| ObjectiveGestational diabetes mellitus(GDM)has been acknowledged as a serious pregnancy complication,which generally induce harm to the fetus.Recent studies reveal that macrosomia has an obviously rising trend among GDM-induced adverse pregnancy outcomes.It is generally considered that the neonates born from diabetic mothers have an increased risk of macrosomia.In the perinatal period,Macrosomia is related to higher incidence rates of asphyxia,birth injury,hypoglycemia,death,etc.Besides,many studies confirm that GDM-induced macrosomia has the long-term effect in later life,such as the high incidence of diabetes,obesity,atherosclerosis(AS)and other metabolic dysfunctions.GDM were found with high risk factors,in terms of body mass index,age,parity.However,the relationship between the risk factors and GDM-induced macrosomia is unclear.Therefore,the research on the relationship of macrosomia with the pregnancy risk factors and early prevention and control of the risk factors,not only can reduce the occurrence of the incidence of GDM,but also can reduce the occurrence of macrosomia in some extent.GDM has metabolic abnormalities such as hyperglycemia,hyperlipidemia and insulin resistance during pregnancy.These metabolic abnormalities,which can cause excessive glucose and lipid metabolism through the placenta into the fetal circulation,further cause fetal energy metabolism to turn out the form of fat in the fetus,resulting in macrosomia.The present study shows that early detection and early control of blood glucose during pregnancy are of great significance in the control of GDM-induced macrosomia.But the study found that,although the clinical treatment of GDM in recent years has been significantly improved,even in ideal glycemic control during pregnancy,the incidence of macrosomia was still significantly increased.It is suggested that the occurrence of macrosomia is not only related to the maternal blood glucose level,but also has more important factors.GDM pregnant women have high perinatal risk and high risk of vascular disease in the later growth.It is pointed out that glucose and lipid metabolism in umbilical cord blood,as the blood supply of the fetus,seriously affects the development of fetus.And the abnormal lipid and glucose metabolism of umbilical cord blood is the basis of perinatal and complications in GDM-induced macrosomia.So it is very important to study the metabolic state of abnormal intrauterine fetal.However,due to the limit of operation,fetal metabolism during pregnancy evaluate mainly through obstetric ultrasound evaluation.Amniotic fluid index,umbilical cord blood flow index are the key indicators of fetal growth,which are also important indexes for clinical assessment and evaluation of fetal growth.The study of the relationship between the changes of blood glucose and lipid metabolism and the occurrence of macrosomia may provide a new starting point for the further study of the mechanism of macrosomia and long term complications.Placental tissue is a bridge connecting maternal nutrition and fetal environment,which plays a role in transporting nutrients.The expression of placental tissue protein directly affects the trans-placental transport of nutrients.Therefore,the study concerning placental tissue proteins can provide a new platform for the study of the mechanism of GDM-induced macrosomia.And the study found that in the placenta of GDM,a key protein expression mediating signal transduction and lipid metabolic pathway,AMP activated protein kinase(Adenosine monophosphate-activated protein kinase,AMPK)changed dramatically.In previous studies,it is suggested that AMPK can mediate the downstream glucose metabolism and lipid metabolism.At the molecular level in GDM-induced macrosomia has been studied,but the role of AMPK-mediated signal pathway in process of GDM-induced macosomia is unclear.The purpose of this study is to investigate lipid and glucose metabolism related risk factors of GDM-induced macrosomia.At the same time,The study concerning the alteration of glucose and lipid metabolic signal pathways in placenta tissue mediated by AMPK can make a further research on risk factors of macrosomia induced by GDM,which will provide a benefit for the early recognition and treatment of GDM-induced macrosomia.MethodsAccording to the unified GDM diagnosis criteria of the international diabetes and pregnancy study group(IADPSG),the pregnancy woman were separated into GDM group(n=100)and NGT group(n=100).Placentas of the neonate were classified into three groups based on the diagnostic criteria of macrosomia,consisting of GDMM group(n = 13),GDMN group(n = 87),NGTM group(n?3)and NGTN group(CON group(n = 97)).Pregnant women need ultrasound examination in late pregnancy,detection of amniotic fluid index,biparietal diameter and femur length,umbilical cord blood flow index and other indicators to estimate fetal development and birth weight.Umbilical artery blood was collected during vaginal delivery or cesarean section to make a determination of blood lipid and blood glucose in umbilical cord blood by wet chemical method.At the same time,placenta tissue was collected:in order to reduce the degradation of RNA and protein in the experiment,the requirements are as follows:after fetal delivery,immediately cut about 1cm3 placenta tissue,tissue rapid flushing with cold-NS,then add to the labeled frozen pipes and stored at 80 C to further extraction of protein and total RNA.Western blotting detected the difference expression of Adenosine monophosphate-activated protein kinase(AMPK)-mediated signal pathway related proteins,including phosphorylated-AMPK?(Thr172)(p-AMPK?(Thr172)),AMPK?,acetyl coenzyme A carboxylase(ACC),phosphorylated-Acetyl-CoA carboxylase(Ser79)(p-ACC(Ser79))and glucose transporter 1(GLUTI)expression in the three groups of placenta.mRNA levels of ACC,GLUT1 and AMPK in placenta tissues were detected by real-time fluorescence quantitative PCR.GraphPad Prism 5.0 database was used to analysis the clinical characteristics datas and differential expression of placental protein and mRNA.All results were showed as meanąSD,when P<0.05,the analysis showed significantly difference.The comparation of the two groups(GDM and NGT group)were assessed by one-sample t test.The placental mRNA and protein expression in three groups were analyzed using the single factor analysis of variance(ANOVA)analysis followed by Student-Newman-Keuls.Pearson correlation analysis was used to measure the relationship between NBW and the levels of mRNA and proteins,and the relationship of the protein exepression of AMPK to p-ACC(Ser79)and GLUT1.Results1.Maternal characteristics(1)Maternal baseline characteristics:In the second trimester,fasting blood glucose(FBG)levels in GDM group was higher 1.06mmol/l than NGT group(P<0.05).While,no obvious difference of FBG was observed in the third trimester(P>0,05).Moreover,there were no significant differences of maternal age,height,primipara and blood pressure between GDM and NGT group(P>0.05).In addition,four cases of family history of diabetes existed in GDM group,but not in NGT group.There was a positive correlation between the blood glucose and the birth weight(NBW)in the second trimester,and there was no significant correlation between fasting blood glucose and NBW in the third trimester.(2)pre-pregnancy body mass index(BMI)and pregnancy weight gain:pregnancy weight gain and pre-pregnancy BMI in GDM group were significantly higher than NGT group(P<0.05).The correlation analysis showed that NBW with pre pregnancy body mass index(BMI)and maternal weight gain during pregnancy have a positive correlation(P<0.05).2.Neonatal characteristicsCompared with NGT group,NBW in GDM group was significant higher(P<0.05).The occur of macrosomia were higher in GDM group.Equally,the average neonatal birth length(NBL)in GDM group was also at a higher level.While,the neonates of two groups had no statistic differences in gestational age,gender proportion,placental weight and umbilical cord length.3.Umbilical blood glucose and lipid metabolism(1)Umbilical blood glucose metabolism:there was no significant difference in umbilical cord blood glucose between the NGT group and the GDM group(P>0.05).The correlation analysis showed that there was no significant linear correlation between umbilical cord blood glucose with materal FBG in late pregnancy(P>0.05)and no significant correlation with neonatal birth weight too.(2)Lipid metabolism of umbilical cord blood:High-density lipoprotein cholesterol(HDL-C)in GDM group was lower 11.4%than that of NGT group.But the Apolipoprotein B/Apolipoprotein A(ApoB/ApoA)ratio was increased by 16%compared with NGT group(P<0.05).There were no significant difference between the two groups in Total Cholesterol(TC),Triglyceride(TG),Low-density lipoprotein cholesterol(LDL-C),Very Low-density lipoprotein cholesterol(VLDL-C),lipoproteins(LP),Apolipoprotein A(ApoA)and Apolipoprotein B(ApoB)(P>0.05).4.Late pregnancy ultrasoundGDM group than the NGT group,The amniotic fluid index(AFI)was higher 2.7,an increase of 29.6%,the difference was statistically significant.Other indicators:gestational age(GA),biparietal diameter(BPD),femur length(FL)?Peak systolic velocity/end diastolic velocity(S/D),the resistance index(Rl)and the pulse index(PI)between the two groups showed no significant difference(P>0.05).Correlation analysis showed that AFI was positively correlated with maternal blood glucose and neonatal birth weight(P<0.05).There was no significant correlation between blood glucose and umbilical cord blood(P>0.05).5.Expression of placental tissue protein(1)the expression of placental proteins:the expression of GLUT1 and ACC protein significantly increased in GDM induced macrosomia placenta tissue(P<0.05).But p-AMPKa(Thr172)and p-ACC(Ser79)protein expression level decreased significantly(P<0.05),AMPK protein expression was no significant difference between the three groups(P>0.05).The correlation analysis of placental protein and NBW showed that the expression of GLUTI and ACC protein was positively correlated with NBW in the placenta tissues of macrosomia induced by GDM(P<0.05),while,p-ACC(Ser79)and p-AMPKa(Thrl 72)were negatively correlated with NBW(P<0.05).However,there was no significant correlation between the NBW and AMPK protein levels.The expression of ACC protein was foxund to be positively correlated with the birth weight only in GDMM group,but not in GDMN group.The correlation analysis showed that the expression of p-AMPK protein was positively correlated with the expression of p-ACC(P<0.05),but not significantly correlated with the expression of GLUT1(P>0.05).(2)the expression of mRNA in placenta tissue:In GDM?induced macosomia group,the mRNA expression of GLUTI was highest compared with other groups.AMPKa and ACC mRNA levels were lowest in placenta of fetal macrosomia induced by GDM(P<0.05).The correlation analysis showed that the mRNA expression of GLUT1 in placenta tissues of GDMM group was positively correlated with NBW,AMPK and ACC were negatively correlated(P<0.05).Conclusion1.Obesity,overweight pre-pregnancy and higher pregnancy weight gain are all risk factors of GDM-induced macrosomia.In addition to fasting blood glucose during pregnancy,control of pre-pregnancy weight and pregnancy weight gain can reduce the occurrence of macrosomia.2.The increased expression of GLUTI protein in placenta tissue,which can lead to the excessive glucose transport into the fetal circulation,can induce the occurrence of macrosomia in GDM.3.The decreased expression of p-ACC protein and the increased expression of ACC protein in placenta tissue can lead to the GDM induced macrosomia by excessive the content of fatty acid.4.AMPK-mediated signal transduction pathway in the process of GDM induced macrosomia,mainly affecting lipid metabolism,rather than glucose metabolism.5.In the intrauterine growth process of macosomia induced by GDM,HDL-C,ApoB/ApoA were found to have abnormal lipid metabolism,and there was a high risk of abnormal glucose and lipid metabolism during the growth and development of macrosomia in the later stage. |
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