Leptin and soluble leptin receptor in association with gestational diabetes: a prospective case control study

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1 GYNECOLOGIC ENDOCRINOLOGY AND REPRODUCTIVE MEDICINE Leptin and soluble leptin receptor in association with gestational diabetes: a prospective case control study Maryam Mosavat 1 Siti Zawiah Omar 1 Peng Chiong Tan 1 Muhammad Fazril Mohamad Razif 2 Pavai Sthaneshwar 3 Received: 4 October 2017 / Accepted: 1 December 2017 Springer-Verlag GmbH Germany, part of Springer Nature 2017 Abstract Purpose To assess the association of serum leptin and its receptor (SLeptinR) with the risk of gestational diabetes mellitus (GDM) and to evaluate the longitudinal circulation of these peptides in pregnancy. Methods This study consisted of 53 subjects diagnosed with GDM and 43 normal glucose tolerance (NGT) pregnant women. Serum leptin and SLeptinR were measured at weeks, prior and after delivery, and post-puerperium. Results Lower levels of leptin and SLeptinR were observed in GDM compared to NGT. Leptin [OR 0.97 (95% CI )] and SLeptinR [OR 0.86 (95% CI ]) were inversely associated with GDM. Participants in the lowest tertile for leptin and SLeptinR had a 2.8-fold (95% CI ) and a 5.7-fold (95% CI ) higher risk of developing GDM compared with the highest tertile, respectively. These relationships were attenuated after adjustment for covariates. In both the groups, peak leptin was observed at weeks, decreasing continuously during pregnancy (p > 0.05) and after delivery (p < 0.017). SLeptinR level increased (p < 0.001) during pregnancy and decreased (p < 0.005) after delivery in GDM, however, levels remained the same in NGT. In GDM, leptin and SLeptinR was positively and inversely correlated with BMI and HOMA-IR at weeks and post-puerperium, respectively. The cord levels of both leptin and SLeptinR were lower than maternal levels. There were no significant differences in serum cord leptin and SLeptinR levels between the groups. Conclusion Leptin and SLeptinR are independently and inversely associated with GDM. Lower levels of these peptides may play an important role in the pathophysiology of GDM and pre-diabetic state in post-puerperium. Keywords Leptin Soluble leptin receptor (SLeptinR) Gestational diabetes (GDM) Abbreviations GDM Gestational diabetes mellitus NGT Normal glucose test BMI Body mass index SLeptinR OR OGTT pgdm Soluble leptin receptor Odd ratio Oral glucose tolerance test Previous GDM Maryam Mosavat and Siti Zawiah Omar are responsible equally for this project and should be considered as the correspondence authors. * Maryam Mosavat Maryam.mst57@um.edu.my * Siti Zawiah Omar szawiah@um.edu.my 1 Department of Obstetrics and Gynaecology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia 2 Department of Molecular Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia 3 Department of Pathology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia Introduction Pregnancy is a state of progressive insulin resistance [1]. Gestational diabetes (GDM) and obesity are the most common metabolic abnormalities that occur during pregnancy. Decreased maternal insulin sensitivity (insulin resistance) coupled with an insufficient insulin response are the pathophysiological mechanisms leading to the development of GDM [2]. Adipokines, and polypeptides derived from the adipose tissue, have been linked to insulin resistance in normal pregnancy and GDM [1, 3 5]. Leptin is one of the most studied adipokines; increasing [6, 7] reduction [8] or unchanged [9] levels of this peptide have been reported Vol.:( )

2 in women with GDM. Leptin is a multi-functional peptide involved in regulation of food intake and energy balance through central hypothalamic pathways, acting as a major signal to the reproductive system inhibiting insulin secretion using the pancreatic β-cells and stimulation of glucose transport [1, 10]. Leptin is produced in maternal and foetal adipose tissue, skeletal muscles and placental trophoblast [1]. It circulates in two forms: free leptin or bound to its specific soluble receptor. In human tissue, the leptin receptor is expressed as different variants [11]. Soluble leptin receptor (SLeptinR) is the main leptin-binding protein in human blood. This receptor isoform can modulate steadystate leptin levels by binding free leptin in circulation, subsequently shielding the hormone from degradation and clearance [12]. Therefore, high SLeptinR levels in blood as observed in lean individuals, act as a potential reservoir for bioactive leptin [13]. However, decreasing SLeptinR concentration could result in increased levels of free bioactive leptin [14 16]. Furthermore, SLeptinR inhibits the effects of leptin by impeding its binding to its membrane receptor [17]. A strong inverse association between plasma SLeptinR levels and risk of type 2 diabetes mellitus (T2DM) has been reported independent of BMI, leptin, and adiponectin levels [18]. Thus far, findings regarding SLeptinR levels are controversial. To clarify the changes in serum leptin levels and its soluble receptor during pregnancy and their association with GDM, we measured serum levels of leptin and SLeptinR levels across pregnancy, after delivery and 6 weeks post-puerperium in women of normal pregnancy and those with GDM. Additionally, umbilical cord blood samples were collected to investigate the levels of leptin and its soluble receptor for comparison with maternal levels. Materials and methods This study was conducted in the Women and Children Health Complex, University Malaya Medical Centre (UMMC). The protocol was approved by the University of Malaya Medical Centre (UMMC) Ethics Committee and written informed consent was obtained from all the participants. The study population comprised of pregnant women who attended the antenatal clinic for GDM screening at weeks of gestation. Inclusion criteria: aged between 18 and 45 years, with singleton pregnancy and planned to carry the pregnancy to term and delivery at UMMC. GDM was diagnosed based on fasting glucose 5.1 or impaired glucose tolerance with a 120 min blood sugar value of 7.8 mmol/l [19]. Exclusion criteria: History of pregestational diabetes, chronic disease, chronic inflammation, infectious disease and multi-foetal pregnancy. Pregnancy outcomes and complications were assessed by extracting information from the prenatal care, delivery and new-born medical record. Subjects from who we were unable to obtain a fasting (7 h or more without nutrient intake) blood sample at the scheduled examination points or developed any pregnancy complications such as preeclampsia, eclampsia, high blood pressure, preterm labour were also excluded from the study. Gestational age was calculated based on gestation from participants last normal menstrual period confirmed or modified by ultrasound. Samples and biochemical analysis The maternal samples were collected on four occasions: (1) at weeks of pregnancy after overnight fasting (2) prior to caesarean section or spontaneous vaginal delivery (3) within 24 h after delivery, and (4) 2 6 months postpartum. Serum was obtained by allowing the blood to clot for 30 min, followed by centrifugation at 2000 g for 10 min. Serum samples were immediately aliquoted into single use tubes and biobanked at 80 C. Repeated freeze thaw cycles were avoided. Serum levels of leptin, SLeptinR and insulin were determined using Magnetic bead-based Multiplex immunoassay, human diabetes panel (Bio-Plex Pro, 171A7001M, USA) according to the manufacturer s protocol. The intra inter assay coefficient of variation (CV) of the assay are as follows: insulin ( ); leptin ( ); SLeptinR ( ). Fasting glucose levels were measured using the glucose oxidase method (ADVIA 2400 Clinical Chemistry System, Siemens, USA). Body mass index and clinical data collection Body mass index (BMI) was calculated at the time of recruitment at weeks of gestation, prior to delivery and postpartum. Homeostasis model assessment (HOMA-IR) index was calculated using the following formula: fasting serum insulin (miu/l) fasting serum glucose (mmol/l)/22.5. Statistical analysis Descriptive statistics were performed using frequencies, percentages, frequency tables for qualitative variables and defined as mean ± standard error (SE) for quantitative variables. We compared the maternal characteristics between GDM and NGT using Student s t test and Mann Whitney U test for parametric and non-parametric variables, respectively. Logistic regression analysis was performed to explore the association between SLeptinR and leptin in GDM. Results from the logistic regression analyses are presented as odds ratio (OR; 95% confidence interval). Paired sample t test and two-related samples Wilcoxon test was performed to assess longitudinal changes between different time points and Bonferroni correction was set at p < The

3 Spearman correlation coefficient was performed for describing the correlation between outcome variables with BMI and HOMA-IR. Statistical analysis was performed using IBM SPSS Results Based on the inclusion and exclusion criteria, a total of 434 patients were initially recruited in this study. However, data from only 96 patients, including 53 GDMs and 43 NGTs, Table 1 Characteristics of subjects at time of first oral glucose tolerance test (OGTT) Variable Women with GDM (n = 53) Healthy pregnant controls (n = 43) p value* Maternal age (year) ± ± < (60.4%) 28 (65.1%) (39.6%) 15 (34.9%) Gestational age (weeks) Family history of diabetes 25.8 ± ± Yes 14 (26.4%) 8 (18.6%) 0.73 No 38 (71.7%) 32 (74.4%) Unclear 1 (1.9%) 3 (7.0%) Parity 2.87 ± ± Pre-gestation BMI (kg/m 2 ) ± ± * p < 0.05 significant different between the two pregnancy groups were used at the end of this study as the remaining patients met at least one of the exclusion criteria. At the time of enrollment (24 28 weeks of gestation), no significant differences (p > 0.05) were observed for maternal age and BMI between both the groups (Table 1). Women who were diagnosed with GDM had significantly lower levels of leptin (19.8 vs. 26.6, p = 0.03) and SLeptinR (13.2 vs ng/ml, p < 0.001) in comparison with NGT. The index of insulin resistance (HOMA-IR) was significantly higher in GDM subjects than NGTs (2.9 vs. 2.1, p < 0.03). Serum leptin [Odds ratio 0.97 (95% CI )] and SLeptinR (Odds ratio 0.86 (95% CI )] were inversely associated with GDM. Participants in the lowest tertile (< 11.3 ng/ml) for SLeptinR had a 5.7-fold higher risk of GDM compared with participants in the highest tertile (> 17.1 ng/ml; 95% CI ). However, this relationship was slightly attenuated and upheld significance after adjustment for confounders including maternal age, gestational age and BMI (a OR 5.1, 95% CI ). Furthermore, the lowest tertile for serum leptin (< 14.4 ng/ml) demonstrated a 2.8-fold higher risk of developing GDM compared to the highest tertile (> 26.4 ng/ml; 95% CI ). This relationship was attenuated and became non-significant after adjustment for confounders (aor 2.6, 95% CI ; Table 2). In all the pregnant women, serum leptin was significantly correlated to fasting levels of insulin (r = 0.43, p = 0.003), HOMA-IR (r = 0.52, p < 0.001) and BMI (r = 0.25, p = 0.01). No significant relationship was found between leptin and age, week of pregnancy and fasting glucose. Furthermore, SLeptinR was negatively correlated with fasting insulin (r = 0.27, p = 0.01), HOMA-IR (r = 0.32, Table 2 Gestational diabetes mellitus (GDM) risk according to tertiles of maternal SLeptinR and leptin concentrations GDM Unadjusted OR (95% CI) Adjusted OR (95% CI) No n = 43 Yes n = 53 SLeptinR (ng/ml) N% N% Tertile 1 < (22.6) 24 (77.4) 5.7 ( )* 5.1 ( )* Tertile < < (41.4) 17 (58.6) 1.8 ( ) 1.5 ( ) Tertile 3 > (66.7) 12 (33.3) Referent Referent Leptin (ng/ml) Tertile 1 < (31.2) 22 (68.8) 2.8 ( )* 2.6 ( ) Tertile < < (46.7) 16 (53.3) 1.5 ( ) 1.3 ( ) Tertile 3 > (55.9) 15 (44.1) Referent Referent OR (95% CI) adjusted for maternal age, gestational age, and BMI * p value < 0.05

4 p = 0.04) and maternal age (r = 0.33, p = 0.01). No significant relationship was found between SLeptinR with duration of pregnancy and fasting glucose. Longitudinal study During pregnancy, GDM expressed significantly (p < 0.05) a lower level of leptin compared to NGT. Peak leptin level was observed at weeks and significantly decreased (p < 0.001) after delivery in both the groups. In post-puerperium, serum leptin concentrations reached its lowest levels compared to pregnancy in both the groups (Fig. 1, Table 3). Progress in pregnancy was accompanied by an elevation in SLeptinR levels in GDM (p < 0.001), whereas its level was significantly unchanged in NGT (p = 0.30). After delivery, SLeptinR concentrations decreased significantly (p < 0.005) in both the pregnancy groups and remained unchanged afterwards. In post-puerperium, women with previous GDM (pgdm) presented higher SLeptinR levels Fig. 1 Examination 1: weeks of pregnancy; Examination 2: prior to caesarean section or spontaneous vaginal delivery; Examination 3: within 24 h after delivery; Examination 4: 2 6 months postpartum Serum leptin ng/ml Serum SLeptinR ng/ml GDM NGT GDM NGT Table 3 Longitudinal circulation of fasting SLeptinR and leptin during pregnancy, after delivery and postpuerperium in subjects with GDM and health pregnant controls (mean ± SE) Examination 1 (during OGTT) Examination 2 (before delivery) Examination 3 (after delivery) Examination 4 (post-puerperium) Weeks ( ) 39.0 ( ) ( ) 13.0 (7 19) Leptin (ng/ml) GDM 19.8 ± ± ± 1.2 a,b 15.7 ± 1.6 a NGT 26.6 ± ± ± 2.5 a,b 17.2 ± 1.7 a p value SLeptinR (ng/ml) GDM 13.2 ± ± 0.9 a 16.7 ± 0.9 a,b 16.8 ± 0.9 a,b NGT 18.2 ± ± ± 0.8 b 18.4 ± 1.0 p value < HOMA-IR GDM 2.9 ± ± ± 0.7 b 2.5 ± 0.2 a,b NGT 2.1 ± ± 0.4 a 2.5 ± ± 0.2 p value BMI (kg/m 2 ) GDM ± ± 0.7 a ± 0.5 a,b NGT ± ± 0.9 a ± 0.5 a,b p value p value < 0.05 difference between groups a p value < from Examination 1 (using Bonferroni correction) b From Examination 2 (using Bonferroni correction) c From Examination 3 (using Bonferroni correction)

5 (16.8 vs. 13.2, p = 0.006) compared to pregnancy, whereas this level was unchanged in NGT women. There was no significant difference in cord serum leptin (6.8 vs. 9.8) and SLeptinR levels (7.37 vs. 7.59) between GDM and NGT subjects. However, in both the pregnancy groups, significantly lower levels (p < 0.005) of leptin and SLeptinR were observed in serum umbilical cord in comparison to maternal levels before and after delivery (Table 4). There was no significant difference in neonatal birth weight between both the pregnancy groups. No association was observed between the maternal concentration of leptin and SLeptinR with cord serum levels and neonatal weights. Discussion Our study revealed that women with GDM had lower leptin and SLeptinR levels than women with normal glucose tolerance; low concentration of leptin and SLeptinR was associated with an increment of GDM risk. This result was relatively unchanged after adjusting for BMI, maternal and gestational age for SLeptinR. Yet, this association became insignificant after adjusting confounders for leptin. The findings of available studies about leptin levels in GDM are conflicting. Similar to our results, hypoleptinemia during pregnancy has been reported by Festa et al. [8] and Noureldeen et al. [20], whereas high [1, 21, 22] and unchanged [9, 23] levels of leptin have been also reported by other studies. We observed that women with serum leptin concentrations lower than 14.4 ng/ml had a 2.8-fold increased risk of GDM compared to women with concentrations of 26.4 ng/ ml or higher. However, this association was moderated after consideration of BMI, maternal and gestational age. In an animal study, mutation of leptin receptor in pregnancy was accompanied with spontaneous GDM [24]. Interestingly, the subsequent administration of leptin prevented the development of gestational diabetes in the mice [24]. Comparable to our results, the study by Festa et al. [8] also showed that leptin levels were related to fasting insulin. They found a positive association between leptin and the increment of insulin after an oral glucose load, as a measure of insulin secretion. These findings suggested that insulin may stimulate Table 4 Cord serum leptin and SLeptinR concentrations in women with GDM and NGT subjects a p value < from Examination 2 b p value from Examination 3 GDM NGT p value Leptin (ng/ml) 6.8 ± 0.8 a,b 9.08 ± 1.3 a,b 0.14 SLeptinR(ng/ml) 7.37 ± 0.4 a,b 7.59 ± 0.6 a,b 0.77 Birth weight (kg) 3.24 ± ± adipose tissue leptin production. Therefore, it may be possible that the inability to increase insulin secretion, a fault characteristic of GDM, would eventually lead to impaired leptin secretion and hypoleptinaemia. Furthermore, in the present study, peak leptin concentration was observed at weeks which declined continuously throughout the pregnancy period till post-puerperium. It has been reported that placental trophoblasts are primarily responsible for peak leptin secretion in the middle of gestation [25] and this may be an explanation of leptin resistance [26]. Leptin concentrations in pregnancy have been shown to increase two to threefold compared to post-puerperium and non-pregnant status [27]. Therefore, the continuous reduction in leptin levels during pregnancy in the current study may be due to impairment of placental function synchronous with the progression of pregnancy. In the present study, at weeks of pregnancy and post-puerperium, leptin levels in maternal serum of GDM subjects strongly correlated to weight and BMI. Our results is in accordance with the previous studies [8, 9]. The correlation coefficient between these parameters decreased with pregnancy development and became insignificant at the end of pregnancy. However, the BMI in pregnancy is not a precise measure of maternal body fat, as it includes foetal weight, placenta, amniotic fluid, and maternal fluid expansion; therefore, these may not be comparable to postpartum values. Furthermore, we did not notice any significant difference in gestational weight between normal and GDM subjects. It might be explained that women with GDM were very well-controlled metabolically. Whilst free leptin exerts a physiological effect, SLeptinR prevents the leptin effect by inhibiting its binding to its membrane receptor [28]. Low concentration of SLeptinR in GDM subjects in the present study was similar to previously reported studies [20, 29]. Low levels of SLeptinR concentration in the presence of peak leptin levels that observed mid-gestation in the present study may signify leptin resistance due to a low number of leptin receptors, as described previously [29]. Evidence from both in vivo and in vitro studies have shown that SLeptinR serves as an antagonist of leptin transport [30]. Similarly, we observed an inverse correlation between leptin and SLeptinR towards the end of pregnancy and post-puerperium. Limited studies have explored the associations between SLeptinR and GDM. Our investigation revealed that participants with SLeptinR level 11.3 ng/ml are at risk of GDM, ~ 5.7-fold (95% CI ) which is higher than pregnant women with SLeptinR 17.1 ng/ml or more. Furthermore, an inverse correlation was observed between SLeptinR and HOMA-IR. Our findings are in accordance with the results of a recent study by Sommer et al. [29] that showed an independent inverse association between SLeptinR and risk of GDM in a prospective population-based cohort study. Similarly, Sun et al. [18] have shown an independent inverse association between

6 SLeptinR and future risk of T2DM in a nested case control study in middle-aged American women. In our experiment, SLeptinR concentrations were elevated during pregnancy and declined after delivery and remained unchanged postpuerperium. SLeptinR level elevation during pregnancy in the presence of leptin reduction and their inverse correlation may be indicative of the antagonist effects of SLeptinR which led to relative modification in leptin resistance in late pregnancy. In contrast, SLeptinR was constant during pregnancy, declining slightly after delivery and remained unchanged afterwards in normal pregnant women. Sommer et al. [29] reported a reduction in SLeptinR concentration from early pregnancy to 3 months postpartum. However, in women with GDM, higher level of SLeptinR concentration was observed in post-puerperium compared to early pregnancy, which was inversely correlated to HOMA-IR. Furthermore, an inverse correlation between SLeptinR and BMI was observed in the present study at weeks of gestation and post-puerperium. The inverse correlation between body fat and SLeptinR has been reported recently [29]. Our study on umbilical cord level of leptin and its receptor revealed that the maternal levels of it both at birth and after delivery were significantly higher than umbilical cord levels. Our finding is in agreement with the results of another study [27]. It has been described that the placenta is a major source of leptin for pregnant women and most of the leptin is released into the maternal circulation, whilst a smaller percentage is released on the foetal side [31]. Moreover, from the present study, the lower but not significant serum cord leptin and SLeptinR concentrations were observed in neonates of mothers with GDM compared to healthy control mothers. Likewise, no difference in leptin levels was reported between babies from normal or GDM mothers by previous studies [32]. It has been shown that the release of leptin was lower in placenta, amnion and choriodecidua obtained from women with GDM in comparison to normal pregnant subjects [33]. In contrast with our findings, higher leptin levels were observed in the umbilical cords of newborns whose mothers had GDM compared to NGT [34, 35]. However, the reported differences in the study by Okereke et al. [34] did not persist after adjustment for fat mass. It has been stated that higher leptin levels in neonates of mothers with GDM might be related to the increased foetal adiposity [34, 35]. Therefore, in the present study, the absence of any difference between foetal birth weights in both the studied groups is an explanation for the insignificant difference in cord leptin and SLeptinR levels. We conclude that lower levels of leptin and SLeptinR are independently associated with higher risk of GDM. It is important to note that one limitation of this study is the failure to measure adiposity; instead, we used BMI which is known to poorly reflect adiposity during pregnancy. Nonetheless, our findings further add to the understanding of the changes in leptin levels and its receptor during pregnancy. Acknowledgements We greatly acknowledge the contributions of the research staff and women who participated in this study. Author contributions All the persons who meet the authorship criteria are listed as authors. Specific contributions by each author: Conception, design, and funding of study: Professor Siti Zawiah Omar and Professor Peng Chiong Tan. Data collection, data analysis, interpretation of data and drafting the manuscript: Maryam Mosavat. Revising the manuscript: Professor Siti Zawiah Omar, Associated Professor Pavai Sthaneshwar and Dr. Muhammad FM Razif. 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