is consistent with previous studies on pre-gravid BMI and fetal HOMA-IR (R = 0.31) among obese and lean mothers during pregnancy10,13 and confirm the relationship between maternal BMI and fetal insulin resistance. Further, because our data focuses on overweight mothers, our results help to fill the gap between obese and lean pregnant women. Thus, we can draw a conclusion that fetuses from both obese and overweight mothers are more likely to develop insulin resistance in the uterus.
According to the developmental origins of health and disease (DOHaD) theory, maternal environment affects the long-term health of a fetus, especially concerning energy metabolism. Previous studies demonstrated that macrosomia or intrauterine growth restriction (IUGR), results of GDM or maternal obesity, tend to develop insulin resistance in childhood and adulthood.18–20 Here, we presume that mothers who are overweight could also cause long-term effects on the fetus as similar trends in fetal insulin resistance were observed.
As maternal overweight has such relevance to fetal insulin resistance, which can have a negative impact on fetal health, it is necessary to investigate whether weight gain control during pregnancy will improve fetal IR or not. Results in the present study show that after adjusting for several cofactors, maternal weight gain is negatively associated with fetal SHBG. This result indicates that besides pre-gravidity BMI, greater weight gain during pregnancy will also increase fetal insulin resistance. That is, even fetuses from lean mothers can develop IR during pregnancy if the mother does not control her body weight within an appropriate range. In addition, weight gain control in pregnancy is also beneficial for reducing maternal insulin resistance,21 fetal overgrowth, shoulder dystocia, cesarean delivery, hypertensive disorders,22 brachial plexus injury and hypertensive disorders.23 Therefore, it is of great importance for a pregnant woman to manage her weight in order to prevent disease, especially IR-related disease, in herself and her offspring.
Besides overweight, we also investigated GDM, another IR-related disease, for its relation to overweight and its potential influence on fetal insulin resistance. Results show that, in the present cohort, GDM did not increase the risk for developing fetal insulin resistance, either as an independent factor or as co-effecter with maternal BMI. This result is consistent with recently published data,24 revealing that maternal SHBG is no longer an independent predictor for GDM where obesity is concerned. Interestingly, an overweight GDM mother is more prone to have higher H1Ac levels than their lean counterparts, indicating that overweight GDM patients should pay more strict attention to their long-term blood glucose control than their lean counterparts.
Measuring fetal insulin resistance still remains a difficult task. HOMA-IR is a commonly used method for measuring levels in adults, while its accuracy in fetal samples is questionable as the energy intake rhythm of a fetus is still unclear. The glucose clamp, the gold standard for measuring insulin resistance in adults, also appears to be ineffective for measuring levels in fetal/neonatal samples.25 In the present study, we used sex hormone binding globulin (SHBG) as an index of insulin resistance. SHBG, a glycoprotein mainly produced by the liver, has a major biological function to bind sex hormones (testosterone and estradiol) in circulation.26 Insulin resistance inhibits the production of SHBG in the liver,27 and hence is negatively associated with SHBG levels.28 In the clinic, patients with disorders associated with insulin resistance, such as diabetes mellitus29 and polycystic ovary syndrome (PCOS)30 typically have lower SHBG concentrations in circulation. Recently, SHBG has been taken as a sensitive biomarker for insulin resistance in adults28 and fetuses.31 As SHBG is easy to measure with commercially available kits and stable, but is not influenced by food intake, we chose it as the IR marker in the present study.
In conclusion, being overweight during gestation is relevant to fetal IR, whereas weight gain control during pregnancy improves fetal IR. As the overweight population is much larger than the obese population, the necessity is now apparent to make overweight mothers a major public health focus for the prevention of IR disease developed in the next generation. Further studies based on a larger population would be beneficial for uncovering multiple factors associated with fetal insulin resistance and providing more rigorous evidence for clinical practice.
This work was supported by the Science and Technology Planning Project of Guangdong Province, China (No. 2009B03081099, to Zi-lian Wang) and Scholarship Award for Excellent Doctoral Student (to Bin Liu and Zi-lian Wang as supervisor) granted by the Ministry of Education of China.
The authors declare that they have no competing interests.
- 11World Health Organization. Obesity and Overweight. Geneva: WHO, 2010.