Atlas of fetal metabolism during mid-to-late gestation and diabetic pregnancy.

Mounting evidence suggests metabolism instructs stem cell fate decisions. However, how fetal metabolism changes during development and how altered maternal metabolism shapes fetal metabolism remain unexplored. We present a descriptive atlas of in vivo fetal murine metabolism during mid-to-late gestation in normal and diabetic pregnancy. Using 13C-glucose and liquid chromatography-mass spectrometry (LC-MS), we profiled the metabolism of fetal brains, hearts, livers, and placentas harvested from pregnant dams between embryonic days (E)10.5 and 18.5. Our analysis revealed metabolic features specific to a hyperglycemic environment and signatures that may denote developmental transitions during euglycemic development. We observed sorbitol accumulation in fetal tissues and altered neurotransmitter levels in fetal brains isolated from hyperglycemic dams. Tracing 13C-glucose revealed disparate fetal nutrient sourcing depending on maternal glycemic states. Regardless of glycemic state, histidine-derived metabolites accumulated in late-stage fetal tissues. Our rich dataset presents a comprehensive overview of in vivo fetal tissue metabolism and alterations due to maternal hyperglycemia.

RANK links thymic regulatory T cells to fetal loss and gestational diabetes in pregnancy.

Successful pregnancies rely on adaptations within the mother1, including marked changes within the immune system2. It has long been known that the thymus, the central lymphoid organ, changes markedly during pregnancy3. However, the molecular basis and importance of this process remain largely obscure. Here we show that the osteoclast differentiation receptor RANK4,5 couples female sex hormones to the rewiring of the thymus during pregnancy. Genetic deletion of Rank (also known as Tnfrsf11a) in thymic epithelial cells results in impaired thymic involution and blunted expansion of natural regulatory T (Treg) cells in pregnant female mice. Sex hormones, in particular progesterone, drive the development of thymic Treg cells through RANK in a manner that depends on AIRE+ medullary thymic epithelial cells. The depletion of Rank in the mouse thymic epithelium results in reduced accumulation of natural Treg cells in the placenta, and an increase in the number of miscarriages. Thymic deletion of Rank also results in impaired accumulation of Treg cells in visceral adipose tissue, and is associated with enlarged adipocyte size, tissue inflammation, enhanced maternal glucose intolerance, fetal macrosomia, and a long-lasting transgenerational alteration in glucose homeostasis, which are all key hallmarks of gestational diabetes. Transplantation of Treg cells rescued fetal loss, maternal glucose intolerance and fetal macrosomia. In human pregnancies, we found that gestational diabetes also correlates with a reduced number of Treg cells in the placenta. Our findings show that RANK promotes the hormone-mediated development of thymic Treg cells during pregnancy, and expand the functional role of maternal Treg cells to the development of gestational diabetes and the transgenerational metabolic rewiring of glucose homeostasis.

Implications of pregnancy on cardiometabolic disease risk: preeclampsia and gestational diabetes.

Cardiometabolic disorders, such as obesity, insulin resistance, and hypertension, prior to and within pregnancy are increasing in prevalence worldwide. Pregnancy-associated cardiometabolic disease poses a great risk to the short- and long-term well-being of the mother and offspring. Hypertensive pregnancy, notably preeclampsia, as well as gestational diabetes are the major diseases of pregnancy growing in prevalence as a result of growing cardiometabolic disease prevalence. The mechanisms whereby obesity, diabetes, and other comorbidities lead to preeclampsia and gestational diabetes are incompletely understood and continually evolving in the literature. In addition, novel therapeutic avenues are currently being explored in these patients to offset cardiometabolic-induced adverse pregnancy outcomes in preeclamptic and gestational diabetes pregnancies. In this review, we discuss the emerging pathophysiological mechanisms of preeclampsia and gestational diabetes in the context of cardiometabolic risk as well as the most recent preclinical and clinical updates in the pathogenesis and treatment of these conditions.

Sex-Specific Alterations in Placental Proteomics Induced by Intrauterine Hyperglycemia.

Gestational diabetes mellitus (GDM) with intrauterine hyperglycemia induces a series of changes in the placenta, which have adverse effects on both the mother and the fetus. The aim of this study was to investigate the changes in the placenta in GDM and its gender differences. In this study, we established an intrauterine hyperglycemia model using ICR mice. We collected placental specimens from mice before birth for histological observation, along with tandem mass tag (TMT)-labeled proteomic analysis, which was stratified by sex. When the analysis was not segregated by sex, the GDM group showed 208 upregulated and 225 downregulated proteins in the placenta, primarily within the extracellular matrix and mitochondria. Altered biological processes included cholesterol metabolism and oxidative stress responses. After stratification by sex, the male subgroup showed a heightened tendency for immune-related pathway alterations, whereas the female subgroup manifested changes in branched-chain amino acid metabolism. Our study suggests that the observed sex differences in placental protein expression may explain the differential impact of GDM on offspring.

ChIP-seq and RNA-seq Reveal the Involvement of Histone Lactylation Modification in Gestational Diabetes Mellitus.

Lactylation is a novel post-translational modification of proteins. Although the histone lactylation modification has been reported to be involved in glucose metabolism, its role and molecular pathways in gestational diabetes mellitus (GDM) are still unclear. This study aims to elucidate the histone lactylation modification landscapes of GDM patients and explore lactylation-modification-related genes involved in GDM. We employed a combination of RNA-seq analysis and chromatin immunoprecipitation sequencing (ChIP-seq) analysis to identify upregulated differentially expressed genes (DEGs) with hyperhistone lactylation modification in GDM. We demonstrated that the levels of lactate and histone lactylation were significantly elevated in GDM patients. DEGs were involved in diabetes-related pathways, such as the PI3K-Akt signaling pathway, Jak-STAT signaling pathway, and mTOR signaling pathway. ChIP-seq analysis indicated that histone lactylation modification in the promoter regions of the GDM group was significantly changed. By integrating the results of RNA-seq and ChIP-seq analysis, we found that CACNA2D1 is a key gene for histone lactylation modification and is involved in the progression of GDM by promoting cell vitality and proliferation. In conclusion, we identified the key gene CACNA2D1, which upregulated and exhibited hypermodification of histone lactylation in GDM. These findings establish a theoretical groundwork for the targeted therapy of GDM.

Analysis of early-pregnancy metabolome in early- and late-onset gestational diabetes reveals distinct associations with maternal overweight.

AIMS/HYPOTHESIS: It is not known whether the early-pregnancy metabolome differs in patients with early- vs late-onset gestational diabetes mellitus (GDM) stratified by maternal overweight. The aims of this study were to analyse correlations between early-pregnancy metabolites and maternal glycaemic and anthropometric characteristics, and to identify early-pregnancy metabolomic alterations that characterise lean women (BMI <25 kg/m2) and women with overweight (BMI ≥25 kg/m2) with early-onset GDM (E-GDM) or late-onset GDM (L-GDM). METHODS: We performed a nested case-control study within the population-based prospective Early Diagnosis of Diabetes in Pregnancy cohort, comprising 210 participants with GDM (126 early-onset, 84 late-onset) and 209 normoglycaemic control participants matched according to maternal age, BMI class and primiparity. Maternal weight, height and waist circumference were measured at 8-14 weeks' gestation. A 2 h 75 g OGTT was performed at 12-16 weeks' gestation (OGTT1), and women with normal results underwent repeat testing at 24-28 weeks' gestation (OGTT2). Comprehensive metabolomic profiling of fasting serum samples, collected at OGTT1, was performed by untargeted ultra-HPLC-MS. Linear models were applied to study correlations between early-pregnancy metabolites and maternal glucose concentrations during OGTT1, fasting insulin, HOMA-IR, BMI and waist circumference. Early-pregnancy metabolomic features for GDM subtypes (participants stratified by maternal overweight and gestational timepoint at GDM onset) were studied using linear and multivariate models. The false discovery rate was controlled using the Benjamini-Hochberg method. RESULTS: In the total cohort (n=419), the clearest correlation patterns were observed between (1) maternal glucose concentrations and long-chain fatty acids and medium- and long-chain acylcarnitines; (2) maternal BMI and/or waist circumference and long-chain fatty acids, medium- and long-chain acylcarnitines, phospholipids, and aromatic and branched-chain amino acids; and (3) HOMA-IR and/or fasting insulin and L-tyrosine, certain long-chain fatty acids and phospholipids (q<0.001). Univariate analyses of GDM subtypes revealed significant differences (q<0.05) for seven non-glucose metabolites only in overweight women with E-GDM compared with control participants: linolenic acid, oleic acid, docosapentaenoic acid, docosatetraenoic acid and lysophosphatidylcholine 20:4/0:0 abundances were higher, whereas levels of specific phosphatidylcholines (P-16:0/18:2 and 15:0/18:2) were lower. However, multivariate analyses exploring the early-pregnancy metabolome of GDM subtypes showed differential clustering of acylcarnitines and long-chain fatty acids between normal-weight and overweight women with E- and L-GDM. CONCLUSIONS/INTERPRETATION: GDM subtypes show distinct early-pregnancy metabolomic features that correlate with maternal glycaemic and anthropometric characteristics. The patterns identified suggest early-pregnancy disturbances of maternal lipid metabolism, with most alterations observed in overweight women with E-GDM. Our findings highlight the importance of maternal adiposity as the primary target for prevention and treatment.

In utero exposure to maternal diabetes exacerbates dietary sodium intake-induced endothelial dysfunction by activating cyclooxygenase 2-derived prostanoids.

Prenatal exposure to maternal diabetes has been recognized as a significant cardiovascular risk factor, increasing the susceptibility to the emergence of conditions such as high blood pressure, atherosclerosis, and heart disease in later stages of life. However, it is unclear if offspring exposed to diabetes in utero have worse vascular outcomes on a high-salt (HS) diet. To test the hypothesis that in utero exposure to maternal diabetes predisposes to HS-induced vascular dysfunction, we treated adult male wild-type offspring (DM_Exp, 6 mo old) of diabetic Ins2+/C96Y mice (Akita mice) with HS (8% sodium chloride, 10 days) and analyzed endothelial function via wire myograph and cyclooxygenase (COX)-derived prostanoids pathway by ELISA, quantitative PCR, and immunochemistry. On a regular diet, DM_Exp mice did not manifest any vascular dysfunction, remodeling, or inflammation. However, HS increased aortic contractility to phenylephrine and induced endothelial dysfunction (analyzed by acetylcholine-induced endothelium-dependent relaxation), vascular hydrogen peroxide production, COX2 expression, and prostaglandin E2 (PGE2) overproduction. Interestingly, ex vivo antioxidant treatment (tempol) or COX1/2 (indomethacin) or COX2 (NS398) inhibitors improved or reverted the endothelial dysfunction in DM_Exp mice fed a HS diet. Finally, DM_Exp mice fed with HS exhibited greater circulating cytokines and chemokines accompanied by vascular inflammation. In summary, our findings indicate that prenatal exposure to maternal diabetes predisposes to HS-induced vascular dysfunction, primarily through the induction of oxidative stress and the generation of COX2-derived PGE2. This supports the concept that in utero exposure to maternal diabetes is a cardiovascular risk factor in adulthood.NEW & NOTEWORTHY Using a unique mouse model of prenatal exposure to maternal type 1 diabetes, our study demonstrates the novel observation that prenatal exposure to maternal diabetes results in a predisposition to high-salt (HS) dietary-induced vascular dysfunction and inflammation in adulthood. Mechanistically, we demonstrated that in utero exposure to maternal diabetes and HS intake induces vascular oxidative stress, cyclooxygenase-derived prostaglandin E2, and inflammation.

Impaired microvascular insulin-dependent dilation in women with a history of gestational diabetes.

Women with a history of gestational diabetes mellitus (GDM) have a significantly greater lifetime risk of developing cardiovascular disease and type 2 diabetes compared with women who had an uncomplicated pregnancy (HC). Microvascular endothelial dysfunction, mediated via reduced nitric oxide (NO)-dependent dilation secondary to increases in oxidative stress, persists after pregnancy complicated by GDM. We examined whether this microvascular dysfunction reduces insulin-mediated vascular responses in women with a history of GDM. We assessed in vivo microvascular endothelium-dependent vasodilator function by measuring cutaneous vascular conductance responses to graded infusions of acetylcholine (10-10-10-1 M) and insulin (10-8-10-4 M) in control sites and sites treated with 15 mM l-NAME [NG-nitro-l-arginine methyl ester; NO-synthase (NOS) inhibitor] or 5 mM l-ascorbate. We also measured protein expression of total endothelial NOS (eNOS), insulin-mediated eNOS phosphorylation, and endothelial nitrotyrosine in isolated endothelial cells from GDM and HC. Women with a history of GDM had reduced acetylcholine (P < 0.001)- and insulin (P < 0.001)-mediated dilation, and the NO-dependent responses to both acetylcholine (P = 0.006) and insulin (P = 0.006) were reduced in GDM compared with HC. Insulin stimulation increased phosphorylated eNOS content in HC (P = 0.009) but had no effect in GDM (P = 0.306). Ascorbate treatment increased acetylcholine (P < 0.001)- and insulin (P < 0.001)-mediated dilation in GDM, and endothelial cell nitrotyrosine expression was higher in GDM compared with HC (P = 0.014). Women with a history of GDM have attenuated microvascular vasodilation responses to insulin, and this attenuation is mediated, in part, by reduced NO-dependent mechanisms. Our findings further implicate increased endothelial oxidative stress in this microvascular insulin resistance.NEW & NOTEWORTHY Women who have gestational diabetes during pregnancy are at a greater risk for cardiovascular disease and type 2 diabetes in the decade following pregnancy. The mechanisms mediating this increased risk are unclear. Herein, we demonstrate that insulin-dependent microvascular responses are reduced in women who had gestational diabetes, despite the remission of glucose intolerance. This reduced microvascular sensitivity to insulin may contribute to increased cardiovascular disease and type 2 diabetes risk in these women.

Gestational diabetes mellitus induces congenital anomalies of the kidney and urinary tract in mice by altering RET/MAPK/ERK pathway.

Gestational diabetes mellitus (GDM) presents a substantial population health concern. Previous studies have revealed that GDM can ultimately influence nephron endowment. In this study, we established a GDM mouse model to investigate the embryological alterations and molecular mechanisms underlying the development of congenital anomalies of the kidney and urinary tract (CAKUT) affected by GDM. Our study highlights that GDM could contribute to the manifestation of CAKUT, with prevalent phenotypes characterized by isolated hydronephrosis and duplex kidney complicated with hydronephrosis in mice. Ectopic ureteric buds (UBs) and extended length of common nephric ducts (CNDs) were noted in the metanephric development stage. The expression of Ret and downstream p-ERK activity were enhanced in UBs, which indicated the alteration of RET/MAPK/ERK pathway may be one of the mechanisms contributing to the increased occurrence of CAKUT associated with GDM.

Linking the reversal of gestational insulin resistance to postpartum depression.

BACKGROUND: Postpartum depression (PPD) constitutes a significant mental health disorder affecting almost one fifth of pregnancies globally. Despite extensive research, the precise etiological mechanisms underlying PPD remain elusive. However, several risk factors like genetic predisposition, hormonal fluctuations, and stress-related environmental and psychosocial triggers have been found to be implicated in its development. MAIN: Recently, an increased risk of PPD has been reported to be associated with gestational diabetes mellitus (GDM), which is characterized by the disruption of glucose metabolism, primarily attributed to the emergence of insulin resistance (IR). While IR during pregnancy seems to be an evolutionary adaptative mechanism to handle the profound metabolic alterations during pregnancy, its subsequent resolution following delivery necessitates a reconfiguration of the metabolic landscape in both peripheral tissues and the central nervous system (CNS). Considering the pivotal roles of energy metabolism, particularly glucose metabolism, in CNS functions, we propose a novel model that such pronounced changes in IR and the associated glucose metabolism seen postpartum might account for PPD development. This concept is based on the profound influences from insulin and glucose metabolism on brain functions, potentially via modulating neurotransmitter actions of dopamine and serotonin. Their sudden postpartum disruption is likely to be linked to mood changes, as observed in PPD. CONCLUSIONS: The detailed pathogenesis of PPD might be multifactorial and still remains to be fully elucidated. Nevertheless, our hypothesis might account in part for an additional etiological factor to PPD development. If our concept is validated, it can provide guidance for future PPD prevention, diagnosis, and intervention.

Effect of high-fat diet on the fatty acid profiles of brain in offspring mice exposed to maternal gestational diabetes mellitus.

OBJECTIVE: Fatty acids play a critical role in the proper functioning of the brain. This study investigated the effects of a high-fat (HF) diet on brain fatty acid profiles of offspring exposed to maternal gestational diabetes mellitus (GDM). METHODS: Insulin receptor antagonist (S961) and HF diet were used to establish the GDM animal model. Brain fatty acid profiles of the offspring mice were measured by gas chromatography at weaning and adulthood. Protein expressions of the fatty acid transport pathway Wnt3/ß-catenin and the target protein major facilitator superfamily domain-containing 2a (MFSD2a) were measured in the offspring brain by Western blot. RESULTS: Maternal GDM increased the body weight of male offspring (P < 0.05). In weaning offspring, factorial analysis showed that maternal GDM increased the monounsaturated fatty acid (MUFA) percentage of the weaning offspring's brain (P < 0.05). Maternal GDM decreased offspring brain arachidonic acid (AA), but HF diet increased brain linoleic acid (LA) (P < 0.05). Maternal GDM and HF diet reduced offspring brain docosahexaenoic acid (DHA), and the male offspring had higher DHA than the female offspring (P < 0.05). In adult offspring, factorial analysis showed that HF diet increased brain MUFA in offspring, and male offspring had higher brain MUFA than female offspring (P < 0.05). The HF diet increased brain LA in the offspring. Male offspring had higher level of AA than female offspring (P < 0.05). HF diet reduced DHA in the brains of female offspring. The brain protein expression of ß-catenin and MFSD2a in both weaning and adult female offspring was lower in the HF + GDM group than in the CON group (P < 0.05). CONCLUSIONS: Maternal GDM increased the susceptibility of male offspring to HF diet-induced obesity. HF diet-induced adverse brain fatty acid profiles in both male and female offspring exposed to GDM.

Interactions between host and gut microbiota in gestational diabetes mellitus and their impacts on offspring.

Gestational diabetes mellitus (GDM) is characterized by insulin resistance and low-grade inflammation, and most studies have demonstrated gut dysbiosis in GDM pregnancies. Overall, they were manifested as a reduction in microbiome diversity and richness, depleted short chain fatty acid (SCFA)-producing genera and a dominant of Gram-negative pathogens releasing lipopolysaccharide (LPS). The SCFAs functioned as energy substance or signaling molecules to interact with host locally and beyond the gut. LPS contributed to pathophysiology of diseases through activating Toll-like receptor 4 (TLR4) and involved in inflammatory responses. The gut microbiome dysbiosis was not only closely related with GDM, it was also vital to fetal health through vertical transmission. In this review, we summarized gut microbiota signature in GDM pregnancies of each trimester, and presented a brief introduction of microbiome derived SCFAs. We then discussed mechanisms of microbiome-host interactions in the physiopathology of GDM and associated metabolic disorders. Finally, we compared offspring microbiota composition from GDM with that from normal pregnancies, and described the possible mechanism.

Prolactin effects on the pathogenesis of diabetes mellitus.

BACKGROUND: Prolactin (PRL) is a pituitary hormone promoting lactation in response to the suckling reflex. Beyond its well-known effects, novel tissue-specific and metabolic functions of PRL are emerging. AIMS: To dissect PRL as a critical mediator of whole-body gluco-insulinemic sensitivity. METHODS: PubMed-based search with the following terms 'prolactin', 'glucose metabolism', 'type 2 diabetes mellitus', 'type 1 diabetes mellitus', 'gestational diabetes mellitus' was performed. DISCUSSION: The identification of the PRL-glucose metabolism network poses the basis for unprecedented avenues of research in the pathogenesis of diabetes mellitus type 1 or 2, as well as of gestational diabetes. In this regard, it is of timely relevance to define properly the homeostatic PRL serum levels since glucose metabolism could be influenced by the circulating amount of the hormone. RESULTS: This review underscores the basic mechanisms of regulation of pancreatic ß-cell functions by PRL and provides a revision of articles which have investigated the connection between PRL unbalancing and diabetes mellitus. Future studies are needed to elucidate the burden and the role of PRL in the regulation of glucose metabolism and determine the specific PRL threshold that may impact the management of diabetes. CONCLUSION: A careful evaluation and context-driven interpretation of PRL levels (e.g., pregnancy, PRL-secreting pituitary adenomas, drug-related hyper- and hypoprolactinemia) could be critical for the correct screening and management of glucometabolic disorders, such as type 1 or 2 as well as gestational diabetes mellitus.

Unravelling the Metabolic Underpinnings of Gestational Diabetes Mellitus: A Comprehensive Mendelian Randomisation Analysis Identifying Causal Metabolites and Biological Pathways.

BACKGROUND: Gestational diabetes mellitus (GDM) has a strong genetic predisposition. Integrating metabolomics with Mendelian randomisation (MR) analysis offers a potent method to uncover the metabolic factors causally linked to GDM pathogenesis. OBJECTIVES: This study aims to identify specific metabolites and metabolic pathways causally associated with GDM susceptibility through a comprehensive MR analysis. Additionally, it seeks to explore the potential of these identified metabolites as circulating biomarkers for early GDM detection and risk assessment. Furthermore, it aims to evaluate the implicated metabolic pathways as potential therapeutic targets for preventive or interventional strategies against GDM. METHODS: A two-sample MR study was conducted using summary statistics from a metabolite genome-wide association study (GWAS) of 8299 individuals and a GDM GWAS comprising 13,039 cases and 197,831 controls. Rigorous criteria were applied to select robust genetic instruments for 850 metabolites. RESULTS: MR analysis revealed 47 metabolites exhibiting putative causal associations with GDM risk. Among these, five metabolites demonstrated statistically significant associations after multiple-testing correction: Beta-citrylglutamate, Isobutyrylcarnitine (c4), 1,2-dilinoleoyl-GPC (18:2/18:2), Alliin and Cis-3,4-methyleneheptanoylcarnitine. Importantly, all these metabolites exhibited protective effects against GDM development. Additionally, metabolic pathway enrichment analysis implicated the methionine metabolism and spermidine and spermine biosynthesis pathways in the pathogenesis of GDM. CONCLUSION: This comprehensive MR study has robustly identified specific metabolites and metabolic pathways with causal links to GDM susceptibility. These findings provide novel insights into the metabolic underpinnings of GDM aetiology and offer promising translational implications. The identified metabolites could serve as potential circulating biomarkers for early detection and risk stratification, while the implicated metabolic pathways may represent therapeutic targets for preventive or interventional strategies against GDM.

Gestational diabetes mellitus is associated with distinct folate-related metabolites in early and mid-pregnancy: A prospective cohort study.

AIMS: This study aimed to evaluate the association between gestational diabetes mellitus (GDM) and circulating folate metabolites, folic acid (FA) intake, and the methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) genotype. MATERIALS AND METHODS: A prospective pregnancy cohort study was conducted in Beijing, China, from 2022 to 2023. Circulating folate metabolites, including red blood cell (RBC) 5-methyltetrahydrofolate (5-MTHF), 5, 10-methylene-tetrahydrofolate (5,10-CH2-THF), 5- formyltetrahydrofolate (5-CHO-THF), and unmetabolised folic acid (UMFA), and plasma homocysteine (HCY), 5-MTHF, and methylmalonic acid (MMA), were determined at 6-17 weeks and 20-26 weeks of gestation. FA intake and the MTHFR and MTRR genotype were also examined. GDM was diagnosed between 24 and 28 weeks of pregnancy by a 75-g oral glucose tolerance test (OGTT). The association between the folate status and GDM was ascertained using multivariate generalised linear models, logistic regression models, and restricted cubic spline regression, adjusting for potential confounders. RESULTS: The study included 2032 pregnant women, of whom 392 (19.29%) developed GDM. UMFA above the 75th percentile (≥P75) [adjusted OR (aOR) (95% confidence interval [CI]) = 1.36 (1.01-1.84)], UMFA ≥ P90 [aOR (95% CI) = 1.82 (1.23-2.69)], and HCY ≥ P75 [aOR (95% CI) = 1.40 (1.04-1.88)] in early pregnancy, and RBC 5-MTHF [aOR (95% CI) = 1.48 (1.10-2.00)], RBC 5,10-CH2-THF [aOR (95% CI) = 1.55 (1.15-2.10)], and plasma 5-MTHF [aOR (95% CI) = 1.36 (1.00-1.86)] in mid-pregnancy ≥ P75 are associated with GDM. Higher UMFA levels in early pregnancy show positive associations with the 1-h and 2-h glucose levels during the OGTT, and higher HCY levels are associated with increased fasting glucose levels during the OGTT. In comparison, RBC 5- MTHF and 5,10-CH2-THF, and plasma 5- MTHF in mid-pregnancy are positively associated with the 1-h glucose level (p < 0.05). The MTHFR and MTRR genotype and FA intake are not associated with GDM. CONCLUSIONS: Elevated levels of UMFA and HCY during early pregnancy, along with elevated RBC 5-MTHF and 5,10-CH2-THF and plasma 5-MTHF during mid-pregnancy, are associated with GDM. These findings indicate distinct connections between different folate metabolites and the occurrence of GDM.

Oxidative stress biomarkers in pregnancy: a systematic review.

BACKGROUND: This systematic review explores the level of oxidative stress (OS) markers during pregnancy and their correlation with complications. Unlike previous studies, it refrains from directly investigating the role of OS but instead synthesises data on the levels of these markers and their implications for various pregnancy-related complications such as preeclampsia, intrauterine growth restrictions, preterm premature rupture of membranes, preterm labour, gestational diabetes mellitus and miscarriages. METHOD: STUDY DESIGN: Utilizing a systematic review approach, we conducted a comprehensive search across databases, including MEDLINE, CINAHL (EBSCOhost), ScienceDirect, Web of Science, and SCOPUS. Our search encompassed all publication years in English. RESULTS: After evaluating 54,173 records, 45 studies with a low risk of bias were selected for inclusion. This systematic review has underscored the importance of these markers in both physiological and pathological pregnancy states such as preeclampsia, intrauterine growth restrictions, preterm premature rupture of membranes, preterm labour, gestational diabetes mellitus and miscarriages. CONCLUSION: This systematic review provides valuable insights into the role of OS in pregnancy and their connection to complications. These selected studies delved deeply into OS markers during pregnancy and their implications for associated complications. The comprehensive findings highlighted the significance of OS markers in both normal and pathological pregnancy conditions, paving the way for further research in this field.

Gestational Diabetes Mellitus Remodels the Fetal Brain Fatty Acid Profile Through Placenta-Brain Lipid Axis in C57BL/6J Mice.

BACKGROUND: Polyunsaturated fatty acids (PUFAs), especially docosahexaenoic acid (DHA), are critical for proper fetal brain growth and development. Gestational diabetes mellitus (GDM) could affect maternal-fetal fatty acid metabolism. OBJECTIVE: This study aimed to explore the effect of GDM and high-fat (HF) diet on the DHA transport signaling pathway in the placenta-brain axis and fatty acid concentrations in the fetal brain. METHODS: Insulin receptor antagonist (S961) and HF diet were used to establish an animal model of GDM. Eighty female C57BL/6J mice were randomly divided into control (CON), GDM, HF, and HF+GDM groups. The fatty acid profiles of the maternal liver and fetal brain were analyzed by gas chromatography. In addition, we analyzed the protein amounts of maternal liver fatty acid desaturase (FADS1/3), elongase (ELOVL2/5) and the regulatory factor sterol-regulatory element-binding protein (SREBP)-1c, and the DHA transport signaling pathway (Wnt3/ß-catenin/MFSD2a) of the placenta and fetal brain using western blotting. RESULTS: GDM promoted the decrease of maternal liver ELOVL2, ELOVL5, and SREBP-1c. Accordingly, we observed a significant decrease in the amount of maternal liver arachidonic acid (AA), DHA, and total n-3 PUFA and n-6 PUFA induced by GDM. GDM also significantly decreased the amount of DHA and n-3 PUFA in the fetal brain. GDM downregulated the Wnt3/ß-catenin/MFSD2a signaling pathway, which transfers n-3 PUFA in the placenta and fetal brain. The HF diet increased n-6 PUFA amounts in the maternal liver, correspondingly increasing linoleic acid, gamma-linolenic acid, AA, and total n-6 PUFA in the fetal brain, but decreased DHA amount in the fetal brain. However, HF diet only tended to decrease placental ß-catenin and MFSD2a amounts (P = 0.074 and P = 0.098, respectively). CONCLUSIONS: Maternal GDM could affect the fatty acid profile of the fetal brain both by downregulating the Wnt3/ß-catenin/MFSD2a pathway of the placental-fetal barrier and by affecting maternal fatty acid metabolism.

The role of microRNAs in pregnancies complicated by maternal diabetes.

With the global prevalence of diabetes increasing, more people of reproductive age are experiencing hyperglycaemic pregnancies. Maternal Type 1 (T1DM) or Type 2 (T2DM) diabetes mellitus, and gestational diabetes mellitus (GDM) are associated with maternal cardiovascular and metabolic complications. Pregnancies complicated by maternal diabetes also increase the risk of short- and long-term health complications for the offspring, including altered fetal growth and the onset of T2DM and cardiometabolic diseases throughout life. Despite advanced methods for improving maternal glucose control, the prevalence of adverse maternal and offspring outcomes associated with maternal diabetes remains high. The placenta is a key organ at the maternal-fetal interface that regulates fetal growth and development. In pregnancies complicated by maternal diabetes, altered placental development and function has been linked to adverse outcomes in both mother and fetus. Emerging evidence suggests that microRNAs (miRNAs) are key molecules involved in mediating these changes. In this review, we describe the role of miRNAs in normal pregnancy and discuss how miRNA dysregulation in the placenta and maternal circulation is associated with suboptimal placental development and pregnancy outcomes in individuals with maternal diabetes. We also discuss evidence demonstrating that miRNA dysregulation may affect the long-term health of mothers and their offspring. As such, miRNAs are potential candidates as biomarkers and therapeutic targets in diabetic pregnancies at risk of adverse outcomes.

The role of chemerin in the regulation of cGAS-STING pathway in gestational diabetes mellitus placenta.

Recent studies already confirmed that placenta mitochondrial dysfunction is associated with the progression of gestational diabetes mellitus (GDM). Besides, a possible relationship between adipokine chemerin and disulfide-bond A oxidoreductase-like protein (DsbA-L) had been revealed, whereas the potential interaction remains unclear. In addition, very little is still known about the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway and its mechanisms of action in the context of GDM. The present study aims to investigate the underlying mechanism of cGAS-STING pathway and its regulatory relationship with chemerin in GDM. A total of 50 participants, including 25 cases of GDM patients and 25 pregnant women with normal glucose tolerance, were enrolled, and their placenta tissues at term labor were collected. Besides, an insulin resistance cell model was established on the human trophoblastic cell line to explore the molecular mechanism of chemerin on cGAS-STING pathway. Results showed that there were mitochondrial pathological changes in GDM placenta, accompanied by the decreased expression of DsbA-L, increased level of chemerin, and the activation of cGAS-STING pathway. In the insulin resistant cell model, overexpression of chemerin upregulated protein expression of DsbA-L, and recombinant chemerin presented time-dependent inhibition on the cGAS-STING pathway, but this effect was not dependent on DsbA-L. In conclusion, elevated chemerin is probably a protective mechanism, which may be a potential therapeutic strategy for GDM.

One-year postpartum weight retention and glucose intolerance in women with prediabetes after gestational diabetes.

AIMS: To determine risk factors for 1-year postpartum weight retention (PPWR) and glucose intolerance (prediabetes + diabetes) in women with a previous history of gestational diabetes (GDM) and prediabetes in early postpartum. METHODS: In this exploratory analysis of the MELINDA randomized controlled trial, we report data of 167 women with prediabetes at the 6-16 weeks (early) postpartum oral glucose tolerance test after a recent history of GDM. RESULTS: Of all participants, 45% (75) had PPWR >0 kg at 1-year postpartum. Compared to women without PPWR, women with PPWR had higher gestational weight gain [10.5 ± 6.4 vs. 6.5 ± 4.5 kg, p < 0.001], higher BMI (p < 0.01) and a worse metabolic profile (higher waist circumference, worse lipid profile and more insulin resistance) (all p < 0.05) both in early and late postpartum. Of all women with PPWR, 40.0% developed metabolic syndrome, compared to 18.9% of women without late PPWR (p = 0.003). The only independent predictor for late PPWR was weight retention in early postpartum (p < 0.001). Of all participants, 55.1% (92) had glucose intolerance (84 prediabetes, 8 diabetes) 1-year postpartum. Independent predictors for late postpartum glucose intolerance were lower gestational age at start insulin therapy in pregnancy and delivery by caesarean section (resp. p = 0.044 and 0.014). CONCLUSIONS: In women with a previous history of GDM and prediabetes in early postpartum, PPWR in early postpartum was a strong independent predictor for late PPWR, while earlier start of insulin therapy during pregnancy and delivery by caesarean section were independent predictors of glucose intolerance in late postpartum.