Human embryonic stem cells as an in vitro model for studying developmental origins of type 2 diabetes

The developmental origins of health and diseases(DOHaD)is a concept stating that adverse intrauterine environments contribute to the health risks of offspring.Since the theory emerged more than 30 years ago,many epidemiological and animal studies have confirmed that in utero exposure to environmental insults,including hyperglycemia and chemicals,increased the risk of developing noncommunicable diseases(NCDs).These NCDs include metabolic syndrome,type 2 diabetes,and complications such as diabetic cardiomyopathy.Studying the effects of different environmental insults on early embryo development would aid in understanding the underlying mechanisms by which these insults promote NCD development.Embryonic stem cells(ESCs)have also been utilized by researchers to study the DOHaD.ESCs have pluripotent characteristics and can be differentiated into almost every cell lineage;therefore,they are excellent in vitro models for studying early developmental events.More importantly,human ESCs(hESCs)are the best alternative to human embryos for research because of ethical concerns.In this review,we will discuss different maternal conditions associated with DOHaD,focusing on the complications of maternal diabetes.Next,we will review the differentiation protocols developed to generate different cell lineages from hESCs.Additionally,we will review how hESCs are utilized as a model for research into the DOHaD.The effects of environmental insults on hESC differentiation and the possible involvement of epigenetic regulation will be discussed.

Heteroplasmy Level of the Mitochondrial tRNA^(Leu(UUR)) A3243G Mutation in a Chinese Family Is Positively Associated with Earlier Age-of-onset and Increasing Severity of Diabetes

Objective To investigate the mutations of mitochondrial genome in a pedigree with suspected maternally inherited diabetes and deafness and to explore the correlations between the mutations and clinical features. Methods Genomic DNA was isolated from blood leucocytes of each member of the pedigree. The mitochondrial genome was amplified with 24-pair primers that could cover the entire mitochondrial DNA. Direct sequencing of PCR products was used to identify any mitochondrial DNA mutations. Results Family members on the maternal side all harbored the tRNA^Lcu（UUR） A3243G mutation. The paternal side family members did not have the mutation. The age-of-onset of diabetes of the 4 maternal side family members was 15, 41, 44, and 65 years old, and their corresponding heteroplasmy level of the mutation was 34.5%, 14.9%, 14.6%, and 5.9%, respectively. The age-of-onset of diabetes and heteroplasmy level of A3243G mutation were negatively correlated with a correlation coefficient of -0.980（P=0.02）. Meanwhile, patient with high heteroplasmy level of A3243G mutation had relatively low severity of disease. Moreover, 6 reported polymorphisms and 2 new variants were found. Conclusions The main cause of diabetes in this pedigree is the tRNA^Lcu（UUR） A3243G mutation. However, other gene variants may contribute to its pathogenicity. The heteroplasmy level of the tRNA^Lcu（UUR） A3243G mutation is positively associated with earlier age-of-onset and increasing severity of diabetes.

Effect of maternal pregestational diabetes mellitus on congenital heart diseases

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.