Hepatic IGF2/H19 Epigenetic Alteration Induced Glucose Intolerance in Gestational Diabetes Mellitus Offspring via FoxO1 Mediation.

Objective: The offspring of women with gestational diabetes mellitus (GDM) have a high predisposition to developing type 2 diabetes during childhood and adulthood. The aim of the study was to evaluate how GDM exposure in the second half of pregnancy contributes to hepatic glucose intolerance through a mouse model. Methods: By creating a GDM mouse model, we tested glucose and insulin tolerance of offspring by intraperitoneal glucose tolerance test (IPGTT), insulin tolerance test (ITT), and pyruvate tolerance test (PTT). In addition, we checked the expression of genes IGF2/H19, FoxO1, and DNMTs in the mouse liver by RT-qPCR. Pyrosequencing was used to detect the methylation status on IGF2/H19 differentially methylated regions (DMRs). In vitro insulin stimulation experiments were performed to evaluate the effect of different insulin concentrations on HepG2 cells. Moreover, we detect the interaction between FoxO1 and DNMT3A by chromatin immunoprecipitation-quantitative PCR (Chip-qPCR) and knock-down experiments on HepG2 cells. Results: We found that the first generation of GDM offspring (GDM-F1) exhibited impaired glucose tolerance (IGT) and insulin resistance, with males being disproportionately affected. In addition, the expression of imprinted genes IGF2 and H19 was downregulated in the livers of male mice via hypermethylation of IGF2-DMR0 and IGF2-DMR1. Furthermore, increased expression of transcriptional factor FoxO1 was confirmed to regulate DNMT3A expression, which contributed to abnormal methylation of IGF2/H19 DMRs. Notably, different insulin treatments on HepG2 demonstrated those genetic alterations, suggesting that they might be induced by intrauterine hyperinsulinemia. Conclusion: Our results demonstrated that the intrauterine hyperinsulinemia environment has increased hepatic FoxO1 levels and subsequently increased expression of DNMT3A and epigenetic alterations on IGF2/H19 DMRs. These findings provide potential molecular mechanisms responsible for glucose intolerance and insulin resistance in the first male generation of GDM mice.

MiRNAs in Gestational Diabetes Mellitus: Potential Mechanisms and Clinical Applications.

Gestational diabetes mellitus (GDM) is a common pregnancy complication which is normally diagnosed in the second trimester of gestation. With an increasing incidence, GDM poses a significant threat to maternal and offspring health. Therefore, we need a deeper understanding of GDM pathophysiology and novel investigation on the diagnosis and treatment for GDM. MicroRNAs (miRNAs), a class of endogenic small noncoding RNAs with a length of approximately 19-24 nucleotides, have been reported to exert their function in gene expression by binding to proteins or being enclosed in membranous vesicles, such as exosomes. Studies have investigated the roles of miRNAs in the pathophysiological mechanism of GDM and their potential as noninvasive biological candidates for the management of GDM, including diagnosis and treatment. This review is aimed at summarizing the pathophysiological significance of miRNAs in GDM development and their potential function in GDM clinical diagnosis and therapeutic approach. In this review, we summarized an integrated expressional profile and the pathophysiological significance of placental exosomes and associated miRNAs, as well as other plasma miRNAs such as exo-AT. Furthermore, we also discussed the practical application of exosomes in GDM postpartum outcomes and the potential function of several miRNAs as therapeutic target in the GDM pathological pathway, thus providing a novel clinical insight of these biological signatures into GDM therapeutic approach.

Placental Delta-Like 1 Gene DNA Methylation Levels Are Related to Mothers' Blood Glucose Concentration.

PURPOSE: We aim to identify the methylation status of delta-like 1 (DLK1) in the placenta and the correlation between DLK1 methylation and maternal serum glucose level and fetal birth weight. METHODS: We analyzed the gene expression of DLK1 gene in both maternal and fetal sides of the placenta in a GDM group (n = 15) and a control group (n = 15) using real-time polymerase chain reaction. With MethylTargetTM technique, we detected the methylation status of DLK1 promotor in the placenta. Furthermore, Pearson's correlation was used to confirm the association of methylation alteration of DLK1 promoter and maternal 2 h OGTT glucose level and fetal birth weight. RESULTS: In our study, we found that DLK1 expression in both maternal and fetal sides of the placenta decreased significantly in GDM group compared with control group, and it was caused by hypermethylation of DLK1 promoter region. Additionally, the methylation status of DLK1 gene in the maternal side of the placenta highly correlated with maternal 2 h OGTT glucose level (coefficient = 0.7968, P < 0.0001), while the methylation status in the fetal side of the placenta was closely related to fetal birth weight (coefficient = 0.6233, P < 0.0001). CONCLUSIONS: Our results demonstrated that altered expression of DLK1 was caused by the hypermethylation of DLK1 promoter region in the placenta, and intrauterine exposure to GDM has long-lasting effects on the epigenome of the offspring.

Whole-Exome Sequencing Revealed Mutations of MED12 and EFNB1 in Fetal Agenesis of the Corpus Callosum.

Agenesis of the corpus callosum (ACC) is a birth defect in which the corpus callosum is either partially or completely missing. With recent advances in prenatal ultrasound, detection of ACC in obstetric practices is becoming more common. Etiologies of ACC include chromosome errors, genetic factors, prenatal infections, and other factors related to the prenatal environment. In an effort to elucidate more about the genetic influence in the pathogenesis of ACC, we identified, through whole-exome sequencing (WES), two gene mutations in two families with complete agenesis of the corpus callosum. These two mutations are located on chromosome X: one is a hemizygous missense mutation c.3746T>C (p. L1249P) in the gene mediator complex subunit 12 (MED12); the other one is a heterozygous missense mutation c.128+5G>C in gene ephrin B1 (EFNB1). Historically, early diagnosis of complete ACC during pregnancy has been difficult; however, WES has provided us with a creative avenue of diagnosis, combining identification of genetic mutations with prenatal imaging.

Early Postpartum Venous Thromboembolism: Risk Factors and Predictive Index.

The aim of our study was to quantify risk factors for venous thromboembolism (VTE) during the puerperal period. The case-control study was conducted in Women's Hospital, Zhejiang University, China, from January 2006 to December 2016; cases of hospitalized VTE within 1 week after delivery were identified according to International Classification of Diseases, Ninth Revision, Clinical Modification codes. Control postpartum women without VTE were randomly selected, matched on birth day, age, delivery mode, and number of fetus with 4:1 ratio. Clinical risk factors for postpartum VTE and coagulation parameters were analyzed. We found independent variables that were significantly related to postpartum VTE (all P < .05) in a binary logistic regression analysis included preeclampsia/eclampsia (odds ratio [OR], 2.89; 95% confidence interval [CI], 1.56-5.37) and postpartum hemorrhage (OR, 4.6; 95% CI, 1.71-12.40). D-dimer was the only biomarker that statistically significant associated with postpartum VTE in 3 days after delivery (all P < .05). These findings showed preeclampsia/eclampsia and postpartum hemorrhage were important risk factors for early VTE during puerperal period. A higher level of D-dimer was more meaningful than other coagulation parameters to suspect early thrombotic disease after delivery.

Decreased expression of elastin, fibulin-5 and lysyl oxidase-like 1 in the uterosacral ligaments of postmenopausal women with pelvic organ prolapse.

AIM: Pelvic organ prolapse is associated with defects in connective tissues, including elastic fibers. The purpose of this study was to investigate the expression of fibulin-5 and lysyl oxidase-like 1 (LOXL1), which play an essential role in the synthesis and assembly of elastic fibers, in the uterosacral ligaments of women with advanced pelvic organ prolapse (POP) compared with controls. METHOD: Specimens were obtained prospectively during transvaginal or abdominal hysterectomy from 30 women with advanced pelvic organ prolapse and 30 controls matched to the POP group for age and parity among postmenopausal women with benign gynecologic diseases. The expressions of elastin, fibulin-5 and LOXL1 in uterosacral ligaments were measured by immunohistochemistry. RESULTS: We detected a decreased, sometimes absent, expression of fibulin-5 and LOXL1 in the uterosacral ligaments of women with POP, despite a positive expression of elastin. There was a decrease in positive percentage of LOXL1 in the POP group (23.3%) compared with the controls (60%) (P = 0.004). With immunolabeling intensity classified as negative, weak, moderate or strong, there was a decrease in the expression of fibulin-5 in the POP group (P = 0.049). We also detected a significantly decreased expression of LOXL1 in the POP group (P = 0.001). CONCLUSIONS: There was decreased expression of fibulin-5 and LOXL1 in the uterosacral ligaments of patients with pelvic organ prolapse, while the elastin expression was equivalent, which may suggest the possibility of defects in elastic fiber remodeling in the postpartum period and contribute to POP.