Currently,60 million women of reproductive age(18-44 years old) worldwide,and approximately 3 million American women have diabetes mellitus,and it has been estimated that this number will double by 2030.Pregestational...Currently,60 million women of reproductive age(18-44 years old) worldwide,and approximately 3 million American women have diabetes mellitus,and it has been estimated that this number will double by 2030.Pregestational diabetes mellitus(PGD) is a significant public health problem that increases the risk for structural birth defects affecting both maternal and neonatal pregnancy outcome.The most common types of human structural birth defects associated with PGD are congenital heart defects and central nervous system defects.However,diabetes can induce birth defects in any other fetal organ.In general,the rate of birth defects increases linearly with the degree of maternal hyperglycemia,which is the major factor that mediates teratogenicity of PGD.Stringent prenatal care and glycemic control are effective means to reduce birth defects in PGD pregnancies,but cannot reduce the incidence of birth defects to the rate of that is seen in the nondiabetic population.Studies in animal models have revealed that PGD induces oxidative stress,which activates cellular stress signalling leading to dysregulation of gene expression and excess apoptosis in the target organs,including the neural tube and embryonic heart.Activation of the apoptosis signalregulating kinase 1(ASK1)-forkhead transcription factor 3a(Fox O3a)-caspase 8 pathway causes apoptosis in the developing neural tube leading to neural tube defects(NTDs).ASK1 activates the c-Jun-N-Terminal kinase 1/2(JNK1/2),which leads to activation of the unfolded protein response and endoplasmic reticulum(ER) stress.Deletion of the ASK1 gene,the JNK1 gene,or the JNK2 gene,or inhibition of ER stress by 4-Phenylbutyric acid abrogates diabetes-induced apoptosis and reduces the formation of NTDs.Antioxidants,such as thioredoxin,which inhibits the ASK1-Fox O3a-caspase 8 pathway or ER stress inhibitors,may prevent PGD-induced birth defects.展开更多
Background The increasing population of diabetes mellitus in adolescent girls and women of childbearing age contributes to a large number of pregnancies with maternal pregestational diabetes mellitus.Congenital heart ...Background The increasing population of diabetes mellitus in adolescent girls and women of childbearing age contributes to a large number of pregnancies with maternal pregestational diabetes mellitus.Congenital heart diseases are a common adverse outcome in mothers with pregestational diabetes mellitus.However,there is little systematic information between maternal pregestational diabetes mellitus and congenital heart diseases in the offspring.Data sources Literature selection was performed in PubMed.One hundred and seven papers were cited in our review,includ-ing 36 clinical studies,26 experimental studies,31 reviews,eight meta-analysis articles,and six of other types.Results Maternal pregestational diabetes mellitus poses a high risk of congenital heart diseases in the offspring and causes variety of phenotypes of congenital heart diseases.Factors such as persistent maternal hyperglycemia,oxidative stress,polymorphism of uncoupling protein 2,polymorphism of adiponectin gene,Notch 1 pathway,Nkx2.5 disorders,dysregula-tion of the hypoxia-inducible factor 1,and viral etiologies are associated with the occurrence of congenital heart diseases in the offspring of mothers with pregestational diabetes mellitus.Treatment options including blood sugar-reducing,anti-oxidative stress drug supplements and exercise can help to prevent maternal pregestational diabetes mellitus from inducing congenital heart diseases.Conclusions Our review contributes to a better understanding of the association between maternal pregestational diabetes mellitus and congenital heart diseases in the offspring and to a profound thought of the mechanism,preventive and therapeutic measurements of congenital heart diseases caused by maternal pregestational diabetes mellitus.展开更多
基金Supported by NIH R01DK083243,R01DK101972 and R56 DK095380(to Yang P),R01DK103024(to Yang P and Reece EA)Basic Science Award(1-13-BS-220)American Diabetes Association(to Yang P)
文摘Currently,60 million women of reproductive age(18-44 years old) worldwide,and approximately 3 million American women have diabetes mellitus,and it has been estimated that this number will double by 2030.Pregestational diabetes mellitus(PGD) is a significant public health problem that increases the risk for structural birth defects affecting both maternal and neonatal pregnancy outcome.The most common types of human structural birth defects associated with PGD are congenital heart defects and central nervous system defects.However,diabetes can induce birth defects in any other fetal organ.In general,the rate of birth defects increases linearly with the degree of maternal hyperglycemia,which is the major factor that mediates teratogenicity of PGD.Stringent prenatal care and glycemic control are effective means to reduce birth defects in PGD pregnancies,but cannot reduce the incidence of birth defects to the rate of that is seen in the nondiabetic population.Studies in animal models have revealed that PGD induces oxidative stress,which activates cellular stress signalling leading to dysregulation of gene expression and excess apoptosis in the target organs,including the neural tube and embryonic heart.Activation of the apoptosis signalregulating kinase 1(ASK1)-forkhead transcription factor 3a(Fox O3a)-caspase 8 pathway causes apoptosis in the developing neural tube leading to neural tube defects(NTDs).ASK1 activates the c-Jun-N-Terminal kinase 1/2(JNK1/2),which leads to activation of the unfolded protein response and endoplasmic reticulum(ER) stress.Deletion of the ASK1 gene,the JNK1 gene,or the JNK2 gene,or inhibition of ER stress by 4-Phenylbutyric acid abrogates diabetes-induced apoptosis and reduces the formation of NTDs.Antioxidants,such as thioredoxin,which inhibits the ASK1-Fox O3a-caspase 8 pathway or ER stress inhibitors,may prevent PGD-induced birth defects.
基金supported by Sichuan Vocational College of Health and Rehabilitation(No.CWKY-2020Z-02)the Department of Science and Technology of Sichuan Province(No.2019YJ0079)the National Natural Science Foundation of China(No.81900283).
文摘Background The increasing population of diabetes mellitus in adolescent girls and women of childbearing age contributes to a large number of pregnancies with maternal pregestational diabetes mellitus.Congenital heart diseases are a common adverse outcome in mothers with pregestational diabetes mellitus.However,there is little systematic information between maternal pregestational diabetes mellitus and congenital heart diseases in the offspring.Data sources Literature selection was performed in PubMed.One hundred and seven papers were cited in our review,includ-ing 36 clinical studies,26 experimental studies,31 reviews,eight meta-analysis articles,and six of other types.Results Maternal pregestational diabetes mellitus poses a high risk of congenital heart diseases in the offspring and causes variety of phenotypes of congenital heart diseases.Factors such as persistent maternal hyperglycemia,oxidative stress,polymorphism of uncoupling protein 2,polymorphism of adiponectin gene,Notch 1 pathway,Nkx2.5 disorders,dysregula-tion of the hypoxia-inducible factor 1,and viral etiologies are associated with the occurrence of congenital heart diseases in the offspring of mothers with pregestational diabetes mellitus.Treatment options including blood sugar-reducing,anti-oxidative stress drug supplements and exercise can help to prevent maternal pregestational diabetes mellitus from inducing congenital heart diseases.Conclusions Our review contributes to a better understanding of the association between maternal pregestational diabetes mellitus and congenital heart diseases in the offspring and to a profound thought of the mechanism,preventive and therapeutic measurements of congenital heart diseases caused by maternal pregestational diabetes mellitus.
