Maternal Glucose Concentrations Research Articles

Maternal glucose homeostasis during pregnancy in women with overweight or obesity and offspring metabolic health

Gestational diabetes mellitus (GDM) adversely affects offspring glucose homeostasis and risk of developing obesity. Here, we examined the association between glycemia in pregnant women with overweight or obesity without GDM and offspring metabolic health. Maternal fasting glucose concentrations and glucose 2-h after an oral glucose tolerance test (OGTT) were measured in 208 women with a pre-pregnancy body mass index (BMI) of 28–45 kg/m2 without GDM. Offspring outcomes were collected at birth, 3, and 5 years of age. Linear mixed models with time as fixed factor and subject ID as random effects were used for analysis. No associations were found between maternal fasting or 2-h glucose concentrations with offspring glucose and insulin concentrations from birth to 5 years of age. However, maternal fasting glucose in GW 28 and 36, and 2-h OGTT glucose in GW 28 were positively associated with C-peptide concentration at birth. Maternal fasting glucose concentrations in GW 28 and 36 were positively associated with weight-for-length, and maternal fasting glucose in GW 36 was associated with BMI z-score at birth. In summary, blood glucose in pregnant women with overweight or obesity is positively associated with offspring C-peptide concentration, weight-for-length, and BMI z-score at birth, even in the absence of GDM.

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

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). 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. 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. 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.

Triglyceride-glucose index: A promising biomarker for predicting risks of adverse pregnancy outcomes in Hangzhou, China

IntroductionThe triglyceride-glucose (TyG) index has been recommended as an alternative indicator of insulin resistance (IR). However, the association between the TyG index and adverse pregnancy outcomes remains to be elucidated. MethodsThe present retrospective study was conducted at Women's Hospital, Zhejiang University School of Medicine and involved a total of 8,514 participants. Maternal fasting lipid profiles and glucose concentrations were measured. Based on the TyG index, the participants were categorized into quartiles. Logistic regression analysis was used to calculate odds ratios (ORs) for each quartile with reference to the first quartile, while receiver operating characteristic (ROC) curve analysis, Hosmer–Lemeshow test, and calibration curve analysis were employed to evaluate the predictive ability of the TyG index for adverse pregnancy outcomes. ResultsThe TyG index was higher in patients with preeclampsia, preterm birth, and macrosomia. On univariate analysis, there was an increased risk of developing adverse pregnancy outcomes with increasing quartiles of the TyG. After adjusting for potential confounders in multivariable logistic regression analysis, a positive independent correlation was found between the TyG index and preeclampsia, preterm birth, and macrosomia. In ROC curve analysis for predicting the risks of preeclampsia, preterm birth, and macrosomia, the area under the curve (AUC) could reach 0.665, 0.588, and 0.606, respectively. These predictive models demonstrated good calibration (all P > 0.05). ConclusionsThe TyG index showed a good predictive capacity for assessing the risk of adverse pregnancy outcomes, and it should receive sufficient clinical attention.

Increasing maternal glucose concentrations is insufficient to restore placental glucose transfer in chorionic somatomammotropin RNA interference pregnancies.

We previously demonstrated impaired placental nutrient transfer in chorionic somatomammotropin (CSH) RNA interference (RNAi) pregnancies, with glucose transfer being the most impacted. Thus, we hypothesized that despite experimentally elevating maternal glucose, diminished umbilical glucose uptake would persist in CSH RNAi pregnancies, demonstrating the necessity of CSH for adequate placental glucose transfer. Trophectoderm of sheep blastocysts (9 days of gestational age; dGA) were infected with a lentivirus expressing either nontargeting control (CON RNAi; n = 5) or CSH-specific shRNA (CSH RNAi; n = 7) before transfer into recipient sheep. At 126 dGA, pregnancies were fitted with vascular catheters and underwent steady-state metabolic studies (3H2O transplacental diffusion) at 137 ± 0 dGA, before and during a maternal hyperglycemic clamp. Umbilical glucose and oxygen uptakes, as well as insulin and IGF1 concentrations, were impaired (P ≤ 0.01) in CSH RNAi fetuses and were not rescued by elevated maternal glucose. This is partially due to impaired uterine and umbilical blood flow (P ≤ 0.01). However, uteroplacental oxygen utilization was greater (P ≤ 0.05) during the maternal hyperglycemic clamp, consistent with greater placental oxidation of substrates. The relationship between umbilical glucose uptake and the maternal-fetal glucose gradient was analyzed, and while the slope (CON RNAi, Y = 29.54X +74.15; CSH RNAi, Y = 19.05X + 52.40) was not different, the y-intercepts and elevation were (P = 0.003), indicating reduced maximal glucose transport during maternal hyperglycemia. Together, these data suggested that CSH plays a key role in modulating placental metabolism that ultimately promotes maximal placental glucose transfer.NEW & NOTEWORTHY The current study demonstrated a novel, critical autocrine role for chorionic somatomammotropin in augmenting placental glucose transfer and maintaining placental oxidative metabolism. In pregnancies with CSH deficiency, excess glucose in maternal circulation is insufficient to overcome fetal hypoglycemia due to impaired placental glucose transfer and elevated placental metabolic demands. This suggests that perturbations in glucose transfer in CSH RNAi pregnancies are due to compromised metabolic efficiency along with reduced placental mass.

Comparison of nutrient supply from the dam to fetus and placental development in Holstein and Japanese black cows pregnant with similar or different fetus breeds.

A lower nutrient supply from Holstein (HOL) dams to beef fetuses than HOL fetuses has been demonstrated, but the underlying factors remain unclear. We investigated maternal, umbilical vein, and calf blood glucose and amino acid concentrations at calving, along with placental development at term, in HOL dams with similar fetuses (HOL-HOL, n = 12), F1 crosses (HOL × Japanese Black [JB]; HOL-F1, n = 4), JB fetuses (HOL-JB, n = 7), and JB dams with similar fetuses (JB-JB, n = 11). Calf birth weight, total cotyledonary weight, and surface area were greater in HOL-HOL compared to JB-JB or HOL-JB (P < 0.05), whereas those of HOL-F1 were similar. Blood amino acid concentrations in the umbilical veins and calves were similar among HOL-HOL, HOL-F1, and HOL-JB. Calf blood glucose concentrations were lower in HOL-F1 than HOL-HOL (P < 0.05), despite similar maternal blood glucose levels. HOL-JB exhibited higher maternal, umbilical vein, and calf blood glucose concentrations than JB-JB (P < 0.05). Therefore, the glucose supply to the fetus may be inhibited in HOL-F1 due to maternal-fetal breed differences. Higher maternal blood glucose concentrations in HOL-JB may result in elevated fetal glucose exposure, potentially affecting postnatal growth and metabolism.

Relationships Between Exposure to Gestational Diabetes Treatment and Neonatal Anthropometry: Evidence from the Born in Bradford (BiB) Cohort

ObjectivesTo examine the relationships between gestational diabetes mellitus (GDM) treatment and neonatal anthropometry.MethodsCovariate-adjusted multivariable linear regression analyses were used in 9907 offspring of the Born in Bradford cohort. GDM treatment type (lifestyle changes advice only, lifestyle changes and insulin or lifestyle changes and metformin) was the exposure, offspring born to mothers without GDM the control, and birth weight, head, mid-arm and abdominal circumference, and subscapular and triceps skinfold thickness the outcomes.ResultsLower birth weight in offspring exposed to insulin (− 117.2 g (95% CI − 173.8, − 60.7)) and metformin (− 200.3 g (− 328.5, − 72.1)) compared to offspring not exposed to GDM was partly attributed to lower gestational age at birth and greater proportion of Pakistani mothers in the treatment groups. Higher subscapular skinfolds in offspring exposed to treatment compared to those not exposed to GDM was partly attributed to higher maternal glucose concentrations at diagnosis. In fully adjusted analyses, offspring exposed to GDM treatment had lower weight, smaller abdominal circumference and skinfolds at birth than those not exposed to GDM. Metformin exposure was associated with smaller offspring mid-arm circumference (− 0.3 cm (− 0.6, − 0.07)) than insulin exposure in fully adjusted models with no other differences found.Conclusions for PracticeOffspring exposed to GDM treatment were lighter and smaller at birth than those not exposed to GDM. Metformin-exposed offspring had largely comparable birth anthropometric characteristics to those exposed to insulin.

Breastfeeding is associated with a delayed decrease in postprandial maternal glucose concentration.

Breastfeeding has long-term benefits in reducing the risk of diabetes; however, information about the acute influence on maternal glucose profile is scarce. Thus, the aim of the study was to assess maternal glucose fluctuations associated with breastfeeding episodes in women with normal glucose status. We performed an observational study of glucose fluctuations with breastfeeding episodes in 26 women with normal glucose status in fasting and postprandial state. Continuous glucose monitoring was performed using CGMS MiniMed Gold®/iPro2® (Medtronic, Dublin, Ireland) three months after delivery under real-life conditions. We compared fasting and postprandial periods of 150 minutes affected or not by a breastfeeding episode. Mean glucose concentration of postprandial periods affected by breastfeeding was lower than not affected (-6.31 mg/dL [95% CI: -11.17, -1.62] P<0.01). Glucose concentration was significantly lower between 50 and 105 minutes after meal initiation (maximum difference -9.19 mg/dL [95% CI: -16.03, -2.16] at 91-95 min). Mean glucose concentrations of fasting periods affected by breastfeeding were similar to those not affected (-0.18 mg/dL [95% CI: -2.7, 0] P=0.831). In women with normal glucose status, breastfeeding episodes are associated with a lower glucose concentration in the postprandial but not in the fasting state.

Physical Activity, but Not Glycaemic Load, Is Associated with Lower Real-Time Glycaemic Control in Free-Living Women with Gestational Diabetes Mellitus.

Maintaining blood glucose within the target range is the primary treatment goal for women with gestational diabetes mellitus (GDM). Foods with low glycaemic loads are recommended in clinical practice; however, the relative importance of other key lifestyle variables is unexplored. This pilot study explored the associations of glycaemic load, carbohydrates and physical activity parameters on blood glucose concentrations in free-living women with GDM. Twenty-nine women (28-30 weeks gestation, 34 ± 4 years) with GDM were enrolled. Continuous glucose monitoring, physical activity (ActivPAL inclinometer) and dietary intake and dietary quality were measured concurrently for 3 days. Pearson correlation analyses determined the association between glucose levels and lifestyle variables. Despite all receiving the same nutrition education, only 55% of women were following a low glycaemic load diet with a large range of carbohydrate intakes (97-267 g/day). However, the glycaemic load did not correlate with 3-hr postprandial glucose (r2 = 0.021, p = 0.56) or 24-h glucose iAUC (r2 = 0.021, p = 0.58). A significant relationship between total stepping time and lower 24-h glucose iAUC (r2 = 0.308, p = 0.02) and nocturnal glucose (r2 = 0.224, p = 0.05) was found. In free-living women with diet-controlled GDM, more physical activity, i.e., steps accumulated across the day, may be a simple and effective strategy for improving maternal blood glucose concentrations.

Human Placental LRP5 and Sclerostin are Increased in Gestational Diabetes Mellitus Pregnancies.

The low-density lipoprotein receptor-related protein 5 (LRP5) and its inhibitor sclerostin, are key components of bone metabolism and potential contributors to type 2 diabetes mellitus susceptibility. This study aims at evaluating the expression of placental LRP5 and sclerostin in pregnancies with gestational diabetes mellitus (GDM) and investigate possible associations with umbilical sclerostin concentrations and clinical outcomes in mothers and their neonates. Twenty-six GDM-mothers and 34 non-GDM mothers of Caucasian origin and their neonates admitted in a gynecology and obstetrics department of a university hospital were included in this study. Demographic data and maternal fasting glucose concentrations (24-28 weeks of gestation) were retrieved from the patients' medical records. Placental LRP5 was determined by immunohistochemistry (IHC) and Western blotting analysis; placental sclerostin was determined by IHC. Umbilical serum sclerostin concentrations were measured by ELISA. Placental sclerostin IHC intensity values were positively correlated with LRP5 values as detected either by IHC (r = 0.529; P < .001) or Western blotting (r = 0.398; P = .008), with pregestational maternal body mass index values (r = 0.299; P = .043) and with maternal fasting glucose concentrations (r = 0.475; P = .009). Placental sclerostin and LRP5 were significantly greater in GDM compared with non-GDM placentas (histo-score: 65.08 ± 17.09 vs 11.45 ± 2.33, P < .001; 145.53 ± 43.74 vs 202.88 ± 58.65, P < .001; respectively). Sclerostin and LRP5 were detected in human placentas. The overexpression of placental sclerostin and LRP5 values in GDM compared with non-GDM pregnancies, as well as the positive association of placental sclerostin values with pregestational maternal body mass index and maternal fasting glucose concentrations may indicate the development of an adaptive mechanism in face of maternal hyperglycemia.

Association of Maternal Glucose Concentrations During Pregnancy With Cardiovascular Alterations in Early Childhood: A Prospective Birth Cohort Study

BackgroundMaternal hyperglycemia has been associated with cardiovascular disease risks in offspring. Previous studies were mostly conducted to test this association in pregnancies with (pre)gestational diabetes mellitus. However, the association may not be limited to populations with diabetes only. ObjectivesThe aim of this study was to assess the association between gestational glucose concentrations in women without (pre)gestational diabetes mellitus and childhood cardiovascular alterations at the age of 4 y. MethodsOur study was based on the Shanghai Birth Cohort. Briefly, among 1016 nondiabetic mothers (age: 30.8 ± 3.42 y; BMI: 21.3 ± 2.94) and their offsprings (age: 4.41 ± 0.22 y; BMI: 15.0 ± 1.56; 53.0% males), results of maternal 1-h oral OGTT between 24 and 28 gestational weeks were obtained. Childhood blood pressure (BP) measurement, echocardiography, and vascular ultrasound were performed at 4 y old. Linear regression and binary logistic regression were conducted to test the association between maternal glucose and childhood cardiovascular outcomes. ResultsCompared with children from mothers with glucose concentrations in the lowest quartile, children from mothers in the highest quartile had higher BP (systolic: 97.0 ± 7.41 compared with 98.9 ± 7.82 mmHg, P = 0.006; diastolic: 56.8 ± 5.83 compared with 57.9 ± 6.03 mmHg, P = 0.051) and lower left ventricular ejection fraction (92.5 ± 9.15 compared with 90.8 ± 9.16 %, P = 0.046). Also, higher maternal OGTT 1-h glucose concentrations across the full range were associated with higher childhood BP (systolic: β: 0.56; 95% CI: 0.19, 0.93; diastolic: β: 0.36; 95% CI: 0.05, 0.66). Logistic regression showed, compared with children from mothers in the lowest quartile, children from mothers in the highest quartile had a 58% (OR=1.58; 95% CI: 1.01, 2.47) higher odds of elevated systolic BP (≥90th percentile). ConclusionsIn a population without (pre)gestational diabetes mellitus, higher maternal OGTT 1-h glucose were associated with childhood cardiovascular structure and function alterations. Further studies are needed to assess whether interventions to reduce gestational glucose will mitigate subsequent cardiometabolic risks in offspring.

Effect of a 60-day weight reduction intervention prior to IVF/ICSI on perinatal outcomes in overweight or obese infertile women.

The aim of this study was to determine whether a 60-day weight reduction intervention prior to in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) and a higher weight loss ratio effectively improved perinatal outcomes for infertile overweight or obese women. This was a retrospective cohort study conducted at a university-affiliated fertility center. Two thousand three hundred and eighty-one overweight or obese infertile women who underwent or did not undergo a 60-day weight reduction intervention prior to IVF/ICSI between February 27, 2017 and November 11, 2020 were included in this study. All of these women achieved clinical pregnancy and delivered a single child after assisted reproductive technology (ART). Primary outcomes included neonatal birth weight and the incidence of pregnancy complications, premature delivery, and low birth weight. The body mass index (BMI), blood glucose concentration, serum insulin level, and homeostasis model assessment of insulin resistance (HOMA-IR) of the intervention group decreased significantly after the weight reduction intervention. Neonatal birth weight was significantly higher in the intervention group (3519.6g ±484.8 g) than the control group (3406.8g ± 554.2g; P < 0.001). There was no significant difference in the incidence of pregnancy complications between the two groups. Linear regression analysis found that the weight reduction intervention prior to IVF/ICSI and lower HOMA-IR at ovulation induction were associated with increased birth weight. As the weight loss ratio increased, the incidence of hypertensive disorders of pregnancy, premature membrane rupture, premature delivery, stillbirth, and low birth weight showed a downward trend. A 60-day weight reduction intervention prior to IVF/ICSI may increase neonatal birth weight, reduce maternal blood glucose concentration, and improve maternal insulin resistance in infertile overweight or obese women. This results require to be further verified by prospective randomized controlled trials with a larger sample size.

First-Trimester Triglyceride-Glucose Index and Risk of Pregnancy-Related Complications: A Prospective Birth Cohort Study in Southeast China.

To evaluate the relationships of the triglyceride-glucose (TyG) index with pregnancy-related complications (PRCs) and to clarify the predictability of the TyG index for PRCs. Totally of 11,387 women with a singleton pregnancy were prospectively followed until after delivery. Maternal fasting lipids and glucose concentration were measured in the first trimester (11 weeks gestation on average). The TyG index was calculated as ln [triglyceride (mg/dL) × fasting plasma glucose (mg/dL)/2]. We used generalized linear models to calculate the relative risks and 95% confidence intervals. Receiver-operating characteristic curve analysis was employed to assess the ability of the TyG index to predict the risks of PRCs. Smooth spline reveals that the probability of gestational diabetes mellitus (GDM) is intensified with the increasing TyG index. Multivariate logistic regression adjusted for risk factors demonstrates a 1-unit and a 1-SD increment in the TyG index raises the risk of GDM by 3.63 and 1.57 times, respectively. Identically, the risk of GDM maximizes in the TyG quintile 5 (OR: 3.14; 95% CI: 2.55~3.85) relative to the lowest TyG index group. However, no association between TyG index and the risk of other PRCs was observed after full adjustment. The area under receiver operating characteristic curves is 0.647 (95% CI: 0.632-0.66) for GDM, and the optimal predictive cut-off is 8.55, with a specificity of 0.679 and sensitivity of 0.535. The first-trimester TyG index is significantly associated with the risk of incident GDM, while the relationships between the TyG index and other PRCs need further exploration.

Maternal Cardiovascular Health in Early Pregnancy and Childhood Brain Structure.

Background Poor cardiovascular health during pregnancy has been associated with adverse neurocognitive outcomes in the offspring. We examined the associations of maternal cardiovascular health factors with brain structure in 10-year-old children. Methods and Results We included 2797 mother-offspring pairs from the Generation R Study. Maternal body mass index, gestational weight gain, blood pressure, insulin, glucose, and lipid blood concentrations were obtained in early pregnancy. Childhood structural brain measures, including global metrics of brain tissue volumes and white matter microstructure, were quantified by magnetic resonance imaging at 10 years. As compared with offspring of mothers with normal weight, those of mothers with underweight had smaller total brain volume (difference, -28.99 [95% CI -56.55 to -1.45] cm3). Similarly, as compared with offspring of mothers with gestational weight gain between the 25th and 75th percentile, those of mothers with gestational weight loss or no gestational weight gain (<25th percentile), had smaller total brain volume (difference, -13.07 [95% CI, -23.82 to -2.32] cm3). Also, higher maternal diastolic blood pressure in early pregnancy was associated with lower offspring white matter mean diffusivity (difference, -0.07 [95% CI, -0.11 to -0.02] SD score). After multiple testing correction, only the association of maternal diastolic blood pressure with lower offspring white matter mean diffusivity remained statistically significant. No associations were observed of maternal insulin, glucose, and lipid concentrations with childhood brain outcomes. Conclusions Our findings suggest that maternal cardiovascular health during pregnancy might be related to offspring brain development in the long term. Future studies are needed to replicate our findings and to explore the causal nature of the associations.

Maternal lipid profile in pregnancy and embryonic size: a population-based prospective cohort study

BackgroundLipids are crucial for fetal growth and development. Maternal lipid concentrations are associated with fetal growth in the second and third trimester of pregnancy and with birth outcomes. However, it is unknown if this association starts early in pregnancy or arises later during fetal development. The aim of this study was to investigate the association between the maternal lipid profile in early pregnancy and embryonic size.MethodsWe included 1474 women from the Generation R Study, a population based prospective birth cohort. Both embryonic size and the maternal lipid profile were measured between 10 weeks + 1 day and 13 weeks + 6 days gestational age. The maternal lipid profile was defined as total cholesterol, triglycerides (TG), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), remnant cholesterol, non-high-density (non-HDL-c) lipoprotein cholesterol concentrations and the triglycerides/high-density lipoprotein (TG/HDL-c) ratio. Additionally, maternal glucose concentrations were assessed. Embryonic size was assessed using crown-rump length (CRL) measurements. Associations were studied with linear regression models, adjusted for confounding factors: maternal age, pre-pregnancy body mass index (BMI), parity, educational level, ethnicity, smoking and folic acid supplement use.ResultsTriglycerides and remnant cholesterol concentrations are positively associated with embryonic size (fully adjusted models, 0.17 SDS CRL: 95% CI 0.03; 0.30, and 0.17 SDS: 95% CI 0.04; 0.31 per 1 MoM increase, respectively). These associations were not present in women with normal weight (triglycerides and remnant cholesterol: fully adjusted model, 0.44 SDS: 95% CI 0.15; 0.72). Associations between maternal lipid concentrations and embryonic size were not attenuated after adjustment for glucose concentrations. Total cholesterol, HDL-c, LDL-c, non-HDL-c concentrations and the TG/HDL-c ratio were not associated with embryonic size.ConclusionsHigher triglycerides and remnant cholesterol concentrations in early pregnancy are associated with increased embryonic size, most notably in overweight women.Trial registrationThe study protocol has been approved by the Medical Ethics Committee of the Erasmus University Medical Centre (Erasmus MC), Rotterdam (MEC-2007-413). Written informed consent was obtained from all participants.

The influence of maternal blood glucose during pregnancy on weight outcomes at birth and preschool age in offspring exposed to hyperglycemia first detected during pregnancy, in a South African cohort.

Little is known about the influence of hyperglycemia first detected in pregnancy (HFDP) on weight outcomes in exposed offspring in Africa. We investigated the influence of maternal blood glucose concentrations during pregnancy on offspring weight outcomes at birth and preschool age, in offspring exposed to HFDP, in South Africa. Women diagnosed with HFDP had data routinely collected during the pregnancy and at delivery, at a referral hospital, and the offspring followed up at preschool age. Maternal fasting, oral glucose tolerance test 1 and 2-hour blood glucose were measured at diagnosis of HFDP and 2-hour postprandial blood glucose during the third trimester. Offspring were classified as either those exposed to diabetes first recognized in pregnancy (DIP) or gestational diabetes (GDM). At birth, neonates were classified into macrosomia, low birth weight (LBW), large for gestational age (LGA), appropriate (AGA) and small for gestational age (SGA)groups. At preschool age, offspring had height and weight measured and Z-scores for weight, height and BMI calculated. Four hundred and forty-three neonates were included in the study at birth, with 165 exposed to DIP and 278 exposed to GDM. At birth, the prevalence of LGA, macrosomia and LBW were 29.6%, 12.2% and 7.5%, respectively, with a higher prevalence of LGA and macrosomia in neonates exposed to DIP. At pre-school age, the combined prevalence of overweight and obesity was 26.5%. Maternal third trimester 2-hour postprandial blood glucose was significantly associated with z-scores for weight at birth and preschool age, and both SGA and LGA at birth. In offspring exposed to HFDP, there is a high prevalence of LGA and macrosomia at birth, and overweight and obesity at preschool age, with higher prevalence in those exposed to DIP, compared to GDM. Maternal blood glucose control during the pregnancy influences offspring weight at birth and preschool age.

Foetal hyperinsulinaemia and increased fat mass correlate negatively with circulating fatty acid concentrations in neonates of gestational diabetic mothers with dietary-controlled glycaemia.

Higher accretion of prenatal fat is associated with a higher proportion of obesity in children. However, most of the data on regulatory factors involved in fetal adipogenesis come from animal studies; in humans there is no evidence on how fetal insulin affects fatty acid concentrations and fetal adiposity. We evaluate the relationship between fetal adipose tissue accretion with insulin and fetal consumption of circulating fatty acid (FA). In fasting maternal blood at term and cord samples, from 41 gestational diabetes mellitus women (GDM) and 68 non-diabetic controls, serum compounds were determined. Individual FA were analyzed and expressed as concentrations of FA (mmol/L). Both groups had similar maternal serum glucose, insulin, triacylglycerol (TAG), non-esterified FA (NEFA), glycerol and leptin concentrations, but most individual maternal serum FA were lower in GDM than controls. Neonatal fat mass (FM) was higher in the GDM group even though neonatal birth weights were similar. In GDM cord serum glucose, insulin, NEFA and leptin were higher than controls, but glycerol and all individual FA were lower. In GDM neonates only, a negative correlation was found between each FA and FM, and there was a strong negative correlation between the concentrations of umbilical blood insulin and five major FA. Our results show for the first time that hyperinsulinemia in fetuses of GDM women increases FA utilization, which may contribute to to their increased adiposity.

Maternal Early-Pregnancy Glucose Concentrations and Liver Fat Among School-Age Children.

Background and AimsGestational diabetes seems to be associated with offspring NAFLD. We hypothesized that maternal glucose concentrations across the full range may have persistent effects on offspring liver fat accumulation.Approach and ResultsIn a multiethnic, population‐based, prospective cohort study among 2,168 women and their offspring, maternal early‐pregnancy glucose concentrations were measured at a median of 13.1 weeks’ gestation (95% CI, 9.6‐17.2). Liver fat fraction was measured at 10 years by MRI. NAFLD was defined as liver fat fraction ≥5.0%. We performed analyses among all mothers with different ethnic backgrounds and those of European ancestry only. The multiethnic group had a median maternal early‐pregnancy glucose concentration of 4.3 mmol/L (interquartile range, 3.9‐4.9) and a 2.8% (n = 60) prevalence of NAFLD. The models adjusted for child age and sex only showed that in the multiethnic group, higher maternal early‐pregnancy glucose concentrations were associated with higher liver fat accumulation and higher odds of NAFLD, but these associations attenuated into nonsignificance after adjustment for potential confounders. Among mothers of European ancestry only, maternal early‐pregnancy glucose concentrations were associated with increased odds of NAFLD (OR, 1.95; 95% CI, 1.32; 2.88, after adjustment for confounders) per 1‐mmol/L increase in maternal early‐pregnancy glucose concentration. These associations were not explained by maternal prepregnancy and childhood body mass index, visceral fat, and metabolic markers.ConclusionsIn this study, maternal early‐pregnancy glucose concentrations were only among mothers of European ancestry associated with offspring NAFLD. The associations of higher maternal early‐pregnancy glucose concentrations with offspring NAFLD may differ between ethnic groups.

Role of Placental Glucose Transporters in Determining Fetal Growth.

Maternal nutrient availability and its transport through the placenta are crucial for fetal development. Nutrients are transported to the fetus via specific transporters present on the microvillous (MVM) and basal membrane (BM) of the placenta. Glucose is the most abundant nutrient transferred to the fetus and plays a key role in the fetal growth and development. The transfer of glucose across the human placenta is directly proportional to maternal glucose concentrations, and is mediated by glucose transporter family proteins (GLUTs). Maternal glucose concentration influences expression and activity of GLUTs in the MVM (glucose uptake) and BM (glucose delivery). Alteration in the number and function of these transporters may affect the growth and body composition of the fetus. The thin-fat phenotype of the Indian baby (low ponderal index, high adiposity) is proposed as a harbinger of future metabolic risk. We propose that placental function mediated through nutrient transporters contributes to the phenotype of the baby, specifically that glucose transporters will influence neonatal fat. This review discusses the role of various glucose transporters in the placenta in determining fetal growth and body composition, in light of the above hypothesis.

Associations of maternal early-pregnancy dietary glycemic index with childhood general, abdominal and ectopic fat accumulation

SummaryBackground & aimsMaternal hyperglycemia during pregnancy is an important risk factor for childhood adiposity. Maternal dietary glycemic index during pregnancy directly influences maternal and fetal glucose concentrations. We examined the associations of maternal early-pregnancy dietary glycemic index with offspring general, abdominal and ectopic fat accumulation among normal weight and overweight or obese pregnant women and their offspring.MethodsIn a population-based cohort study among 2488 Dutch pregnant women and their children, we assessed maternal dietary glycemic index by food frequency questionnaire at median 13.4 (95% range 10.7; 21.1) weeks gestation. Dietary glycemic index was used continuously and categorized into low (≤55), normal (56–69) and high (≥70) glycemic index diet. We measured offspring BMI, total fat mass and android/gynoid fat mass ratio by DXA, and visceral fat mass and liver fat fraction by MRI at 10 years.ResultsNo associations of maternal early-pregnancy dietary glycemic index with offspring adiposity were present among normal weight women and their children. Among overweight and obese women and their children, 1-Standard Deviation Score (SDS) increase in maternal early-pregnancy dietary glycemic index was associated with higher childhood BMI (0.10 SDS, 95% Confidence Interval (CI) 0.01; 0.19), total fat mass index (0.13 SDS, 95% CI 0.05; 0.22), visceral fat mass index (0.19 SDS, 95% CI 0.07; 0.32) and tended to be associated with a higher android/gynoid fat mass ratio (0.09 SDS, 95% CI −0.01; 0.19) and higher risk of childhood overweight (Odds Ratio (OR) 1.20, 95% CI 0.97; 1.48). Overweight and obese women consuming an early-pregnancy low-glycemic index diet, as compared to an early-pregnancy normal-glycemic index diet, had children with lower BMI, total fat mass index, visceral fat mass index and android/gynoid fat mass ratio at 10 years (p-values<0.05). No women consumed a high-glycemic index diet. No associations were explained by maternal socio-economic, lifestyle and dietary characteristics, birth or childhood characteristics. No associations with liver fat fraction were present.ConclusionsIn overweight or obese women and their children, a higher maternal early-pregnancy dietary glycemic index is associated with childhood general, abdominal and visceral fat accumulation, but not with liver fat. Intervention studies among overweight and obese pregnant women may need to target the dietary glycemic index to prevent childhood adiposity.

Maternal Hyperglycemia Induces Changes in Gene Expression and Morphology in Mouse Placentas.

Pregestational diabetes complicates one million pregnancies in the United States and is associated with placental dysfunction. Placental dysfunction can manifest as stillbirth, spontaneous abortions, fetal growth restriction, and preeclampsia in the mother. However, the underlying mechanisms of placental dysfunction are not well understood. We hypothesize that maternal hyperglycemia disrupts cellular processes important for normal vascular development and function. Hyperglycemia, defined as a non-fasting glucose concentration of >250 mg/dL was induced in eight-week-old female CD1 mice by injecting a one-time intraperitoneal dose of 150mg/kg streptozotocin. Control mice received an equal volume of normal saline. Hyperglycemic and control females were mated with CD-1 males. At Embryonic Day 17.5, the pregnant mice were euthanized. Sixty-eight placentas were harvested from the six euglycemic dams and twenty-six placentas were harvested from three hyperglycemic dams. RNA was extracted from homogenized placental tissue (N=12/group; 2-4 placentas per litter of each group). Total RNA was prepared and sequenced. Differentially expressed genes that were >2-fold change was considered significant. Placentas (9-20/group) were fixed in paraffin wax and sectioned at 6 μm. Cross-sectional areas of placental zones were evaluated using slides stained for hematoxylin and eosin, glycogen, collagen, proliferation and apoptosis. Quantification of staining intensity and percent positive nuclei was done using Leica Image Hub Data software. Data were compared between the control and experimental group using t-tests. Values of p < 0.05 were considered to be statistically significant. The average maternal blood glucose concentrations for control and diabetic dams were 112+/-24 and 473+/-47 respectively (p<0.0001). A higher rate of resorptions was noted in the hyperglycemia exposed placentas compared to euglycemic exposed placentas (24% vs 7%; p=0.04). A total of 24 RNA libraries (12/group) were prepared. Placentas from hyperglycemic pregnancies exhibited 1374 differentially expressed genes (DEGs). The 10 most significantly differentially expressed genes are Filip 1, Prom 2, Fam 78a, Pde4d, Pou3f1, Kcnk5, Dusp4, Cxcr4, Slc6a4 and D430019H16Rik. Their corresponding biologic functions are related to chemotaxis, ossification, cellular and vascular development. Histologically, we found that hyperglycemia exposed placentas demonstrated increased proliferation, apoptosis, and glycogen content and decreased collagen deposition. There was a higher rate of resorptions in the pregnancies of hyperglycemic dams. Pregestational diabetes resulted in significant changes in placental morphology, including increased glycogen content in the spongiotrophoblast, decreased collagen deposition, increased apoptosis and proliferation in the junction zone. Maternal diabetes causes widespread disruption in multiple cellular processes important for normal vascular development and sets the platform for placenta dysfunction.