The unexplored role of sedentary time and physical activity in glucose and lipid metabolism-related placental mRNAs in pregnant women who are obese: the DALI lifestyle randomised controlled trial.

OBJECTIVE: We aimed to explore: (i) the association of sedentary time (ST) and physical activity (PA) during pregnancy with the placental expression of genes related to glucose and lipid metabolism in pregnant women who are obese; (ii) maternal metabolic factors mediating changes in these placental transcripts; and (iii) cord blood markers related to the mRNAs mediating neonatal adiposity. DESIGN: Multicentre randomised controlled trial. SETTING: Hospitals in nine European countries. POPULATION: A cohort of 112 pregnant women with placental tissue. METHODS: Both ST and moderate-to-vigorous PA (MVPA) levels were measured objectively using accelerometry at three time periods during pregnancy. MAIN OUTCOME MEASURES: Placental mRNAs (FATP2, FATP3, FABP4, GLUT1 and PPAR-γ) were measured with NanoString technology. Maternal and fetal metabolic markers and neonatal adiposity were assessed. RESULTS: Longer periods of ST, especially in early to middle pregnancy, was associated with lower placental FATP2 and FATP3 expression (P < 0.05), whereas MVPA at baseline was inversely associated with GLUT1 mRNA (P = 0.02). Although placental FATP2 and FATP3 expression were regulated by the insulin-glucose axis (P < 0.05), no maternal metabolic marker mediated the association of ST/MVPA with placental mRNAs (P > 0.05). Additionally, placental FATP2 expression was inversely associated with cord blood triglycerides and free fatty acids (FFAs; P < 0.01). No cord blood marker mediated neonatal adiposity except for cord blood leptin, which mediated the effects of PPAR-γ on neonatal sum of skinfolds (P < 0.05). CONCLUSIONS: In early to middle pregnancy, ST is associated with the expression of placental genes linked to lipid transport. PA is hardly related to transporter mRNAs. Strategies aimed at reducing sedentary behaviour during pregnancy could modulate placental gene expression, which may help to prevent unfavourable fetal and maternal pregnancy outcomes. TWEETABLE ABSTRACT: Reducing sedentary behaviour in pregnancy might modulate placental expression of genes related to lipid metabolism in women who are obese.

Metabolic phenotypes of early gestational diabetes mellitus and their association with adverse pregnancy outcomes.

AIMS: To describe the metabolic phenotypes of early gestational diabetes mellitus and their association with adverse pregnancy outcomes. METHODS: We performed a post hoc analysis using data from the Vitamin D And Lifestyle Intervention for gestational diabetes prevention (DALI) trial conducted across nine European countries (2012-2014). In women with a BMI ≥29 kg/m2 , insulin resistance and secretion were estimated from the oral glucose tolerance test values performed before 20 weeks, using homeostatic model assessment of insulin resistance and Stumvoll first-phase indices, respectively. Women with early gestational diabetes, defined by the International Association of Diabetes and Pregnancy Study Groups criteria, were classified into three groups: GDM-R (above-median insulin resistance alone), GDM-S (below-median insulin secretion alone), and GDM-B (combination of both) and the few remaining women were excluded. RESULTS: Compared with women in the normal glucose tolerance group (n = 651), women in the GDM-R group (n = 143) had higher fasting and post-load glucose values and insulin levels, with a greater risk of having large-for-gestational age babies [adjusted odds ratio 3.30 (95% CI 1.50-7.50)] and caesarean section [adjusted odds ratio 2.30 (95% CI 1.20-4.40)]. Women in the GDM-S (n = 37) and GDM-B (n = 56) groups had comparable pregnancy outcomes with those in the normal glucose tolerance group. CONCLUSIONS: In overweight and obese women with early gestational diabetes, higher degree of insulin resistance alone was more likely to be associated with adverse pregnancy outcomes than lower insulin secretion alone or a combination of both.

Leptin and vascular endothelial growth factor A: a cross-talk in obese women with gestational diabetes and with diabetes in pregnancy - a cohort study.

Vascular endothelial growth factor A (VEGF A) synthesis is intensified by leptin in: hypoxia-inducible factor 1 alpha (HIF-1A) and nuclear factor kappa-light-chain-enhancer of activated B cells (NfκB)-dependent manners. The study aimed to investigate the association between leptin and VEGF A serum levels in obese women with hyperglycaemia in the third trimester of pregnancy. Sixty obese pregnant women with hyperglycaemia were divided into groups according to body mass index (BMI): group 1: BMI 30.0-34.9 kg/m2; group 2: BMI 35.0-39.9 kg/m2; group 3: BMI ≥40 kg/m2. On the enrolment visit, waist circumference, body mass and height were measured. At visit 1 (V1; gestational week (GW) 28-32) and visit 2 (V2; GW 36-38), anthropometric, blood pressure and heart rate measurements, and blood sample collection were performed. Blood levels of leptin, VEGF A, VEGF receptor 2, HIF-1A, NfκB, interleukin 1 alpha, protein delta homolog 1, nitric oxide and glycated haemoglobin were determined. To analyse the predictors of the biochemical parametres involved in leptin and VEGF A cross-talk, multivariate logistic regression was implemented. Positive correlations between serum levels of leptin and VEGF A were found. Serum level of HIF-1A at V1 was a predictor for the highest quartile of the serum levels of VEGF A at V1 and V2. Leptin serum level at V1 was a predictor for the highest quartile of HIF-1A serum concentration at V2. In group 3 HIF-1A level was higher at V2 compared to V1. We conclude that in obese women with hyperglycaemia in the third trimester of pregnancy there is a significant positive influence of serum leptin on VEGF A synthesis and serum level and HIF-1A seems to play more important role in leptin and VEGF A cross-talk than NfκB.

Maternal endothelial dysfunction and its association with abnormal fetal growth in diabetic pregnancy.

AIMS: Some authors consider the vascular endothelium to be a target organ in diabetes. However, there have only been a few studies of the function of the maternal endothelium during pregnancy in women with diabetes. We analysed the relationship between maternal vascular endothelial dysfunction and fetal growth in such pregnancies. METHODS: Markers of endothelial dysfunction (serum concentration of sE-selectin and sVCAM-1) were measured at admission (baseline) and before delivery in 97 women with pregestational diabetes and a singleton pregnancy,. After delivery, the group with pregestational diabetes was divided retrospectively according to neonatal birthweight into three groups-appropriate, small and large for gestational age- and the maternal variables were analysed in relation to birthweight. RESULTS: The baseline concentration of sE-selectin was significantly higher in the large-for-gestational-age group vs. the small-for-gestational-age group (median: 53.1 vs. 39.0 ng/ml, P<0.05). The concentration of sVCAM-1 at baseline was significantly higher in the small-for-gestational-age vs. the appropriate- and large-for-gestational-age groups (median: 846.2 vs. 576.8 and 524.1 ng/ml, respectively; P<0.01 and P<0.001, respectively). The concentration of sE-selectin at baseline and gestational changes in the concentration of sVCAM-1 were related to birthweight. The baseline concentrations of sE-selectin and sVCAM-1 and the gestational change in sVCAM-1 concentration were predictive factors for large for gestational age (cut-off values: 45.0, 644.6 and 38.4 ng/ml; sensitivity: 67.7, 89.3 and 34.4%; specificity: 65.5, 39.7 and 85.5%, respectively). CONCLUSIONS: Our study showed a relationship between maternal endothelial dysfunction and fetal growth disturbances during pregnancy in women with diabetes that was not associated with maternal metabolic control. Higher levels of maternal sE-selectin in early pregnancy were associated with increased risk of the large-for-gestational-age condition. High levels of maternal sVCAM-1 in early pregnancy were characteristic of gestation complicated by the small-for-gestational-age condition. Further studies in larger groups are warranted to determine whether markers of maternal endothelial dysfunction are of use in the prediction of abnormal birthweight (large or small for gestational age) in pregnant women with diabetes.

Concentration of chemokines in peripheral blood in first trimester of diabetic pregnancy.

BACKGROUND: Several types of regulators (i.e. chemokines and metalloproteinases) are considered to play a crucial role in pregnancy by local modulation of the immune system at the level of peripheral leukocytes. The aim of this study was to determine whether changes in chemokines (interferon-gamma-inducible protein (IP-10), monocyte chemotactic peptide-1(MCP-1), cytokines regulated upon activation normal T cell expressed and secreted (RANTES) and matrix metalloproteinase-9 (MMP-9)) concentrations in diabetic patients could affect the course of pregnancy. METHODS: The study group consisted of 65 diabetics in the first trimester of pregnancy. Some 47 pregnancies were successfully continued to delivery, 18 were terminated with spontaneous miscarriages. Twenty healthy women matched for gestational age served as a control group. RESULTS: Glycated haemoglobin (HbA1C), vascular complications and lipoproteins (cholesterol, HDL-cholesterol, low density lipoprotein (LDL)-cholesterol and triglicerides) concentrations in maternal blood did not influence the chemokines concentrations. Lower RANTES level and higher MMP-9 concentrations were found in diabetic women. MCP-1 and RANTES levels differed significantly between pregnancies with good and poor perinatal outcome. A logistic regression model revealed that not only duration of diabetes, age of patients, HbA1C and insulin requirements, but also MMP-9,RANTES, MCP-1 and LDL-cholesterol levels seem to be involved in first trimester metabolism. CONCLUSIONS: Our results suggest the possible role of chemokines in early pregnancy development, especially in well-controlled diabetic patients, when hyperglycaemia is unlikely to be the main reason for an unfavourable outcome. Our results show that MCP-1 and RANTES might serve as predictive factors for an unfavourable outcome in diabetic pregnancy, whereas MMP-9 seems to be a marker of immunological changes related to mild hyperglycaemia. However, the open question of how the modulation of chemokines concentrations might be applied to prevent miscarriage in diabetic patients remains.

Short-term antidiabetic treatment with insulin or metformin has a similar impact on the components of metabolic syndrome in women with gestational diabetes mellitus requiring antidiabetic agents: results of a prospective, randomised study.

Gestational diabetes mellitus (GDM) is associated with an increased prevalence of fetal and maternal complications primarily caused by maternal hyperglycemia, which results in abnormal fetal growth. Diet modification is a common first step in the treatment of GDM, followed by antidiabetic pharmacotherapy if this approach fails. Insulin therapy is generally accepted; however, oral hypoglycemic agents have been used in this population. In this prospective, randomised study, we compared maternal metabolic status after treatment with insulin or metformin. Pregnant women (gestational age: ≥ 20 weeks) with GDM requiring medical hypoglycemic treatment were randomly allocated to the Metformin (n = 35) or Insulin (n = 43) Groups. Maternal metabolic status - assessed by glycated hemoglobin (HBA1c) level, glycemic profile, insulin concentration, Homeostatic Model Assessment - Insulin Resistance index, and lipids - was recorded at booking and throughout pregnancy. The characteristics of the study group were: maternal age 33.5 ± 5.9 years, gestational age at baseline 28.5 ± 3.5 weeks, prepregnancy body mass index (BMI) 32.2 ± 3.5 kg/m(2), HbA1c at baseline 5.6 ± 0.6%, and average daily glycemia 5.9 ± 0.6 mmol/dl. Fasting glycemia at term was significantly lower in the Insulin Group but there were no significant differences in mean daily glycemia, HbA1c and BMI at term between the groups. Longitudinally, there was a small but significant increase in BMI and a significant increase in high-density lipoprotein-cholesterol in the Insulin Group and a significant increase in the atherogenic index of plasma (AIP) and a trend towards higher triglycerides in the Metformin Group. Both fasting and average daily glycemia were significantly reduced following treatment in both groups. No such change was evident for HbA1c. In a relative risk analysis, metformin treatment was associated with an insignificant elevated risk of HbA1c, triglycerides and lipid indices falling within the highest quartile at term. The risk of gestational weight gain and total cholesterol falling within the highest quartile at term was insignificantly reduced in the Metformin Group. In conclusion, short-term antidiabetic treatment with insulin or metformin has a similar impact on markers of metabolic syndrome in women with GDM requiring antidiabetic treatment. Secondly, treatment with metformin is associated with increased triglyceride levels and higher AIP in the third trimester in pregnant women with GDM.

Concentrations of endothelial nitric oxide synthase, angiotensin-converting enzyme, vascular endothelial growth factor and placental growth factor in maternal blood and maternal metabolic status in pregnancy complicated by hypertensive disorders.

Hypertensive disorders of pregnancy (HDPs) are associated with altered maternal metabolism, impaired perinatal outcome and increased risk for remote maternal complications. The aim of our study was to analyse associations between circulating levels of angiogenic factors and markers of oxidative stress and metabolic status in women with HDP. Forty-six women in singleton pregnancies complicated by HDP and 30 healthy controls were enrolled in a prospective observational study. Serum concentrations of endothelial nitric oxide synthase (eNOS), angiotensin-converting enzyme, vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) were measured in the third trimester and correlated with maternal anthropometrics and metabolic status. We found significantly lower eNOS levels in patients with severe hypertension vs controls, a strong association between eNOS and PlGF in the study group, a significant association between maternal prepregnancy body mass index (BMI) and VEGF levels and an inverse correlation between VEGF and PlGF. Maternal prepregnancy BMI was the only independent predictor for VEGF concentrations. We noted reduced levels of PlGF and eNOS and increased VEGF levels in women with severe hypertension/preeclampsia. First, different forms of HDP are associated with different alteration patterns in concentrations of angiogenic factors and markers of oxidative stress. Second, maternal prepregnancy BMI, but not body weight, is a significant predictor for VEGF levels in late pregnancy.

Placental vascular endothelial growth factor expression in pregnancies complicated by type 1 diabetes.

UNLABELLED: Type 1 diabetes mellitus (T1DM) is still associated with increased risk of severe maternal and foetal complications but their pathomechanism remains unclear. OBJECTIVES: we investigated the possible role of placental vascular endothelial growth factor (VEGF) and VEGF single nucleotide polymorphisms (SNP) in foetal development in T1DM pregnancies. Sixty seven pregnant women with T1DM and singleton pregnancy were enrolled into the study. Results demonstrated higher expression of placental VEGF in women who delivered neonates with birth weight (NBW)>4000g. No such correlation was found in the overall T1DM group and in women who delivered appropriate for gestational age (AGA) and small for gestational age (SGA) newborns. We also demonstrated a significant correlation between 3(rd) trimester mean blood glucose, HbA1C and placental VEGF. No such correlation was found for the 1(st) and 2(nd) trimesters. Top placental VEGF expression and placental mass were found in women who delivered large for gestational age (LGA) newborns. We also found a statistically significant difference in homozygous and heterozygous frequency variants of VEGF SNPs in study groups. We conclude that the increased placental VEGF together with impaired metabolic control may have a role in stimulating foetal overgrowth in T1DM pregnancy.

Placental leptin and its receptor genes expression in pregnancies complicated by type 1 diabetes.

Type 1 diabetes mellitus (T1DM) is still associated with increased risk for severe maternal and fetal complications but their pathomechanism remains unclear. We investigated into possible role of placental leptin (LEP) and its receptor gene (LEPR) in T1DM pregnancies. Fourty nine pregnant women with T1DM and singleton pregnancy were enrolled into the study. Control group consisted of 15 healthy pregnant women in uncomplicated, singleton gestation. We observed higher expression of LEP and LEPR in T1DM placentas in comparison to healthy subjects. We also noticed greater expression of LEP and LEPR in T1DM pregnancies with large for gestational age (LGA) and appropriate for gestational age (AGA) fetuses in comparison to small for gestational age (SGA) diabetic fetuses and controls. We found a significant positive correlation between placental LEP and LEPR expression and neonatal birthweight in overweight T1DM subjects. No such a correlation was found in T1DM subjects with normal weight and controls. We conclude that increased placental LEP and LEPR expression may have a role in stimulating fetal overgrowth in T1DM pregnancy.

Associations of Body Mass Index (Maternal BMI) and Gestational Diabetes Mellitus with Neonatal and Maternal Pregnancy Outcomes in a Multicentre European Database (Diabetes and Pregnancy Vitamin D and Lifestyle Intervention for Gestational Diabetes Mellitus Prevention).

Objective. Assess the impact of Gestational Diabetes Mellitus (GDM) and obesity on neonatal and maternal pregnancy outcomes. Methods. Cross-sectional data (3343 pregnancies) from seven European centres were included in a multilevel analysis of the association between GDM/obesity and caesarean section, macrosomia and neonatal morbidities. Results. Comparison of databases identified reporting differences between countries due to the inclusion of true population based samples or pregnancies from specialised tertiary centres, resulting in higher prevalences of GDM for some countries. The analysis showed that obesity and GDM were independent risk factors of perinatal complications. Only BMI had a dose-dependent effect on the risk of macrosomia and caesarean section. Both obesity (BMI > 30 kg/m(2)) and GDM were independent risk factors of neonatal morbidities. Conclusions. Obesity and GDM were independent risk factors of perinatal complications. The effect of the worldwide obesity and diabetes epidemic is extending to the next generation.

Metabolic syndrome in type 1 diabetes mellitus. Does it have any impact on the course of pregnancy?

UNLABELLED: To determine whether the symptoms of metabolic syndrome (MS), if accompanied by oxidative stress (OS), in type 1 diabetes mellitus (DM) patients could affect the course of pregnancy and the perinatal outcome. Oxidized low density lipoproteins (ox-LDL) and total lipid peroxides (TLP) were studied in 98 pregnant women with type 1 DM in the I(st) and III(rd) trimesters. 24% of the participants met the criteria of MS. Vascular complications were significantly more frequent in the MS-group (41.9% vs. 17.4% in the non-MS group, p<0.05). No differences in the markers of OS between the MS and the non-MS groups were noted in either the I(st) or the III(rd) trimester. A significant gestational rise in Per-Ox was found in both groups. Chronic hypertension was associated with significant differences in ox-LDL levels in both the I(st) and III(rd) trimester. No differences in perinatal outcome, as measured by abnormal birth weight or poor neonatal status (Apgar score<6, umbilical venous and/or arterial pH<7.20), were found. CONCLUSIONS: 1) MS in type 1 DM is associated with some changes in markers of oxidative stress, but it poses no additional risk to the course of pregnancy and perinatal outcome in properly controlled and treated pregnant women with type 1 DM. 2) Maternal hypertension is the only component of MS in diabetic pregnancy that is associated with significant changes in markers of oxidative stress. 3) MS is significantly more frequent in diabetic pregnant women with co-existing vascular complications and obesity.

Components of metabolic syndrome and their impact on fetal growth in women with gestational diabetes mellitus.

UNLABELLED: Gestational diabetes mellitus (GDM) is associated with increased maternal insulin resistance. Maternal hyperglycemia is a well known risk factor for fetal overgrowth. However, despite improved glycemia control, macrosomia complicates a significant proportion of diabetic pregnancies, resulting in increased perinatal risk. The aim of our retrospective study was to investigate the association between fetal growth and different maternal metabolic characteristics in women with GDM. The study group included 357 women (singleton pregnancy, and GDM diagnosed following WHO criteria). The following parameters were studied: maternal pre-pregnancy BMI, 75 g OGTT results, HbA(1c), triglycerides (TAG), total, HDL- and LDL-cholesterol levels at admission. Neonatal birth weight and the prevalence of being large for gestational age birth weight (LGA) was an end-point. We found a significant association between birth weight and HbA(1c), TAG, fasting OGTT glycemia, BMI and a birth weight of a large child born previously. BMI and birth weight of a large child was the strongest independent predictors for LGA. A significant increase in birth weight and the prevalence of LGA (from 10.5% to 83.3%) was related to a number of altered maternal metabolic features. CONCLUSIONS: Fetal growth in a diabetic pregnancy is a complex process and maternal metabolic parameters other than glucose levels should be addressed to reduce the risk of macrosomia in these groups of patients.

Plasma anhydro-D-glucitol (1,5-AG) as an indicator of hyperglycaemic excursions in pregnant women with diabetes.

AIMS: To evaluate the use of the plasma 1,5-anhydro-d-glucitol (1,5-AG) level as a possible marker for glucose excursions in pregnant women with diabetes. METHODS: The study group consisted of 55 pregnant women with diabetes (gestational diabetes mellitus-GDM, n = 28 or pre-gestational diabetes mellitus -PGDM, n = 27), without hepatic or renal insufficiency, gestational age range 5-38 weeks. In each patient, 24-h glucose profile, glycated haemoglobin and 1,5-AG plasma levels were measured. Mean blood glucose (MBG) and M-value (by Schlichtkrull) were calculated. MBG, M-value and maximal daily glycaemia (MxG) were used as indexes of daily glycaemic excursions. RESULTS: A significant correlation was found between the 1,5-AG plasma level and MxG [r = (-0.3)] and between the 1,5-AG level and M-value [r = (-0.36)]. There was no association between the 1,5-AG level and gestational age. Multivariate regression analysis, with 24-h glucose profile, gestational age and MxG as independent variables, showed that MxG was the main parameter determining the 1,5-AG plasma level [beta = (-0.68)]. The M-value, the coefficient of glucose fluctuations, also determined the 1,5-AG level but with lower statistical power [beta = (0.41)]. No statistical differences were found in the group with HbA(1c) < 6% or > 6% for 1,5-AG and M-value, while MBG was higher in poorly controlled patients (HbA(1c) > 6%). CONCLUSIONS: The plasma 1,5-AG level may be a useful marker of daily glucose excursion in pregnant women with diabetes, as an adjunct to HbA(1c) monitoring.

Threshold values of maternal blood glucose in early diabetic pregnancy--prediction of fetal malformations.

BACKGROUND: The prevention of congenital malformations in the newborns of diabetic mothers still constitutes one of the main problems in this group of patients. AIM: The aim of this study was to analyze the prevalence of fetal malformations in diabetic pregnancies, as well as detection of the cut-off points for the first-trimester glycemia levels, relating to diabetes-induced fetal malformations. METHODS: The data for analysis were collected retrospectively from the case histories of diabetic pregnant women and their newborns, treated in our departments. For the evaluation of maternal diabetes control, the whole-day glycemia profiles as well as glycated hemoglobin (HbA1C) levels were registered. To establish the glucose cut-off values for malformations, we have used receiver operating characteristic (ROC) curves for fasting, 1-hr, and 2-hr postprandial glucose levels. To determine how metabolic control influences the risk of giving birth to a malformed infant, we followed 198 newborns of diabetic mothers and 4700 infants born of healthy mothers (control group). RESULTS: We detected malformations in the infants of 8.6% (n = 17) of diabetic mothers and 3.8% of the control (odds ratio: 2.35, 95% CI = 1.40-3.96). We compared this group of diabetic patients to another diabetic pregnancy group, analyzed over a period of 1988-93 (n = 209), in which 13 newborns (6.2%) manifested congenital malformations (odds ratio: 1.41, 95% CI = 0.67-2.99) (the difference was statistically insignificant). HbA1C level during organogenesis was not significantly higher in women whose infants were malformed. We proved, however, that the risk of malformations was higher, when HbA1C value exceeded 9.3%. The malformation rate in diabetes classes D-H (according to White) was higher than in classes B and C, but the difference was not significant. A wide spectrum of anomalies has been observed in the newborns of diabetic mothers. CONCLUSIONS: Our results confirm the view that diabetic pregnancy, despite the improved metabolic control, is still a strong risk factor for alterations in fetal development, particularly in patients with a tendency to brittle glycemia during first trimester of pregnancy. It seems that keeping fasting glucose levels in first trimester below 5.8 mmol/l and postprandial glucose levels below 9.1 mmol/l can contribute to decreasing number of fetal malformations in pregestational diabetes mellitus (PGDM) pregnancy. The ROC curves appear to be useful and adequate tool for the analysis of factors influencing fetal development in diabetic pregnancy.