| Gestational diabetes mellitus(GDM)refers to abnormal glucose tolerance that occurs during pregnancy and is first found.The incidence rate of GDM in the world is0.15%～15%,especially in China.The occurrence of GDM is affected by many factors,the main reasons may be the decrease of insulin sensitivity,insufficient insulin secretion and oxidative stress.GDM will have a negative impact on the health of the mothers and their offspring,such as increasing the risk of premature delivery,abortion,dystocia,intrauterine growth retardation and other adverse pregnancy outcomes,and the risk of type 2 diabetes in postpartum GDM women.In addition,GDM can also cause obesity and abnormal glucose metabolism in macrosomia and offspring.As an essential trace element of human body,selenium is mainly obtained from food.In the world,China is a region with low selenium level,and the area from northeast to southwest is a region with extremely low selenium level.The selenium level in soil is low,the selenium level in plant food is low,and the human body is insufficient.Selenium has insulin-like effect,and has synergistic effect with insulin in reducing blood sugar.In addition,selenium also plays an important role in avoiding oxidative damage to islet cells,predicting and preventing diabetes.The occurrence of GDM is related to oxidative stress.Glutathione Peroxidase(GSH-Px)is the most important antioxidant enzyme in the body.Selenium is the active component of GSH-Px.Selenium deficiency will lead to the elimination of free radicals in the body,and oxidative stress damage.Based on this,this study suggests that oxidative stress may be an important mechanism of abnormal glucose metabolism,insulin resistance and diabetes.Therefore,this study explored the relationship between GDM and serum selenium of pregnant women through meta-analysis,analyzed the possible mechanism of GDM and selenium deficiency,and explored the effects of GDM and selenium deficiency on the growth,oxidative stress and glucose metabolism of mothers and offspring,as well as whether there was gender difference in the effects on offspring,and studied its possible mechanism from the perspective of molecular biology,to provide theoretical basis for the treatment or prevention of GDM and its progeny dysplasia.This study mainly includes three parts:Part 1: Meta-analysis of serum selenium and gestational diabetes mellitus Objectives:To explore the relationship between serum selenium content and GDM by meta-analysis of published Chinese and English studies.Methods:Retrieve the Chinese and English literature on GDM and serum selenium level in seven databases(PubMed,The Cochrane Library,EMBASE,Web of science,CNKI,Wanfang database and Vip journal)until January 31,2022.Review Manager 5.4software was used for meta-analysis,and random effect model was used for estimation.Stata 14.0 software was used for the sensitivity analysis and meta-regression.The overall effect was described by STD Mean Difference(SMD)and 95% confidence interval(CI),and subgroup analysis was carried out according to regional distribution,pregnancy trimester,detection method and GDM diagnostic criteria.Results:A total of 27 articles were included in this study,including 1588 GDM patients and2450 non-GDM women.1.The serum selenium level of pregnant women with GDM was significantly lower than that of pregnant women in the non-GDM group(SMD =-1.29;95% CI:-1.60 ～-0.97,P < 0.00001).2.Subgroup analysis based on regional distribution found that the serum selenium level of pregnant women in GDM group was significantly lower than that in non-GDM group in Asia(SMD =-1.44;95% CI:-1.79 ～-1.08,P < 0.00001)and Africa(SMD =-2.62;95% CI:-4.50 ～-0.74,P = 0.006)population,but this phenomenon was not found in European population.3.Subgroup analysis based on pregnancy trimester found that the serum selenium level of GDM group was significantly lower than that of non-GDM group at the second trimester(SMD =-1.41;95% CI:-1.82 ～-0.99,P < 0.00001)and the third trimester(SMD =-1.54;95% CI:-2.09 ～-0.98,P < 0.00001),but this phenomenon was not found in the first trimester.4.Subgroup analysis based on GDM diagnostic criteria found that the serum selenium level of GDM group was significantly lower than that of non-GDM group in C&C(SMD =-1.27;95% CI:-1.80 ～-0.74,P < 0.00001),Dong Zhiguang(SMD =-1.71;95% CI:-2.63 ～-0.79,P = 0.0003),ADA(SMD =-1.80;95% CI:-2.79 ～-0.81,P = 0.0004)and IADPSG(SMD =-1.31;95% CI:-1.96 ～-0.66,P < 0.0001)standards,but this phenomenon was not found in WHO.Conclusions:1.The serum selenium level of pregnant women with GDM was significantly lower than that of non-GDM group.2.In Asia and Africa population,the serum selenium level of pregnant women in GDM group was significantly lower than that in non-GDM group.3.The serum selenium level of pregnant women in GDM group was significantly lower than that in non-GDM group at the second and third trimester of pregnancy.Part 2: Effects of gestational diabetes mellitus and selenium deficiency on maternal and fetal mice and their mechanisms Objectives:The effects of GDM and selenium deficiency on glucose metabolism and oxidative stress in maternal mice and on placental fetal mice were investigated by using GDM and selenium deficiency animal models.Methods:Forty eight female C57BL/6J mice were randomly divided into four groups: control group(CON)and GDM group(GDM)were fed with basic diet;Selenium deficiency group(Low Selenium,LSe)and selenium deficiency and GDM group(LSe-GDM)were fed with low selenium diet.Four weeks later,the mice with successful pregnancy were included in the study.The GDM model was established by subcutaneous injection of insulin receptor antagonist(S961)on the 7th day of pregnancy(GD7),and the tissue samples of the pregnant mice on GD18 were collected.The selenium content in the kidney of pregnant mice was detected by atomic fluorescence spectrometry.The oxidative stress indexes of liver and placenta of pregnant mice were detected by the kit,including glutathione peroxidase(GSH-Px),superoxide dismutase(SOD)and malonaldehyde(MDA).Real-time quantitative PCR detection system(q-PCR)was used to detect Phosphatidylinositol 3-kinase(PI3K),Protein Kinase B(Akt),Phosphatidylinositol 4-phosphate 5-kinase Type-1 Alpha(PIP5K1A)and Nicotinamide Adenine Dinucleotide Phosphate Oxidase 1(NOX1)genes mRNA levels.Western blot was used to detect the protein expression level of PI3K/Akt signal pathway in liver and placenta of pregnant mice,including PI3 K,Akt,PIP5K1 A and NOX1.Results:1.On GD14,the results of oral glucose tolerance test(OGTT)showed that the blood glucose in GDM and LSe-GDM groups was significantly higher than that in CON and LSe groups at 30,60,120 and 180 min;the area under the blood glucose curve in GDM and LSe-GDM groups was significantly higher than that in CON and LSe groups.On GD18,the fasting blood glucose level in CON group(P < 0.001),GDM group(P = 0.009)and LSe group(P < 0.001)was significantly higher than that in LSe-GDM group;the fasting insulin levels in GDM group(P < 0.001)and LSe-GDM group(P = 0.009)were significantly higher than that in CON group,and that in GDM group was significantly higher than that in LSe group(P = 0.002).GDM animal model was successfully established.2.The selenium content in the kidney of pregnant mice in the low-selenium feeding group was significantly lower than that in the basic diet feeding group(LSe vs.CON:P = 0.001;LSe-GDM vs.CON: P = 0.002;GDM vs.LSe: P = 0.003;LSe-GDM vs.GDM: P = 0.006).Animal models of selenium deficiency were successfully established.3.The results of the effects of GDM and selenium deficiency on the fetal weight of mice showed that in CON group(P = 0.002),LSe group(P = 0.012)and LSe-GDM group(P = 0.012)were significantly higher than that in GDM group.The factorial analysis showed that GDM caused the decrease of fetal mice’s body weight(P =0.008).4.The results of the effects of GDM and selenium deficiency on oxidative stress in the liver of pregnant mice showed that the activity of GSH-Px in the low-selenium feeding group was significantly lower than that in the basic diet feeding group(LSe vs.CON: P < 0.001;LSe-GDM vs.CON: P < 0.001;GDM vs.LSe: P < 0.001;LSe-GDM vs.GDM: P < 0.001);the SOD activity was significantly higher in the non-GDM group than in the GDM group(GDM vs.CON: P = 0.034;GDM vs.LSe:P = 0.001),but the activity in the LSe-GDM group was significantly higher than that in the GDM group(P = 0.025).The factorial analysis showed that selenium deficiency caused a decrease in GSH-Px activity(P < 0.001)and an increase in SOD activity(P = 0.009),and GDM caused a decrease in SOD activity(P = 0.017).The results of the effects of GDM and selenium deficiency on oxidative stress in the placenta of pregnant mice showed that the activity of GSH-Px in selenium deficiency group was significantly lower than that in basic diet group(LSe vs.CON: P = 0.001;LSe-GDM vs.CON: P = 0.010;GDM vs.LSe: P = 0.011).The factorial analysis showed that selenium deficiency caused a decrease in GSH-Px activity(P = 0.001).5.The results of the effects of GDM and selenium deficiency on PI3K/Akt signaling pathway related gene mRNA in the liver of pregnant mice showed that the mRNA expression level of PI3 K and Akt gene were significantly lower in GDM group than in CON group(P < 0.001,P < 0.001),LSe group(P = 0.001,P = 0.008)and LSe-GDM group(P < 0.001,P < 0.001).6.The results of the effects of GDM and selenium deficiency on PI3K/Akt signaling pathway related proteins in the liver of pregnant mice showed that the protein expression level of PI3 K and Akt were significantly lower in GDM group than in CON group(P = 0.003,P = 0.006)and LSe-GDM group(P = 0.002,P = 0.002),and significantly lower in LSe group than in LSe-GDM group(P = 0.044,P =0.008).The factorial analysis showed that the interaction between GDM and selenium deficiency would affect the protein expression levels of PI3K(P = 0.001)and Akt(P= 0.001).7.The results of the effects of GDM and selenium deficiency on PI3K/Akt signaling pathway related proteins in the placenta of pregnant mice showed that the protein expression level of PI3 K in GDM group was significantly lower than that in CON group(P = 0.003),LSe group(P = 0.004)and LSe-GDM group(P =0.012).The protein expression level of Akt in LSe group was significantly higher than that in CON group(P = 0.028),GDM group(P = 0.002)and LSe-GDM group(P =0.030).The protein expression level of PIP5K1 A was significantly lower in GDM group than in CON group(P = 0.007)and LSe group(P = 0.034).The factorial analysis showed that GDM could reduce the protein expression levels of PI3K(P =0.010),Akt(P = 0.015)and PIP5K1A(P = 0.009).Selenium deficiency can increase the protein expression level of Akt(P = 0.014).Conclusions:1.In liver of pregnant mice,selenium deficiency leads to the decrease of GSH-Px activity,and GDM leads to the decrease of SOD activity,both of which lead to oxidative stress;GDM and selenium deficiency lead to the decrease of PI3 K and Akt protein expression,and lead to the increase of blood glucose.2.In placenta of pregnant mice,selenium deficiency leads to the decrease of GSH-Px activity and oxidative stress;GDM leads to a decrease in the expression of PIP5K1 A,PI3K and Akt proteins,and exposes the fetus to hyperglycemia or oxidative stress at the early stage of life,resulting in the weight loss of fetal mice.Part 3: Effects of gestational diabetes mellitus and selenium deficiency on growth and glucose metabolism of offspring Objectives:The effects of GDM and selenium deficiency on the growth and development,glucose metabolism and oxidative stress of offspring during weaning and adulthood were investigated by using animal models.Methods:Forty C57BL/6J female mice aged aged 6-8 weeks were randomly divided into 4groups(CON,GDM,LSe,LSe-GDM).The grouping method,feeding method and modeling method were the same as those in the second part.The animals in the 4groups were fed with the original feed after delivery,and their offspring were weighed weekly.After 4 weeks,six and more female and male mice were randomly selected from each group,and tissues were taken after death;The remaining offspring were divided into cages according to sex.All groups were fed with basic diet until adulthood(8 weeks).Their weight and fasting blood glucose were measured weekly,and tissues were taken after death.Results:1.The results of the effects of GDM and selenium deficiency on the body weight of pre-weaning offspring showed that the birth weight in CON group was significantly higher than that in LSe group(P = 0.039)and LSe-GDM group(P = 0.003),and that in GDM group was significantly higher than that in LSe-GDM group(P = 0.016).The1-week-old weight in GDM group was significantly higher than that in LSe group(P= 0.037);the 2-week-old weights in GDM group(P < 0.001),LSe-GDM group(P =0.027)and CON group(P = 0.002)were significantly higher than that in LSe group,and GDM group was significantly higher than that in LSe-GDM group(P =0.026);the 3-week-old weights in GDM group(P < 0.001),LSe-GDM group(P <0.001)and CON group(P < 0.001)were significantly higher than that in LSe group;the 4-week-old weight in GDM group was significantly higher than that in CON group(P = 0.014),GDM group(P < 0.001)and CON group(P = 0.010)were significantly higher than that in LSe-GDM group,GDM group(P < 0.001)and CON group(P = 0.011)were significantly higher than that in LSe group.2.The results of the effects of GDM and selenium deficiency on the body weight of female offspring from weaning to adulthood showed that on the 4th week,the weight in CON group was significantly higher than that in LSe-GDM group(P = 0.035);on the 4th-7th week,the weight in CON group was significantly higher than that in LSe group(week 4: P < 0.001;week 5: P = 0.002;week 6: P = 0.009;week 7: P =0.006),that in LSe-GDM group was significantly higher than in LSe group(week 4: P = 0.016;week 5: P = 0.022;week 6: P = 0.002;week 7: P = 0.013),it was significantly higher in GDM group than in LSe group(week 4: P < 0.001;week 5: P= 0.005;week 6: P = 0.006;week 7: P = 0.030);on the 8th week,the weight in CON group was significantly higher than that in LSe group(P = 0.035).The results of the effects of GDM and selenium deficiency on the body weight of male offspring from weaning to adulthood showed that on the 4th-7th week,the body weight in GDM group was significantly higher than that in LSe group(week 4: P = 0.003;week 5: P =0.001;week 6: P = 0.035;week 7: P = 0.035),and that in LSe-GDM group was significantly higher than that in LSe group(week 4: P = 0.001;week 5: P = 0.021;week 6: P = 0.018;week 7: P = 0.035).The body weight in GDM group was significantly higher than that in LSe-GDM group on the 6th and the 8th week(week 6:P = 0.026;week 8: P = 0.038).3.The results of the effects of GDM and selenium deficiency on fasting blood glucose in offspring from weaning to adulthood showed that when the female offspring were on the 4th week,the fasting blood glucose in GDM group and LSe-GDM group was significantly higher than that in CON group and LSe group(GDM vs.CON: P = 0.006;GDM vs.LSe: P = 0.004;LSe-GDM vs.CON: P = 0.003;LSe-GDM vs.LSe: P = 0.002);on the 7th week,the fasting blood glucose in LSe group was significantly higher than that in CON group(P = 0.002);on the 8th week,fasting blood glucose in GDM group was significantly higher than that in CON group(P = 0.007).When the male offspring were on the 4th week,the fasting blood glucose in CON group(P = 0.003)and GDM group(P = 0.001)were significantly higher than that in LSe group.The factorial analysis showed that GDM resulted in the increase of fasting blood glucose in female offspring on 4-week-old(P < 0.001)and 8-week-old(P = 0.021).Selenium deficiency in female mice led to the increase of fasting blood glucose in 7-week-old female offspring(P = 0.023)and 4-week-old male offspring(P= 0.001).The interaction between maternal GDM and selenium deficiency has an effect on the fasting blood glucose of female offspring on 5-week-old(P = 0.033)and7-week-old(P = 0.019).4.The results of the effects of GDM and selenium deficiency on selenium content in the kidneys of offspring during weaning period showed that the selenium content of female offspring was significantly lower in the low-selenium feeding group than in the basic diet feeding group(LSe vs.CON: P < 0.001;LSe-GDM vs.CON: P = 0.017;GDM vs.LSe: P < 0.001;LSe-GDM vs.GDM: P < 0.001).In addition,the GDM group was significantly higher than the CON group(P = 0.006).The selenium content of male offspring was significantly higher in CON group(P = 0.011)and GDM group(P = 0.014)than that in LSe group.5.The results of the effects of GDM and selenium deficiency on oxidative stress in the liver of weaning offspring showed that the activities of GSH-Px of female and male offspring were significantly lower in LSe group and LSe-GDM group than in CON group and GDM group(Female: LSe vs.CON: P < 0.001;LSe-GDM vs.CON:P < 0.001;GDM vs.LSe: P < 0.001;LSe-GDM vs.GDM: P < 0.001)(Male: LSe vs.CON: P < 0.001;LSe-GDM vs.CON: P < 0.001;GDM vs.LSe: P < 0.001;LSe-GDM vs.GDM: P < 0.001).The activity of GSH-Px of male offspring was higher in GDM group than in CON group(P = 0.003),and the activity of SOD was significantly higher in CON group and GDM group than in LSe group and LSe-GDM group(LSe vs.CON: P = 0.047;LSe-GDM vs.CON: P = 0.013;GDM vs.LSe: P =0.007;LSe-GDM vs.GDM: P = 0.002).6.The results of the effects of GDM and selenium deficiency on PI3K/Akt signaling pathway related gene mRNA in the liver of weaning offspring showed that in female offspring,the mRNA expression level of PI3 K gene was significantly higher in LSe-GDM group than that in CON group(P = 0.023),GDM group(P = 0.030)and LSe group(P = 0.017);the mRNA expression level of Akt gene was significantly higher in LSe-GDM group than in CON group(P = 0.002),GDM group(P < 0.001)and LSe group(P < 0.001),and CON group was significantly higher than GDM group(P = 0.030);the mRNA expression level of PIP5K1 A gene was significantly higher in LSe-GDM group than in CON group(P = 0.017)and GDM group(P = 0.017).In male offspring,the mRNA expression level of PI3 K gene was significantly higher in GDM group than in CON group(P < 0.001),LSe group(P = 0.007)and LSe-GDM group(P = 0.012),and than in LSe group(P = 0.046)and LSe-GDM group(P =0.046)was significantly higher than CON group;the mRNA expression level of PIP5K1 A gene was significantly lower in CON group than in GDM group(P < 0.001),LSe group(P = 0.002),and LSe-GDM group(P < 0.001).7.The results of the effects of GDM and selenium deficiency on PI3K/Akt signaling pathway related proteins in the liver of weaning offspring showed that in female offspring,the protein expression level of PI3 K was significantly lower in LSe group than that in CON group(P = 0.010),GDM group(P = 0.004)and LSe-GDM group(P < 0.001);the protein expression level of Akt was significantly higher in LSe-GDM group than in CON group(P < 0.001),GDM group(P < 0.001)and LSe group(P < 0.001);the protein expression level of PIP5K1 A was significantly lower in LSe group than in CON group(P = 0.015)and LSe-GDM group(P = 0.005),and significantly lower in GDM group than in LSe-GDM group(P = 0.022).The factorial analysis showed that GDM could increase the protein expression levels of PI3K(P =0.002)and Akt(P < 0.001).Selenium deficiency in maternal mice can reduce the protein expression level of Akt(P < 0.001).The interaction between maternal GDM and selenium deficiency will affect the protein expression levels of PI3K(P = 0.007),Akt(P < 0.001)and PIP5K1A(P = 0.002).In male offspring,the protein expression level of PI3 K was significantly lower in LSe group than in CON group(P = 0.001),GDM group(P = 0.004)and LSe-GDM group(P < 0.001);the protein expression level of Akt in LSe-GDM group was significantly higher than that in CON group(P =0.011),GDM group(P = 0.002)and LSe group(P = 0.004);the protein expression level of PIP5K1 A in GDM group was significantly lower than that in CON group(P =0.001)and LSe-GDM group(P < 0.001),and that in LSe group was significantly lower than that in LSe-GDM group(P = 0.018);the protein expression level of NOX1 in GDM group was significantly lower than that in CON group(P = 0.003),LSe group(P = 0.036)and LSe-GDM group(P = 0.001).The factorial analysis showed that maternal GDM increased the protein expression level of PI3K(P =0.001).Selenium deficiency in maternal mice will affect the protein expression level of Akt(P = 0.046).The interaction between maternal GDM and selenium deficiency will affect the protein expression levels of PI3K(P = 0.001),Akt(P = 0.009),PIP5K1A(P < 0.001)and NOX1(P = 0.003).8.The results of the effects of GDM and selenium deficiency on selenium content in the kidney of adult offspring showed that the selenium content of female offspring was significantly higher in CON group(P < 0.001),GDM group(P < 0.001)and LSe-GDM group(P = 0.004)than in LSe group.The selenium content of male offspring was significantly higher in CON group(P < 0.001),GDM group(P < 0.001)and LSe-GDM group(P < 0.001)than in LSe group,and that in CON group was significantly higher than in LSe-GDM group(P = 0.022).9.The results of the effects of GDM and selenium deficiency on oxidative stress in the liver of adult offspring show that in female offspring,the activity of GSH-Px was significantly higher in CON group(P < 0.001),GDM group(P < 0.001)and LSe-GDM group(P < 0.001)than in LSe group,and was significantly higher in GDM group than in LSe-GDM group(P = 0.042);the activity of SOD in CON group and GDM group was significantly higher than that in LSe group and LSe-GDM group.In male offspring,the activity of GSH-Px was significantly higher in CON group(P <0.001),GDM group(P < 0.001)and LSe-GDM group(P < 0.001)than in LSe group.10.The results of the effects of GDM and selenium deficiency on PI3K/Akt signaling pathway related gene mRNA in the liver of adult offspring showed that in female offspring,the mRNA expression level of NOX1 gene was significantly higher in LSe-GDM group than in CON group(P < 0.001),GDM group(P < 0.001)and LSe group(P = 0.010),and LSe group was significantly higher than GDM group(P =0.018).There was no significant difference in the mRNA expression levels of PI3 K,Akt,PIP5K1 A and NOX1 gene in male offspring among the four groups.11.The results of the effects of GDM and selenium deficiency on PI3K/Akt signaling pathway related proteins in the liver of adult offspring showed that in female offspring,the protein expression level of PI3 K was significantly higher in LSe group and LSe-GDM group than in CON group and GDM group;the protein expression level of Akt was significantly higher in CON group than in GDM group(P = 0.035)and LSe group(P = 0.016),and significantly higher in LSe-GDM group than in GDM group(P = 0.017)and LSe group(P = 0.007).The factorial analysis showed that maternal selenium deficiency would increase the protein expression level of PI3K(P< 0.001),and the interaction between maternal GDM and selenium deficiency would affect the protein expression level of Akt(P = 0.001).The protein levels of PI3 K,Akt,PIP5K1 A and NOX1 in the liver of adult male offspring were not statistically different among the four groups.Conclusions:1.GDM will increase the obesity susceptibility of lactating offspring.There is gender difference in the obesity susceptibility of adult offspring,which has an impact on males,but females do not show this effect.2.There are gender differences in the effects of GDM and selenium deficiency on glucose metabolism of offspring,which will increase the risk of abnormal glucose metabolism of female offspring from weaning to adulthood,but the impact on male offspring will gradually decrease until adulthood.3.Selenium deficiency in female mice increases oxidative stress,and its effect on SOD activity has gender difference.The effect on female offspring is not shown in weaning period but appears in adulthood,but the effect on male offspring is shown in weaning period and disappears in adulthood.4.The effects of GDM and selenium deficiency on the expression of PI3K/Akt signal pathway related proteins in offspring have gender differences.The effects of the same diet on females continue until adulthood after weaning;the effect on males disappears in adulthood. |
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