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We have previously described regulation of syncytial GLUT1 glucose transporters by IGF-I. Despite this, it is not clear what signal regulates transplacental glucose transport. In this report we asked whether changes in GLUT1 expression and glucose transport activity in diabetic pregnancies were associated with alterations in the fetal IGF axis. Cord blood samples and paired syncytial microvillous and basal membranes were isolated from normal term pregnancies and pregnancies characterized by gestational diabetes type A2 (GDM A2) and pre-existing insulin-dependent diabetes mellitus (IDDM). Circulating IGF-I, basal membrane GLUT1 expression and glucose transporter activity were correlated with birth weight, but only in control, not diabetic groups. Basal membrane GLUT1 and transporter activity were correlated with IGF-I concentrations in control, but not diabetic groups. IGF binding protein (IGFBP) binding capacity showed a ≥50% reduction in the diabetic groups compared to control; both showed a higher level of free IGF-I. The absence of a correlation between birth weight and factors such as fetal IGF-I or GLUT1 expression in the diabetic groups suggests that IGF-I-stimulated effects may have reached a limiting threshold, such that further increases in IGF-I (or GLUT1) are without effect. These data support that fetal IGF-I acts as a fetal nutritional signal, modulating placental GLUT1 expression and birth weight via altered levels of fetal circulating IGFBPs. Diabetes appears to exert its effects on fetal and placental factors prior to the third trimester and, despite good glycemic control immediately prior to, and in the third trimester, these effects persist to term.

Objectives Explore the maternal body mass index (BMI) relationship with peripheral deiodinase activity further. Examine associations between deiodinase activity, glucose, and C-peptide. Consider findings in the historical context of related existing literature. Design Identify fasting plasma samples and selected demographic, biophysical, and biochemical data from a subset of 600 randomly selected non-Hispanic white women recruited in the Hyperglycemia Adverse Pregnancy Outcomes (HAPO) study, all with glucose tolerance testing [545 samples sufficient to measure TSH, free T4 (fT4), and T3]. Exclude highest and lowest 1% TSH values (535 available for analysis). Assess deiodinase activity by using T3/fT4 ratios. Among women with and without gestational diabetes mellitus (GDM), compare thyroid measurements, C-peptide, and other selected data. Examine relationships independent of GDM status between BMI and thyroid hormones and between thyroid hormones and glucose and C-peptide. Results Levels of BMI, T3/fT4 ratio, and T3 were significantly higher among women with GDM (P = 0.01, 0.005, and 0.001, respectively). Irrespective of GDM status, maternal BMI was associated directly with both T3/fT4 ratio (r = 0.40, P < 0.001) and T3 (r = 0.34, P < 0.001) but inversely with fT4 (r = −0.21, P < 0.001). In turn, fasting thyroid hormone levels (most notably T3/fT4 ratio) were directly associated with maternal glucose [z score sum (fasting, 1, 2 hours); r = 0.24, P < 0.001] and with C-peptide [z score sum (fasting, 1 hour); r = 0.27, P < 0.001]. Conclusions Higher BMI was associated with increased deiodinase activity, consistent with reports from elsewhere. Increased deiodinase activity, in turn, was associated with higher glucose. Deiodinase activity accounts for a small percentage of z score sum glucose.

The placenta participates in maternal insulin sensitivity changes during pregnancy; however, mechanisms remain unclear. We investigated associations between maternal insulin sensitivity and placental DNA methylation markers across the genome. We analyzed data from 430 mother-offspring dyads in the Gen3G cohort. All women underwent 75-g oral glucose tolerance tests at ∼26 weeks of gestation; we used glucose and insulin measures to estimate insulin sensitivity (Matsuda index). At delivery, we collected samples from placenta (fetal side) and measured DNA methylation using Illumina EPIC arrays. Using linear regression models to quantify associations at 720,077 cytosine-guanine dinucleotides (CpGs), with adjustment for maternal age, gravidity, smoking, BMI, child sex, and gestational age at delivery, we identified 188 CpG sites where placental DNA methylation was associated with Matsuda index (P < 6.94 × 10−8). Among genes annotated to these 188 CpGs, we found enrichment in targets for miRNAs, in histone modifications, and in parent-of-origin DNA methylation including the H19/MIR675 locus (paternally imprinted). We identified 12 known placenta imprinted genes, including KCNQ1. Mendelian randomization analyses revealed five loci where placenta DNA methylation may causally influence maternal insulin sensitivity, including the maternally imprinted gene DLGAP2. Our results suggest that placental DNA methylation is fundamentally linked to the regulation of maternal insulin sensitivity in pregnancy.

Obesity triggers complex inflammatory networks within the innate immune system. During pregnancy, the placenta amplifies the low-grade inflammation through activation of Toll-like receptor 4 (TLR4) signalling pathways. The purpose of this study was to investigate the impact of obesity on placental TLR4 expression and inflammatory signals. The secondary aim was to analyse the placental cell type responsible for TLR4 activation.Thirty-nine women recruited at term-scheduled Caesarean section were grouped according to their pre-gravid BMI (25 kg/m(2) and30 kg/m(2)). Placenta, venous maternal and cord blood were obtained at delivery for analysis. Data were analysed with linear regression and Spearman's rank correlation coefficient analysis.TLR4, IL6 and IL8 expression was increased three- to ninefold (p 0.001) in the placenta of obese vs lean women. There was a positive correlation between placental TLR4 and maternal systemic and placental IL6 and IL8 concentrations. Placental TLR4 expression was correlated with maternal pre-gravid BMI, insulin resistance index, plasma insulin and C-reactive protein (r = 0.57, 0.31, 0.35, 0.53, respectively; p 0.001) but not with plasma glucose, maternal age, gestational age and gestational weight gain (r 0.2; p 0.1). TLR4 was located in both trophoblast and macrovascular endothelial cells lining fetal vasculature. Lipopolysaccharide-induced TLR4 activation was more robust in trophoblasts than in endothelial vascular cells (100-fold vs tenfold; p 0.001).Trophoblastic TLR4 is strongly implicated in the propagation of placental inflammation. Placental inflammation is related to maternal metabolic conditions such as pre-gravid BMI, whilst gestational weight gain or gestational age are not. These results implicate the pre-gravid condition as a significant contributor to metabolic inflammation in late pregnancy.

During pregnancy, progesterone is exclusively produced by the placenta. As in all steroidogenic tissues, the first and rate-limiting step for the biosynthesis of placental progesterone is the import of cholesterol into the mitochondria via specific transporters. Plasma progesterone is 20% lower in pregnant obese women despite increased cholesterol availability suggesting an impairment in cholesterol import mechanisms. We investigated the role of the outer mitochondrial translocator protein (TSPO), the placental analog of StAR, as a potential regulator of placental progesterone production. Study design: Villous fragments of placentas were collected at term scheduled Cesarean delivery of lean and obese women with normal glucose tolerance. Trophoblast cells were isolated and plated for primary culture. In vitro silencing of TSPO was performed by transfecting primary trophoblast cells with siRNA. Progesterone production was measured in lysates of trophoblast cells before and after TSPO silencing. Results and Discussion: TSPO mRNA and protein expression were 2 to 3-fold lower in placentas of obese vs. lean women. TSPO siRNA silencing in trophoblast cells induced a 90% (p Disclosure M. Haghiac: None. J. Minium: None. Y. Skomorovska-Prokvolit: None. P. Catalano: None. S. Hauguel de Mouzon: None.

Maternal metabolic alterations are essential to achieve healthy pregnancy outcomes, but increasing maternal parity may be associated with long-term metabolic dysfunction risk. As existing data are limited by study design, our aim was to employ robust metabolic measures to determine whether or not physiological pregnancy alterations in maternal metabolic function persist at 1 year postpartum.We evaluated 21 healthy women, of whom 11 had an interval pregnancy (IP) and assessment at preconception, during pregnancy and 1 year postpartum, and 10 had no IP and assessment at baseline and a 1 year interval. Assessment measures included body composition, insulin sensitivity and response, and basal metabolic rate. For each measure, IP vs no IP and time intervals within each group were compared using nonparametric analyses, reporting median (IQR).IP and no IP women were similar at enrolment, and no IP women had similar metabolic profiles at enrolment and the 1 year interval. IP women exhibited expected metabolic changes during pregnancy compared with preconception. In IP women, preconception and postpartum measures, including fat mass (20.7 [13.7-37.4] kg vs 18.4 [13.8-41.3] kg; p = 0.2), total insulin response (AUC 11,459 [9,230-13,696] pmol/ml × min vs 11,522 [5,882-17,404] pmol/ml × min; p = 0.9), insulin sensitivity (0.12 [0.06-0.13] mg [kg fat-free mass (FFM)](-1) min(-1) vs 0.11 [0.10-0.15] mg [kg FFM](-1) min(-1); p = 0.1) and basal metabolic rate (0.092 [0.092-0.105] kJ min(-1) FFM vs 0.096 [0.088-0.096] kJ min(-1) FFM; p = 0.5), were similar.Our findings suggest pregnancy might not irreversibly alter maternal metabolic profile, measured at preconception through to 1 year postpartum. This result might be explained by a return to pre-pregnancy weight.

Low concentrations of estradiol and progesterone are hallmarks of adverse pregnancy outcomes as is maternal obesity. During pregnancy, placental cholesterol is the sole source of sex steroids. Cholesterol trafficking is the limiting step in sex steroid biosynthesis and is mainly mediated by the translocator protein (TSPO), present in the mitochondrial outer membrane.The objective of the study was to investigate the effects of maternal obesity in placental sex steroid biosynthesis and TSPO regulation.One hundred forty-four obese (body mass index 30-35 kg/m(2)) and 90 lean (body mass index 19-25 kg/m(2)) pregnant women (OP and LP, respectively) recruited at scheduled term cesarean delivery. Placenta and maternal blood were collected.This study was conducted at MetroHealth Medical Center (Cleveland, Ohio).Maternal metabolic components (fasting glucose, insulin, leptin, estradiol, progesterone, and total cholesterol) and placental weight were measured. Placenta (mitochondria and membranes separated) and cord blood cholesterol values were verified. The expression and regulation of TSPO and mitochondrial function were analyzed.Plasma estradiol and progesterone concentrations were significantly lower (P.04) in OP as compared with LP women. Maternal and cord plasma cholesterol were not different between groups. Placental citrate synthase activity and mitochondrial DNA, markers of mitochondrial density, were unchanged, but the mitochondrial cholesterol concentrations were 40% lower in the placenta of OP. TSPO gene and protein expressions were decreased 2-fold in the placenta of OP. In vitro trophoblast activation of the innate immune pathways with lipopolysaccharide and long-chain saturated fatty acids reduced TSPO expression by 2- to 3-fold (P.05).These data indicate that obesity in pregnancy impairs mitochondrial steroidogenic function through the negative regulation of mitochondrial TSPO.

Changes in adipose tissue metabolism are central to adaptation of whole body energy homeostasis to pregnancy. To gain insight into the molecular mechanisms supporting tissue remodeling, we have characterized the longitudinal changes of the adipose transcriptome in human pregnancy. Healthy nonobese women recruited pregravid were followed in early (8–12 wk) and in late (36–38 wk) pregnancy. Adipose tissue biopsies were obtained in the fasting state from the gluteal depot. The adipose transcriptome was examined via whole genome DNA microarray. Expression of immune-related genes and extracellular matrix components was measured using real-time RT-PCR. Adipose mass, adipocyte size, and cell number increased in late pregnancy compared with pregravid measurements ( P < 0.001) but remained unchanged in early pregnancy. The adipose transcriptome evolved during pregnancy with 10–15% of genes being differently expressed compared with pregravid. Functional gene cluster analysis revealed that the early molecular changes affected immune responses, angiogenesis, matrix remodeling, and lipid biosynthesis. Increased expression of macrophage markers (CD68, CD14, and the mannose-6 phosphate receptor) emphasized the recruitment of the immune network in both early and late pregnancy. The TLR4/NF-κB signaling pathway was enhanced specifically in relation to inflammatory adipokines and chemokines genes. We conclude that early recruitment of metabolic and immune molecular networks precedes the appearance of pregnancy-related physiological changes in adipose tissue. This biphasic pattern suggests that physiological inflammation is an early step preceding the development of insulin resistance, which peaks in late pregnancy.

OBJECTIVE—Women with gestational diabetes mellitus (GDM) demonstrate chronic and progressive insulin resistance and a markedly increased risk of converting to type 2 diabetes after pregnancy. However, the cellular mechanisms underlying this insulin resistance are unknown. RESEARCH DESIGN AND METHODS—We investigated the progression of insulin resistance in nine obese women with GDM during late pregnancy (30–36 weeks) and 1 year postpartum. Skeletal muscle biopsies were obtained at each visit, and insulin resistance was determined by the hyperinsulinemic-euglycemic clamp technique. RESULTS—Insulin resistance was not significantly improved in GDM women (4.1 ± 0.4 vs. 5.8 ± 1.1 10−2 mg · kg FFM · min−1/μU · ml−1). Subjects did not experience significant weight loss postpartum. Body weight, fat mass, fasting glucose, and plasma tumor necrosis factor (TNF)-α remained higher 1 year postpartum than seen in previously studied normal glucose-tolerant women. Skeletal muscle TNF-α mRNA was elevated five- to sixfold in GDM women and remained higher 1 year postpartum. While levels of insulin receptor (IR), IR substrate (IRS)-1, and p85α improved postpartum, insulin-stimulated IR tyrosine phosphorylation and receptor tyrosine kinase activity did not significantly improve postpartum in GDM. The levels of 312Ser-IRS-1 also did not improve postpartum and correlated with TNF-α mRNA (r2 = 0.19, P < 0.03), consistent with a state of subclinical inflammation and chronic skeletal muscle insulin resistance. CONCLUSIONS—These results suggest the mechanisms underlying chronic insulin resistance in GDM women may be driven by increased inflammation that impinges on the IR and IRS-1 signaling cascade in skeletal muscle. These findings have important implications for the health of GDM women during subsequent pregnancies and their risk for progression to type 2 diabetes.

Objective Long-chain omega 3 fatty acids, eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3) exert potent anti-inflammatory properties in humans. This study characterized the effects of omega-3 ω-3 fatty acids supplements (ω-3 FA) on the inflammatory status in the placenta and adipose tissue of overweight/obese pregnant women. Study Design A randomized, double-masked controlled trial was conducted in overweight/obese pregnant women that were randomly assigned to receive DHA plus EPA (2g/day) or the equivalent of a placebo twice a day from week 10–16 to term. Inflammatory pathways were characterized in: 1) adipose tissue and placenta of treated vs. untreated women; and 2) adipose and trophoblast cells cultured with long chain FAs. Results The sum of plasma DHA and EPA increased by 5.8 fold and ω-3 FA/ ω-6 FA ratio was 1.5 in treated vs. untreated women (p< 0.005). Plasma CRP concentrations were reduced (p25 weeks reduced inflammation in maternal adipose and the placental tissue. TLR4 appears as a central target of the anti-inflammatory effects at the cellular level. Trial Registration ClinicalTrials.gov NCT00957476

STUDY QUESTION What are the effects of fatty acids on placental inflammatory cytokine with respect to toll-like receptor-4/nuclear factor-kappa B (TLR4/NF-kB)? SUMMARY ANSWER Exogenous fatty acids induce a pro-inflammatory cytokine response in human placental cells in vitro via activation of TLR4 signaling pathways. WHAT IS KNOWN ALREADY The placenta is exposed to changes in circulating maternal fatty acid concentrations throughout pregnancy. Fatty acids are master regulators of innate immune pathways through recruitment of toll-like receptors and activation of cytokine synthesis. STUDY DESIGN, SIZE, DURATION Trophoblast cells isolated from 14 normal term human placentas were incubated with long chain fatty acids (FA) of different carbon length and degree of saturation. The expression and secretion of interleukin-6 (IL-6), IL-8 and tumor necrosis factor-alpha (TNF-α) were measured by reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. Antibodies against TLR4 ligand binding domain, downstream signaling and anti-p65 NFkB-inhibitor were used to characterize the pathways of FA action. PARTICIPANTS/MATERIALS, SETTING, METHODS General approach used primary human term trophoblast cell culture. Methods and end-points used real-time quantitative PCR, cytokine measurements, immunohistochemistry, western blots. MAIN RESULTS AND THE ROLE OF CHANCE The long chain saturated fatty acids, stearic and palmitic (PA), stimulated the synthesis as well as the release of TNF-α, IL-6 and IL-8 by trophoblast cells (2- to 6-fold, P < 0.001). In contrast, the unsaturated (palmitoleic, oleic, linoleic) acids did not modify cytokine expression significantly. Palmitate-induced inflammatory effects were mediated via TLR4 activation, NF-kB phosphorylation and nuclear translocation. LIMITATIONS, REASONS FOR CAUTION TNF-α protein level was close to the limit of detection in the culture medium even when cells were cultured with PA. WIDER IMPLICATIONS OF THE FINDINGS These mechanisms open the way to a better understanding of how changes in maternal lipid homeostasis may regulate placental inflammatory status. STUDY FUNDING/COMPETING INTERESTS X.Y. was recipient of fellowship award from West China Second University Hospital, Sichuan University (NIH HD 22965-19). The authors have nothing else to disclose. TRIAL REGISTRATION NUMBER None.

Adiponectin is upregulated during adipogenesis and downregulated in insulin-resistant states. The mechanism(s) governing the re-arrangements from adipogenesis to facilitated lipolysis during pregnancy are unknown. Our purpose was to analyse the role of adiponectin relative to the metabolic changes in human pregnancy.Lean women (BMI25 kg/m(2)) were evaluated longitudinally before conception, and in early (12-14 weeks) and late (34-36 weeks) pregnancy. Insulin sensitivity was measured using the glucose clamp technique. Venous blood and subcutaneous adipose tissue biopsies were obtained at each time point.Adiponectin concentrations were lower in the third trimester than in the pregravid condition (9.9+/-1.4 vs 13.5+/-1.8 microg/ml). The hypoadiponectinaemia was reflected by a 2.5-fold decrease in white adipose tissue adiponectin mRNA. These changes were associated with a 25% increase in fat mass (23.7+/-2.9 vs 18.9+/-2.9 kg). Insulin infusion decreased high molecular weight adiponectin complexes in pregravid women (9.9+/-0.6 vs 6.2+/-0.06) and the suppressive effect of insulin was lost during pregnancy. The pregnancy-mediated changes in adiponectin were strongly correlated with basal insulin levels and insulin sensitivity (p0.0001). The relationship between adiponectin and insulin sensitivity was related to the decreased insulin regulation of glucose utilisation (r=0.55, p0.001) but not of endogenous hepatic glucose production.These data demonstrate that pregnancy is associated with adiponectin changes in lean women. Hypoadiponectinaemia is reflected by a lower amount of high molecular weight adiponectin and by the ratio of high to low molecular weight multimers. The adiponectin changes relate to decreased insulin sensitivity of glucose disposal rather than alterations of lipid metabolism.

A physiological state of insulin resistance is required to preferentially direct maternal nutrients toward the feto-placental unit, allowing adequate growth of the fetus. When women develop gestational diabetes mellitus (GDM), insulin resistance is more severe and disrupts the intrauterine milieu, resulting in accelerated fetal development with increased risk of macrosomia. As a natural interface between mother and fetus, the placenta is the obligatory target of such environmental changes. However, the molecular basis for the imbalance that leads to fetal, neonatal, and adult metabolic compromises is not well understood. We report that GDM elicits major changes in the expression profile of placental genes with a prominent increase in markers and mediators of inflammation. Within the 435 transcripts reproducibly modified, genes for stress-activated and inflammatory responses represented the largest functional cluster (18.5% of regulated genes). Upregulation of interleukins, leptin, and tumor necrosis factor-α receptors and their downstream molecular adaptors indicated an activation of pathways recruiting stress-activated protein/c-Jun NH2-terminal kinases. Transcriptional activation of extracellular matrix components and angiogenic activators pointed to a major structural reorganization of the placenta. Thus, placental transcriptome emerges as a primary target of the altered environment of diabetic pregnancy. The genes identified provide the basis to elucidate links between inflammatory pathways and GDM-associated insulin resistance.

The sensitivity of the placenta to maternal insulin remains controversial. Early pregnancy may be a time of increased placental sensitivity to maternal insulin because insulin receptors are abundant on the syncytiotrophoblast in the first trimester but are far fewer at term.Maternal insulin secretory response in early, but not late, pregnancy is positively associated with placental growth.This is a secondary analysis of a cohort of women (n = 40) recruited before pregnancy.An iv glucose tolerance test was administered before pregnancy and in early (12-14 weeks) and late (34-36 weeks) pregnancy. Placental volume throughout gestation (in a subset of women via 3-dimensional ultrasound) and weight at birth were recorded.Total insulin secretory response in early pregnancy was positively associated with placental volume in early pregnancy (R = 0.79, P = 0.04) and placental weight at term (R = 0.42, P = 0.007). Insulin secretory response before and in late pregnancy was not significantly associated with placental growth. Although neonatal fat mass was strongly correlated with placental weight at term (R = 0.449, P = 0.0003), maternal insulin secretory response was related to neonatal fat mass only at birth in male offspring (R = 0.59, P = 0.008).Maternal insulin secretory response in early pregnancy was strongly related to placental weight at birth. Thus, in early pregnancy, increased maternal insulin response as seen in obesity and gestational diabetes mellitus may be a key influence on placental growth, possibly due to the enhanced presence of placental insulin receptors on the maternal villous membrane early in gestation.

Adiponectin (adpN) production is down-regulated in several situations associated with insulin resistance. The hypoadiponectinemia, which develops in late pregnancy, suggests a role of adpN in pregnancy-induced insulin resistance.In obese pregnancy there is a decreased systemic adpN, which results from down-regulation of gene expression in adipose tissue.One hundred and thirty-three women with uncomplicated pregnancies and a wide range in pre-gravid body mass index (18-62 kg/m(2)) were recruited at term for a scheduled cesarean delivery. Maternal blood, placenta, and sc abdominal adipose tissue were obtained in the fasting state. DNA methylation was analyzed by MBD-based genome-wide methylation sequencing and methyl-specific PCR of placenta and maternal adipose tissue. mRNA and protein expression were characterized by real-time RT-PCR and immunodetection. Plasma adpN, leptin, and insulin were assayed by ELISA.Maternal adipose tissue was the prominent site of adpN gene expression with no detectable mRNA or protein in placenta. In obese women, adipose tissue adpN mRNA was significantly decreased (P.01) whereas DNA methylation was significantly increased (P.001) compared with lean women. The decreased adipose tissue expression resulted in normal-weight women having significantly greater plasma adpN compared with the severely obese (12.8 ± 4.3 ng/mL vs 8.6 ± 3.1, P.001). Plasma adpN was negatively correlated with maternal body mass index (r = -0.28, P.001) and homeostasis model assessment indices of insulin sensitivity (r = -0.32, P.001) but not with gestational weight gain.Maternal adipose tissue is the primary source of circulating adpN during pregnancy. Further, based on our results, the placenta does not synthesize adiponectin at term. Obesity in pregnancy is associated with negative regulation of adpN adipose expression with increase in adpN DNA methylation associated with lower mRNA concentrations and hypoadiponectinemia. Maternal hypoadiponectinemia may have functional consequences in down-regulating biological signals transmitted by adpN receptors in various tissues, including the placenta.

Women with normal glucose tolerance pre-gravid and developing gestational diabetes in late gestation have subclinical metabolic dysfunction prior to conception compared with women with normal glucose tolerance. Because of the 60 % decrease in insulin sensitivity with normal pregnancy, these women develop clinical hyperglycaemia/gestational diabetes in late gestation. The metabolic dysfunction includes impaired insulin response, decreased hepatic suppression of glucose production during insulin infusion and decreased insulin-stimulated glucose uptake in skeletal muscle, i.e. peripheral insulin resistance. The insulin resistance in normal glucose tolerance pregnancy is related to a decrease in the post-receptor insulin signalling cascade, specifically decreased insulin receptor substrate 1 tyrosine phosphorylation. In women with normal glucose tolerance this is reversed post-partum. In contrast, in gestational diabetes, in addition to the decrease in insulin receptor substrate 1 tyrosine phosphorylation, there is an additional decrease in tyrosine phosphorylation of the intracellular portion of the insulin receptor that is not related to the insulin receptor protein content. Post-partum women with gestational diabetes, who had retention of gestational weight gain, had no significant improvement in insulin sensitivity and increased inflammation expressed as increased plasma and skeletal muscle tumour necrosis factor alpha. The increased inflammation or meta-inflammation is a hallmark of obesity and during pregnancy develops in both white adipose tissue and placenta. Last gene array studies of placenta were associated with alterations in gene expression relating primarily to lipid in contrast to glucose metabolic pathways in gestational diabetes compared with Type 1 diabetes. Future studies are directed at decreasing inflammation prior to and during pregnancy using various lifestyle and nutritional interventions.

Women who develop gestational diabetes mellitus (GDM) have severe insulin resistance and markedly increased risk to develop subsequent type 2 diabetes. We investigated the effects of pregnancy and GDM on glucose transport activity and the expression and phosphorylation of the insulin receptor and insulin receptor substrate (IRS)-1 in human skeletal muscle fiber strips in vitro. Rectus abdominis muscle biopsies were obtained at the time of cesarean section from 11 pregnant women with normal glucose tolerance (pregnant control), 7 pregnant women with GDM, and 11 nonpregnant women undergoing elective surgery (nonpregnant control). Subjects were matched for age and similar degree of obesity. The rate of maximal insulin (10(-7) mol/l)-stimulated 2-deoxyglucose transport was reduced by 32% (P < 0.05) in muscle strips from the pregnant control group and even further in GDM subjects by 54% (P < 0.05 vs. pregnant control). The maximal effect of insulin on tyrosine phosphorylation of the insulin receptor was 37% lower (P < 0.05) in GDM subjects than in pregnant control subjects and was not related to changes in the abundance of the insulin receptor. Compared with nonpregnant control subjects, maximal insulin-stimulated IRS-1 tyrosine phosphorylation was significantly lower by 59 +/- 24% (mean +/- SD) (P < 0.05) and 62 +/- 28% (P < 0.05) in pregnant control and GDM subjects, respectively. This was reflected by a 23% (P < 0.05) and 44% (P < 0.002) reduction in IRS-1 protein levels in muscle from pregnant control and GDM subjects. Both pregnant control and GDM subjects exhibited a 1.5- to 2-fold increase in the levels of IRS-2 (P < 0.01) and p85alpha regulatory subunit of phosphatidylinositol (PI) 3-kinase (P < 0.05), despite reduced glucose transport activity. These data indicate that insulin resistance to glucose transport during pregnancy is uniquely associated with a decrease in IRS-1 tyrosine phosphorylation, primarily due to decreased expression of IRS-1 protein. However, in GDM subjects, a decrease in tyrosine phosphorylation of the insulin receptor beta-subunit is associated with further decreases in glucose transport activity. Thus, impaired insulin receptor autophosphorylation is an important early distinction underlying muscle insulin resistance in young women with GDM, and it may underlie future risk for the development of type 2 diabetes.

In 2010, the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) panel published consensus-based recommendations on the diagnosis and classification of hyperglycemia in pregnancy (1). Within that document, the recommendations regarding early pregnancy testing were designed to facilitate early detection and treatment of hyperglycemia (HbA1c ≥6.5% [48 mmol/mol], fasting venous plasma glucose ≥7.0 mmol/L, random plasma glucose ≥11.1 mmol/L with confirmation) that, outside pregnancy, would be classified as diabetes. The term “overt diabetes” was suggested to describe these women. Subsequently, the World Health Organization (WHO) adopted the IADPSG criteria with some modifications and promoted the use of the term “diabetes in pregnancy” (2) for this group. Cognizant that milder degrees of hyperglycemia would also be detected by early pregnancy testing, the IADPSG also recommended that fasting …

OBJECTIVE: Our purpose was to correlate maternal carbohydrate metabolism and parental morphometric measurements with neonatal birth weight, body composition, and placental weight. STUDY DESIGN: Sixteen singleton (six control and 10 abnormal glucose tolerance) infants had placental weight, birth weight, and estimates of body composition performed within 24 hours of birth. Independent variables considered were (1) maternal and paternal demographic and morphometric measures, (2) neonatal sex and gestational age, and (3) estimates of maternal carbohydrate metabolism, including basal hepatic glucose production, insulin response, and insulin sensitivity. All metabolic measurements were performed before conception and in early (12 to 14 weeks) and late (34 to 35 weeks) gestation. Best-fit stepwise regression analysis was used to relate the independent variables with placental weight, neonatal birth weight, fat-free mass, and fat mass. RESULTS: Insulin sensitivity in late gestation had the strongest correlation with placental weight ( R 2 = 0.28), neonatal birth weight ( R 2 = 0.28), and fat-free mass ( R 2 = 0.33). In contrast, insulin sensitivity before conception had the best correlation with neonatal fat mass ( R 2 = 0.15). Including all significant independent variables in the model improved the correlations for placental weight ( R 2 = 0.58), birth weight ( R 2 = 0.48) fat-free mass ( R 2 = 0.53), and fat mass ( R 2 = 0.46). CONCLUSION: Maternal insulin sensitivity had stronger correlations with fetoplacental growth in comparison with maternal demographic or mophometric factors.

Increasing maternal obesity is a challenge that has an impact on all aspects of female reproduction. Lean and obese pregnant women gain similar fat mass, but lean women store fat in the lower-body compartment and obese women in central compartments. In the non-pregnant, central storage of fat is associated with adipocyte hypertrophy and represents a failure to adequately store excess fatty acids, resulting in metabolic dysregulation and ectopic fat accumulation (lipotoxicity). Obese pregnancy is associated with exaggerated metabolic adaptation, endothelial dysfunction and increased risk of adverse pregnancy outcome. We hypothesize that the preferential storage of fat in central rather than ‘safer’ lower-body depots in obese pregnancy leads to lipotoxicity. The combination of excess fatty acids and oxidative stress leads to the production of oxidized lipids, which can be cytotoxic and influence gene expression by acting as ligands for nuclear receptors. Lipid excess and oxidative stress provoke endothelial dysfunction. Oxidized lipids can inhibit trophoblast invasion and influence placental development, lipid metabolism and transport and can also affect fetal developmental pathways. As lipotoxicity has the capability of influencing both maternal endothelial function and placental function, it may link maternal obesity and placentally related adverse pregnancy outcomes such as miscarriage and pre-eclampsia. The combination of excess/altered lipid nutrient supply, suboptimal in utero metabolic environment and alterations in placental gene expression, inflammation and metabolism may also induce obesity in the offspring.

High plasma adiponectin concentrations in human fetuses and neonates are unique features of early developmental stages. Yet, the origins of the high adiponectin concentrations in the perinatal period remain elusive.This study was undertaken to identify the sources and functional properties of adiponectin in utero.Tissue specimens were obtained at autopsy from 21- to 39-wk-old stillborn human fetuses. Adipose tissue and placenta were obtained at term elective cesarean section. Adiponectin complexes and expression were measured by immunodetection and real-time PCR.Adiponectin mRNA transcripts were detected in fetal sc and omental adipose depots at lower concentrations than in maternal adipose tissue. Immunoreactive adiponectin was also observed in vascular endothelial cells of fetal organs, including skeletal muscle, kidney, and brain. The absence of adiponectin in all placental cell types and lack of correlation between maternal and umbilical adiponectin indicate that umbilical adiponectin reflects its exclusive production by fetal tissues. The most prominent forms of adiponectin in fetal plasma were high and low molecular mass (HMW and LMW) multimers of 340 and 160 kDa, respectively. The proportion of the HMW complexes was 5-fold (P0.001) higher in umbilical plasma than in adult. The high HMW and total adiponectin levels were associated with lower insulin concentration and lower homeostasis model of assessment of insulin resistance indices in umbilical plasma, reflecting higher insulin sensitivity of the fetus compared with adult.The abundance of HMW adiponectin and its vascular expression are characteristics of human fetal adiponectin. Combined with high insulin sensitivity, fetal adiponectin may be a critical determinant of in utero growth.

Obesity and pregnancy are associated with a combination of insulin resistance and inflammatory changes which exacerbate in combination. Based on the similarity between the inflammatory transcriptomes of adipose tissue and placenta, we hypothesized that the placenta develops exaggerated inflammation in response to obesity. The aim of this study was to characterize placental inflammatory mediators and macrophage accumulation in relation to peripheral inflammation in obesity. Placental macrophages and maternal peripheral blood mononuclear cells (PBMC) from 20 obese and 15 lean women were functionally and phenotypically characterized using immunohistochemistry, flow cytometry and expression for macrophage markers and inflammatory cytokines. The number of resident CD68+ and CD14+ cells was increased 2–3 fold in the placenta of obese as compared to lean women. The macrophage population was characterized by a marked phenotypic heterogeneity with complex subsets of CD14+, CD68+ and CD11b+ (mac-1) cells and by an increased expression of the pro-inflammatory cytokines IL-1, TNF-alpha, IL-6. Placental inflammation was associated with an activation of PBMC gene expression with an increase in the monocyte differentiation and maturation markers CD14 and CD68 in maternal but not fetal PBMC. The inflammatory changes were associated with higher plasma concentrations of C-reactive protein and IL-6 in obese compared to lean women. In conclusion, the chronic inflammation state of pre-gravid obesity is extending to in utero life with accumulation of a heterogeneous macrophage population and pro-inflammatory mediators in the placenta. The resulting inflammatory milieu in which the fetus develops may have critical consequences for short and long term programming of obesity.

Islet cell antibodies (ICAs) are markers for patients at risk for insulin-dependent diabetes and are associated with progressive β-cell destruction. This prospective study was performed to estimate the incidence of these antibodies in 187 women with previous gestational diabetes. With a specific protein A monoclonal antibody (MoAb) assay, the incidence of ICAs was only 1.6% (3 of 187). Oral and intravenous glucose tolerance tests were performed in these 3 women and compared with 6 women with previous gestational diabetes without ICAs and 5 control women. Glucose tolerance was impaired only in the 3 women with ICAs, who also had an increase (P < 0.03) in fasting plasma glucose and a decrease (P < 0.03) in early first-phase insulin response. We conclude that the more specific MoAb method indicates a lower incidence of ICA in women with a history of gestational diabetes than previously reported and that a decreased first-phase insulin response is associated with the presence of ICAs, suggesting progressive islet cell damage.

The purpose of this study was to investigate the effects of insulin on human placental transcriptome and biological processes in first-trimester pregnancy.Maternal plasma and placenta villous tissue were obtained at the time of voluntary termination of pregnancy (7-12 weeks) from 17 lean (body mass index, 20.9±1.5 kg/m2) and 18 obese (body mass index, 33.5±2.6 kg/m2) women. Trophoblast cells were immediately isolated for in vitro treatment with insulin or vehicle. Patterns of global gene expression were analyzed using genome microarray profiling after hybridization to Human Gene 1.1 ST and real time reverse transcription-polymerase chain reaction.The global trophoblast transcriptome was qualitatively separated in insulin-treated vs untreated trophoblasts of lean women. The number of insulin-sensitive genes detected in the trophoblasts of lean women was 2875 (P.001). Maternal obesity reduced the number of insulin-sensitive genes recovered by 30-fold. Insulin significantly impaired several gene networks regulating cell cycle and cholesterol homeostasis but did not modify pathways related to glucose transport. Obesity associated with high insulin and insulin resistance, but not maternal hyperinsulinemia alone, impaired the global gene profiling of early gestation placenta, highlighting mitochondrial dysfunction and decreased energy metabolism.We report for the first time that human trophoblast cells are highly sensitive to insulin regulation in early gestation. Maternal obesity associated with insulin resistance programs the placental transcriptome toward refractoriness to insulin with potential adverse consequences for placental structure and function.

Introduction. Increased adiposity in fetuses of women with abnormal glucose tolerance has been associated with an increased risk to develop obesity and type-2 diabetes in later life. Maternal anthropometric and metabolic parameters can explain only part of the fetal fat mass variance, suggesting that other factors may be involved. As the primary interface between maternal and fetal circulation, the placenta is a major determinant of nutrient flux from mother to fetus. However the role of placental genes in controlling nutrient availability has not been widely studied. Knowledge is even more limited in understanding diabetes-induced modifications of placental functions. To gain insight into the molecular mechanisms that alter placental metabolic pathways, we have constructed the gene expression profile of placenta from women with normal glucose tolerance and with gestational diabetes (GDM). Methods. Global gene screening was performed by oligonucleotide microarray analysis (Human U133 Affymetrix) of placenta obtained at term from lean controls, obese controls and women with gestational diabetes (GDM). Anthropometric data were obtained in the neonates within 48 hours from the delicery; neonatal body composition was estimated by total body electrical conductivity (TOBEC) and macrosomia was defined as % body fat > 14. Results. A four-step selection criteria was applied to identify significantly modified genes in relation to fetal macrosomia. 136 genes encoding proteins for glucose and lipid metabolism were expressed in normal placenta. 38.2 % of these genes were significantly regulated in placenta of macrosomic neonates from GDM patients and only 5.1 % were modified in placenta of macrosomic neonates from obese women. In GDM, about half of the regulated genes were related to lipid metabolism, primarily encoding rate-limiting enzymes for fatty acid transport, triglycerides and cholesterol synthesis. Genes for leptin and leptin receptor were also up-regulated while lipoprotein lipase and NPY receptor were the only genes down-regulated in the lipid cluster. Despite the diabetic milieu, no genes were modified in relation to glucose transport but, the expression of glycogenin 2, a self initiator of glycogen synthesis was increased.

Context: Obesity and diabetes during pregnancy are associated with increased insulin resistance and higher neonatal adiposity. In turn, insulin resistance triggers inflammatory pathways with accumulation of placental cytokines.Objective: To determine placental signals that translate into development of excess adipose tissue, we investigated the role of phospholipases A2 (PLA2) as targets of inflammatory mediators.Setting: The study was conducted at Case Western Reserve University, Department of Reproductive Biology.Subjects: Volunteers gave informed written consent in accordance with the Institutional Review Board guidelines. Placenta and cord blood samples were obtained at the time of elective cesarean section in 15 term pregnancies.Intervention: Neonatal anthropometric measurements were performed within 48 h of delivery. Placentas were grouped based on neonatal percentage body fat as obese (body fat ≥ 16%) and lean control (body fat ≤ 8%).Main Outcome Measures: The primary outcomes were placenta PLA2 expression and fatty acid concentration.Results: Expression of PLA2G2A and PLA2G5, the main placenta phospholipases, was greater (P < 0.05) in placenta of obese compared with control neonates and was associated with increased 20:3 and 20:5 omega-3 polyunsaturated fatty acids. TNF-α and leptin content was increased 3-fold in placenta of obese neonates. TNF-α and leptin both induced a time-dependent activation of PLA2G2 and PLA2G5 in placental cells.Conclusion: Accumulation of omega-3 fatty acids through secretory PLA2 activation is associated with high neonatal adiposity. We propose that the generation of placental lipid mediators through TNF-α and leptin stimulation represents a key mechanism to favor excess fetal fat accretion.

The restoration of maternal insulin sensitivity postpartum represents an important physiological and metabolic adaptation in a woman's reproductive lifespan. The present study was conducted to examine the potential cellular mechanisms underlying the changes in insulin sensitivity from late pregnancy to postpartum in human skeletal muscle. Nine nonobese women (age, 32 +/- 2 yr; body mass index, 21.2 +/- 0.8 kg/m(2)) with normal glucose tolerance were studied during late pregnancy (30-36 wk) and again approximately 1 yr postpartum using a euglycemic-hyperinsulinemic clamp (5 mm glucose, 40 mU/m(2).min insulin) to determine insulin sensitivity. Biopsies of the vastus lateralis muscle were obtained in the basal state before each clamp. Insulin sensitivity improved by 74% from late pregnancy to 1 yr postpartum (5.5 +/- 0.6 vs. 9.6 +/- 0.9 mg/kg fat-free mass.min; P < 0.005). Skeletal muscle insulin receptor (IR) protein expression increased by 42% postpartum, as measured by ELISA (4.0 +/- 0.6 vs. 5.7 +/- 0.6 ng/g protein; P < 0.05) and by Western blotting of the IR beta-subunit (28.7 +/- 4.7 vs. 42.0 +/- 4.8 arbitrary units; P < 0.003). However, in vitro studies showed that when adjusted for IR concentration, maximal insulin-stimulated (100 nm) IR tyrosine phosphorylation (0.75 +/- 0.06 vs. 0.92 +/- 0.08 U) and IR tyrosine kinase activity (183.8 +/- 27.0 vs. 204.3 +/- 23.7 fmol ATP/ng IR) were unchanged. There was a 69% increase in IR substrate-1 (IRS-1) protein expression (P = 0.05) in muscle postpartum. In addition, the p85alpha regulatory subunit of phosphatidylinositol 3-kinase was markedly reduced by 55% (P < 0.02) postpartum. The change in insulin sensitivity from late pregnancy to postpartum correlated highly with the corresponding change in IRS-1 protein (r = 0.84; P < 0.007). Downstream signaling proteins, including total Akt and p70s6 kinase, and the glucose transporter protein GLUT-4, were similar at both time points. These data suggest that reduced IR tyrosine kinase activity is not a major factor in the IR of pregnancy in lean women with normal glucose tolerance. Rather, the reversal of insulin resistance 1 yr postpartum is accompanied by increased skeletal muscle IRS-1 along with a down-regulation of the p85alpha subunit of phosphatidylinositol 3-kinase. These changes may allow for greater p85/p110 binding to IRS-1 and play a significant physiological role in the underlying metabolic adaptation to normal human pregnancy and restoration of insulin sensitivity postpartum.

Our primary objective was to evaluate changes in energy expenditure and body composition in women with normal glucose tolerance (NGT) and gestational diabetes mellitus (GDM). A secondary objective was to examine the relationship between maternal leptin and nutrient metabolism. Fifteen obese women, eight with NGT and seven with GDM, were evaluated before conception (P), at 12–14 wk (E), and at 34–36 wk (L). Energy expenditure and glucose and fat metabolism were measured using indirect calorimetry. Basal hepatic glucose production was measured using [6,6-2H2]glucose and insulin sensitivity by euglycemic clamp. There was a significant increase (6.6 kg, P = 0.0001) in fat mass from P to L. There was a 30% ( P = 0.0001) increase in basal O2 consumprion (V̇o2, ml/min). There were no significant changes in carbohydrate oxidation during fasting or storage from P to L. There was, however, a significant ( P = 0.0001) 150% increase in basal fat oxidation (mg/min) from P to L. Under hyperinsulinemic conditions, there were similar 25% increases in V̇o2 ( P = 0.0001) from P to L in both groups. Because of the significant increases in insulin resistance from P to L, there was a significant ( P = 0.0001) decrease in carbohydrate oxidation and storage. There was a net change from lipogenesis to lipolysis, i.e., fat oxidation (30–40 mg/min, P = 0.0001) from P to L. Serum leptin concentrations had a significant positive correlation with fat oxidation at E ( r = 0.76, P = 0.005) and L ( r = 0.72, P = 0.009). Pregnancy in obese women is associated with significant increases in fat mass and basal metabolic rate and an increased reliance on lipids both in the basal state and during the clamp. These modifications are similar in women with NGT and GDM. The increased reliance on fat metabolism is accompanied by a concomitant decrease in carbohydrate metabolism during hyperinsulinemia. The increase in fat oxidation may be related to increased maternal serum leptin.

Historically, insulin resistance during pregnancy has been ascribed to increased production of placental hormones and cortisol. The purpose of this study was to test this hypothesis by correlating the longitudinal changes in insulin sensitivity during pregnancy with changes in placental hormones, cortisol, leptin, and tumor necrosis factor (TNF)-α. Insulin resistance was assessed in 15 women (5 with gestational diabetes mellitus [GDM] and 10 with normal glucose tolerance) using the euglycemic-hyperinsulinemic clamp procedure, before pregnancy (pregravid) and during early (12–14 weeks) and late (34–36 weeks) gestation. Body composition, plasma TNF-α, leptin, cortisol, and reproductive hormones (human chorionic gonadotropin, estradiol, progesterone, human placental lactogen, and prolactin) were measured in conjunction with the clamps. Placental TNF-α was measured in vitro using dually perfused human placental cotyledon from five additional subjects. Compared with pregravid, insulin resistance was evident during late pregnancy in all women (12.4 ± 1.2 vs. 8.1 ± 0.8 10−2 mg · kg−1 fat-free mass · min−1 · μU−1 · ml−1). TNF-α, leptin, cortisol, all reproductive hormones, and fat mass were increased in late pregnancy (P < 0.001). In vitro, most of the placental TNF-α (94%) was released into the maternal circulation; 6% was released to the fetal side. During late pregnancy, TNF-α was inversely correlated with insulin sensitivity (r = −0.69, P < 0.006). Furthermore, among all of the hormonal changes measured in this study, the change in TNF-α from pregravid to late pregnancy was the only significant predictor of the change in insulin sensitivity (r = −0.60, P < 0.02). The placental reproductive hormones and cortisol did not correlate with insulin sensitivity in late pregnancy. Multivariate stepwise regression analysis revealed that TNF-α was the most significant independent predictor of insulin sensitivity (r = −0.67, P < 0.0001), even after adjustment for fat mass by covariance (r = 0.46, P < 0.01). These observations challenge the view that the classical reproductive hormones are the primary mediators of change in insulin sensitivity during gestation and provide the basis for including TNF-α in a new paradigm to explain insulin resistance in pregnancy.

Gestational diabetes mellitus (GDM) is associated with elevated postprandial free fatty acids (FFA) and insulin resistance; however, little is known about the cellular mechanisms underlying insulin resistance to suppress lipolysis during gestation. We evaluated the longitudinal changes in insulin suppression of FFA before pregnancy and in early (12–14 wk) and late (34–36 wk) gestation in obese subjects with normal glucose tolerance and in obese GDM subjects. Abdominal subcutaneous adipose tissue biopsies were also obtained during cesarean delivery from normal obese pregnant (Preg-Con), GDM, and nonpregnant obese control (Non-Preg-Con) subjects during gynecological surgery. GDM subjects had higher basal plasma FFA before pregnancy ( P = 0.055). Insulin's ability to suppress FFA levels declined from early to late gestation in both GDM and Preg-Con subjects and was significantly less in GDM subjects compared with Preg-Con subjects over time ( P = 0.025). Adipose tissue insulin receptor substrate (IRS)-1 protein levels were 43% lower ( P = 0.02) and p85α subunit of phosphatidylinositol 3-kinase was twofold higher ( P = 0.03) in GDM compared with Preg-Con subjects. The levels of peroxisome proliferator-activated receptor-γ (PPARγ) mRNA and protein were lower by 38% in Preg-Con ( P = 0.006) and by 48% in GDM subjects ( P = 0.005) compared with Non-Preg controls. Lipoprotein lipase and fatty acid-binding protein-2 mRNA levels were 73 and 52% lower in GDM compared with Preg-Con subjects ( P < 0.002). Thus GDM women have decreased IRS-1, which may contribute to reduced insulin suppression of lipolysis with advancing gestation. Decreased PPARγ and its target genes may be part of the molecular mechanism to accelerate fat catabolism to meet fetal nutrient demand in late gestation.

The cellular mechanisms for the insulin resistance of pregnancy and gestational diabetes mellitus (GDM) are unknown. The membrane protein plasma cell membrane glycoprotein-1 (PC-1) has been identified as an inhibitor of insulin receptor tyrosine kinase (IRTK) activity. We investigated insulin receptor function and PC-1 levels in muscle from three groups of obese subjects: women with GDM, pregnant women with normal glucose tolerance, and nonpregnant control subjects. Subjects (n = 6 for each group) were similar in age and degree of obesity (body fat >30%). IRTK activity, insulin receptor tyrosine phosphorylation, and protein levels of membrane glycoprotein PC-1 were determined in rectus abdominus muscle biopsies obtained at the time of either elective cesarean section or gynecological surgery. No significant differences were evident in basal insulin receptor tyrosine phosphorylation or IRTK activity in the three groups. After maximal insulin (10(-7) mol/l) stimulation, IRTK activity measured with the artificial substrate poly(Glu,Tyr) increased in all subjects but was lower in women with GDM by 25% (P < 0.05) and 39% (P < 0.001) compared with pregnant and nonpregnant control subjects, respectively. Similarly, insulin receptor tyrosine phosphorylation was significantly decreased in subjects with GDM (P < 0.05) compared with pregnant and nonpregnant control subjects. Treatment of the insulin receptors with alkaline phosphatase to dephosphorylate serine/threonine residues increased insulin-stimulated IRTK activity significantly in pregnant control and GDM subjects (P < 0.05), but these rates were still lower compared with nonpregnant control subjects (P < 0.05). PC-1 content in muscle from GDM subjects was increased by 63% compared with pregnant control subjects (P < 0.05) and by 206% compared with nonpregnant control subjects (P < 0.001). PC-1 content was negatively correlated with insulin receptor phosphorylation (r = -0.55, P < 0.05) and IRTK activity (r = -0.66, P < 0.05). These results indicate that pregnant control and GDM subjects had increased PC-1 content and suggest excessive phosphorylation of serine/threonine residues in muscle insulin receptors and that both may contribute to decreased IRTK activity. These changes worsen in women with GDM when controlling for obesity. These postreceptor defects in insulin signaling may contribute to the pathogenesis of GDM and the increased risk for type 2 diabetes later in life.

The longitudinal changes in glucose homeostasis that occur during normal human pregnancy provide for both maternal and fetoplacental metabolic demands. There are major adaptations in maternal glucose metabolism during pregnancy in nonobese women that result in increased maternal fat stores in early gestation and increased glucose availability for oxidative needs of the fetus and placenta in late gestation. In industrialized countries, problems relating to insufficient glucose availability are fortunately quite rare. In contrast, maternal and fetal problems associated with a surfeit of maternal glucose are becoming ever more common, particularly in various ethnic groups immigrating to industrialized countries.1

Exposure of the fetus to the intrauterine milieu can have profound effects on the health of the offspring in adulthood. Results of a series of studies demonstrate the powerful influence of the mother's metabolic state on whether the emerging adult develops obesity and hyperinsulinemia. Importantly, these attributes can be passed on to the next generation nongenetically and can be reversed and prevented.

hypothesis. STUDY DESIGN: This open-label multicentre randomised controlled trial took place at 13 French university hospitals and included women with singleton pregnancies admitted at 24 0 through 31 6 weeks of gestation with a cervical length 25 mm for an episode of preterm labour that was then successfully arrested by tocolytic treatment. A course of betamethasone 12 mg, repeated after 24 hours, was given intramuscularly in all patients. Women were randomly assigned (by a centralised, computer-generated randomisation process) in a 1:1 ratio to receive either 500 mg of intramuscular 17 alpha-hydroxyprogesterone caproate (17P), started after tocolysis ended and repeated twice weekly until 36 weeks or until preterm delivery, or no treatment with 17P. Additional management in the two arms was left to the discretion of the attending physician, except that progesterone was not allowed in the control group. The primary outcome was time from randomisation to delivery, assessed according to the intention-totreat principle. RESULTS: A total of 188 women were randomised. The two groups were similar with respect to baseline characteristics. Outcome data were available for 184 women. There was no significant difference between the 17P and control groups in median [Q1-Q3] time to delivery (64 [42-79] and 67 [46-83] days, respectively; mean difference, -2; 95% confidence interval, -9 to 6) or in the rates of delivery before 37 (39% and 38%, p 0.99), 34 (16% and 20%, p 0.57), or 32 (9% vs 14%, p 0.35) weeks of gestation. Finally, rates of adverse perinatal outcomes did not differ significantly between the groups. CONCLUSION: Biweekly injections of 500 mg of 17P did not prolong pregnancy significantly in women with an episode of preterm labour successfully arrested by tocolytic treatment.

Objective The purpose of this study was to gain insight into the pathways that are associated with inflammation at the maternal–fetal interface. This study examined the molecular characteristics of monocytes that were derived from the maternal circulation and the placenta of obese women. Study Design Mononuclear cells were isolated from placenta, venous maternal, and umbilical cord blood at term delivery; activated monocytes were separated with CD14 immunoselection. The genotype and expression pattern of the monocytes were analyzed by microarray and real-time reverse transcriptase–polymerase chain reaction. Results The transcriptome of the maternal blood and placental CD14 monocytes exhibited 73% homology, with 10% (1800 common genes) differentially expressed. Genes for immune sensing and regulation, matrix remodeling, and lipid metabolism were enhanced 2-2006 fold in placenta, compared with maternal monocytes. The CD14 placental monocytes exhibited a maternal genotype (9% DYS14 expression) as opposed to the fetal genotype (90% DYS14 expression) of the trophoblast cells. Conclusion CD14 monocytes from the maternal blood and the placenta share strong phenotypic and genotypic similarities with an enhanced inflammatory pattern in the placenta. The functional traits of the CD14 blood and placental monocytes suggest that they both contribute to propagation of inflammation at the maternal–fetal interface.

A total of 143 women with known risk factors for genital herpes simplex virus had cultures performed at the time of delivery. A total of 123 were without symptoms, of which three (2.4%) had positive herpes simplex virus cultures at the time of delivery. Fifteen women had lesions clinically consistent with genital herpes simplex virus at the time of delivery and five (33.3%) were culture positive. Five women had only prodromal symptoms of genital herpes simplex virus, but two of these (40%) had positive herpes simplex virus cultures from the site of previous lesions. Of the 10 women with positive herpes simplex virus cultures in this group of 143, no infant was delivered with evidence of neonatal herpes simplex virus infection, including two who had vaginal deliveries. The results of this study support the recommendations that in women without symptoms but with known risk factors for genital herpes simplex virus, a trial of vaginal delivery be allowed and that in women with either a lesion clinically consistent with genital herpes simplex virus or prodromal symptoms of genital herpes simplex virus a cesarean section be the mode of delivery.