Insulin Resistance In Gestational Diabetes Mellitus Research Articles

Excessive palmitic acid disturbs macrophage α-ketoglutarate/succinate metabolism and causes adipose tissue insulin resistance associated with gestational diabetes mellitus

Abnormal polarization of adipose tissue macrophages (ATMs) results in low-grade systemic inflammation and insulin resistance (IR), potentially contributing to the development of diabetes. However, the underlying mechanisms that regulate the polarization of ATMs associated with gestational diabetes mellitus (GDM) remain unclear. Thus, we aimed to determine the effects of abnormal fatty acids on macrophage polarization and development of insulin resistance in GDM. Levels of fatty acids and inflammation were assessed in the serum samples and adipose tissues of patients with GDM. An in vitro cell model treated with palmitic acid was established, and the mechanisms of palmitic acid in regulating macrophage polarization was clarified. The effects of excessive palmitic acid on the regulation of histone methylations and IR were also explored in the high-fat diet induced GDM mice model. We found that pregnancies with GDM were associated with increased levels of serum fatty acids, and inflammation and IR in adipose tissues. Increased palmitic acid could induce mitochondrial dysfunction and excessive ROS levels in macrophages, leading to abnormal cytoplasmic and nuclear metabolism of succinate and α-ketoglutarate (αKG). Specifically, a decreased nuclear αKG/succinate ratio could attenuate the enrichment of H3K27me3 at the promoters of pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, leading to cytokine secretion. Importantly, GDM mice treated with GSK-J4, an inhibitor of histone lysine demethylase, were protected from abnormal pro-inflammatory macrophage polarization and excessive production of pro-inflammatory cytokines. Our findings highlight the importance of the metabolism of αKG and succinate as transcriptional modulators in regulating the polarization of ATMs and the insulin sensitivity of adipose tissue, ensuring a normal pregnancy. This novel insight sheds new light on gestational fatty acid metabolism and epigenetic alterations associated with GDM.

First-Trimester Triglyceride-Glucose Index and Triglyceride/High-Density Lipoprotein Cholesterol are Predictors of Gestational Diabetes Mellitus Among the Four Surrogate Biomarkers of Insulin Resistance.

This study seeks to assess the potential of early pregnancy Triglyceride Glucose Index (TyG), triglyceride to High-Density Lipoprotein Cholesterol ratio (TG/HDL-c), Low-Density Lipoprotein Cholesterol to High-Density Lipoprotein Cholesterol ratio (LDL-C/HDL-C), and Total Cholesterol to High-Density Lipoprotein Cholesterol ratio (TC/HDL-C) in predicting Gestational Diabetes Mellitus (GDM). A total of 1073 adults singleton pregnant women were enrolled from June 2017 to September 2019. Complete anthropometric data and lipid profiles were measured in the first trimester (before 12 weeks gestation) and a 75g oral glucose tolerance test (OGTT) at 24-28 weeks was performed. Based on OGTT results, participants were categorised into Normal Glucose Tolerance (NGT) group (n=872) and GDM group (n=201). General data, laboratory test results, and surrogate insulin resistance indicators such as TyG index, TG/HDL-C, LDL-C/HDL-C, and TC/HDL-C were documented and compared. To compare differences between the two groups, t-test was used, Spearman correlation analysis and linear regression analysis were performed to establish associations between these indicators and insulin resistance in GDM. Receiver Operating Characteristic (ROC) curves were generated to compare the thresholds of these indicators for predicting GDM during pregnancy and to quantify overall diagnostic accuracy. Individuals with GDM had higher TyG, TG/HDL-C, and LDL-C/HDL-C levels (P < 0.001), but with no significant difference observed in TC/HDL-C. All four ratios were positively correlated with Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), yet only TyG emerged as an independent risk factor for HOMA-IR. The Area under the Curve (AUC) of TyG index (0.692) was comparable to that of HOMA-IR (0.703). The cut-off points for TyG index, TG/HDL-C, and HOMA-IR in predicting GDM were 7.088, 0.831, and 1.8, respectively. HOMA-IR exhibited the highest sensitivity (79.1%), while TyG index (64.3%) and TG/HDL-C ratio (64.3%) demonstrated better specificity compared to HOMA-IR (56.3%). LDL-C/HDL-C and TC/HDL-C offered no discernible predictive advantage. Early pregnancy TyG index and TG/HDL-C can aid in identifying pregnant women at risk for GDM, potentially facilitating early and effective intervention to improve prognosis. TyG index exhibited superior predictive capability compared to TG/HDL-C.

Correlation of Serum Th1/Th2 Cytokines with Insulin Resistance in Gestational Diabetes Mellitus

Objective: To investigate the correlation between serum Th1/Th2 cytokines and insulin resistance in gestational diabetes mellitus (GDM). Methods: A total of 50 cases of pregnant women diagnosed with GDM and 50 healthy pregnant women who visited the Affiliated Hospital of Hebei University from January 2019 to December 2022 were recruited and divided into the GDM group and control group. Serum Th1/Th2 cytokines were observed and analyzed. Results: In the GDM group, serum IFN-γ levels were significantly higher than in the control group (P &lt; 0.01), while there was no statistically significant difference in IL-4 levels (P &gt; 0.05). Within the GDM group, HOMA-IR showed a positive correlation with IFN-γ (r = 0.67, P &lt; 0.01) and no correlation with IL-4 (r = 0.19, P &gt; 0.05). Within the control group, HOMA-IR did not correlate with either IFN-γ or IL-4 (r = 0.23, P &gt; 0.05; r = 0.15, P &gt; 0.05). Conclusion: The study concludes that the serum Th1 cytokine IFN-γ is correlated with insulin resistance in GDM, providing a novel perspective on the pathogenesis of GDM. Future studies should further explore the mechanisms and interventions to offer improved treatment options for patients with GDM.

Low-Grade Inflammation in Gestational Diabetes Mellitus and Its Correlation with Maternal Insulin Resistance and Fetal Growth Indices.

Chronic low-grade inflammation (LGI) plays a role in the pathogenesis of gestational diabetes mellitus (GDM). LGI, on the one hand, promotes insulin resistance and at the same time, affects fetal development. The study aimed to use clinically feasible means to evaluate the association between maternal LGI and maternal insulin resistance and fetal growth indices by ultrasound in the third trimester. A crossectional and descriptive study on 248 first-time diagnosed GDM in Vietnam. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte (PLR) indices were significantly higher in GDM than in normal glucose-tolerant pregnancies (p = 0.048 and 0.016, respectively). GDM with LGI witnessed significantly higher systolic blood pressure, BMI, HbA1c, and significantly lower quantitative Insulin Sensitivity Check Index (QUICKI) than those without LGI. After adjusting for maternal BMI, fasting plasma glucose (FPG), age, and parity, C-reactive protein (CRP) was positively correlated with HOMA2-IR (B=0.13, p<0.01) and Mathews index (B=0.29, p<0.01). Regarding fetal characteristics, LGI was associated with fetal growth indices in the third trimester of GDM. NLR was negatively correlated with estimated fetal weight (EFW) (B=-64.4, p<0.05) after adjusting for maternal BMI and FPG. After adjusting for maternal BMI, FPG, age, and parity, PLR was negatively correlated with biparietal diameter (B=-0.02, p<0.01) and abdominal circumference (AC) (B=-0.16, p<0.05), and EFW (B=-1.1, p<0.01), and head circumference (HC) (B=-0.06, p<0.01); CRP was negatively correlated with AC (B=-0.16, p<0.001), EFW (B=-85.3, p<0.001), and HC (B=-5.0, p<0.001). In the third trimester, LGI was associated with maternal glucose and insulin resistance in GDM. Moreover, LGI was associated with fetal characteristics in ultrasonic images. There were negative correlations between LGI and fetal developmental characteristics.

β-Carotene regulates glucose transport and insulin resistance in gestational diabetes mellitus by increasing the expression of SHBG.

The aim of this work was to study the effect and mechanism of β-carotene on insulin resistance and glucose transport in gestational diabetes mellitus (GDM). Placental tissue and venous blood of 26 GDM patients and 18 normal women were collected. Mice fed a high-fat diet were established as GDM models and treated with β-carotene, from which peripheral blood and placenta tissue were collected. HTR-8/SVneo cells were treated with 10-7 mol/L insulin for 48 h and established as insulin resistance cell models. The expression of SHBG, GLUT1, GLUT3, GLUT4, IRS-1, IRS-2, PI3Kp85α, and p-CREB/CREB in placental tissues and HTR-8/SVneo cells was detected. Insulin resistance index was calculated from the values of fasting blood glucose and fasting insulin. The glucose consumption of insulin-resistant cells was calculated by detecting the glucose content of the supernatant. The cyclic adenosine monophosphate (cAMP) kit was applied to measure the concentration of cAMP in cells. SHBG was lowly expressed in GDM. β-Carotene treatment upregulated SHBG in the placenta of GDM mice and in insulin-resistant HTR-8/SVneo cells. Overexpression of SHBG upregulated GLUT3, GLUT4, and IRS-1 and enhanced glucose consumption in insulin-resistant cells. β-Carotene treatment promoted the expression of SHBG, GLUT4 and IRS-1 and increased glucose consumption in insulin-resistant cells underexpressing SHBG. Silencing of SHBG decreased the levels of cAMP and pCREB/CREB but β-carotene treatment increased their expression despite SHBG silencing in insulin-resistant cells. β-Carotene promotes glucose transport and inhibits insulin resistance in GDM by increasing the expression of SHBG.

Role of Insulin Resistance in Gestational Diabetes Mellitus: A Literature Review

Several physiologic, hormonal, and molecular processes contribute to the emergence of hyperglycaemia during pregnancy. Increased insulin resistance is seen during the course of a healthy pregnancy. During the early stages of normal pregnancies, the pancreatic β-cells secrete more insulin, which slows the rise in plasma glucose levels. This regulation explains the abnormally modest increases in plasma glucose levels brought on by elevated insulin resistance. The aim of this review was to evaluate the role of insulin resistance in gestational diabetes mellitus (GDM). The authors extensively searched various electronic databases like PubMed, Scopus, and Google Scholar for the collection of material regarding the role of insulin resistance in GDM. It was seen that hyperglycaemia results from the combination of the pregnancy’s increased insulin tolerance and pancreatic beta-cell insufficiency. Scientific studies have revealed that individuals who present with GDM are more likely to acquire chronic insulin resistance because of the superimposition of lower insulin production by the cells in that condition (GDM). Due to their significance in the development of postpartum diabetes mellitus, inflammation markers in GDM have been widely researched. Inflammation during GDM induces adaptive reactions in the placenta, which can have a substantial effect on the programming of foetal development.

Association of Plasma Fibrinogen and Insulin Resistance in Women with Gestational Diabetes Mellitus

Gestational diabetes mellitus (GDM) is thought to be developed as a consequence of high insulin resistance (IR). It has been proposed that IR may involve in the pathogenesis of hyperfibrinogenemia in GDM. This study was aimed to evaluate the plasma fibrinogen levels and its association with insulin resistance in GDM. This cross sectional study was performed with 44 GDM women and 44 pregnant women with normal glucose tolerance (NGT) at or after 24 weeks of their gestation. Glucose was measured by glucose oxidase method, fasting insulin was measured by chemiluminescent immunoassay and plasma fibrinogen was measured by STA-fibrinogen kit with an automated coagulation analyzer. GDM women had significantly increased age and higher BMI than pregnant women with NGT (p=0.008). Plasma fibrinogen level was significantly higher in GDM (p<0.001). Fasting insulin level and Homeostasis Model Assessment of Insulin Resistance [HOMA-IR] were also significantly higher in GDM (p<0.001). Fibrinogen showed positive correlation with fasting insulin level (r=0.470, p<0.001) as well as with HOMA-IR (r=0.470, p<0.001) in GDM. Using HOMA-IR at cut-off value 2.89, it was observed that a significant number of GDM women had higher HOMA-IR values than pregnant women with NGT (p=0.002) and GDM women with HOMA-IR values ≥2.89 had significantly higher fibrinogen values (p=0.002). Gestational diabetes mellitus is associated with higher plasma fibrinogen level and increased insulin resistance, indicating a state of hypercoagulability than that of pregnant women with normal glucose tolerance. There is a clear association between hyperfibrinogenemia and insulin resistance.

A cross-sectional study on the association of single nucleotide polymorphism of leptin receptor (Gln223Arg) and insulin resistance in gestational diabetes mellitus

BackgroundThe role of genetics in pathophysiology of gestational diabetes mellitus (GDM) is least explored. Objective of the study is to find the association of leptin receptor (LEPR) gene polymorphism with GDM and its role in altered leptin levels, insulin resistance, and dyslipidemia in GDM. MethodsHundred GDM patients and an equal number of BMI and gestational age matched normal glucose tolerant pregnant women were recruited as cases and controls. Five milliliters of venous blood was drawn for biochemical and genetic analysis. Genotyping of LEPR (Gln223Arg) was performed by PCR-RFLP. Fasting blood sugar, leptin, insulin, C-peptide, and lipid profile estimations were done. Various insulin resistance models were constructed using suitable formulae. The statistical analysis was performed using SPSS 23.0 software. ResultsThere was no significant association found between LEPR gene polymorphism with leptin levels and insulin resistance in GDM. However, Odd’s ratio showed that individuals with the “A” allele were at 1.25 times higher risk of developing GDM. HOMA B-cell significantly varied among LEPR genotypes (p < 0.0001), values being double in AA genotype, compared to AG (p < 0.05), ten times higher in AA compared to GG (p < 0.0001). There was no significant deviation of the genotype frequency distributions for rs1137101 variants from HWE in GDM cases, suggesting that alleles were in equilibrium. ConclusionThe study established a cycle of gene polymorphism altering leptin levels which in turn can alter insulin secretion and insulin resistance, contributing to dyslipidemia of pregnancy as well as gestational diabetes.

LncRNA RPL13p5 gene expression promotes insulin resistance in patients with gestational diabetes.

Gestational diabetes mellitus (GDM) is a universal disease caused by a combination of environmental and genetic factors and resulting in abnormal signaling pathway function and eventual islet cell insufficiency. According to co-expression profile network data between messenger RNA (mRNA)-long non-coding RNA (lncRNA) in our laboratory, we selected lncRNA RPL13P5 as a candidate lncRNA related to the GDM insulin signaling pathway and which is upregulated in GDM patients. The study included a gestational diabetes group (n=25) and normal pregnancy group (n=19). Expression was detected by quantitative polymerase chain reaction (qPCR) and showed the expression levels of lncRNA RPL13P5 in peripheral blood were significantly different between the two groups (P<0.05). The correlation between the homeostasis model assessment insulin resistance (HOMA-IR) and lncRNA expression was analyzed. The lncRNA RPL13p5 forms a co-expression strand with the TSC2 gene via the PI3K-Akt signaling pathway. The sequencing of lncRNA RPL13P5 showed high expression and the qPCR validation results were consistent with the sequencing results. An association was observed between the expression level of lncRNA RPL13P5 and other clinicopathological features of GDM. LncRNA RPL13P5 forms a co-expression chain with the TSC2 gene through the PI3K-Akt signaling pathway and becomes part of the process of insulin resistance in GDM.

Aberrantly Expressed Non-Coding RNAs in the Placenta and Their Role in the Pathophysiology of Gestational Diabetes Mellitus.

Gestational diabetes mellitus (GDM), one of the most common complications during pregnancy, is associated with a high risk of short- and long-term adverse effects on the mother and offspring. Placenta-derived hormones and cytokines aggravate maternal insulin resistance (IR) during pregnancy, which in turn contribute to GDM. The hyperglycemia and IR in GDM result in aberrant placental structure and function adversely affecting fetal growth and well-being. Therefore, it is reasonable to assume that structural and functional alterations in the placenta contribute to the pathogenesis of GDM and GDM-related complications. Increasing evidence suggests that multiple non-coding RNAs (ncRNAs), including microRNAs, long non-coding RNAs, and circular RNAs, are dysregulated in placentas of patients with GDM and linked to abnormal placental structure, metabolism, and function. Manipulation of ncRNA expression led to some key pathophysiological features of GDM, such as trophoblast dysfunction, changes in intracellular glucose metabolism, and inflammation. Moreover, placenta-specific ncRNAs may be potential diagnostic biomarkers and even therapeutic targets for GDM. This review summarizes data published on the involvement of aberrantly expressed placental ncRNAs in GDM and provides information on their role in the pathogenesis of GDM and GDM-associated complications.

948-P: Serum Elabela Is Associated with Inflammatory Abnormalities in Gestational Diabetes Mellitus

Gestational diabetes mellitus (GDM) is a common disease in pregnant women, which mechanisms remain unclear. Apelin-APJ system contributes to the energy homeostasis in middle and terminal pregnancy. Elabela (ELA) is another endogenous ligand of apelin receptor (APJ), which is expressed highly in the placenta. Few studies have focused on the role of ELA in GDM and the association between ELA and inflammatory cytokines. In this study we mainly compare the concentrations of serum Elabela between 33 diabetes pregnant women (GDM group) with 33 healthy pregnant women (control group). The inflammatory biomarkers including IL-1β, IL-6 and TNF-α were measured and evaluated the relationship with ELA. There were significant differences in serum Elabela (P&amp;lt;0.05), fasting plasma glucose (FPG), one-hour glucose, two-hour glucose in the OGTT (P&amp;lt;0.001), HOMA-IR (P&amp;lt;0.001), cytokine IL-1β(P&amp;lt;0.05) between GDM group and control group. ELA had significant correlations with FPG (r=-0.254, P=0.039), fasting insulin (r=-0.258, P=0.036), HOMA-IR (r=-0.275, P=0.026), and IL-1β (r=-0.789, P=0.000). And stepwise multiple linear regression analysis presented IL-1β and FPG most significantly affected the ELA levels. This study showed that decreased ELA levels were significantly associated with increased glucose levels and insulin resistance in GDM, which might be mediated by inflammatory factors, such as IL-1β. Serum ELA levels might be a clinical biomarker for GDM. Disclosure Y. Chen: None. M. Shi: None. H. Zhang: None. Funding National Natural Science Foundation of China (81200595, 81400807)

Oestrogen receptor α in T cells controls the T cell immune profile and glucose metabolism in mouse models of gestational diabetes mellitus.

The imbalance between maternal insulin resistance and a relative lack of insulin secretion underlies the pathogenesis of gestational diabetes mellitus (GDM). Alterations in T cell subtypes and increased levels of circulating proinflammatory cytokines have been proposed as potential mechanisms underlying the pathophysiology of insulin resistance in GDM. Since oestrogen modulates T cell immunity, we hypothesised that oestrogen plays a homeostatic role in visceral adipose tissue by coordinating T cell immunity through oestrogen receptor α (ERα) in T cells to prevent GDM. Female CD4-cre ERαfl/fl (KO) mice on a C57BL/6 background with ERα ablation specifically in T cells, and ERαfl/fl (ERα-floxed [FL]) mice were fed 60kJ% high-fat diet (HFD) for 4weeks. Female mice mated with male BALB/c mice to achieve allogenic pregnancy and were maintained on an HFD to generate the GDM model. Mice were divided into four experimental groups: non-pregnant FL, non-pregnant KO, pregnant FL (FL-GDM) and pregnant KO (KO-GDM). GTTs and ITTs were performed on day 12.5 or 13.5 and 16.5 after breeding, respectively. On day 18.5 after breeding, mice were killed and T cell subsets in the gonadal white adipose tissue (gWAT) and spleen were analysed using flow cytometry. Histological examination was also conducted and proinflammatory gene expression in gWAT and the liver was evaluated. KO mice that mated with BALB/c mice showed normal fertility rates and fetal weights as compared with FL mice. Body and tissue weights were similar between FL and KO mice. When compared with FL-GDM mice, KO-GDM mice showed decreased insulin secretion (serum insulin concentration 15min after glucose loading: 137.3 ± 18.3pmol/l and 40.1 ± 36.5pmol/l, respectively; p < 0.05), impaired glucose tolerance (glucose AUC in GTT: 2308.3 ± 54.0mmol/l × min and 2620.9 ± 122.1mmol/l × min, respectively; p < 0.05) and increased numbers of T helper (Th)17 cells in gWAT (0.4± 0.0% vs 0.8± 0.1%; p < 0.05). However, the contents of Th1 and regulatory T cells (Tregs) in gWAT remained similar between FL-GDM and KO-GDM. Glucose-stimulated insulin secretion was similar between isolated islets derived from FL and KO mice, but was reduced by IL-17A treatment. Moreover, the levels of proinflammatory gene expression, including expression of Emr1 and Tnfa in gWAT, were significantly higher in KO-GDM mice than in FL-GDM mice (5.1-fold and 2.7-fold, respectively; p < 0.01 for both). Furthermore, KO-GDM mice showed increased expression of genes encoding hepatokines, Ahsg and Fgf21 (both were 2.4-fold higher vs FL-GDM mice; p < 0.05 and p = 0.09, respectively), with no changes in inflammatory gene expression (e.g., Tnfa and Ifng) in the liver compared with FL-GDM mice. Deletion of ERα in T cells caused impaired maternal adaptation of insulin secretion, changes in hepatokine profiles, and enhanced chronic inflammation in gWAT alongside an abnormal increase in Th17 cells. These results suggest that the ERα-mediated oestrogen signalling effects in T cells regulate T cell immunity and contribute to glucose homeostasis in pregnancy.

Improving of Metabolic Profile With Vitamin D Supplements in Pregnant Women

Background. Serum 25-hydroxy-vitamin D deficiency is related to metabolic diseases as polycystic ovary syndrome, obesity, insulin resistance, cardiovascular diseases, cancer, gestational diabetes mellitus (GDM). Objective: To evaluate the effect of vitamin D therapy on metabolic parameters in pregnant women. Methods: There was a 16-week study of 62 participants with gestational diabetes mellitus. All pregnant women followed an appropriate diet and physical activity. Management of 37 women included 2,000 IU/day of cholecalciferol per os. Body mass index (BMI), hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), plasma 25- (OH) vitamin D, low‐density lipoprotein cholesterol (LDL‐C), homeostatic model assessment of insulin resistance (HOMA-ir) were estimated in pregnant women with GDM before and after the 16-week period. Quantitative data are expressed as the mean ± SD. The correlation between variables was assessed using the Pearson correlation coefficient. P-value <0.05 was considered statistically significant. All information was processed with SPSS 21.0. Results: The mean BMI was (30,2±2,34) kg/m2, baseline serum 25-(OH) vitamin D levels in all women were in a deficient limit (less than 30 nmol/L). HOMA in both groups was more than 3. The mean LDL‐C was (3,3±0,63) mmol/l and didn`t differ in the two groups. 25-(OH) vitamin D levels were inversely associated with BMI (r=–0.4; P=0.05), HOMA (r=–0.6; P=0.005), LDL‐C (r=–0.3; P=0.04). Vitamin D therapy has had significant improvement in plasma LDL‐C concentration, HbA1c, FPG in women with GDM (P<0.05). Compared with the Ist group cholecalciferol therapy had lead to a reduction of HOMA in the IInd group by (2,3±0,94) in 4 months (P < 0.05). Conclusions. The daily intake of vitamin D was accompanied by the significant glycemic improvement and the majority of women achieved diabetes control without insulin injections. Strong inverse correlation between 25 (OH) vitamin D levels and HOMA, reduction of HOMA can indicate improved sensitivity to insulin and benefits of vitamin D supplementation for the management of insulin resistance in GDM with vitamin D insufficiency.

CTRP-1 levels are related to insulin resistance in pregnancy and gestational diabetes mellitus

Recent studies have shown higher levels of CTRP-1 (C1QTNF-related protein) in patients with type 2 diabetes compared to controls. We aimed at investigating CTRP-1 in gestational diabetes mellitus (GDM). CTRP-1 levels were investigated in 167 women (93 with normal glucose tolerance (NGT), 74 GDM) of a high-risk population for GDM. GDM was further divided into GDM subtypes depending on a predominant insulin sensitivity issue (GDM-IR) or secretion deficit (GDM-IS). Glucose tolerance was assessed with indices [Matsuda index, Stumvoll first phase index, insulin-secretion-sensitivity-index 2 (ISSI-2), area-under-the-curve (AUC) insulin, AUC glucose] derived from an oral glucose tolerance test (oGTT) performed at < 21 and 24–28 weeks of gestation. In pregnancy, CTRP-1 levels of GDM (76.86 ± 37.81 ng/ml) and NGT (82.2 ± 35.34 ng/ml; p = 0.104) were similar. However, GDM-IR women (65.18 ± 42.18 ng/ml) had significantly lower CTRP-1 levels compared to GDM-IS (85.10 ± 28.14 ng/ml; p = 0.009) and NGT (p = 0.006). CTRP-1 levels correlated negatively with weight, AUC insulin, Stumvoll first phase index, bioavailable estradiol and positively with HbA1c, Matsuda Index and ISSI-2. A multiple regression analysis revealed bioavailable estradiol (β = − 0.280, p = 0.008) and HbA1c (β = 0.238; p = 0.018) as the main variables associated with CTRP-1 in GDM. Postpartum, waist and hip measurements were predictive of CRTP-1 levels instead. CTRP-1 levels were higher postpartum than during pregnancy (91.92 ± 47.27 vs.82.44 ± 38.99 ng/ml; p = 0.013). CTRP-1 is related to insulin resistance in pregnancy and might be a metabolic biomarker for insulin resistance in GDM. CTRP-1 levels were significantly lower during pregnancy than postpartum, probably due to rising insulin resistance during pregnancy.

Association between retinol-binding protein 4 concentrations and gestational diabetes mellitus (A1GDM and A2GDM) in different pregnancy and postpartum periods.

Gestational diabetes mellitus (GDM) can cause severe adverse effects on fetal and neonatal outcomes. The following study investigates the relationship between retinol-binding protein 4 (RBP4) and GDM in pregnant women with different grades (A1 and A2) and different gestational weeks. In this retrospective study, 194 GDM patients (GDM group) and 67 normal glucose tolerance pregnant women (control group) were enrolled from 2014 to 2017. Elbow venous blood samples were collected from all subjects. Enzyme electrode method and enzyme linked immunosorbent assay (ELISA) were used for fasting plasma glucose (FPG) and RBP4/insulin levels (FINS) analysis, respectively. At middle pregnancy and late stage, FINS, insulin resistance index (HOMA-IR) and RBP4 were all significantly higher in the GDM group compared to control group (P<0.05). Higher HOMA-IR and RBP4 levels, and lower levels of FPG were observed at late stage than those middle pregnancy in the GDM group (P<0.05). Moreover, FINS and RBP4 gradually decreased from middle pregnancy and late stage after delivery in the GDM group. Levels of FINS and RBP4 in postpartum GDM group were higher than those in normal control group (P<0.05). The optimal cut-off value of RBP4 at middle pregnancy diagnostic GDM was 34.84 µg/mL with sensitivity of 79.4% and specificity of 79.1%. The OGTT0h, 2h in A2GDM group was higher than that in A1GDM group, but there was no difference in OGTT1h, age and FINS, RBP4 in both A1GDM and A2GDM group. RBP4 is closely related to GDM, and its levels increases with the increase of gestational weeks, which may reflect the development of insulin resistance in GDM. RBP4 suggests that the impaired insulin function of GDM in pregnant women is still difficult to recover in the short term after delivery. Compared with OGTT1h, the increase in OGTT0h and 2h levels during middle pregnancy is more helpful for predicting the risk of developing A2GDM at late stage.

Endogenous SHBG levels correlate with that of glucose transporters in insulin resistance model cells.

Gestational diabetes mellitus (GDM) is defined as glucose intolerance of any degree that occurs after onset of pregnancy. Sex hormone binding globulin (SHBG) plays an important regulatory role in insulin resistance and is a risk factor in GDM. In the current study, we aimed to examine whether SHBG can regulate glucose metabolism through glucose transporters (GLUTs). SHBG was transfected into established human insulin model cells and the expression of SHBG, GLUT1, GLUT3, and GLUT4 was detected and analyzed in normal cells, model cells, and all groups of transfected cells by real-time PCR and western blotting. Further, immunofluorescence staining was performed on cells from each group to observe protein expression. In insulin resistance model cells, the expression of SHBG was low, whereas that of GLUT1 was high and of GLUT3 and GLUT4 was low, when compared with expression in control cells. Moreover, the overexpression of SHBG inhibited the expression of GLUT1 mRNA and protein, and promoted the expression of GLUT3 and GLUT4. Our results indicate that SHBG could be involved in glucose metabolism through its regulation of multiple GLUTs. Transfection of SHBG into insulin-resistant cells may partially improve the level of GLUTs, providing a potential therapeutic approach for the treatment of insulin resistance in GDM. Although SHBG can regulate glucose metabolism through GLUTs and thus cause insulin resistance and induce gestational diabetes, the regulation mechanism of GLUTs mediated by SHBG has not been elucidated, which will be the focus of further studies.

Gestational Diabetes Mellitus a Dysfunctional Metabolic State-A Perspective

Pregnancy is considered as a test for beta cell reserve. If there is a good function, insulin resistance will overcome. If not, gestational diabetes will occur. Insulin resistance (IR) present in normal pregnancy is required to provide nutrients to the growing fetus. There is a rapid increase of insulin in such an insulin resistant state. The possibility of lipid deposition in muscle fibers (intramyocellular) could be one of the possible mechanism of IR in gestational diabetes mellitus (GDM). The poor response of insulin release, possible fat deposition in the skeletal muscle or ectopic fat deposition may cause dysfunctional homeostasis in GDM. This will definitely influence the fine tuning of metabolic machinery of a growing fetus. Children born with such subtle metabolic state will probably be more prone to glucose intolerance and ectopic lipid deposition. The finding that children born to GDM mothers are prone to glucose intolerance may be an eye-opener to monitor such children for beta cell function.

Quantitative Proteomics by SWATH-MS Suggest an Association Between Circulating Exosomes and Maternal Metabolic Changes in Gestational Diabetes Mellitus.

Several factors including placental hormones (PH) released from the human placenta have been associated with the development of insulin resistance and gestational diabetes mellitus (GDM). However, circulating levels of PH does not correlate well with maternal insulin sensitivity across gestation, suggesting that other, previously unrecognized, mechanisms may be involved. The levels of circulating exosomes are higher in GDM compared to normal. GDM derived exosomes produce greater release of pro-inflammatory cytokines from endothelial cells compared to exosomes from normal, suggesting that their contents may differ compared to normal pregnancies. Using a quantitative, information-independent acquisition (Sequential Windowed Acquisition of All Theoretical Mass Spectra [SWATH]) approach, differentially abundant circulating exosome proteins are identified in women with normal glucose tolerance (NGT) and GDM at the time of GDM diagnosis. A total of 78 statistically significant proteins in the relative expression of exosomal proteins in GDM are compared with NGT. Bioinformatic analysis shows that the exosomal proteins in GDM target pathways are mainly associated with energy production, inflammation, and metabolism. Finally, an independent cohort of patients is used to validate some of the proteins identified by SWATH. The data obtained may be of utility in elucidating the underlying physiological mechanisms associated with insulin resistance in GDM.

Activation of Browning Adipose Tissues by Placental Growth Factor

Background: Gestational diabetes mellitus (GDM) is a type of metabolic disorders. Browning adipose tissue (BAT) activity is reduced which strengthens insulin resistance in GDM. Placenta growth factor (PlGF) is one of the main factors produced by placenta during pregnancy. Once secreted into circulation, it participates in angiogenesis in peripheral tissues. However, whether and how PlGF modulates BAT function is yet unknown. Methods: We recruited 91 nondiabetic pregnant participants and 73 GDM patients. Serum levels of PlGF were quantified by ELISA. Skin temperature was measured by Far infrared thermography in the supraclavicular region where classical BAT was located. Primary human preadipocytes isolated from intercapsular BAT were differentiated under different concentrations of PlGF in vitro. Terminally differentiated adipocytes were characterized by qPCR, western blot and oxygen consumption rates by respirometry. Phosphorylation signaling pathways in differentiated cells were dissected using Bio-Plex target assay (Bio-Rad). Cells were exposed with 1 ng PlGF in the presence or absence of 1 nM AMPK inhibitor Compound C to assess UCP-1 expression. Results: Serum levels of PlGF were lower in GDM patients than non GDM controls, which was accompanied by decreased skin temperature in the supraclavicular region. By qPCR, PlGF dose-dependently induced BAT marker expression in differentiated brown adipocytes (BAC) and peaked at 1 ng as evidenced by the increased mRNA expression of UCP-1 and Oxphos. The increased BAT marker expression was further confirmed by western blot in differentiated BAC exposed to 1 ng PlGF. Accordingly, PlGF-exposed BAC showed higher oxygen consumption rates than control and stimulated AMPK phosphorylation. Blockade of AMPK phosphorylation abrogated UCP-1 and Oxphos expression in BAC induced by PlGF. Conclusions: Physically, PlGF improves preadipocyte differentiation into active BAC. Decreased PlGF levels might contribute to the reduced BAC activity in GDM. Disclosure R. Yin: None. J. Zhou: None. C. Zhang: None. C. Yan: None. W. Ma: None. N. Wu: None. D. Zhao: None. Y. Feng: None.

The relationship between gestational diabetes mellitus and selenoprotein-P plasma 1 (SEPP1) gene polymorphisms

Our aim is to demonstrate any correlation between gestational diabetes mellitus (GDM) and polymorphism of the selenoprotein P (SEPP1) gene encoding the SEPP1 protein, having a role in the insulin resistance in GDM. Forty pregnant women with GDM and 40 healthy pregnant women were included in the study. In both groups, single nucleotide polymorphisms (SNPs), specifically, rs4987017, rs13154178, rs146125471, rs28919926, and rs16872762 were studied. There was no difference between the groups in terms of polymorphism rs146125471, rs28919926, or rs16872762 (p > .05). There was a significant difference in SNP rs13154178 polymorphism between the two groups (p < .01). When rs13154178 gene polymorphism was compared with AA homozygous individuals, fasting blood glucose levels were significantly higher in carriers of either polymorphism than in those with no polymorphism (p < .001). We suggest rs13154178 gene polymorphism may lead to GDM in the Turkish society.