Pathophysiology Of Gestational Diabetes Mellitus Research Articles

Impairments of insulin and glucagon sensitivity in Chinese women with gestational diabetes mellitus.

To evaluate insulin and glucagon sensitivity in Han Chinese women with and without gestational diabetes mellitus (GDM). In total, 81 women with GDM and 81 age-matched healthy controls were evaluated with a 75 g oral glucose tolerance test (OGTT) at gestational weeks 24-28. Plasma glucose concentrations were measured at fasting and 1 h and 2 h post-OGTT. Fasting plasma insulin, glucagon and amino acids were also measured. Insulin and glucagon sensitivity were assessed by the homeostatic model assessment of insulin resistance (HOMA-IR) and glucagon-alanine index, respectively. As expected, plasma glucose concentrations were higher at fasting and 1 h and 2 h post-OGTT in GDM participants (p < .001 each). Both the HOMA-IR and the glucagon-alanine index were higher in GDM participants. There was a weak positive correlation between HOMA-IR and glucagon-alanine index (r = 0.24, p = .0024). Combining the HOMA-IR and the glucagon-alanine index yielded better capacity (area under the curve = 0.878) than either alone (area under the curve = 0.828 for HOMA-IR and 0.751 for glucagon-alanine index, respectively) in differentiating GDM from healthy participants. While the majority of GDM participants (64%) exhibited both reduced insulin and glucagon sensitivity, a third of them presented either reduced insulin (20%) or glucagon (14%) sensitivity alone. HOMA-IR and glucagon-alanine index correlated differentially with fasting glucose, triglycerides, low-density lipoprotein cholesterol, sum of amino acids and hepatic steatosis index. Impairments of both insulin and glucagon sensitivity occur frequently in Chinese women with GDM, which may, individually or together, drive metabolic derangements in GDM. These observations provide new insights into the pathophysiology of GDM and support the need to target insulin or glucagon resistance, or both, in the management of GDM.

FABP4 as potential indicator for GDM-induced fetal endothelial dysfunction

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): DFG project no. 288034826—International Research Training Group (IRTG) 2251 Background Gestational diabetes mellitus (GDM) is linked to an elevated risk of developing cardiovascular diseases (CVD) both for the mother and the baby in later life. Previous studies have identified fatty acid-binding protein 4 (FABP4) as a prime candidate involved in the pathophysiology of GDM. FABP4 is known to promote an inflammatory response and vascular permeability, induce oxidative stress in endothelial cells (ECs), and impair the nitric oxide signaling pathway, thereby promoting endothelial dysfunction. Indeed, women with GDM exhibit elevated blood levels of FABP4, suggesting its potential as a biomarker for endothelial dysfunction and cardiovascular risk assessment in GDM. However, the role that FABP4 plays in the fetal endothelial function remains poorly understood. Purpose Thus, our aim is to understand the role of FABP4 in fetal endothelial dysfunction and its regulation to mitigate the impact of GDM on the vasculature. Methods Fetoplacental vessels and primary human umbilical vein endothelial cells (HUVECs) were isolated from placentas and umbilical cords obtained from both normoglycemic (NG) and GDM pregnancies. We also obtained the clinical data from the mothers and collected the cord blood. Total mRNA from HUVECs was used for bulk RNA sequencing to compare gene expression, while gene expression analysis in the vessels was conducted using RT-qPCR. Additionally, NG HUVECs were pooled and cultured under high laminar flow conditions (30 dyn/cm²) or subjected to various treatments, including insulin (5nM), glucose (25mM), simvastatin (10nm), or VEGF-A stimulation. Subsequent RT-qPCRs were performed to analyze the gene expression of several genes of interest. Results The bulk RNA sequencing data analysis revealed FABP4 as an overexpressed gene in GDM HUVECs compared to NG. Furthermore, the analysis of data through Gene Set Enrichment Analysis provided a list of different gene sets that are enriched in GDM samples. Among these gene sets are pathways or processes implicated in endothelial dysfunction, such as angiogenesis, PI3K/AKT/mTOR signaling, reactive oxygen species pathway, or inflammatory response. In vitro experiments provided evidence for an elevated FABP4 mRNA expression after VEGF treatment of HUVECs. Conversely, both simvastatin treatment and exposure to laminar flow reduced FABP4 mRNA expression and increased eNOS expression, suggesting a potential inhibitory effect of nitric oxide on FABP4. Conclusion We provided evidence that FABP4 could be involved in fetal GDM-induced endothelial dysfunction. Shear stress and statins might protect the endothelium against the negative impact of FABP4.

Angiopoietin-like protein 4 induces growth hormone variant secretion and aggravates insulin resistance during pregnancy, linking obesity to gestational diabetes mellitus.

Angiopoietin-like protein 4 (ANGPTL4) is a secretory glycoprotein involved in regulating glucose homeostasis in non-pregnant subjects. However, its role in glucose metabolism during pregnancy and the pathophysiology of gestational diabetes mellitus (GDM) remains elusive. Thus, this study aimed to clarify the relationship between ANGPTL4 and GDM and investigate the pathophysiology of placental ANGPTL4 in glucose metabolism. We investigated this issue using blood and placenta samples in 957 pregnant women, the human 3A-sub-E trophoblast cell line, and the L6 skeletal muscle cell line. We found that ANGPTL4 expression in the placenta was higher in obese pregnant women than in lean controls. Palmitic acid significantly induced ANGPTL4 expression in trophoblast cells in a dose-response manner. ANGPTL4 overexpression in trophoblast cells resulted in endoplasmic reticulum (ER) stress, which stimulated the expression and secretion of growth hormone-variant (GH2) but not human placental lactogen. In L6 skeletal muscle cells, soluble ANGPTL4 suppressed insulin-mediated glucose uptake through the epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinases 1/2 (ERK 1/2) pathways. In pregnant women, plasma ANGPTL4 concentrations in the first trimester predicted the incidence of GDM and were positively associated with BMI, plasma triglyceride, and plasma GH2 in the first trimester. However, they were negatively associated with insulin sensitivity index ISI0,120 in the second trimester. Overall, placental ANGPTL4 is induced by obesity and is involved in the pathophysiology of GDM via the induction of ER stress and GH2 secretion. Soluble ANGPTL4 can lead to insulin resistance in skeletal muscle cells and is an early biomarker for predicting GDM.

Investigation of Serum Cartonectin Concentrations in Pregnant Women with Gestational Diabetes Mellitus; a Prospective Non-Interventional Cohort Study

OBJECTIVE: To investigate serum cartonectin concentrations in pregnant women diagnosed with Gestational Diabetes Mellitus (GDM). STUDY DESIGN: This prospective non-interventional cohort study was conducted on 176 pregnant women. The study group consisted of 88 pregnant women diagnosed with GDM, and the control group consisted of 88 pregnant women with normal 75-g OGTT results. First, the study and control groups, and then the subgroups were compared in terms of serum cartonectin concentrations. RESULTS: The study and control groups were similar in terms of BMI and gestational age at blood sampling (p=0.599, p=0.854). The study and control groups were similar in terms of median serum cartonectin concentrations (6.28 ng/ml and 7.13 ng/ml, respectively, p=0.165). In the subgroup analysis, the normal weight control group, overweight control group, normal weight study group, and overweight study group were compared in terms of serum cartonectin concentrations. The lowest median cartonectin concentration was detected in the overweight study group, followed by the overweight control group, normal weight study group, and normal weight control group (5.8 ng/ml, 6.5 ng/ml, 6.9 ng/ml, and 8.2 ng/ml, respectively, p=0.235). CONCLUSION: Serum cartonectin concentrations were found to be similar in the GDM and control groups. However, the number of participants in this study is limited to draw a definitive conclusion. Many studies with larger series are needed to reveal whether serum cartonectin is involved in the pathophysiology of GDM.

A Simplified Screening Model to Predict the Risk of Gestational Diabetes Mellitus in Caucasian and Latin American Pregnant Women.

The pathophysiology of gestational diabetes mellitus (GDM) comprises clinical and genetic factors. In fact, GDM is associated with several single nucleotide polymorphisms (SNPs). This study aimed to build a prediction model of GDM combining clinical and genetic risk factors. A total of 1588 pregnant women from the San Carlos Cohort participated in the present study, including 1069 (67.3%) Caucasian (CAU) and 519 (32.7%) Latin American (LAT) individuals, and 255 (16.1%) had GDM. The incidence of GDM was similar in both groups (16.1% CAU and 16.0% LAT). Genotyping was performed via IPLEX Mass ARRAY PCR, selecting 110 SNPs based on literature references. SNPs showing the strongest likelihood of developing GDM were rs10830963, rs7651090, and rs1371614 in CAU and rs1387153 and rs9368222 in LAT. Clinical variables, including age, pre-pregnancy body mass index, and fasting plasma glucose (FPG) at 12 gestational weeks, predicted the risk of GDM (AUC 0.648, 95% CI 0.601-0.695 in CAU; AUC 0.688, 95% CI 0.628-9.748 in LAT), and adding SNPs modestly improved prediction (AUC 0.722, 95%CI 0.680-0.764 in CAU; AUC 0.769, 95% CI 0.711-0.826 in LAT). In conclusion, adding genetic variants enhanced the prediction model of GDM risk in CAU and LAT pregnant women.

Genetics and epigenetics of gestational diabetes mellitus

Gestational diabetes mellitus (GDM) is one of the most common complications of pregnancy. Its prevalence is increasing every year with increasing obesity, sedentary lifestyle, poor or unhealthy diet and increasing age of pregnant women. GDM is known to be accompanied by multiple short- and long-term complications for both mother and child. Research in genetics and epigenetics has provided new insights into the pathophysiology of GDM, which provides an opportunity to develop new strategies to improve the diagnosis, prevention and treatment of GDM and its complications.This review describes the role of genetic and epigenetic factors on the risks of developing GDM and its complications. The review also discusses the similarities in the genetic changes underlying type 2 diabetes mellitus and GDM, indicating a multifactorial pathogenesis of GDM.

Investigation of serum isthmin 1 concentration in pregnant women diagnosed with gestational diabetes mellitus; a case-control study

Objective Isthmin 1 (ISM1) is an adipokine that improves hyperglycemia by increasing glucose uptake in a non-insulin-dependent manner. Studies have shown that ISM is associated with the development of type 2 diabetes mellitus. Based on this, we aimed to investigate serum ISM1 concentrations of pregnant women with gestational diabetes mellitus (GDM). Methods This case-control study was conducted with 80 pregnant women who applied to the Gynecology and Obstetrics Clinic of Umraniye Training and Research Hospital between April 2022 and November 2022. While 40 pregnant women diagnosed with GDM according to 75 g OGTT results formed the GDM group, 40 pregnant women with normal OGTT results formed the control group. The two groups were compared in terms of serum ISM1 concentrations. Results Both groups were similar in terms of demographic characteristics (p > 0.05). Fasting blood glucose levels, 1st-hour and 2nd-hour blood glucose levels in 75 g OGTT, fasting insulin levels, and HOMA-IR were significantly higher in the GDM group (p > 0.05, for each). Both groups were similar in terms of maternal waist circumference, periumbilical, and epigastric subcutaneous adipose tissue thickness (p > 0.05, for each). Both groups were similar in terms of the gestational week at blood sampling for ISM1 (p = 0.253). The median maternal serum ISM1 concentration was found to be 3243.94 pg/ml in the GDM group, while it was determined as 2785.29 pg/ml in the non-GDM group (p = 0.026). ROC analysis was performed to determine the value of maternal serum ISM1 concentration in predicting GDM. AUC analysis of maternal serum ISM1 for estimation of GDM was 0.645 (p = 0.026, 95% CI = 0.523 − 0.766). The optimal threshold value for maternal serum ISM1 concentration was determined as 3124.41 pg/ml with 62.5% sensitivity and 62.5% specificity. Conclusions Serum ISM1 concentrations were found to be higher in pregnant women with GDM than in healthy controls. Whether or how ISM1 participates in the pathophysiology of GDM remains to be investigated.

Association of Leptin with Glucose Intolerance and Gestational Diabetes Mellitus in Pregnant Women: Prospective Analytical Case-Control Study.

This study aimed to investigate the use of leptin as a marker for gestational diabetes by analyzing any correlation between serum leptin levels versus oral glucose tolerance tests (at 24 to 28weeks of pregnancy) and increased body weight (during pregnancy). A total of 110 female cases (81 pregnant and 29 non-pregnant) were included in the study. The 81 pregnant cases were divided into 3 groups according to their oral glucose tolerance test results. A chi-square test was used for categorical variables. The distribution of numerical variables was tested with the Shapiro-Wilk test. ANOVA and a post-hoc Bonferroni test was used for parametric data. Kruskal-Wallis variance analysis was used for non-parametric data. The Mann-Whitney U-test was used for pairwise comparisons. Spearman correlation analysis and multivariate regression analysis were performed for the evaluation of the correlation analysis between the parameters. Oral glucose tolerance test results were compared with leptin levels with a cut-off value of 11.43 for leptin. The ROC curve demonstrated an 83.3% sensitivity and 72.1% specificity for leptin. Leptin may play a role in the pathophysiology of gestational diabetes mellitus. However, the relationship between leptin levels and maternal weight gain during pregnancy is still unknown.

Increased Circulating IL-32 Is Associated With Placenta Macrophage-derived IL-32 and Gestational Diabetes Mellitus.

Placenta-derived inflammation plays a vital role in the pathophysiology of gestational diabetes mellitus (GDM). IL-32 is a novel pro-inflammatory cytokine and metabolic regulator involved in the development of metabolic disease. We investigated the effect of IL-32 in GDM. First-trimester C-reactive protein (CRP) level was monitored in a case-control study of 186 women with GDM and 186 women without. Placental tissue was lysed and analyzed by high-resolution liquid chromatography-tandem mass spectrometry. Circulating level of inflammatory cytokines IL-32, IL-6, and TNF-α were measured by ELISA kits. The expression of placenta-derived macrophages, inflammatory cytokines, and related pathway proteins were assessed by reverse transcriptase-quantitative PCR, western blot, immunohistochemistry, or immunofluorescence. First-trimester CRP level in peripheral blood was closely associated with glucose and insulin resistance index and was an independent correlation with the development of GDM. High-resolution liquid chromatography-tandem mass spectrometry revealed that placenta-derived CRP expression was dramatically elevated in women with GDM. Interestingly, the expression of placenta-derived IL-32 was also increased and located in the macrophages of placental tissue. Meanwhile, the expression of IL-6, TNF-α, and p-p38 were up-regulated in the placental tissues with GDM. Either IL-6 or TNF-α was colocated with IL-32 in the placental tissue. Importantly, circulating IL-32 throughout pregnancy was increased in GDM and was related to placental-derived IL-32 expression, circulating IL-6, and TNF-α, glucose and insulin resistance index. Increased circulating IL-32 throughout pregnancy was closely associated with placenta macrophage-derived IL-32 expression and GDM. First trimester IL-32 level in peripheral blood may serve to predict the development of GDM.

Placenta-derived exosomal miR-135a-5p promotes gestational diabetes mellitus pathogenesis by activating PI3K/AKT signalling pathway via SIRT1.

Most people are aware of gestational diabetes mellitus (GDM), a dangerous pregnancy complication in which pregnant women who have never been diagnosed with diabetes develop chronic hyperglycaemia. Exosomal microRNA (miRNA) dysregulation has been shown to be a key player in the pathophysiology of GDM. In this study, we looked into how placental exosomes and their miRNAs may contribute to GDM. When compared to exosomes from healthy pregnant women, it was discovered that miR-135a-5p was elevated in placenta-derived exosomes that were isolated from the maternal peripheral plasma of GDM women. Additionally, we discovered that miR-135a-5p encouraged HTR-8/SVneo cell growth, invasion and migration. Further research revealed that miR-135a-5p activates HTR-8/SVneo cells' proliferation, invasion and migration by promoting PI3K/AKT pathway activity via Sirtuin 1 (SIRT1). The transfer of exosomal miR-135a-5p generated from the placenta could be viewed as a promising agent for targeting genes and pertinent pathways involved in GDM, according to our findings.

Gestational diabetus mellitus and its complications, role of desynchronosis in pathogenesis (a review)

Diabetes mellitus is the most common metabolic disorder during pregnancy. The International Diabetes Federation estimates that one in six pregnant women (16.8 %) has diabetes. The prevalence of this disease in the human population is striking and, according to various sources, accounts for 14–25 % of all pregnant women. Most cases of hyperglycemia during pregnancy (75–90 %) is due to gestational diabetes mellitus (GDM). Risk factors, etiology and pathophysiology of GDM are being actively studied, but there are still some controversial issues. For example, the development of GDM in the aspect of circadian rhythm disorders. This problem is especially relevant in connection with pregnancy. After all, there is a two-way relationship here – circadian rhythm disorders affect the course of pregnancy, and pregnancy can be the cause of these disorders. In addition, this problem is relevant for women with a history of endocrine disorders, including diabetes mellitus, as there is a clear link between circadian rhythms and the production of hormones, including insulin. The aim of this review was to show the relationship between the development of GDM, its complications, and circadian rhythm disorders in women. Pregnancy complicated by GDM can have a negative effect on the myocardium and liver. Moreover, this disease has a significant impact on the myocardium of the offspring. GDM also can cause other complications for the mother’s health and fetus or newborn. Scientists have identified a fairly significant number of risk factors for GDM. However, circadian rhythm disorders accompanying pregnancy are often underestimated as a risk factor. In general, there are many controversies regarding the relationship between long / short sleep duration and quality and the risk of developing diabetes, as well as how melatonin and its precursor serotonin affect metabolism in critical organs. Thus, the role of circadian rhythm disorders in the development of diabetes and its consequences is not yet fully understood. It is likely that solving the problem of circadian rhythm disorders will be the key to overcoming a significant proportion of cases of GDM. Therefore, there is an urgent need for further, larger-scale studies to investigate the causal links between circadian rhythm disorders, diabetes mellitus, and pregnancy.

Regulatory mechanisms underlying endoplasmic reticulum stress involvement in the development of gestational diabetes mellitus entail the CHOP-PPARα–NF–κB pathway

ObjectiveWe investigated the proinflammatory functions of endoplasmic reticulum stress and peroxisome proliferator-activated receptor α (PPARα) in the development of gestational diabetes mellitus (GDM) and their relationship in regulating inflammation in GDM. MethodsThis study was performed on placentas of normal pregnant women, women with GDM, and HTR8 cells. Transmission electron microscopy, immunohistochemistry, Western blot analysis, and RT-PCR were performed to analyze ERS and PPARα expression on both normal and GDM pregnancy placentas. ELISA was performed to analyze inflammatory biomarkers. To generate models of the GDM-like state, placentas of normal pregnancy were treated with LPS and polyinosinic-polycytidylic acid (poly [I:C]). TG, CHOP plasmid, and CHOP siRNA were assessed as to their regulation of HTR8 cells to discern the relationship between ERS and PPARα in regulating the inflammation associated with GDM. ResultsERS was elevated in GDM placentas, induced the secretion of IL-6 and TNF-α, and attenuated the expression of GLUT-4. PPARα was diminished in GDM placentas and inhibited the inflammatory responses via the NF-κB nuclear-transport process. 4-PBA reduced CHOP and augmented PPARα, and it decreased IL-6 and TNF-α in our GDM-like explant. However, with both 4-PBA and MK886 treatment, we noted no significant difference in CHOP expression. The level of PPARα was reduced, and that of NF-κB p65 in the nucleus was elevated with TG treatment in the HTR8/Svneo. Knockdown of CHOP increased PPARα and reduced NF-κB p65, while expression of PPARα declined, and that of NF-κB p65 rose with the application of CHOP when HTR8 cells were treated with TG. ConclusionsERS contributes to the pathophysiology of GDM in pregnancy via the CHOP-PPARα–NF–κB-signalling pathway by inducing aberrant activation of inflammation and insulin resistance.

GCKR and ADIPOQ gene polymorphisms in women with gestational diabetes mellitus

AimsTo investigate the associations of GCKR and ADIPOQ variants with the risk of gestational diabetes mellitus (GDM) in Chinese women.MethodsGCKR rs1260326, ADIPOQ rs266729, and rs1501299 were selected and genotyped in 519 GDM patients and 498 controls. Candidate SNPs were genotyped using multiplex polymerase chain reaction (PCR) combined with next-generation sequencing methods, and the association of these SNPs with GDM was analyzed.ResultsWe found that GCKR rs1260326 was significantly associated with an increased risk of GDM in the allele model, the codominant model (CC vs. TT), the dominant model, the recessive model, and the genotypic model distributions (p = 0.0029, p = 0.0022, p = 0.0402, p = 0.0038, and p = 0.0028, respectively). The rs1260326 polymorphism was shown to be associated with 1 h-OGTT level and gravidity in GDM patients (CC vs. TT: p = 0.0475 and p = 0.0220, respectively). Diastolic blood pressure (DBP) was significantly higher in the GDM patients with the rs266729 GG genotype compared to those with the CC or CG genotype (p = 0.0444 and p = 0.0339, respectively). The DBP of the GDM patients with the rs1501299 GT genotype was lower than that of those with the GG genotype (p = 0.0197). There was a weak linkage disequilibrium value between the GCKR and ADIPOQ SNPs.ConclusionsThe genes GCKR and ADIPOQ may be involved in the pathophysiology of GDM.

Is maternal serum endocan level a novel marker in gestational diabetes mellitus?

To determine whether there was a significant difference between serum endocan levels of pregnant women with and without gestational diabetes mellitus (GDM). A total of 90 pregnant women, 45 with gestational diabetes and 45 healthy pregnant women, between 24 and 28 gestational weeks, were included in this prospective case-control study. The pregnant women were screened for gestational diabetes using a two-step protocol. Serum endocan levels were measured using a commercially available enzyme-linked immunosorbent assay (ELISA) kit. A p-value of <0.05 was considered statistically significant. Serum endocan level was significantly higher in the GDM group than in healthy controls (168.46 ± 160.6 vs. 105.66 ± 26.52 pg/mL, respectively; p < 0.001). Serum endocan concentrations were positively correlated with the results of 50 g oral glucose challenge test (GCT) (p < 0.001). Receiver operating characteristic curve analysis showed that endocan with a cut-off point of 133.9 ng/dL indicated women with GDM with a sensitivity of 55.6% and specificity of 88.9% (area under the curve [AUC]: 0.737, 95% CI: 0.634-0.824). The overall differential performance of endocan according to the GDM groups was determined as 73.7% (p < 0.001). Maternal serum endocan level was positively correlated with fasting glucose, postprandial glucose, and glycated hemoglobin (HbA1c) (p < 0.001). Elevated endocan levels in gestational diabetes were correlated with fasting glucose, postprandial glucose, HbA1c, and oral glucose tolerance test (OGTT) results. Despite the low sensitivity of 55.6% and the high specificity of 88.9%, we found a high differential performance rate indicating that serum endocan levels were important for the pathophysiology of GDM and should be investigated for the possibility of being a novel marker in larger populations.

Gut Microbiota and Critical Metabolites: Potential Target in Preventing Gestational Diabetes Mellitus?

Gestational diabetes mellitus (GDM) is an intractable issue that negatively impacts the quality of pregnancy. The incidence of GDM is on the rise, becoming a major health burden for both mothers and children. However, the specific etiology and pathophysiology of GDM remain unknown. Recently, the importance of gut microbiota and related metabolic molecules has gained prominence. Studies have indicated that women with GDM have significantly distinct gut microbiota and gut metabolites than healthy pregnant women. Given that the metabolic pathways of gut flora and related metabolites have a substantial impact on inflammation, insulin signaling, glucose, and lipid metabolism, and so on, gut microbiota or its metabolites, such as short-chain fatty acids, may play a significant role in both pathogenesis and progression of GDM. Whereas the role of intestinal flora during pregnancy is still in its infancy, this review aims to summarize the effects and mechanisms of gut microbiota and related metabolic molecules involved in GDM, thus providing potential intervention targets.

1175-P: The Alteration of Serum Level and Expression of c-MET in Gestational Diabetes Mellitus (GDM)

Objective: The aim of this study was to explore changes in serum levels and tissue expression of HGF and c-MET, and to determine how HGF/c-MET signaling contributes to the pathophysiology of GDM. Methods: A total of 44 pregnant women with normal glucose tolerance (NGT) and 32 pregnant women with GDM were studied. Blood samples were taken just before delivery, and placenta and visceral adipose tissue were taken immediately after cesarean delivery. Serum levels of HGF, soluble c-MET and insulin were measured by enzyme-linked immunosorbent assay (ELISA). The mRNA expression of HGF and c-MET was measured in the placenta and visceral adipose tissue. In addition, we investigated pregnancy of high fat diet (HFD) mice as an animal model of GDM. The glucose tolerance test (GTT) was performed at GD 10, and measured the serum levels of Hgf and soluble c-Met at GD 16. After scarifying mice, we measured the weight and expression of mRNA of Hgf and c-Met in WAT, placenta, liver and muscle. Results: Serum soluble c-MET levels were significantly higher in the GDM group (p &amp;lt;0.001). In multiple logistic regression analysis, soluble serum c-MET level was strongly associated with GDM (OR 9.063, p=0.027). There were more patients with increased mRNA expression of HGF and c-MET in placenta. Interestingly, the protein expression of HGF and c-MET in maternal visceral fat tissue was significantly higher in the GDM group. In mouse study, maternal serum levels of soluble c-Met in pregnant HFD (PH) mice were higher than in non-pregnant HFD (NPH) mice and pregnant chow diet (PC) mice. Relative mRNA expression of Hgf was significantly increased in eWAT of PH than PC mice. Relative c-Met mRNA expression was significantly increased in sWAT of PH than PC mice. Conclusion: We observed the differences in serum levels and expression of HGF and c-MET between GDM and control pregnant women in human and mice model. Our results suggest that HGF/c-MET signaling may be altered in GDM, which associated with insulin resistance and pathophysiology in GDM. Disclosure H.Kim: None. J.Lee: None. Y.Jung: None. M.Lee: None. J.Kim: None. K.Joung: None. B.Ku: Speaker's Bureau; AstraZeneca, Boehringer-Ingelheim, Eli Lilly and Company, Sanofi, Novo Nordisk, LG Chem. Funding National Research Foundation of Korea (2022R1F1A1074608)

Pharmaco-epi-genetic and patho-physiology of gestational diabetes mellitus (GDM): An overview

Pharmaco-epi-genetic and patho-physiology of gestational diabetes mellitus (GDM): An overview

Myeloid-derived suppressor cells: Are they involved in gestational diabetes mellitus?

Gestational diabetes mellitus (GDM) is currently the most common metabolic complication during pregnancy, with an increasing prevalence worldwide. Maternal immune dysregulation might be partly responsible for the pathophysiology of GDM. Myeloid derived suppressor cells (MDSCs) are a heterogeneous population of cells, emerging as a new immune regulator with potent immunosuppressive capacity. Although the fate and function of these cells were primarily described in pathological conditions such as cancer and infection, accumulating evidences have spotlighted their beneficial roles in homeostasis and physiological conditions. Recently, several studies have explored the roles of MDSCs in the diabetic microenvironment. However, the fate and function of these cells in GDM are still unknown. The current review summarized the existing knowledges about MDSCs and their potential roles in diabetes during pregnancy in an attempt to highlight our current understanding of GDM-related immune dysregulation and identify areas where further study is required.

Gestational Diabetes Is Characterized by Decreased Medium-Chain Acylcarnitines and Elevated Purine Degradation Metabolites across Pregnancy: A Case-Control Time-Course Analysis.

Gestational Diabetes Mellitus (GDM) results in complications affecting both mothers and their offspring. Metabolomic analysis across pregnancy provides an opportunity to better understand GDM pathophysiology. The objective was to conduct a metabolomics analysis of first and third trimester plasma samples to identify metabolic differences associated with GDM development. Forty pregnant women with overweight/obesity from a multisite clinical trial of a lifestyle intervention were included. Participants who developed GDM (n = 20; GDM group) were matched with those who did not develop GDM (n = 20; Non-GDM group). Plasma samples collected at the first (10-16 weeks) and third (28-35 weeks) trimesters were analyzed with ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). Cardiometabolic risk markers, dietary recalls, and physical activity metrics were also assessed. Four medium-chain acylcarnitines, lauroyl-, octanoyl-, decanoyl-, and decenoylcarnitine, significantly differed over the course of pregnancy in the GDM vs Non-GDM group in a group-by-time interaction (p < 0.05). Hypoxanthine and inosine monophosphate were elevated in the GDM group (p < 0.04). In both groups over time, bile acids and sorbitol increased while numerous acylcarnitines and α-hydroxybutyrate decreased (p < 0.05). Metabolites involved in fatty acid oxidation and purine degradation were altered across the first and third trimesters of GDM-affected pregnancies, providing insight into metabolites and metabolic pathways altered with GDM development.

Myeloperoxidase G-463A and CYBA C242T genetic variants in gestational diabetes mellitus.

Oxidative stress plays an important role in the pathophysiology of gestational diabetes mellitus (GDM). We investigated the relationship between NADPH oxidase p22phox subunit (CYBA) C242T (rs4673) and myeloperoxidase (MPO) G-463A (rs2333227) genetic variants and GDM in 719 patients with GDM and 1205 control women. Clinical, metabolic, and oxidative stress parameters were analyzed. We found that frequencies of the A allele (15.6% vs 12.3%) and GA + AA genotype (28.5% vs 23.2%) of the MPO G-463A variation were significantly higher in patients with GDM than in the control women (OR = 1.318, 95% CI: 1.068-1.625, P = 0.010 for the dominant model; OR = 1.999, 95% CI: 1.040-3.843, P = 0.034 for the recessive model; OR = 1.320, 95% CI: 1.095-1.591, P = 0.004 for the allele model). Genotype GA + AA remained a significant predictor of GDM in a logistic regression model including age and BMI at delivery (OR = 1.282, 95% CI: 1.037‒1.583, P = 0.021). Furthermore, the ‒463A allele was associated with higher TG and the 242T allele was related to higher pre-pregnancy BMI and oxidative stress index in all subjects (P < 0.05). The 242T allele was also associated with higher homeostatic model assessment of insulin resistance but lower serum total antioxidant capacity in patients with GDM (P < 0.05). We conclude that the MPO G-463A, but not the CYBA C242T, genetic variation is associated with an increased risk of GDM in Chinese women. These two genetic polymorphisms may be linked to obesity, dyslipidemia, insulin resistance, and oxidative stress.