Genomics and Epigenomics of Gestational Diabetes Mellitus: Understanding the Molecular Pathways of the Disease Pathogenesis

One of the most common complications during pregnancy is gestational diabetes mellitus (GDM), hyperglycemia that occurs for the first time during pregnancy. The condition is multifactorial, caused by an interaction between genetic, epigenetic, and environmental factors. However, the underlying mechanisms responsible for its pathogenesis remain elusive. Moreover, in contrast to several common metabolic disorders, molecular research in GDM is lagging. It is important to recognize that GDM is still commonly diagnosed during the second trimester of pregnancy using the oral glucose tolerance test (OGGT), at a time when both a fetal and maternal pathophysiology is already present, demonstrating the increased blood glucose levels associated with exacerbated insulin resistance. Therefore, early detection of metabolic changes and associated epigenetic and genetic factors that can lead to an improved prediction of adverse pregnancy outcomes and future cardio-metabolic pathologies in GDM women and their children is imperative. Several genomic and epigenetic approaches have been used to identify the genes, genetic variants, metabolic pathways, and epigenetic modifications involved in GDM to determine its etiology. In this article, we explore these factors as well as how their functional effects may contribute to immediate and future pathologies in women with GDM and their offspring from birth to adulthood. We also discuss how these approaches contribute to the changes in different molecular pathways that contribute to the GDM pathogenesis, with a special focus on the development of insulin resistance.     

Lipid Metabolism Is Dysregulated before,during and after Pregnancy in a Mouse Model of Gestational Diabetes

The aim of the current study was to test the hypothesis that maternal lipid metabolism was modulated during normal pregnancy and that these modulations are altered in gestational diabetes mellitus (GDM). We tested this hypothesis using an established mouse model of diet-induced obesity with pregnancy-associated loss of glucose tolerance and a novel lipid analysis tool, Lipid Traffic Analysis, that uses the temporal distribution of lipids to identify differences in the control of lipid metabolism through a time course. Our results suggest that the start of pregnancy is associated with several changes in lipid metabolism, including fewer variables associated with de novo lipogenesis and fewer PUFA-containing lipids in the circulation. Several of the changes in lipid metabolism in healthy pregnancies were less apparent or occurred later in dams who developed GDM. Some changes in maternal lipid metabolism in the obese-GDM group were so late as to only occur as the control dams’ systems began to switch back towards the non-pregnant state. These results demonstrate that lipid metabolism is modulated in healthy pregnancy and the timing of these changes is altered in GDM pregnancies. These findings raise important questions about how lipid metabolism contributes to changes in metabolism during healthy pregnancies. Furthermore, as alterations in the lipidome are present before the loss of glucose tolerance, they could contribute to the development of GDM mechanistically.     

Gestational Diabetes Mellitus and Maternal Immune Dysregulation: What We Know So Far

Gestational diabetes mellitus (GDM) is an obstetric complication that affects approximately 5–10% of all pregnancies worldwide. GDM is defined as any degree of glucose intolerance with onset or first recognition during pregnancy, and is characterized by exaggerated insulin resistance, a condition which is already pronounced in healthy pregnancies. Maternal hyperglycaemia ensues, instigating a ‘glucose stress’ response and concurrent systemic inflammation. Previous findings have proposed that both placental and visceral adipose tissue play a part in instigating and mediating this low-grade inflammatory response which involves altered infiltration, differentiation and activation of maternal innate and adaptive immune cells. The resulting maternal immune dysregulation is responsible for exacerbation of the condition and a further reduction in maternal insulin sensitivity. GDM pathology results in maternal and foetal adverse outcomes such as increased susceptibility to diabetes mellitus development and foetal neurological conditions. A clearer understanding of how these pathways originate and evolve will improve therapeutic targeting. In this review, we will explore the existing findings describing maternal immunological adaption in GDM in an attempt to highlight our current understanding of GDM-mediated immune dysregulation and identify areas where further research is required.     

Epigenetic Alterations Related to Gestational Diabetes Mellitus

Gestational diabetes mellitus (GDM) is the most common metabolic complication in pregnancy, which affects the future health of both the mother and the newborn. Its pathophysiology involves nutritional, hormonal, immunological, genetic and epigenetic factors. Among the latter, it has been observed that alterations in DNA (deoxyribonucleic acid) methylation patterns and in the levels of certain micro RNAs, whether in placenta or adipose tissue, are related to well-known characteristics of the disease, such as hyperglycemia, insulin resistance, inflammation and excessive placental growth. Furthermore, epigenetic alterations of gestational diabetes mellitus are observable in maternal blood, although their pathophysiological roles are completely unknown. Despite this, it has not been possible to determine the causes of the epigenetic characteristics of GDM, highlighting the need for integral and longitudinal studies. Based on this, this article summarizes the most relevant and recent studies on epigenetic alterations in placenta, adipose tissue and maternal blood associated with GDM in order to provide the reader with a general overview of the subject and indicate future research topics.     

Changes in Maternal Platelet Physiology during Gestation and Their Interaction with Trophoblasts

Upon activation, maternal platelets provide a source of proinflammatory mediators in the intervillous space of the placenta. Therefore, platelet-derived factors may interfere with different trophoblast subtypes of the developing human placenta and might cause altered hormone secretion and placental dysfunction later on in pregnancy. Increased platelet activation, and the subsequent occurrence of placental fibrinoid deposition, are linked to placenta pathologies such as preeclampsia. The composition and release of platelet-derived factors change over gestation and provide a potential source of predicting biomarkers for the developing fetus and the mother. This review indicates possible mechanisms of platelet-trophoblast interactions and discusses the effect of increased platelet activation on placenta development.     

Maternal C-Peptide and Insulin Sensitivity,but Not BMI,Associate with Fatty Acids in the First Trimester of Pregnancy

Maternal obesity in pregnancy is a pro-inflammatory condition exposing the fetus to an adverse environment. Here, we tested associations of maternal obesity (primary exposures: BMI, leptin) and metabolic parameters (secondary exposures: glucose, C-peptide, and insulin sensitivity) with total serum concentrations of fatty acids in the first trimester of human pregnancy. This cross-sectional study included 123 non-smoking women with singleton pregnancy. In maternal serum, cotinine, leptin, and C-peptide (ELISA), glucose (hexokinase-based test) and fatty acids (gas chromatography) were quantified, and the insulin sensitivity index (IS_HOMA) was calculated. Concentrations of fatty acid classes and total fatty acids did not differ between BMI or leptin categories. However, n-3 polyunsaturated fatty acids (PUFA) were decreased in the category with the highest C-peptide concentration (n-3 PUFA: CI −35.82–−6.28, p < 0.006) and in the lowest IS_HOMA category (n-3 PUFA: CI −36.48–−5.61, p < 0.008). In a subcohort, in which fetal sex was determined (RT-qPCR of placental tissue), C-peptide was significantly associated with docosahexaenoic acid (DHA) in mothers bearing a female (n = 46), but not male (n = 37) fetus. In conclusion, pregnant women with high fasting C-peptide and low IS_HOMA had decreased n-3 PUFA, and DHA was lower with higher C-peptide only in mothers bearing a female fetus.     

Previous Gestational Diabetes Increases Atherogenic Dyslipidemia in Subsequent Pregnancy and Postpartum

In a cohort of women with previous gestational diabetes mellitus (GDM), we aimed to ascertain whether women with abnormal glucose tolerance 1‐year postdelivery had a more atherogenic lipid profile during and after pregnancy than those with normal glucose tolerance. A prospective cohort study with longitudinal design between January 2004 and March 2016 was conducted. Three hundred and six (56.8%) of 537 women diagnosed with GDM during the studied period attended a control visit during the first year after delivery. Of these, 112 (36.6%) had prediabetes and 16 (5.2%) had type 2 diabetes mellitus. No significant differences during pregnancy were found in total, low‐density lipoprotein, high‐density lipoprotein (HDL) cholesterol, and triacylglycerol (TAG) concentrations among the three groups. Only HDL cholesterol and TAG levels differed significantly among groups at 2 and 12 months after delivery. Logistic regression analysis revealed pregnancy HDL and glucose metabolism status to be associated with the HDL cholesterol concentration 1‐year postdelivery. Furthermore, the only independent factor associated with TAG levels 1 year after delivery was the gestational TAG concentration. In summary, an overweight multiethnic group of women with prior GDM presented a high incidence of postpartum dysglycemia (41.8%). HDL‐cholesterol and TAG levels, both components of the metabolic syndrome, differed significantly among the three study groups in the glucose‐metabolism status at 2 and 12 months after delivery. Women with previous GDM must be followed up in the postpartum period for early detection and management of lipid and glucose disorders.     

Interaction between Metformin,Folate and Vitamin B12 and the Potential Impact on Fetal Growth and Long-Term Metabolic Health in Diabetic Pregnancies

Metformin is the first-line treatment for many people with type 2 diabetes mellitus (T2DM) and gestational diabetes mellitus (GDM) to maintain glycaemic control. Recent evidence suggests metformin can cross the placenta during pregnancy, thereby exposing the fetus to high concentrations of metformin and potentially restricting placental and fetal growth. Offspring exposed to metformin during gestation are at increased risk of being born small for gestational age (SGA) and show signs of ‘catch up’ growth and obesity during childhood which increases their risk of future cardiometabolic diseases. The mechanisms by which metformin impacts on the fetal growth and long-term health of the offspring remain to be established. Metformin is associated with maternal vitamin B₁₂ deficiency and antifolate like activity. Vitamin B₁₂ and folate balance is vital for one carbon metabolism, which is essential for DNA methylation and purine/pyrimidine synthesis of nucleic acids. Folate:vitamin B₁₂ imbalance induced by metformin may lead to genomic instability and aberrant gene expression, thus promoting fetal programming. Mitochondrial aerobic respiration may also be affected, thereby inhibiting placental and fetal growth, and suppressing mammalian target of rapamycin (mTOR) activity for cellular nutrient transport. Vitamin supplementation, before or during metformin treatment in pregnancy, could be a promising strategy to improve maternal vitamin B₁₂ and folate levels and reduce the incidence of SGA births and childhood obesity. Heterogeneous diagnostic and screening criteria for GDM and the transient nature of nutrient biomarkers have led to inconsistencies in clinical study designs to investigate the effects of metformin on folate:vitamin B₁₂ balance and child development. As rates of diabetes in pregnancy continue to escalate, more women are likely to be prescribed metformin; thus, it is of paramount importance to improve our understanding of metformin’s transgenerational effects to develop prophylactic strategies for the prevention of adverse fetal outcomes.     

糖尿病孕妇血糖水平与围产结局的临床研究

目的研究孕妇妊娠期血糖控制水平与围产结局,降低糖尿病孕产妇及其围产儿死亡率。方法将62例妊娠期糖尿病(GDM)产妇分为2组:a组为经产前血糖筛查发现并确诊,血糖控制达理想程度者45例,b组为产前确诊但孕期血糖控制不理想者9例,未经诊断的8例,共17例。收集并比较分析2组孕产妇及围产儿并发症情况。结果孕妇血糖控制不良其妊高征、羊水过多、羊水过少、胎儿生长受限、剖宫产、巨大胎儿、新生儿窒息和呼吸窘迫综合征、低血糖的发生率明显升高。结论控制母体血糖水平,降低围产期并发症,及时诊断治疗,确保孕产妇及其围产儿的安全与健康。     

Gestational diabetes mellitus enhances arachidonic and docosahexaenoic acids in placental phospholipids

In previous studies, we reported that neonates of women with gestational diabetes mellitus (GDM) have reduced blood levels of arachidonic acid (AA) and docosahexaenoic acid (DHA) that were unrelated to maternal status. Since both AA and DHA are selectively transferred from maternal to fetal circulation by the placenta, we have investigated whether the FA composition of the placenta is altered by GDM. Thirty-six women, 11 with and 25 without GDM, were recruited from Newham General Hospital, London. The women with GDM had higher levels of di-homo-γ-linolenic (P<0.05), docosate-traenoic (n-6 DTA; P<0.0001), docosapentaenoic n-6 (P<0.005), total n-6 (P<0.005), docosapentaenoic (n-3 DPA; P<0.005), and total n-3 (P<0.01) FA, as well as higher levels of AA (P<0.05) and DHA (P<0.01), in placental choline phosphoglycerides (CPG) compared with the healthy women who served as controls. Similarly, the women with GDM had elevated n-6 DTA (P<0.005), AA, total n-6 metabolites (P<0.05), DHA, total n-3 metabolites, and total n-3 FA (P<0.005) in ethanolamine phosphoglycerides (EPG). In contrast to CPG and EPG, the placental TG of the women with GDM had higher linoleic acid (P<0.05) and lower AA, n-6 metabolites, and n-3 DPA (P<0.01). The placenta is devoid of desaturase activity, and it is thought to be reliant on maternal circulation for both AA and DHA. Hence, the enhanced levels of the two FA in the placenta of the GDM group suggests that these FA are taken up from the maternal circulation and retained after esterification into phosphoglycerides instead of being transferred to the fetus. Further study is needed to elucidate the mechanism involved and the effect of the phenomenon on postnatal growth and development of the offspring.     

Diabetes during Pregnancy: A Maternal Disease Complicating the Course of Pregnancy with Long-Term Deleterious Effects on the Offspring. A Clinical Review

In spite of the huge progress in the treatment of diabetes mellitus, we are still in the situation that both pregestational (PGDM) and gestational diabetes (GDM) impose an additional risk to the embryo, fetus, and course of pregnancy. PGDM may increase the rate of congenital malformations, especially cardiac, nervous system, musculoskeletal system, and limbs. PGDM may interfere with fetal growth, often causing macrosomia, but in the presence of severe maternal complications, especially nephropathy, it may inhibit fetal growth. PGDM may also induce a variety of perinatal complications such as stillbirth and perinatal death, cardiomyopathy, respiratory morbidity, and perinatal asphyxia. GDM that generally develops in the second half of pregnancy induces similar but generally less severe complications. Their severity is higher with earlier onset of GDM and inversely correlated with the degree of glycemic control. Early initiation of GDM might even cause some increase in the rate of congenital malformations. Both PGDM and GDM may cause various motor and behavioral neurodevelopmental problems, including an increased incidence of attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Most complications are reduced in incidence and severity with the improvement in diabetic control. Mechanisms of diabetic-induced damage in pregnancy are related to maternal and fetal hyperglycemia, enhanced oxidative stress, epigenetic changes, and other, less defined, pathogenic mechanisms.     

A Glimpse at the Size of the Fetal Liver—Is It Connected with the Evolution of Gestational Diabetes?

Gestational diabetes mellitus (GDM) is defined as an impairment of glucose tolerance, manifested by hyperglycemia, which occurs at any stage of pregnancy. GDM is more common in the third trimester of pregnancy and usually disappears after birth. It was hypothesized that the glycemic status of the mother can modulate liver development and growth early during the pregnancy. The simplest modality to monitor the evolution of GDM employs noninvasive techniques. In this category, routinely obstetrical ultrasound (OUS) examinations (simple or 2D/3D) can be employed for specific fetal measurements, such as fetal liver length (FLL) or volume (FLV). FLL and FLV may emerge as possible predictors of GDM as they positively relate to the maternal glycated hemoglobin (HbA1c) levels and to the results of the oral glucose tolerance test. The aim of this review is to offer insight into the relationship between GDM and fetal nutritional status. Risk factors for GDM and the short- and long-term outcomes of GDM pregnancies are also discussed, as well as the significance of different dietary patterns. Moreover, the review aims to fill one gap in the literature, investigating whether fetal liver growth can be used as a predictor of GDM evolution. To conclude, although studies pointed out a connection between fetal indices and GDM as useful tools in the early detection of GDM (before 23 weeks of gestation), additional research is needed to properly manage GDM and offspring health.     

The Influence of Prenatal Fumonisin Exposure on Bone Properties,as well as OPG and RANKL Expression and Immunolocalization,in Newborn Offspring Is Sex and Dose Dependent

The current study examined the effects of exposure of pregnant dams to fumonisins (FBs; FB1 and FB2), from the seventh day of pregnancy to parturition, on offspring bone metabolism and properties. The rats were randomly divided into three groups intoxicated with FBs at either 0, 60, or 90 mg/kg b.w. Body weight and bone length were affected by fumonisin exposure, irrespective of sex or dose, while the negative and harmful effects of maternal FBs’ exposure on bone mechanical resistance were sex and dose dependent. The immunolocalization of osteoprotegerin (OPG) and receptor activator of nuclear factor kappa-Β ligand (RANKL), in bone and articular cartilage, indicated that the observed bone effects resulted from the FB-induced alterations in bone metabolism, which were confirmed by the changes observed in the Western blot expression of OPG and RANKL. It was concluded that the negative effects of prenatal FB exposure on the general growth and morphometry of the offspring bones, as a result of the altered expression of proteins responsible for bone metabolism, were dose and sex dependent.     

Maternal High Folic Acid Supplement Promotes Glucose Intolerance and Insulin Resistance in Male Mouse Offspring Fed a High-Fat Diet

Maternal nutrition may influence metabolic profiles in offspring. We aimed to investigate the effect of maternal folic acid supplement on glucose metabolism in mouse offspring fed a high-fat diet (HFD). Sixty C57BL/6 female mice were randomly assigned into three dietary groups and fed the AIN-93G diet containing 2 (control), 5 (recommended folic acid supplement, RFolS) or 40 (high folic acid supplement, HFolS) mg folic acid/kg of diet. All male offspring were fed HFD for eight weeks. Physiological, biochemical and genetic variables were measured. Before HFD feeding, developmental variables and metabolic profiles were comparable among each offspring group. However, after eight weeks of HFD feeding, the offspring of HFolS dams (Off-HFolS) were more vulnerable to suffer from obesity (p = 0.009), glucose intolerance (p < 0.001) and insulin resistance (p < 0.001), compared with the controls. Off-HFolS had reduced serum adiponectin concentration, accompanied with decreased adiponectin mRNA level but increased global DNA methylation level in white adipose tissue. In conclusion, our results suggest maternal HFolS exacerbates the detrimental effect of HFD on glucose intolerance and insulin resistance in male offspring, implying that HFolS during pregnancy should be adopted cautiously in the general population of pregnant women to avoid potential deleterious effect on the metabolic diseases in their offspring.     

Sex‐specific Alterations in Serology and the Expression of Liver FATP4 Protein in Offspring Exposed to High‐Fat Diet during Pregnancy and/or Lactation

Changes in dietary composition will have a significant impact on the nutritional status of the mother and the offspring. To examine the relevant hormone level changes during lactation and the expression of fatty acid transporters in the placenta and liver under the condition of a high‐fat (HF) diet, we established HF animal models and conducted a cross‐fostering program to mimic the shift in diet. On gestation day (GD)18, the weight of placenta in the HF group was significantly higher than that in the control group (p < 0.05). HF‐fed male pups had a significantly lower serum insulin level, but the same phenomenon was not found in females. On the contrary, serum triacylglycerol (TAG) level presented a tendency to decrease only in female offspring. Oil red O staining showed lipid accumulation in the HF diet offspring livers. The mRNA levels of FATP4 in the placenta in the HF diet group were significantly upregulated compared to the control diet group (p < 0.05). High‐fat diet (HFD) consumption also altered the liver mRNA levels of FATP4, SREBP‐1, and SCD‐1 in the male offspring, while the changes in protein levels of FATP4 were not observed in either sex. In conclusion, maternal HF diet has a profound impact on offspring growth, metabolism, and the risk of metabolic disorders, which would depend on the exposure period of pregnancy and lactation.     

Polycyclic Aromatic Hydrocarbons in Maternal and Cord Blood Plasma

Abstract

Polycyclic aromatic hydrocarbons (PAH) come from incomplete combustion of organic materials, including tobacco smoke. Some PAH are known to be mutagenic and carcinogenic and of concern for the fetus when women smoke during pregnancy. Known consequences of smoking during pregnancy include low birth weight (LBW) and preterm (PT) delivery. This study was designed to measure concentrations of 3 PAH: anthracene (A), benzo(a)pyrene (BP) and 1-hydroxypyrene (1-HP) in paired maternal (M) and cord blood (CB) samples. Additionally, we explored relationships between the PAH concentrations and LBW or PTD. Cotinine was used as a biomarker of tobacco exposure. All 3 PAH were found in M and CB plasma. A was significantly elevated in CB plasma compared to M plasma at higher M cotinine concentrations. BP in PT infants was significantly lower than in term. There were significant correlations between M and CB concentrations of anthracene. Correlations of 1-HP with cotinine in CB and M plasma were significant but opposite in direction. Anthracene, benzo(a)pyrene and 1-hydroxypyrene are present in measurable concentrations in M and CB plasma at the time of delivery. The higher concentrations of anthracene in CB plasma may be due to differences in maternal metabolism during pregnancy, length of labor or metabolism in the fetus. Long-term effects of anthracene on the infant are unknown and merit further investigation.     

Novel Biomolecules in the Pathogenesis of Gestational Diabetes Mellitus

Gestational diabetes mellitus (GDM) is one of the most common metabolic diseases in pregnant women. Its early diagnosis seems to have a significant impact on the developing fetus, the course of delivery, and the neonatal period. It may also affect the later stages of child development and subsequent complications in the mother. Therefore, the crux of the matter is to find a biopredictor capable of singling out women at risk of developing GDM as early as the very start of pregnancy. Apart from the well-known molecules with a proven and clear-cut role in the pathogenesis of GDM, e.g., adiponectin and leptin, a potential role of newer biomolecules is also emphasized. Less popular and less known factors with different mechanisms of action include: galectins, growth differentiation factor-15, chemerin, omentin-1, osteocalcin, resistin, visfatin, vaspin, irisin, apelin, fatty acid-binding protein 4 (FABP4), fibroblast growth factor 21, and lipocalin-2. The aim of this review is to present the potential and significance of these 13 less known biomolecules in the pathogenesis of GDM. It seems that high levels of FABP4, low levels of irisin, and high levels of under-carboxylated osteocalcin in the serum of pregnant women can be used as predictive markers in the diagnosis of GDM. Hopefully, future clinical trials will be able to determine which biomolecules have the most potential to predict GDM.