| BackgroundThe Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study has already demonstrated even if the maternal blood plasma glucose levels below the diagnosis of overt diabetes, there was also a continuous graded relationship between maternal glucose and the adverse pregnancy outcomes, including macrosomia, cesarean section rate, fetal hyperinsulinemia and clinical neonatal hypoglycemia. Maternal insulin resistance (IR) during pregnancy is the key factor that makes fetal exposure to intrauterine environment of hyperglycaemia and lead to fetal excess growth and other adverse pregnant outcomes. There is a more severe IR in women with gestational diabetes mellitus (GDM) than those with normal glucose tolerance (NGT) has been recognized for many years, but the causal mechanisms remain unclear. However, with the research to understand the pathogenesis of obesity and its metabolic sequelae advancing rapidly, adipose tissue has been found to represent an active endocrine organ that, in addition to regulating fat mass and nutrient homeostasis, releases a large number of bioactive adipokines that signal to important metabolic organs including brain, liver, and skeletal muscle. IR involve in the interaction between nutrition, blood glucose, insulin and some important adipokines which participate in various tissue metabolism. The study in non-pregnant population such as patients with obesity, polycystic ovary syndrome and type2diabetes (T2DM) has showed that there are differences in expression and secretion in certain important factors, such as omentin, islet-1, vaspin in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT), thereby playing a different role in modulating some physiological activities such as blood pressure, glucose and lipid metabolism, inflammation and IR. However, it is not clear whether there are differences in the expressions of these adipokine in GDM and whether these adipokine are associated with the formation of IR during pregnancy. This study aims to compare the expression differences of omentin, islet-1, vaspin mRNA in subcutaneous and visceral adipose tissues in pregnant women with GDM and NGT, to investigate relationship between omentin, islet-1, vaspin mRNA expressions and glucolipid metabolism, IR as well as other classic adipokines in Chinese pregnant women, and to explore the endocrine function of adipose tissue in SAT and VAT, which might play role in the pathophysiology of GDM occurs and provid clues to clinical intervention for GDM.Objective1. To evaluate the differences of metabolic states, insulin secretion and IR in pregnant women with GDM and NGT, and to investigate their impact on neonatal birth weight.2. To compare omentin, islet-1, vaspin mRNA expressions in SAT and VAT in Chinese pregnant women with GDM and NGT, and to analyze the relationship between omentin, islet-1, vaspin mRNA expressions in different sites and glucolipid metabolism as well as IR, which might be help for investigating the role of adipose tissue with expressing specific cytokines in the pathogenesis of GDM.3. To analyze the relationship between omentin, islet-1, vaspin mRNA expression in different sites and serum fasting adiponectin, leptin, TNF-α, IL-6levels before delivery, and to investigate whether or not the expressions and secretions of these adipokines have effects on IR during pregnancy.Methods1. In this prospective study,43pregnant women with GDM undergoing only alimentary control were included in the case group, The GDM group diagnosesed according to WHO criteria was compared with the control group with normal glucose tolerance (NGT) and matched for age (±yr), gravity (±1), exact parity, body mass index (BMI±1.0kg/m2), and gestational weeks at delivery (±wk) each other. Both the GDM and NGT groups delivered by elective cesarean section for obstetric indications between January and Dec2009, in the department of O&G of the1st affiliated hospital of Kunming medical collage.2. Their height, weight, fasting plasma glucose (FPG), total cholesterol (TC), triglycerides (TG), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C) and fasting insulin(FINS) levels before delivery were measured, BMI and weight gain during pregnancy were calculated. Homeostasis model assessment was calculated as insulin resistance index (HOMA-IR), and insulin secretion function was evaluated by homeostasis β-cell index (HBCI). The differences of clinical data between the two groups were compared and the relationship between maternal body parameters, IR and insulin secretion function with neonatal birth weight were analyzed.3. Abdominal subcutaneous (SAT) and visceral adipose tissues (VAT) were obtained in two groups during selective cesarean section. Total RNA was extracted by Trizol and the first strand cDNA was synthesized by reverse transcription. Real-time quantitative polymerase chain reaction (RT-PCR) was used to measure the omentin, islet-1, vaspin mRNA expressions in SAT and VAT in the two groups. The relationship between omentin, islet-1, vaspin mRNA expression in different sites of adipose tissues with maternal metabolic parameters and HOMA-IR were analyzed.4. Serum fasting adiponectin, leptin, tumor necrosis factor alpha (TNF-a) and Interleukin-6(IL-6) levels before delivery were measured by enzyme linked immunosorbent assay (ELISA). The relationship between omentin, islet-1, vaspin mRNA expression in different sites of adipose tissues with maternal serum fasting adiponectin, leptin, TNF-a and IL-6were analyzed.Results1. Compared with the control group (1:1), BMI before pregnancy (23.09±3.59vs.21.26±2.89, P=0.011), OGTT Oh (4.93±0.80vs.4.41±0.48, P=0.000) and2h glucose (8.61±0.71vs.6.17±0.90, P=0.000), FPG (4.88±0.66vs.4.31±0.56, P=0.000), FINS (74.59±27.16vs.50.68±19.38, P=0.000), TG (3.76±1.78vs.2.95±1.13, P=0.014), LDL-C (3.77±0.78vs.3.27±0.84, P=0.005), leptin (4.57±1.03vs.4.10±0.63, P=0.012), TNF-a (346.18±73.10vs.256.85±84.16, P=0.000),IL-6(9.43±1.96vs.5.03±1.56, P=0.000) levels, HOMA-IR transformed to logarithm (1.18±0.17vs.0.96±0.18, P=0.000) in GDM group were significantly higher and HDL-C(1.71±0.34vs.1.97±0.47, P=0.004), adiponectin (362.95±115.53vs.450.33±80.31, P=0.000) in GDM group were significantly lower than those in control group. Received alimentary control in GDM, there were no significant differences in weight gain (15.05±6.35vs.16.20±3.53, P=0.302), HBCI (3.07±0.29vs.3.23±0.45, P=0.059) and neonatal birth weight (3433.30±491.85vs.3322.336±375.08, P=0.243) between two groups to be found.2. Step-wise linear regression analysis showed only maternal weight gain (β=0.364, p=0.001), HOMA-IR transformed to logarithm (β=0.218, p=0.034) were proved as independent predictors of neonatal birth weight in all cases.3. In86cases combined GDM and NGT groups, RT-PCR showed:①.There is significantly higher levels of Omentin mRNA expression in VAT than in SAT in both groups (0.636±0.157vs.0.063±0.016, P=0.000). In pregnant women with various glycometabolism states, omentin mRNA expression in GDM in both SAT (0.057±0.014vs0.070±0.015, P=0.000) and VAT (0.560±0.125vs0.713±0.150, P=0.000) are significantly lower than those in NGT.②.Islet-1mRNA expression was mainly in VAT, and islet-1mRNA expression in VAT in GDM group was significantly lower than that in NGT (0.200±0.031vs.0.268±0.049, P=0.000). However, in SAT obtained from pregnant women with GDM and NGT, islet-1mRNA were trace or virtually absent expressions (53.49%vs.65.12%, P=0.084) and there was no difference in gene expression in two groups (0.035±0.027vs.0.041±0.022, p=0.402).③. There is significantly higher levels of vaspin mRNA expression in VAT than in SAT in both groups (0.53±0.16vs.0.32±0.06, P=0.000). Vaspin mRNA expression in GDM in both SAT (0.33±0.06vs.0.30±0.05, P=0.006) and VAT (0.58±0.16vs.0.48±0.15, P=0.004) are significantly higher than those in NGT.4. In86cases combined GDM and NGT cases, by bivariate Pearson correlation analysis the expression of omentin mRNA in SAT was found to be inversely correlated with BMI before pregnancy (r=-0.251, P=0.020), OGTT2h glucose(2hPG)(r=-0.375, P=0.000), and FPG(r=-0.260, P=0.016), FINS(r=-0.242, P=0.025), HOMA-IR(r=-0.284, P=0.008), IL-6(r=-0.304, P=0.004)before delivery, respectively. Omentin mRNA in VAT was found to be inversely correlated with OGTT Oh (r=-0.274, P=0.011) and2hPG (r=-0.482, P=0.000), FPG (r=-0.259, P=0.016), HOMA-IR(r=-0.236, P=0.029), leptin(r=-0.310, P=0.004), TNF-a(r=-0.231, P=0.032), IL-6(r=-0.279, P=0.009) before delivery, whereas positively correlated with maternal weight gain(r=0.250, P=0.021) during pregnancy and serum adiponectin(r=0.361, P=0.001) levels before delivery.5. In86cases combined GDM and NGT cases, by bivariate Pearson correlation analysis the expression of islet-1mRNA in VAT was found to be inversely correlated with BMI before pregnancy (r=-0.262, P=0.015), OGTT Oh (r=-0.290, P=0.007) and2hPG(r=-0.532, P=0.000), FPG(r=-0.292, P=0.006), FINS(r=-0.310, P=0.004), HOMA-IR(r=-0.347, P=0.001), serum leptin(r=-0.228, P=0.035), TNF-a(r=-0.237, P=0.028), and IL-6(r=-0.555, P=0.000) before delivery, respectively, whereas positively correlated with maternal weight gain(r=0.294, P=0.006) during pregnancy and serum adiponectin levels (r=0.244, P=0.023) before delivery.6. In86cases combined GDM and NGT cases, by bivariate Pearson correlation analysis the expression of vaspin mRNA in SAT was found to be positively correlated with BMI before pregnancy (r=0.594, P=0.000) and before delivery(r=0.472, P=0.000), OGTT0h(r=0.543, P=0.000) and2hPG(r=0.436, P=0.000), FPG(r=0.489, P=0.000), FINS(r=0.441, P=0.000), HOMA-IR(r=0.514, P=0.000), serum leptin (r=0.257, P=0.017), and IL-6(r=0.292, P=0.006) before delivery. Whereas the expression of vaspin mRNA in VAT was found to be positively correlated with BMI before pregnancy (r=0.457, P=0.000) and before delivery(r=0.296, P=0.006), OGTT Oh (r=0.425, P=0.000) and2hPG(r=0.401, P=0.000), FPG(r=0.343, P=0.001), FINS(r=,0.462P=0.000), HOMA-IR(r=0.486, P=0.000), serum leptin(r=0.403, P=0.000), and TNF-a(r=0.259, P=0.016) before delivery, and to be inversely correlated with maternal weight gain (r=-0.221, P=0.041) during pregnancy.7. By multivariate step-wise linear regression analysis, vaspin mRNA expressions in SAT (β=0.543, P=0.000) were proved as independent predictors of OGTT OhPG, whereas only islet-l(β=-0.347, P=0.000), omentin(β=-0.304, P=0.000) mRNA expressions in VAT and vaspin(β=0.265, P=0.002), omentin(β=-0.189, P=0.021) mRNA expressions in SAT were proved as independent predictors of OGTT2hPG.8. By multivariate step-wise linear regression analysis, omentin mRNA expressions in VAT (β=0.361, P=0.001) was proved as independent predictors of adiponectin; vaspin (β=0.340, P=0.001) and omentin mRNA (β=-0.209, P=0.046) expressions in VAT were proved as independent predictors of leptin; vaspin mRNA expressions in VAT(β=0.259, P=0.016) was proved as independent predictors of TNF-a; and islet-1mRNA expressions in VAT(β=-0.513, P=0.000) as well as omentin expressions in SAT were proved as independent predictors of IL-6.9. In order to investigate how these adipokines to influence on the degree of IR during pregnancy, multivariate step-wise linear regression analysis was used, in which maternal body parameters, serum adiponectin, leptin, TNF-a, IL-6levels and omentin, islet-1, vaspin mRNA expressions in SAT and VAT levels served as independent variables. The results showed that only TNF-a (β=0.350, P=0.000), vaspin mRNA expressions in SAT (β=0.390, P=0.000) and serum leptin levels (P=0.237, P=0.008) were proved as independent predictors of HOMA-IR during pregnancy.Conclusions1. The glycolipid metabolic disturbance, hyperinsulinemia, insulin resistance and chronic inflammatory state were the significant clinical features of GDM. Maternal weight gain and HOMA-IR were independent predictors of neonatal birth weight.2. Adipokines-such as omentin, islet-1, vaspin mRNA expressed specifically in visceral adipose tissue is more active than subcutaneous adipose tissue, and the expressions of these adipokines are more closely related to glucose metabolism during pregnancy, and their relationships with lipid metabolism are not significant. The impaired expressions of omentin and islet-1mRNA in VAT may be the potential motivation for glucose intolerance in GDM; and vaspin mRNA expression increased in SAT may be a compensatory mechanism responsing to insulin resistance worsen in GDM.3. Insulin resistance during pregnancy is a complex result by multiple factors, in addition to placental hormones, adipokines also play an important regulating role in the formation of insulin resistance. |
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