http://informahealthcare.com/gye ISSN: 0951-3590 (print), 1473-0766 (electronic) Gynecol Endocrinol, 2014; 30(5): 355–358 ! 2014 Informa UK Ltd. DOI: 10.3109/09513590.2014.887670
GESTATIONAL DIABETES
Relationship of maternal serum resistin and visfatin levels with gestational diabetes mellitus Ahmet Karatas1, Nilu¨fer Tunc¸ay I¸sikkent2, Tu¨lay Ozlu¨1, and Hilmi Demirin3 Department of Obstetrics and Gynecology, Medical Faculty, Abant Izzet Baysal University, Bolu, Turkey, 2Department of Obstetrics and Gynecology, and 3Department of Biochemistry, Medical Faculty, Duzce University, Duzce, Turkey
Abstract
Keywords
Introduction: Adiponectin, resistin and visfatin are thought to play role in the pathophysiology of gestational diabetes (GDM). In this study, we aimed to investigate the association of maternal second trimester serum resistin and visfatin levels with GDM. Materials and methods: Screening and diagnosis for GDM was performed between the 24–28th gestational weeks. About 40 women diagnosed with GDM and 40 non-diabetic women constituted the study and control groups, respectively. Groups were compared for second trimester maternal serum resistin, visfatin and HbA1c levels, HOMA-IR and postpartum 75 g OGTT results. Results: Mean serum resistin (p ¼ 0.071) and visfatin (p ¼ 0.194) levels were similar between the groups. However, mean BMI (p ¼ 0.013), HOMA-IR (p ¼ 0.019), HbA1c (p50.0001) and birth weight (p ¼ 0.037) were significantly higher in GDM group compared to controls. Type 2 diabetes and impaired glucose tolerance were detected in 2 (5%) and 7 (20%) women in the GDM group, respectively, with 75 g OGTT performed at the postpartum 6th week. Resistin levels of patients with GDM and postpartum glucose intolerance were higher than those with GDM but no postpartum glucose intolerance (p ¼ 0.012). Visfatin levels in the GDM group showed a positive correlation with biparietal diameter, head circumference, abdominal circumference and femur length (p50.05). Conclusion: Maternal serum resistin and visfatin levels are unchanged in GDM. In patients with GDM, second trimester resistin levels may be predictive for postpartum glucose intolerance and second trimester visfatin levels may be related with fetal biometric measurements. Further larger studies are needed.
Gestational diabetes, insulin resistance, resistin, visfatin
Introduction Gestational diabetes mellitus (GDM) is a disorder of the carbohydrate metabolism first arising during pregnancy and causing increased morbidity of both the fetus and the mother. GDM constitutes 90% of the diabetes cases during pregnancy [1]. According to American Diabetes Association (ADA), its incidence changes between 1% and 14% and it complicates almost 7% of the pregnant patients, although the numbers can vary among different populations [2]. Furthermore, it is reported that 10–50% of the GDM cases develop type 2 diabetes in the postpartum period [3]. Various different hormones in the body like human placental lactogen (HPL), cortisol, growth hormone, estrogen, progesterone as well as increased insulinase secretion from the placenta may have a role in the pathogenesis of GDM [4]. Besides being a source of energy, adipose tissue also acts as an endocrine tissue. Some novel molecules that are known to be secreted from the adipose tissue including tumor necrosis factor-alpha (TNF-a),
History Received 4 August 2013 Revised 23 November 2013 Accepted 12 December 2013 Published online 10 February 2014
interleukin-6 (IL-6), resistin, visfatin, leptin are also kept responsible from the pathogenesis of GDM [5]. Some adipocytokines like leptin, TNF-a, IL-6, resistin and visfatin have metabolic and immunologic roles in obesity related inflammation and in progression to type 2 diabetes [6]. Resistin is a molecule that resists to the activity of insulin and the circulating levels of this molecule are increased in obese humans [7]. This proinflammatory molecule is reported to play role in the pathogenesis of diabetes and diabetic complications [7]. The expression of visfatin is also reported to increase in cases of abdominal obesity and type 2 diabetes [7,8]. Recent studies about the association of resistin and visfatin levels with GDM have conflicting results. Some of them show that cases with GDM have increased levels of resistin and visfatin compared to the control group [9,10], while others either report no difference for these molecules between the two groups [11] or lower visfatin levels in the GDM group [12]. In this study, we aimed to investigate the association of maternal serum resistin and visfatin levels with GDM.
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1
Materials and methods Address for correspondence: Ahmet Karatas, Department of Obstetrics and Gynecology, Medical Faculty, Abant Izzet Baysal University, 14280 Golkoy, Bolu, Turkey. Tel: +90 374 253 46 56. Fax: +90 374 253 46 15. E-mail: [email protected]
This longitudinal cross-sectional study was carried out in Obstetrics and Gynaecology Department of Duzce University School of Medicine between January and July 2012. Duzce
356
A. Karatas et al.
Gynecol Endocrinol, 2014; 30(5): 355–358
Gynecol Endocrinol Downloaded from informahealthcare.com by University of Laval on 07/15/14 For personal use only.
University Non-Invasive Human Research Ethics Committee approved the study. Informed consent was obtained from all subjects. About 80 women with singleton pregnancies attending to the obstetrics outpatient clinic for routine obstetric care were included in the study. About 40 women diagnosed with GDM and 40 non-diabetic women constituted the study and control groups, respectively. Screening for and diagnosis of GDM was performed by using 50 g glucose challenge test and 100 g oral glucose tolerance test (OGTT), respectively, between 24th and 28th gestational weeks. Groups were compared for maternal and fetal demographic characteristics and maternal serum resistin, visfatin, HbA1c levels and HOMA-IR. Additionally, a 75-g OGTT was performed in women with GDM at the postpartum 6th week. Patients with a multiple pregnancy, pregestational diabetes, chronic medical diseases, collagen vascular diseases and chronic inflammatory diseases were excluded. 100 g OGTT Patients with an abnormal 50 g glucose challenge test applied a diet lasting for 3 days and including an extra 150 g carbohydrate/ day before the 100 g OGTT. The test was performed after 8 h of fasting. Diagnosis of GDM after 100 g OGTT was made according to Carpenter and Couston criteria [13]. Patients with 2 abnormal values in the test were diagnosed to have GDM.
Laboratory measurements Fasting blood samples obtained from all patients to ethylenediaminetetraacetic acid (EDTA) tubes to study resistin and visfatin levels between the 24th and the 28th gestational weeks were centrifuged and stored at 80 until being studied. Serum resistin and visfatin levels were measured by using specific ELISA kits (Bioscience [Quality, Inc, Austria] for resistin and Phoenix [Pharmaceuticals, Inc] for visfatin) and ELISA reader (Epoch, Biotek Inc). Statistical analysis Data were analyzed by using SPSS (Statistical Packages for the Social Sciences) (ver. 16, Chicago, IL). Descriptive statistics were expressed as mean ± SD, median (minimum-maximum) and number [percentage (%)], as appropriate. Independent samples t-test and Mann–Whitney U test was used to compare the parametric and non-parametric numeric data between the groups, respectively. Chi-squared test was used to compare the categorical variables between the groups. Covariance analysis was used to compare the resistin and visfatin levels between the groups. To calculate the correlation coefficients of resistin and visfatin levels with the numerical variables, Pearson or Spearman correlation analysis was used for the parametric and nonparametric data as appropriate. A p value 50.05 was considered to be statistically significant.
75 g OGTT Patients with GDM underwent a 75-g OGTT after 8 h of fasting at the postpartum 6th week. Diagnosis of normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and type 2 DM was made according to ADA criteria [14].
Results A total of 80 pregnant women (40 with GDM and 40 controls) were included in the study. Maternal demographic and biochemical parameters are demonstrated in Table 1. Mean age of the
Table 1. Comparison of maternal demographic characteristics and biochemical parameters, fetal ultrasonographic and post-natal measurements in the control and gestational diabetes mellitus groups.
Age (year) Gravidity (n) Parity (n) Weight gain during pregnancy (kg) BMI (kg/m2) Prepregnancy Pregnancy 100 g OGTT (mg/dl) 1st hour 2nd hour 3rd hour Fasting glucose (mg/dl) Fasting insulin (mIU/ml) HOMA-IR HbA1c (%) Resistin (pg/ml) Visfatin (ng/ml) Pregnancy week at run time Biparietal diameter (mm) Head circumference (mm) Abdominal circumference (mm) Femur length (mm) Estimated fetal weight (g) Amniotic fluid index (cm) Gestational age at delivery Delivery mode (Caesarean section); n (%) Birth weight (g) Large for gestational age; n (%)
Control (n ¼ 40) Mean ± SD M (min–max)
GDM (n ¼ 40) Mean ± SD M (min–max)
p
26.2 ± 4.5 2 (1–7) 1 (0–3) 13.4 ± 4.8
30.1 ± 5.2 2 (1–6) 1 (0–4) 9 ± 4.9
0.001 0.825 0.967 0.001
23.7 ± 4.2 27.1 ± 5.6
27.3 ± 4.4 29.9 ± 4.3
0.001 0.013
– – – 79 (54–123) 7.02 (1.15–55.9) 1.1 (0.09–11.06) 4.5 (4–5.1) 5301 ± 428 8.64 (3.19–20) 25.4 ± 1 64 ± 3.4 237.7 ± 11.8 214.8 ± 14.7 47.6 ± 2.9 843.3 ± 138 8,7 ± 1,4 37.6 ± 2.3 23 (57.5) 3061 ± 574 –
198 ± 22.6 166.5 ± 34.5 124.2 ± 33.7 93 (67–203) 12.8 (1.04–134.4) 2.7 (0.09–41.1) 5.3 (4.4–7) 4177 ± 434 8.58 (3.3–20.32) 25.7 ± 1 65.5 ± 3.2 241.9 ± 12.3 222.1 ± 16.8 55.1 ± 3.8 950.8 ± 181 9,8 ± 1,8 38.1 ± 1.5 26 (65) 3357 ± 595 3 (7.5)
– – – 0.001 0.043 0.019 50.0001 0.071 0.194 0.202 0.045 0.132 0.044 0.426 0.002 0.006 0.262 0.508 0.037 0.241
GDM, gestational diabetes mellitus; Mean ± SD, Mean ± standard deviation; M (min–max), median (minimum–maximum); n (%): number (%); BMI, body mass index.
Resistin and visfatin in GDM
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DOI: 10.3109/09513590.2014.887670
patients, prepregnancy and pregnancy body mass index (BMI) values were higher and weight gain during pregnancy was lower in GDM group than that of the control group (p50.05 for all) (Table 1) Maternal serum resistin and visfatin levels in the GDM group was lower than that of the control group, but the difference was not statistically significant. Information about ultrasound findings and delivery records of the patients are demonstrated in Table 1. Gestational age at the ultrasound date and at delivery, mode of delivery and number of large for gestational age (LGA) infants were similar in the two groups. Biparietal diameter (BPD), fetal abdominal circumference (AC), estimated fetal weight, amniotic fluid index and birth weight were higher in the GDM group (p50.05 for all) (Table 1). There were three large for gestational age (LGA) infants in the GDM group. Within the GDM group, when patients with and without LGA infants were compared, maternal serum resistin levels (3759.1 ± 2784.5 and 4020 ± 2496.9 pg/ml) and maternal serum visfatin levels (9.6 ± 3.9 and 11.1 ± 3.1 ng/ml) were found to be similar (p ¼ 0.864 and p ¼ 0.519), respectively. Correlation analysis of BMI, BPD, head circumference (HC), femur length (FL), AC and birth weight with resistin in both groups showed that, among these parameters tested, there was only a moderate degree of positive correlation between maternal resistin levels and birthweight in the control group (Spearman r ¼ 0.491, p ¼ 0.003). Correlation analysis of visfatin with the same parameters showed no significant correlation in the control group. However, in the GDM group, visfatin level was positively correlated with BMI, BPD, HC, AC, FL, but not with birthweight (Table 2). At the postpartum 6th week, 34 of the 40 GDM cases readmitted for a follow-up visit. About 75 g OGTT performed at this visit resulted in a diagnosis of NGT in 25 (75%) of the cases, IGT in 7 (17.55) of the cases and type 2 diabetes in 2 (5%) of the cases. During statistical analysis, two cases with type 2 diabetes were evaluated in the same group with IGT. Fasting and 2nd hour glucose values in the NGT group were significantly lower than that of the IGT group (p50.05 for both, Table 3). Second trimester maternal serum visfatin levels were similar in both Table 2. Correlation coefficients of maternal serum visfatin levels with body mass index, biparietal diameter, head circumference, abdominal circumference and femur length in gestational diabetes mellitus group. Visfatin (ng/ml) GDM
Correlation coefficient (r) 2
Body mass index (kg/m ) Biparietal diameter (mm) Head circumference (mm) Abdominal circumference (mm) Femur length (mm)
0.491 0.368 0.527 0.380 0.412
(Pearson r) (Pearson r) (Spearman r) (Spearman r) (Spearman r)
p 0.001 0.019 50.001 0.016 0.008
Table 3. Comparison of fasting and 2-h glucose levels of normal glucose tolerance and impaired glucose tolerance groups according to the results of 75 g OGTT at postpartum sixth week and second trimester maternal serum resistin and visfatin levels in gestational diabetes mellitus group.
75 g OGTT (mg/dl) Fasting 2nd hour Resistin (pg/ml) Visfatin (ng/ml)
NGT (n ¼ 25) Mean ± SD
IGT (n ¼ 9) Mean ± SD
p
87.2 ± 10.7 108.5 ± 13.6 3463 ± 2501 9.5 ± 3.6
97.2 ± 12.3 181.5 ± 40.9 5835 ± 1522 9.6 ± 4.8
0.029 0.001 0.012 0.915
NGT, normal glucose tolerance; IGT, impaired glucose tolerance; mean ± SD, mean ± standard deviation.
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groups, however, maternal serum resistin levels in the IGT group were significantly higher than that of the NGT group (p50.05, Table 3).
Discussion In this study, we found that pregnant women with and without GDM had similar second trimester serum resistin and visfatin levels. However, patients with GDM who also had postpartum IGT had significantly higher second trimester levels of serum resistin than those who had postpartum NGT. Second trimester serum visfatin levels of women with GDM showed a positive correlation with BMI, BPD, HC, AC, FL but not with birthweight. Second trimester serum resistin levels of women without GDM showed a positive correlation with birthweight. It is known that plasma resistin levels are higher in pregnant patients when compared to non-pregnants [15]. Kuzmicki et al. [16] reported that pregnant patients with GDM had significantly higher levels of resistin than those with a NGT, while other studies reported no difference between the resistin levels of pregnant patients with or without GDM [11,17]. There is no clear evidence about the relationship of GDM with visfatin. Telejko et al. [18] reported that serum visfatin levels in cases with GDM were similar to the control group. Additionally, they reported an inverse relationship between HbA1c and visfatin levels in patients with GDM. Rezvan et al. [12] reported lower serum visfatin levels in the control group. They found no association between serum visfatin levels and maternal age, BMI, nutritional status but reported a positive correlation with the HbA1c levels. Skvarca et al. [10] investigated the adipocytokines in pregnant women at different insulin resistance levels including NGT, IGT and GDM groups. They found no statistically significant between-group differences in serum resistin and visfatin concentrations. They mentioned that these adipocytokines were not adequately sensitive to replace HOMA-IR in pregnancy. In this study, we also found that the resistin and visfatin levels of pregnant women with and without GDM were similar. Actually, both adipokines seemed to be lower in the GDM group than the control group but the difference was not statistically significant. Finding lower levels of these adipokines in the GDM group contradicts the previous reports [12,16]. But our finding that GDM patients with postpartum IGT had higher second trimester levels of serum resistin than those with postpartum NGT is in accordance to the literature. Because, we know that resistin acts in the opposite direction to insulin and plays a role in the pathogenesis of diabetes [7]. This finding suggests that second trimester resistin levels in patients with GDM may have a predictive role for postpartum glucose intolerance if this finding is supported in further studies. Fetal macrosomia is frequent among patients with GDM and this causes an increase in perinatal complications. Several studies in the literature have investigated the presence of any association between birthweight and adipokines [19–21]. Wang et al. [20] reported a negative correlation between umbilical serum levels and placental expression of resistin with birthweight. Similarly, Shang et al. [21] reported that maternal serum visfatin levels were lower in the macrosomic fetuses than in fetuses with growth restriction and concluded that levels of visfatin could affect intrauterine growth. Mohamed et al. [22] evaluated the resistin levels in the cord blood of the term newborns of the diabetic mothers and found that resistin levels were lower compared to the control group. They reported that the glucose, insulin and resistin levels of the macrosomic and normal weight fetuses of the diabetic mothers were similar [22]. Decrease or increase in visfatin levels in pregnant patients with GDM is reported to be associated with fetal growth [23,24]. In our study, the
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mean birthweight was significantly higher in the GDM group which included three LGA infants. Within the GDM group, serum resistin levels of patients with and without LGA infants were similar, in accordance to the finding of Mohamed et al. [22]. In contrast to the previous studies which reported a negative correlation between resistin level and birthweight [20], we detected a positive correlation between resistin level and birth weight in the control group (r:0.450, p:0.007), but, not in the GDM group. An important finding of our study was the positive correlation observed between visfatin level and the fetal biometric measurements in the GDM group. In the light of this finding, we can think that higher visfatin levels in the second trimester in patients with GDM may be an indicator of hyperglycemia induced accelerated fetal growth. But further well designed larger studies are needed about this issue. Early detection of GDM and prevention of related perinatal complications is important. To assess the association of maternal visfatin levels and GDM in early gestational weeks, Ferreira et al. [25] evaluated the serum levels of 400 pregnant patients between 11 and 13 weeks of gestation. During follow up, 100 of these patients developed GDM while 300 did not. Serum visfatin levels of patients that developed GDM during follow-up was reported to be higher than that of the control group. It was shown that maternal visfatin concentration changes as a function of gestational age with a different pattern in normal and overweight pregnant women [23]. We had no data about the first trimester visfatin levels of our patients, but the second trimester visfatin levels of patients with and without GDM in our study were similar. It is reported that visfatin secretion is higher in obese patient [26]. In our study, we found a positive correlation between serum visfatin levels and maternal BMI, in accordance with the literature.
Limitations The small sample size and assessment of maternal serum resistin and visfatin levels only in second trimester are the limitations of our study. We suggest that longitudinal observation on the profile of these hormones during pregnancy and postpartum period would enhance our insight into the relationship of adipokines with the pathogenesis of GDM.
Conclusion Maternal serum resistin and visfatin levels were found to be unchanged in patients with GDM although the GDM group had a higher BMI than the control group. Patients with GDM with higher second trimester resistin levels may be at higher risk to develop postpartum glucose intolerance. Visfatin levels in the second trimester may be associated with the rate of fetal growth in patients with GDM. Further larger prospective studies are needed.
Acknowledgements The authors thank obstetrics and gynecology clinic employees for their contributions to the study.
Declaration of interest The authors report no declarations of interest. This study was financially endorsed by Duzce University, Medical Faculty Scientific Study Research Commission (registration number 2012.04.HD.060).
References 1. Baptiste-Roberts K, Barone BB, Gary TL. Risk factors for type 2 diabetes among women with gestational diabetes: a systematic review. Am J Med 2009;122:207–14.
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2. American Diabetes Association. Gestational diabetes mellitus (Position Statement). Diabetes Care 2004;27:88–90. 3. Kim C, Newton KM, Knopp RH. Gestational diabetes and the incidence of type 2 diabetes: a systematic review. Diabetes Care 2002;25:1862–8. 4. Catalano P, Tyzbir ED, Roman NM. Longitudinal changes in insulin release and insulin resistance in non-obese pregnant women. Am J Obstet Gynecol 1991;165:1667–72. 5. Kafkasli A. Preterm dog˘um. In: Gabbe SG, Niebyl JR, Simpson JL, eds. Obstetrikte normal ve sorunlu gebelikler. Istanbul: Nobel & Gu¨ne¸s tip kitabevi; 2009:713–32. 6. McTernan PG, Kusminski CM, Kumar S. Resistin. Curr Opin Lipidol 2006;17:170–5. 7. Al-Suhaimi EA, Shehzad A. Leptin, resistin and visfatin: the missing link between endocrine metabolic disorders and immunity. Eur J Med Res 2013;18:12. 8. Fukuhara A, Matsuda M, Nishizawa M, et al. Visfatin: a protein secreted by visceral fat that mimics the effects of insulin. Science 2005;18:426–30. 9. Chen D, Fang Q, Chai Y, et al. Serum resistin in gestational diabetes mellitus and early postpartum. Clin Endocrinol 2007;67: 208–11. 10. Skvarca A, Tomazic M, Krhin B, et al. Adipocytokines and insulin resistance across various degrees of glucose tolerance in pregnancy. J Int Med Res 2012;40:583–9. 11. Akdeniz N, Kuyumcuog˘lu U, Kale A, et al. Resistin may not associate with gestational diabetes mellitus although insulin resistance. Clin Exp Obstet Gynecol 2011;38:236–8. 12. Rezvan N, Hosseinzadeh-Attar MJ, Masoudkabir F, et al. Serum visfatin concentrations in gestational diabetes mellitus and normal pregnancy. Arch Gynecol Obstet 2012;285:1257–62. 13. Carpenter MW, Coustan DR. Criteria for screening tests forgestational diabetes. Am J Obstet Gynecol 1982;144:768–73. 14. American Diabetes Association. Standards of medical care in diabetes – 2011. Diabetes Care 2011;34:S11–61. 15. Steppan CM, Bailey ST, Bhat S, et al. The hormone resistin links obesity to diabetes. Nature 2001;409:307–12. 16. Kuzmicki M, Telejko B, Szamatowicz J, et al. High resistin and interleukin-6 levels are associated with gestational diabetes mellitus. Gynecol Endocrinol 2009;25:258–63. 17. Lappas M, Yee K, Permezel M, Rice GE. Release and regulation of leptin, resistin and adiponectin from human placenta, fetal membranes, and maternal adipose tissue and skeletal muscle from normal and gestational diabetes mellitus-complicated pregnancies. J Endocrinol 2005;186:457–65. 18. Telejko B, Kuzmicki M, Zonenberg A, et al. Visfatin in gestational diabetes: serum level and mRNA expression in fat and placental tissue. Diabetes Res Clin Pract 2009;84:68–75. 19. Chan TF, Yuan SS, Chen HS, et al. Correlations between umbilical and maternal serum adiponectin levels and neonatal birthweights. Acta Obstet Gynecol Scand 2004;83:165–9. 20. Wang J, Shang LX, Dong X, et al. Relationship of adiponectin and resistin levels in umbilical serum, maternal serum and placenta with neonatal birthweight. Aust N Z J Obstet Gynaecol 2010;50: 432–8. 21. Shang LX, Tang QL, Wang J, et al. Relationship of adiponectin and visfatin with fetus intrauterine growth. Zhonghua Fu Chan Ke Za Zhi 2009;44:246–8. 22. Mohamed MH, Gad GI, Ibrahim HY, et al. Cord blood resistin and adiponectin in term newborns of diabetic mothers. Arch Med Sci 2010;6:558–66. 23. Mazaki-Tovi S, Romero R, Kusanovic JP, et al. Maternal visfatin concentration in normal pregnancy. J Perinat Med 2009; 37:206–17. 24. Lewandowski KC, Stojanovic N, Press M, et al. Elevated serum levels of visfatin in gestational diabetes: a comparative study across various degrees of glucose tolerance. Diabetologia 2007;50:1033–7. 25. Ferreira AF, Rezende JC, Vaikousi E, et al. Maternal serum visfatin at 11–13 weeks of gestation in gestational diabetes mellitus. Clin Chem 2011;57:609–13. 26. Revollo JR, Grimm AA, Imai S. The regulation of nicotinamide adenine dinucleotide biosynthesis by Nampt/PBEF/visfatin in mammals. Curr Opin Gastroenterol 2007;23:164–70.
GESTATIONAL DIABETES
Relationship of maternal serum resistin and visfatin levels with gestational diabetes mellitus Ahmet Karatas1, Nilu¨fer Tunc¸ay I¸sikkent2, Tu¨lay Ozlu¨1, and Hilmi Demirin3 Department of Obstetrics and Gynecology, Medical Faculty, Abant Izzet Baysal University, Bolu, Turkey, 2Department of Obstetrics and Gynecology, and 3Department of Biochemistry, Medical Faculty, Duzce University, Duzce, Turkey
Abstract
Keywords
Introduction: Adiponectin, resistin and visfatin are thought to play role in the pathophysiology of gestational diabetes (GDM). In this study, we aimed to investigate the association of maternal second trimester serum resistin and visfatin levels with GDM. Materials and methods: Screening and diagnosis for GDM was performed between the 24–28th gestational weeks. About 40 women diagnosed with GDM and 40 non-diabetic women constituted the study and control groups, respectively. Groups were compared for second trimester maternal serum resistin, visfatin and HbA1c levels, HOMA-IR and postpartum 75 g OGTT results. Results: Mean serum resistin (p ¼ 0.071) and visfatin (p ¼ 0.194) levels were similar between the groups. However, mean BMI (p ¼ 0.013), HOMA-IR (p ¼ 0.019), HbA1c (p50.0001) and birth weight (p ¼ 0.037) were significantly higher in GDM group compared to controls. Type 2 diabetes and impaired glucose tolerance were detected in 2 (5%) and 7 (20%) women in the GDM group, respectively, with 75 g OGTT performed at the postpartum 6th week. Resistin levels of patients with GDM and postpartum glucose intolerance were higher than those with GDM but no postpartum glucose intolerance (p ¼ 0.012). Visfatin levels in the GDM group showed a positive correlation with biparietal diameter, head circumference, abdominal circumference and femur length (p50.05). Conclusion: Maternal serum resistin and visfatin levels are unchanged in GDM. In patients with GDM, second trimester resistin levels may be predictive for postpartum glucose intolerance and second trimester visfatin levels may be related with fetal biometric measurements. Further larger studies are needed.
Gestational diabetes, insulin resistance, resistin, visfatin
Introduction Gestational diabetes mellitus (GDM) is a disorder of the carbohydrate metabolism first arising during pregnancy and causing increased morbidity of both the fetus and the mother. GDM constitutes 90% of the diabetes cases during pregnancy [1]. According to American Diabetes Association (ADA), its incidence changes between 1% and 14% and it complicates almost 7% of the pregnant patients, although the numbers can vary among different populations [2]. Furthermore, it is reported that 10–50% of the GDM cases develop type 2 diabetes in the postpartum period [3]. Various different hormones in the body like human placental lactogen (HPL), cortisol, growth hormone, estrogen, progesterone as well as increased insulinase secretion from the placenta may have a role in the pathogenesis of GDM [4]. Besides being a source of energy, adipose tissue also acts as an endocrine tissue. Some novel molecules that are known to be secreted from the adipose tissue including tumor necrosis factor-alpha (TNF-a),
History Received 4 August 2013 Revised 23 November 2013 Accepted 12 December 2013 Published online 10 February 2014
interleukin-6 (IL-6), resistin, visfatin, leptin are also kept responsible from the pathogenesis of GDM [5]. Some adipocytokines like leptin, TNF-a, IL-6, resistin and visfatin have metabolic and immunologic roles in obesity related inflammation and in progression to type 2 diabetes [6]. Resistin is a molecule that resists to the activity of insulin and the circulating levels of this molecule are increased in obese humans [7]. This proinflammatory molecule is reported to play role in the pathogenesis of diabetes and diabetic complications [7]. The expression of visfatin is also reported to increase in cases of abdominal obesity and type 2 diabetes [7,8]. Recent studies about the association of resistin and visfatin levels with GDM have conflicting results. Some of them show that cases with GDM have increased levels of resistin and visfatin compared to the control group [9,10], while others either report no difference for these molecules between the two groups [11] or lower visfatin levels in the GDM group [12]. In this study, we aimed to investigate the association of maternal serum resistin and visfatin levels with GDM.
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1
Materials and methods Address for correspondence: Ahmet Karatas, Department of Obstetrics and Gynecology, Medical Faculty, Abant Izzet Baysal University, 14280 Golkoy, Bolu, Turkey. Tel: +90 374 253 46 56. Fax: +90 374 253 46 15. E-mail: [email protected]
This longitudinal cross-sectional study was carried out in Obstetrics and Gynaecology Department of Duzce University School of Medicine between January and July 2012. Duzce
356
A. Karatas et al.
Gynecol Endocrinol, 2014; 30(5): 355–358
Gynecol Endocrinol Downloaded from informahealthcare.com by University of Laval on 07/15/14 For personal use only.
University Non-Invasive Human Research Ethics Committee approved the study. Informed consent was obtained from all subjects. About 80 women with singleton pregnancies attending to the obstetrics outpatient clinic for routine obstetric care were included in the study. About 40 women diagnosed with GDM and 40 non-diabetic women constituted the study and control groups, respectively. Screening for and diagnosis of GDM was performed by using 50 g glucose challenge test and 100 g oral glucose tolerance test (OGTT), respectively, between 24th and 28th gestational weeks. Groups were compared for maternal and fetal demographic characteristics and maternal serum resistin, visfatin, HbA1c levels and HOMA-IR. Additionally, a 75-g OGTT was performed in women with GDM at the postpartum 6th week. Patients with a multiple pregnancy, pregestational diabetes, chronic medical diseases, collagen vascular diseases and chronic inflammatory diseases were excluded. 100 g OGTT Patients with an abnormal 50 g glucose challenge test applied a diet lasting for 3 days and including an extra 150 g carbohydrate/ day before the 100 g OGTT. The test was performed after 8 h of fasting. Diagnosis of GDM after 100 g OGTT was made according to Carpenter and Couston criteria [13]. Patients with 2 abnormal values in the test were diagnosed to have GDM.
Laboratory measurements Fasting blood samples obtained from all patients to ethylenediaminetetraacetic acid (EDTA) tubes to study resistin and visfatin levels between the 24th and the 28th gestational weeks were centrifuged and stored at 80 until being studied. Serum resistin and visfatin levels were measured by using specific ELISA kits (Bioscience [Quality, Inc, Austria] for resistin and Phoenix [Pharmaceuticals, Inc] for visfatin) and ELISA reader (Epoch, Biotek Inc). Statistical analysis Data were analyzed by using SPSS (Statistical Packages for the Social Sciences) (ver. 16, Chicago, IL). Descriptive statistics were expressed as mean ± SD, median (minimum-maximum) and number [percentage (%)], as appropriate. Independent samples t-test and Mann–Whitney U test was used to compare the parametric and non-parametric numeric data between the groups, respectively. Chi-squared test was used to compare the categorical variables between the groups. Covariance analysis was used to compare the resistin and visfatin levels between the groups. To calculate the correlation coefficients of resistin and visfatin levels with the numerical variables, Pearson or Spearman correlation analysis was used for the parametric and nonparametric data as appropriate. A p value 50.05 was considered to be statistically significant.
75 g OGTT Patients with GDM underwent a 75-g OGTT after 8 h of fasting at the postpartum 6th week. Diagnosis of normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and type 2 DM was made according to ADA criteria [14].
Results A total of 80 pregnant women (40 with GDM and 40 controls) were included in the study. Maternal demographic and biochemical parameters are demonstrated in Table 1. Mean age of the
Table 1. Comparison of maternal demographic characteristics and biochemical parameters, fetal ultrasonographic and post-natal measurements in the control and gestational diabetes mellitus groups.
Age (year) Gravidity (n) Parity (n) Weight gain during pregnancy (kg) BMI (kg/m2) Prepregnancy Pregnancy 100 g OGTT (mg/dl) 1st hour 2nd hour 3rd hour Fasting glucose (mg/dl) Fasting insulin (mIU/ml) HOMA-IR HbA1c (%) Resistin (pg/ml) Visfatin (ng/ml) Pregnancy week at run time Biparietal diameter (mm) Head circumference (mm) Abdominal circumference (mm) Femur length (mm) Estimated fetal weight (g) Amniotic fluid index (cm) Gestational age at delivery Delivery mode (Caesarean section); n (%) Birth weight (g) Large for gestational age; n (%)
Control (n ¼ 40) Mean ± SD M (min–max)
GDM (n ¼ 40) Mean ± SD M (min–max)
p
26.2 ± 4.5 2 (1–7) 1 (0–3) 13.4 ± 4.8
30.1 ± 5.2 2 (1–6) 1 (0–4) 9 ± 4.9
0.001 0.825 0.967 0.001
23.7 ± 4.2 27.1 ± 5.6
27.3 ± 4.4 29.9 ± 4.3
0.001 0.013
– – – 79 (54–123) 7.02 (1.15–55.9) 1.1 (0.09–11.06) 4.5 (4–5.1) 5301 ± 428 8.64 (3.19–20) 25.4 ± 1 64 ± 3.4 237.7 ± 11.8 214.8 ± 14.7 47.6 ± 2.9 843.3 ± 138 8,7 ± 1,4 37.6 ± 2.3 23 (57.5) 3061 ± 574 –
198 ± 22.6 166.5 ± 34.5 124.2 ± 33.7 93 (67–203) 12.8 (1.04–134.4) 2.7 (0.09–41.1) 5.3 (4.4–7) 4177 ± 434 8.58 (3.3–20.32) 25.7 ± 1 65.5 ± 3.2 241.9 ± 12.3 222.1 ± 16.8 55.1 ± 3.8 950.8 ± 181 9,8 ± 1,8 38.1 ± 1.5 26 (65) 3357 ± 595 3 (7.5)
– – – 0.001 0.043 0.019 50.0001 0.071 0.194 0.202 0.045 0.132 0.044 0.426 0.002 0.006 0.262 0.508 0.037 0.241
GDM, gestational diabetes mellitus; Mean ± SD, Mean ± standard deviation; M (min–max), median (minimum–maximum); n (%): number (%); BMI, body mass index.
Resistin and visfatin in GDM
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DOI: 10.3109/09513590.2014.887670
patients, prepregnancy and pregnancy body mass index (BMI) values were higher and weight gain during pregnancy was lower in GDM group than that of the control group (p50.05 for all) (Table 1) Maternal serum resistin and visfatin levels in the GDM group was lower than that of the control group, but the difference was not statistically significant. Information about ultrasound findings and delivery records of the patients are demonstrated in Table 1. Gestational age at the ultrasound date and at delivery, mode of delivery and number of large for gestational age (LGA) infants were similar in the two groups. Biparietal diameter (BPD), fetal abdominal circumference (AC), estimated fetal weight, amniotic fluid index and birth weight were higher in the GDM group (p50.05 for all) (Table 1). There were three large for gestational age (LGA) infants in the GDM group. Within the GDM group, when patients with and without LGA infants were compared, maternal serum resistin levels (3759.1 ± 2784.5 and 4020 ± 2496.9 pg/ml) and maternal serum visfatin levels (9.6 ± 3.9 and 11.1 ± 3.1 ng/ml) were found to be similar (p ¼ 0.864 and p ¼ 0.519), respectively. Correlation analysis of BMI, BPD, head circumference (HC), femur length (FL), AC and birth weight with resistin in both groups showed that, among these parameters tested, there was only a moderate degree of positive correlation between maternal resistin levels and birthweight in the control group (Spearman r ¼ 0.491, p ¼ 0.003). Correlation analysis of visfatin with the same parameters showed no significant correlation in the control group. However, in the GDM group, visfatin level was positively correlated with BMI, BPD, HC, AC, FL, but not with birthweight (Table 2). At the postpartum 6th week, 34 of the 40 GDM cases readmitted for a follow-up visit. About 75 g OGTT performed at this visit resulted in a diagnosis of NGT in 25 (75%) of the cases, IGT in 7 (17.55) of the cases and type 2 diabetes in 2 (5%) of the cases. During statistical analysis, two cases with type 2 diabetes were evaluated in the same group with IGT. Fasting and 2nd hour glucose values in the NGT group were significantly lower than that of the IGT group (p50.05 for both, Table 3). Second trimester maternal serum visfatin levels were similar in both Table 2. Correlation coefficients of maternal serum visfatin levels with body mass index, biparietal diameter, head circumference, abdominal circumference and femur length in gestational diabetes mellitus group. Visfatin (ng/ml) GDM
Correlation coefficient (r) 2
Body mass index (kg/m ) Biparietal diameter (mm) Head circumference (mm) Abdominal circumference (mm) Femur length (mm)
0.491 0.368 0.527 0.380 0.412
(Pearson r) (Pearson r) (Spearman r) (Spearman r) (Spearman r)
p 0.001 0.019 50.001 0.016 0.008
Table 3. Comparison of fasting and 2-h glucose levels of normal glucose tolerance and impaired glucose tolerance groups according to the results of 75 g OGTT at postpartum sixth week and second trimester maternal serum resistin and visfatin levels in gestational diabetes mellitus group.
75 g OGTT (mg/dl) Fasting 2nd hour Resistin (pg/ml) Visfatin (ng/ml)
NGT (n ¼ 25) Mean ± SD
IGT (n ¼ 9) Mean ± SD
p
87.2 ± 10.7 108.5 ± 13.6 3463 ± 2501 9.5 ± 3.6
97.2 ± 12.3 181.5 ± 40.9 5835 ± 1522 9.6 ± 4.8
0.029 0.001 0.012 0.915
NGT, normal glucose tolerance; IGT, impaired glucose tolerance; mean ± SD, mean ± standard deviation.
357
groups, however, maternal serum resistin levels in the IGT group were significantly higher than that of the NGT group (p50.05, Table 3).
Discussion In this study, we found that pregnant women with and without GDM had similar second trimester serum resistin and visfatin levels. However, patients with GDM who also had postpartum IGT had significantly higher second trimester levels of serum resistin than those who had postpartum NGT. Second trimester serum visfatin levels of women with GDM showed a positive correlation with BMI, BPD, HC, AC, FL but not with birthweight. Second trimester serum resistin levels of women without GDM showed a positive correlation with birthweight. It is known that plasma resistin levels are higher in pregnant patients when compared to non-pregnants [15]. Kuzmicki et al. [16] reported that pregnant patients with GDM had significantly higher levels of resistin than those with a NGT, while other studies reported no difference between the resistin levels of pregnant patients with or without GDM [11,17]. There is no clear evidence about the relationship of GDM with visfatin. Telejko et al. [18] reported that serum visfatin levels in cases with GDM were similar to the control group. Additionally, they reported an inverse relationship between HbA1c and visfatin levels in patients with GDM. Rezvan et al. [12] reported lower serum visfatin levels in the control group. They found no association between serum visfatin levels and maternal age, BMI, nutritional status but reported a positive correlation with the HbA1c levels. Skvarca et al. [10] investigated the adipocytokines in pregnant women at different insulin resistance levels including NGT, IGT and GDM groups. They found no statistically significant between-group differences in serum resistin and visfatin concentrations. They mentioned that these adipocytokines were not adequately sensitive to replace HOMA-IR in pregnancy. In this study, we also found that the resistin and visfatin levels of pregnant women with and without GDM were similar. Actually, both adipokines seemed to be lower in the GDM group than the control group but the difference was not statistically significant. Finding lower levels of these adipokines in the GDM group contradicts the previous reports [12,16]. But our finding that GDM patients with postpartum IGT had higher second trimester levels of serum resistin than those with postpartum NGT is in accordance to the literature. Because, we know that resistin acts in the opposite direction to insulin and plays a role in the pathogenesis of diabetes [7]. This finding suggests that second trimester resistin levels in patients with GDM may have a predictive role for postpartum glucose intolerance if this finding is supported in further studies. Fetal macrosomia is frequent among patients with GDM and this causes an increase in perinatal complications. Several studies in the literature have investigated the presence of any association between birthweight and adipokines [19–21]. Wang et al. [20] reported a negative correlation between umbilical serum levels and placental expression of resistin with birthweight. Similarly, Shang et al. [21] reported that maternal serum visfatin levels were lower in the macrosomic fetuses than in fetuses with growth restriction and concluded that levels of visfatin could affect intrauterine growth. Mohamed et al. [22] evaluated the resistin levels in the cord blood of the term newborns of the diabetic mothers and found that resistin levels were lower compared to the control group. They reported that the glucose, insulin and resistin levels of the macrosomic and normal weight fetuses of the diabetic mothers were similar [22]. Decrease or increase in visfatin levels in pregnant patients with GDM is reported to be associated with fetal growth [23,24]. In our study, the
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mean birthweight was significantly higher in the GDM group which included three LGA infants. Within the GDM group, serum resistin levels of patients with and without LGA infants were similar, in accordance to the finding of Mohamed et al. [22]. In contrast to the previous studies which reported a negative correlation between resistin level and birthweight [20], we detected a positive correlation between resistin level and birth weight in the control group (r:0.450, p:0.007), but, not in the GDM group. An important finding of our study was the positive correlation observed between visfatin level and the fetal biometric measurements in the GDM group. In the light of this finding, we can think that higher visfatin levels in the second trimester in patients with GDM may be an indicator of hyperglycemia induced accelerated fetal growth. But further well designed larger studies are needed about this issue. Early detection of GDM and prevention of related perinatal complications is important. To assess the association of maternal visfatin levels and GDM in early gestational weeks, Ferreira et al. [25] evaluated the serum levels of 400 pregnant patients between 11 and 13 weeks of gestation. During follow up, 100 of these patients developed GDM while 300 did not. Serum visfatin levels of patients that developed GDM during follow-up was reported to be higher than that of the control group. It was shown that maternal visfatin concentration changes as a function of gestational age with a different pattern in normal and overweight pregnant women [23]. We had no data about the first trimester visfatin levels of our patients, but the second trimester visfatin levels of patients with and without GDM in our study were similar. It is reported that visfatin secretion is higher in obese patient [26]. In our study, we found a positive correlation between serum visfatin levels and maternal BMI, in accordance with the literature.
Limitations The small sample size and assessment of maternal serum resistin and visfatin levels only in second trimester are the limitations of our study. We suggest that longitudinal observation on the profile of these hormones during pregnancy and postpartum period would enhance our insight into the relationship of adipokines with the pathogenesis of GDM.
Conclusion Maternal serum resistin and visfatin levels were found to be unchanged in patients with GDM although the GDM group had a higher BMI than the control group. Patients with GDM with higher second trimester resistin levels may be at higher risk to develop postpartum glucose intolerance. Visfatin levels in the second trimester may be associated with the rate of fetal growth in patients with GDM. Further larger prospective studies are needed.
Acknowledgements The authors thank obstetrics and gynecology clinic employees for their contributions to the study.
Declaration of interest The authors report no declarations of interest. This study was financially endorsed by Duzce University, Medical Faculty Scientific Study Research Commission (registration number 2012.04.HD.060).
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