Anorexia nervosa (AN) is associated with profound changes in glucose homeostasis, activity of the GH-IGF-1 axis, and adipose tissue, bone, and protein metabolism. We aimed to characterize the transition from a catabolic to anabolic state during the nutritional rehabilitation of female adolescent inpatients with AN. The study comprised 41 patients (aged 15.6 ± 1.6 yr). Blood samples were obtained at the time of admission and upon attainment of target weight. A subgroup of 18 patients also had blood samples obtained during the early refeeding period. Changes in body mass index (BMI) and BMI-SDS during hospitalization (5.1 ± 2.0 mo) were positively correlated with changes in markers of anabolism including IGF-1 (r = 0.424, P = 0.006), procollagen type I N-terminal propeptide (P1NP) (r = 0.375, P = 0.016), klotho (r = 0.468, P = 0.002), and alkaline phosphatase (ALP) (r = 0.051, P = 0.001) and were negatively correlated with the change in cortisol levels (r = -0.331, P = 0.035). Furthermore, changes in markers of anabolism were intercorrelated. IGF-1 increased consistently throughout the study period (P < 0.001); however, other variables showed a biphasic pattern. During the early refeeding period, there was a decrease in C-terminal telopeptides of type I collagen (CTX-1) (P < 0.001), uric acid (P < 0.001), cortisol (P = 0.056), fatty acid-binding protein 4 (FABP4) (P = 0.04), and klotho (P = 0.038) levels, whereas urea/creatinine ratio (UCR) (P = 0.045) increased. During the later phase, there was an increase in ALP (P = 0.039), insulin (P = 0.04), homeostatic model assessment for insulin resistance (HOMA-IR) (P = 0.06), and klotho levels (P = 0.02). In conclusion, the early refeeding period was characterized by a decrease in markers of catabolism, whereas the later phase was characterized by an increase in anabolic markers. We suggest that IGF-1, UCR, and klotho may be used as markers of reversal of catabolism and shift toward anabolism in patients with severe malnutrition.NEW & NOTEWORTHY We provide a comprehensive temporal characterization of changes in biochemical markers of glucose homeostasis, GH-IGF-1 axis activity, and adipose tissue, bone, and protein metabolism during refeeding of adolescents with anorexia nervosa. Although IGF-I levels increased continuously, other markers showed a biphasic pattern: an early decrease in catabolic markers, followed by an increase in anabolic markers later during hospitalization. IGF-1, urea/creatinine ratio, and klotho emerged as potential clinical biomarkers of catabolic to anabolic transition in patients with severe malnutrition.

Background Animal brain-tumor models have demonstrated a synergistic interaction between radiation therapy and a ketogenic diet (KD). Metformin has in-vitro anti-cancer activity, through AMPK activation and mTOR inhibition. We hypothesized that the metabolic stress induced by a KD combined with metformin would enhance radiation’s efficacy. We sought to assess the tolerability and feasibility of this approach. Methods A single-institution phase I clinical trial. Radiotherapy was either 60 or 35 Gy over 6 or 2 weeks, for newly diagnosed and recurrent gliomas, respectively. The dietary intervention consisted of a Modified Atkins Diet (ModAD) supplemented with medium chain triglycerides (MCT). There were three cohorts: Dietary intervention alone, and dietary intervention combined with low-dose or high-dose metformin; all patients received radiotherapy. Factors associated with blood ketone levels were investigated using a mixed-model analysis. Results A total of 13 patients were accrued, median age 61 years, of whom six had newly diagnosed and seven with recurrent disease. All completed radiation therapy; five patients stopped the metabolic intervention early. Metformin 850 mg three-times daily was poorly tolerated. There were no serious adverse events. Ketone levels were associated with dietary factors (ketogenic ratio, p < 0.001), use of metformin (p = 0. 02) and low insulin levels (p = 0.002). Median progression free survival was ten and four months for newly diagnosed and recurrent disease, respectively. Conclusions The intervention was well tolerated. Higher serum ketone levels were associated with both dietary intake and metformin use. The recommended phase II dose is eight weeks of a ModAD combined with 850 mg metformin twice daily.

OBJECTIVE:The Klotho protein family plays important roles in several metabolic pathways. Soluble Klotho has been recently put forward as an antiaging protein, demonstrating renal and cardiovascular protective traits. Cardiopulmonary bypass (CPB) support during cardiac surgery has been implicated in several adverse outcomes in pediatric and adult patients. Our goal was to assess whether serum Klotho levels can be used to predict outcomes in children undergoing cardiac surgery with CPB due to congenital heart defects (CHDs).METHODS:This prospective study was conducted on pediatric patients admitted to two Pediatric Cardiac Intensive Care Units, between 2012 and 2018. All patients were born with CHD and underwent corrective surgery with CPB. Sequential blood samples were analyzed by enzyme-linked immunosorbent assay for soluble Klotho levels at baseline, 2, 6, and 24 h after surgery. The association between Klotho levels and several demographic, intraoperative, and postoperative clinical and laboratory parameters was studied.RESULTS:Twenty-nine children undergoing cardiac surgery with CPB support were included. Serum Klotho levels were shown to significantly decrease 2 h after surgery and increase to baseline levels after 6 h (p < .001 and p < .05, respectively). Patients with low Klotho levels 2 h after surgery were at a 32-fold higher risk for developing postoperative complications (p = .015, odds ratio < 0.03). Moreover, Klotho levels at each of the four time points were lower in patients who developed postoperative complications.CONCLUSIONS:Cardiac surgery with CPB results in a significant decrease of serum Klotho levels 2 h after surgery in pediatric patients with CHDs, which can be used to predict development of postoperative complications in this patient population.

Design Gestational diabetes mellitus (GDM) is one of the most common pregnancy complications and its prevalence is constantly rising worldwide. Diagnosis is commonly in the late second or early third trimester of pregnancy, though the development of GDM starts early; hence, first-trimester diagnosis is feasible. Objective Our objective was to identify microRNAs that best distinguish GDM samples from those of healthy pregnant women and to evaluate the predictive value of microRNAs for GDM detection in the first trimester. Methods We investigated the abundance of circulating microRNAs in the plasma of pregnant women in their first trimester. Two populations were included in the study to enable population-specific as well as cross-population inspection of expression profiles. Each microRNA was tested for differential expression in GDM vs control samples, and their efficiency for GDM detection was evaluated using machine-learning models. Results Two upregulated microRNAs (miR-223 and miR-23a) were identified in GDM vs the control set, and validated on a new cohort of women. Using both microRNAs in a logistic-regression model, we achieved an AUC value of 0.91. We further demonstrated the overall predictive value of microRNAs using several types of multivariable machine-learning models that included the entire set of expressed microRNAs. All models achieved high accuracy when applied on the dataset (mean AUC = 0.77). The significance of the classification results was established via permutation tests. Conclusions Our findings suggest that circulating microRNAs are potential biomarkers for GDM in the first trimester. This warrants further examination and lays the foundation for producing a novel early non-invasive diagnostic tool for GDM.

MicroRNAs (miRNAs) are small noncoding RNAs that modulate gene expression, thus regulating biological processes in various tissues. In adipose tissue miRNAs regulate metabolic and endocrine functions, as well as the differentiation of adipocytes. The aim of this study was to compare the expression profile of miRNA of visceral and subcutaneous adipose tissues between pregnant and non-pregnant women. The miRNA expression profile from paired visceral and abdominal subcutaneous adipose tissues was characterized using the multiplexed NanoString nCounter system in 3 groups: 1. Normal pregnant women (n=8); 2. Patients with gestational diabetes mellitus (GDM) requiring insulin treatment (n=6); and 3. Non-pregnant women (n=4). Bioinformatics was employed to detect differentially expressed miRNAs and miRNA-regulated biological function. Results were validated using quantitative RT-PCR for selected miRNAs. 1. Expression differences were notable in visceral adipose tissue: 4 differentially expressed miRNAs were detected between normal pregnant women and patients with GDM, 2 between normal pregnant and non-pregnant women and 14 between GDM and non-pregnant women; 2. In subcutaneous adipose tissue the number of differentially expressed miRNA among the three groups was 3, 1 and 2, respectively; 3. miR-221-3p, miR-222-3p, miR-424-5p were the top overexpressed and miR-574-3p was underexpressed in visceral adipose tissue of patients with GDM compared to non-pregnant women and; 4. miR−551b−3p was underexpressed in visceral adipose tissue of patients with GDM compared to normal pregnant women; TaqMan Technology MicroRNA qPCR assays validated these findings for miR-221-3p (fold change=2.1±1.2, p=0.01) and miR-222-3p (fold change=2.3±1.0, p=0.04). miRNA expression profile of visceral and subcutaneous fat depots reveals pregnancy- and GDM-related distinctive pattern, most notably in the visceral adipose tissue. Both miR-221 and miR-222 have been implicated in adipocytes differentiation, adipose tissue oxidative stress, apoptosis and inflammation, providing a putative mechanism in the regulation of adaptations to normal gestation as well as putative novel mechanism of disease in GDM.

OBJECTIVE This pilot study aimed to assess the effect of continuous exposure to the odor of own mothers' breast milk (BM) on the stress parameters of preterm infants. MATERIALS AND METHODS Fifteen healthy preterm infants were included. Mean heart rate and salivary cortisol were measured over three consecutive time periods, each lasting 2 days: (1) preintervention (odor free); (2) intervention, during which a cotton pad soaked with 1.5 mL of BM was placed near the infant's head with the aim of providing continuous exposure to its odor; (3) postintervention period (odor free). RESULTS Saliva cortisol levels differed significantly between the three exposure periods (pre-, during, and post-BM odor exposure): 11.38 ± 5.03, 9.51 ± 4.38, and 4.99 ± 3.42 nmol/L, respectively. A repeated univariate analysis of the cortisol measure showed a significant difference (F = 9.34; df = 2.28, p < 0.001). There was no difference in mean heart rate over the three study periods. CONCLUSIONS Preterm infants exposed to BM odor from their own mothers demonstrate a persistent decrease in saliva cortisol levels, which continues after termination of the intervention. This finding may suggest that exposure to own mothers' BM odor has a soothing effect on preterm infants. Further randomized controlled studies are needed to evaluate this simple, safe, and inexpensive intervention.

Semaphorin 3E (Sema3E) is a novel adipokine implicated in the crosstalk between inflammation, obesity and insulin resistance. The aims of this study were to determine whether there is placental expression of Sema3E and its receptor, PlexinD1, in human placenta, and whether the expression is different in pregnancies complicated by gestational diabetes mellitus. This was a cross sectional study. Placental mRNA expression for Sema3E and its receptor, PlexinD1, was determined in two groups: 1. uncomplicated pregnant women (n=24) and 2. pregnant women with gestational diabetes mellitus (GDM) requiring insulin treatment (n=9). Non-parametric statistical methods were employed. 1. Placental mRNA expression of PlexinD1 was significantly higher in patients with GDM compared to women with normal gestation (1.32 vs. 0.82, p=0.02), but no difference was found in placental mRNA expression of Sema3E between these two groups (1.33 vs. 1.11, p=0.28); 2. In pooled analysis (normal pregnant women and patients with GDM), placental mRNA expression of both PlexinD1 and Sema3E were higher in obese versus lean/normal weight women (1.25 vs. 0.68, p=0.001; 1.43 vs. 0.98, p=0.04, respectively); 3. Among women with normal gestation, obese women had a higher placental mRNA expression of both PlexinD1 (p=0.001) and Sema3E (p=0.05) than normal weight women, while among patients with GDM, placental mRNA expression of both PlexinD1 and Sema3E (p=0.9 for both comparisons) was comparable between obese and normal weight women. The results of this study indicate that the human placenta constitutively expresses Sema3E and its high-affinity receptor, PlexinD1. Higher placental mRNA expression of PlexinD1 in patients with GDM compared to women with normal gestation, as well as higher placental mRNA expression of both PlexinD1 and Sema3E in obese compared to normal weight pregnant women, suggest that higher placental mRNA expression of PlexinD1 and Sema3E might be associated with increased insulin resistance, and that Sema3E and its receptor may be considered a regulatory mediators involved in metabolic adaptations to normal pregnancy as well as in the pathophysiology of pregnancy-related metabolic complications.

BackgroundPoor cardiovascular health (CVH) among ethnic/racial minorities, studied primarily in the USA, may reflect lower access to healthcare. We examined factors associated with minority CVH in a setting of universal access to healthcare.Methods and resultsCVH behaviors and factors were evaluated in a random population sample (551 Arabs, 553 Jews) stratified by sex, ethnicity and age. More Jews (10%) than Arabs (3%) had 3 ideal health behaviors. Only one participant had all four. Although ideal diet was rare (≤1.5%) across groups, Arabs were more likely to meet intake recommendations for whole grains, but less likely to meet intake recommendations for fruits/vegetables and fish. Arabs had lower odds of attaining ideal levels for body mass index and physical activity. Smoking prevalence was 57% among Arab men and 6% among Arab women. Having four ideal health factors (cholesterol, blood pressure, glucose, smoking) was observed in 2% and 8% of Arab and Jewish men, respectively, and 13% of Arab and Jewish women. Higher prevalence of ideal total-cholesterol corresponded to lower high-density lipoprotein cholesterol among Arabs. No participant met ideal levels for all 7 metrics and only 1.8% presented with 6. Accounting for age and lower socioeconomic status, Arabs were less likely to meet a greater number of metric goals (odds ratio (95% confidence interval): 0.62 (0.42–0.92) for men, and 0.73 (0.48–1.12) for women).ConclusionsIdeal CVH, rare altogether, was less prevalent among the Arab minority albeit universal access to healthcare. Health behaviors were the main contributors to the CVH disparity.

Metabolic syndrome (MetS) is a known complication after hematopoietic stem cell transplantations (HSCT) that contributes to long‐term morbidity. We assessed the prevalence of components of the MetS in pediatric survivors of allogeneic HSCT and identified associated risk factors. Thirty‐eight patients, median age at HSCT, 8.5 years, were evaluated at a median of 3.9 years post‐HSCT. Overweight or obesity was seen in 23.7% of the patients, 15.8% had hypertension, 15.8% had hypertriglyceridemia, and 13% had low high‐density lipoprotein cholesterol levels according to age and gender. Four (10.5%) met the criteria of MetS; all were transplanted for malignant disease. Twelve patients (31.6%) had at least one component of the MetS. The 5‐year probability of developing components of the MetS revealed that patients with BMI‐Z score ≥0 at HSCT were significantly at higher risk than those with lower BMI‐Z. Patients who developed components of the MetS had higher levels of insulin, homeostasis model assessment, uric acid, leptin, and lower adiponectin levels. Multivariable regression analysis revealed that BMI‐Z‐score >1.036 at time of evaluation was associated with 4.3‐fold increased risk (P=.050) and adiponectin levels ≤6 μg/mL were associated with 6.7‐fold increased risk of develop components of the MetS (P=.007). Overweight and obesity and adiponectin levels may be useful as markers in HSCT survivors.

Context. Klotho is an aging-modulating protein expressed mainly in the kidneys, which can be cleaved and shed to act as a circulating hormone. Several lines of evidence suggest a tight interaction between klotho and the GH-IGF-I axis. We showed previously that klotho levels are decreased in pediatric patients with growth hormone deficiency (GHD). Our aim now is to investigate the effect of GH therapy on klotho levels in these patients and to elucidate the role of IGF-1 in mediating secretion of klotho.Basic Procedures. Klotho levels were measured in 29 GHD pediatric patients (males = 15, aged 12.2 +/- 3.3 years), treated with GH for 2.5 +/- 2.8 years; nineteen patients had samples obtained both before and during treatment. The effect of IGF-I and its downstream effectors on secretion of klotho to media was studied in COS-7 cells overexpressing klotho.Main Findings. Klotho levels increased under GH treatment (from 1321 +/- 691 pg/ml to 3380 +/- 2120 pg/ml, p < 0.001), and were higher compared to controls (1645 +/- 778 pg/ml, p < 0.001), resulting in supraphysiological levels. Fold-increase in klotho correlated with fold-increase in IGF-I (r = 0.63, p = 0.004). Studies in COS-7 cells overexpressing klotho revealed mTOR-dependent induction of klotho shedding by IGF-I.Principal Conclusions. Klotho levels increased during GH treatment of pediatric GHD patients. This increase was associated with an increase in IGF-I levels. Furthermore, we showed, for the first time, a direct role of IGF-I in the regulation of klotho's shedding which depends on activation of the AKT-mTOR pathway. Our findings add further support for the close association between klotho and the GH/IGF-I axis. (C) 2016 Elsevier Inc. All rights reserved.

Persistent Müllerian duct syndrome (PMDS) is a rare genetic disorder of male internal sexual development defined as lack of regression of Müllerian derivatives in the 46XY male with normally virilized external genitalia and unilateral or bilateral cryptorchidism. Approximately 85% of all cases are caused by mutations in genes encoding anti-Müllerian hormone (AMH) or its receptor (AMHR2) with autosomal recessive transmission. This condition is frequently diagnosed incidentally, during surgical repair of inguinal hernia or cryptorchidism. There is no consensus on surgical approach: malignancy risk in the Müllerian duct remnant or undescended testis encourages early removal of the former and bilateral orchiopexy; however, removal of Müllerian structures can impair testicular and vas deferens blood supply, potentially causing infertility. Herein, we report on a male infant with PMDS caused by a novel homozygous missense mutation in AMHR2 (c.928C>T; p.Q310X), review the literature, and discuss the diverse clinical and surgical approaches to this condition.

Objective: Omentin, a newly identified adipokine, enhances insulin mediated glucose uptake in human adipocytes, thus, inducing systemic insulin-sensitizing effect. The aims of this study were to determine whether circulating maternal omentin levels are associated with insulin resistance indices and to assess which compartment, maternal, fetal, or placental, is the source of omentin in maternal circulation.Methods: Fasting serum glucose, insulin, and omentin were determined in 25 healthy pregnant women at the third trimester, before and 3 days after elective cesarean section. Cord blood omentin was measured in the 25 term neonates. Homeostasis model assessment (HOMA) was used to evaluate insulin sensitivity before and after delivery.Results: Antepartum maternal omentin levels were negatively correlated with insulin levels (r=-0.41, P=0.04) and positively correlated with insulin sensitivity (HOMA% S; r=0.4, P=0.04). Postpartum omentin levels were negatively correlated with maternal body mass index (r=-0.44, P=0.02). Median maternal omentin levels was comparable before and after delivery (57.2, inter-quartile range: 38.2-76.2 ng/mL vs. 53.4, 39.8-69.4 ng/mL, respectively, P=0.25) and highly correlated (r=0.83, P<0.001). Antepartum maternal and neonatal omentin levels did not differ significantly (fetal: 62.2, 44.3-74.2 ng/mL, P=0.77) and did not correlate (P=0.6).Conclusions: Circulating maternal omentin levels are correlated with insulin resistance indices, suggesting that this adipokine may play a role in metabolic adaptations of normal gestation. The strong correlation between anteparum and postpartum maternal omentin levels, as well as the lack of association between maternal and neonatal omentin levels, suggest that placental or fetal compartments are unlikely as the main source of circulating maternal omentin.

Background: Cystic fibrosis related diabetes (CFRD) is associated with a decrease in pulmonary function and nutritional status. We investigated the clinical significance of impaired glucose tolerance (IGT) in cystic fibrosis (CF) patients.Methods: Fifty-five CF patients (aged 22.8 +/- 9.2 years, 29 males, mean FEV1 67.9 +/- 22% predicted, mean BMI-SDS - 0.23 +/- 1.1) underwent a 2-h Oral Glucose Tolerance Test (OGTT) with 30-min interval measurements of glucose and insulin. Additional clinical and laboratory data were obtained from the medical charts.Results: Thirty-eight participants (69%) had normal glucose tolerance (NGT), 13 (23.7%) had IGT, and 4 (7.3%) had newly diagnosed CFRD. Compared to patients with NGT, patients with IGT had significantly lower BMI-SDS (-1.1 +/- 0.8 vs. 0.1 +/- 1.1, p < 0.001), mean FEV1 (57 +/- 19 vs. 74 +/- 21% predicted, p < 0.01), and albumin (3.9 +/- 0.3 vs. 4.3 +/- 0.2 g/dl, p = 0.004), and higher fibrinogen (376 +/- 56 vs. 327 +/- 48 g/dl, p = 0.02). Patients with IGT had impaired beta-cell function, with reduced first phase insulin secretion, a delayed insulin peak, and significantly lower total insulin secretion, HOMA-%B and insulinogenic index. Seven patients had HbA1c in the "diabetic'' range (>= 6.5%; 47.5 mmol/mol), however, HbA1c was not a sensitive or specific marker of glucose tolerance status.Conclusions: IGT in CF patients is associated with increased inflammation and decreased nutritional status and pulmonary function. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

ObjectiveSemaphorin 3E (SEMA3E), a previously known axon guiding molecule, has recently been shown to be a novel adipokine involved in adipose tissue inflammation and insulin resistance. The aim of this study was to determine circulating SEMA3E levels and their correlation with insulin resistance indices in pregnant and non-pregnant women.Study DesignFasting serum glucose, insulin and SEMA3E levels were determined in 45 healthy non-pregnant women and 67 pregnant women at the third trimester, including 9 women with GDMA2. The Homeostasis Model Assessment (HOMA) was used to evaluate insulin resistance. Non-parametric statistical methods were employed.ResultsIn non-pregnant women, SEMA3E levels were higher in lean versus obese/overweight women (1.27, IQR: 0.66-1.73 vs. 0.67, IQR: 0.45-1.11 ng/ml, respectively, p=0.02), and were highly negatively correlated with their BMI (r=-0.5, p<0.001). In normal pregnancy, maternal SEMA3E levels were positively correlated with insulin resistance (HOMA-IR; r=0.31, p=0.02), however, they did not differ significantly between lean and obese/overweight pregnant women (0.90, 0.51-0.148 vs. 1.13, 0.69-1.54 ng/ml, p=0.26). Maternal SEMA3E levels were significantly lower in GDMA2 compared with normal pregnancy (0.3, 0.3-0.4 vs. 0.95, 0.58-1.56 ng/ml, p<0.001). Finally, circulating maternal SEMA3E levels were higher in normal pregnancy compared with non-pregnant state (1.13, 0.69-1.54 vs. 0.67, 0.45-1.11 ng/ml, p=0.02) in obese/overweight individuals while in lean women, SEMA3E levels did not differ between non pregnant and normal pregnant women (0.91, 0.57-1.5 vs. 0.95, 0.58-1.56 ng/ml, p=0.93).ConclusionThis is the first study to report the presence of SEMA3E in maternal blood. Circulating maternal SEMA3E levels are positively correlated with insulin resistance in normal gestation. The unexpectedly reduced SEMA3E levels in GDMA2 may indicate a down-regulation effect of exogenous insulin on SEMA3E. These findings suggest that SEMA3E may play a role in metabolic adaptations to normal pregnancy as well as in the pathophysiology of pregnancy-related metabolic complications. ObjectiveSemaphorin 3E (SEMA3E), a previously known axon guiding molecule, has recently been shown to be a novel adipokine involved in adipose tissue inflammation and insulin resistance. The aim of this study was to determine circulating SEMA3E levels and their correlation with insulin resistance indices in pregnant and non-pregnant women. Semaphorin 3E (SEMA3E), a previously known axon guiding molecule, has recently been shown to be a novel adipokine involved in adipose tissue inflammation and insulin resistance. The aim of this study was to determine circulating SEMA3E levels and their correlation with insulin resistance indices in pregnant and non-pregnant women. Study DesignFasting serum glucose, insulin and SEMA3E levels were determined in 45 healthy non-pregnant women and 67 pregnant women at the third trimester, including 9 women with GDMA2. The Homeostasis Model Assessment (HOMA) was used to evaluate insulin resistance. Non-parametric statistical methods were employed. Fasting serum glucose, insulin and SEMA3E levels were determined in 45 healthy non-pregnant women and 67 pregnant women at the third trimester, including 9 women with GDMA2. The Homeostasis Model Assessment (HOMA) was used to evaluate insulin resistance. Non-parametric statistical methods were employed. ResultsIn non-pregnant women, SEMA3E levels were higher in lean versus obese/overweight women (1.27, IQR: 0.66-1.73 vs. 0.67, IQR: 0.45-1.11 ng/ml, respectively, p=0.02), and were highly negatively correlated with their BMI (r=-0.5, p<0.001). In normal pregnancy, maternal SEMA3E levels were positively correlated with insulin resistance (HOMA-IR; r=0.31, p=0.02), however, they did not differ significantly between lean and obese/overweight pregnant women (0.90, 0.51-0.148 vs. 1.13, 0.69-1.54 ng/ml, p=0.26). Maternal SEMA3E levels were significantly lower in GDMA2 compared with normal pregnancy (0.3, 0.3-0.4 vs. 0.95, 0.58-1.56 ng/ml, p<0.001). Finally, circulating maternal SEMA3E levels were higher in normal pregnancy compared with non-pregnant state (1.13, 0.69-1.54 vs. 0.67, 0.45-1.11 ng/ml, p=0.02) in obese/overweight individuals while in lean women, SEMA3E levels did not differ between non pregnant and normal pregnant women (0.91, 0.57-1.5 vs. 0.95, 0.58-1.56 ng/ml, p=0.93). In non-pregnant women, SEMA3E levels were higher in lean versus obese/overweight women (1.27, IQR: 0.66-1.73 vs. 0.67, IQR: 0.45-1.11 ng/ml, respectively, p=0.02), and were highly negatively correlated with their BMI (r=-0.5, p<0.001). In normal pregnancy, maternal SEMA3E levels were positively correlated with insulin resistance (HOMA-IR; r=0.31, p=0.02), however, they did not differ significantly between lean and obese/overweight pregnant women (0.90, 0.51-0.148 vs. 1.13, 0.69-1.54 ng/ml, p=0.26). Maternal SEMA3E levels were significantly lower in GDMA2 compared with normal pregnancy (0.3, 0.3-0.4 vs. 0.95, 0.58-1.56 ng/ml, p<0.001). Finally, circulating maternal SEMA3E levels were higher in normal pregnancy compared with non-pregnant state (1.13, 0.69-1.54 vs. 0.67, 0.45-1.11 ng/ml, p=0.02) in obese/overweight individuals while in lean women, SEMA3E levels did not differ between non pregnant and normal pregnant women (0.91, 0.57-1.5 vs. 0.95, 0.58-1.56 ng/ml, p=0.93). ConclusionThis is the first study to report the presence of SEMA3E in maternal blood. Circulating maternal SEMA3E levels are positively correlated with insulin resistance in normal gestation. The unexpectedly reduced SEMA3E levels in GDMA2 may indicate a down-regulation effect of exogenous insulin on SEMA3E. These findings suggest that SEMA3E may play a role in metabolic adaptations to normal pregnancy as well as in the pathophysiology of pregnancy-related metabolic complications. This is the first study to report the presence of SEMA3E in maternal blood. Circulating maternal SEMA3E levels are positively correlated with insulin resistance in normal gestation. The unexpectedly reduced SEMA3E levels in GDMA2 may indicate a down-regulation effect of exogenous insulin on SEMA3E. These findings suggest that SEMA3E may play a role in metabolic adaptations to normal pregnancy as well as in the pathophysiology of pregnancy-related metabolic complications.

Semaphorin 3E (SEMA3E), a newly identified adipokine, has been implicated in adipose tissue inflammation and systemic insulin resistance. The aims of this study were to determine circulating maternal and fetal SEMA3E levels and to assess which compartment, maternal, fetal or placental, is the source of this novel adipokine. Fasting serum glucose, insulin and SEMA3E levels were determined in 3 groups: (a) 32 healthy pregnant women at term, before and 3 days after elective cesarean section; (b) 51 normal pregnant women and their term neonates; (c) 9 women with gestational diabetes mellitus (GDMA2) and their term neonates. The Homeostasis Model Assessment (HOMA) was used to evaluate insulin resistance. Non-parametric statistical methods were employed. Median maternal SEMA3E levels were comparable before and after delivery (1.21, IQR: 0.64-1.60 vs. 1.05, 0.79-1.44 ng/ml, respectively, p=0.83), and highly correlated (p<0.001). SEMA3E levels in the neonates were almost twice as high as in their mothers (1.63, 1.08-2.37 vs. 0.87, 0.40-1.41 ng/ml, p<0.001), and were highly correlated (p=0.004). Neonatal SEMA3E levels of GDMA2 complicated pregnancy were lower than those of normal pregnancy (1.3, 0.55-1.95 ng/ml vs. 1.90, 1.20-2.60 ng/ml, p=0.39). Neonatal male and female SEMA3E levels were comparable (p=0.72). SEMA3E levels were not correlated with birth weight (p=0.88), percentile (p=0.66), gestational age (p=0.75) or metabolic indices in cord blood (HOMA-IR; p=0.63). To our knowledge, this is the first report to determine that SEMA3E is a physiologic constituent of human fetus plasma. The strong correlation between antepartum and postpartum maternal SEMA3E levels, the lack of postpartum decrease in concentrations, as well as the correlation between maternal and fetal SEMA3E levels, suggest that the fetal rather than the placental compartment may be a significant source of circulating maternal SEMA3E. High circulating fetal levels of SEMA3E and low levels of SEMA3E in infants of diabetic mothers, suggest that SEMA3E may be implicated in regulation of fetal metabolism.

Autoantibodies to the 65 kDa isoform of glutamate acid decarboxylase (GAD65Ab) are associated with a range of clinical disorders, including type 1 diabetes (T1D) and stiff-person syndrome (SPS). In this article we describe a young girl who was diagnosed with T1D at the end of her first year of life and developed drug-resistant epilepsy 18 months later, followed by behavioral disturbances. She was admitted to our center at the age of 5 yr, at which time high GAD65Ab titers were detected in the patient's serum and cerebrospinal fluid (CSF). The titer remained elevated during 19 months of follow-up. Furthermore, GAD65Ab in both serum and CSF showed epitope binding characteristics similar to those observed for GAD65Ab in SPS patients, and GAD65Ab in the serum reduced GAD65 enzyme activity. Our results suggest an association between high GAD65Ab titers and epilepsy in children with T1D. Careful titration and characterization of GAD65Ab regarding inhibition of enzyme activity and epitope specificity may be helpful in identifying T1D patients at risk for neurological complications.

Background & aims: Klotho is a trans-membrane protein which can be shed to act as a hormone; its blood levels may be regulated by the GH/IGF-1 axis. Klotho deficient mice exhibit short lifespan and characteristics of aging and malnutrition, including decreased fat and muscle mass, osteopenia, and impaired fertility. As anorexia nervosa (AN) is characterized by malnutrition and GH resistance, we hypothesized klotho levels would be altered in AN, and aimed to assess klotho levels in undernourished AN patients and changes in klotho following weight rehabilitation.Participants and methods: 19 adolescent female AN inpatients (aged 16.1 +/- 1.8 years) admitted to an inpatient service for eating disorders in a tertiary center were recruited. Blood samples were obtained on admission and after weight restoration (interval 4.0 +/- 2.3 months) and analyzed for klotho, IGF-1, calcium, phosphorus, and alkaline phosphatase.Results: Klotho levels on admission were lower than expected for age, and correlated with lumbar spine BMD Z-score (r = -0.81, p < 0.001) and alkaline phosphatase levels (r = 0.66, p = 0.003) but not with age, height-SDS, weight-SDS, BMI-SDS, or serum calcium, phosphorus and IGF-1 levels. Both IGF-1 and klotho levels increased significantly during hospitalization (IGF-1: 44 +/- 17 nmol/1 to 53 +/- 11 nmol/1, p = 0.008; klotho: 1061 +/- 421 pg/ml to 1519 +/- 781 pg/ml, p = 0.008.Conclusions: Klotho levels are low in the acute stage of AN and increase with nutritional rehabilitation. Low klotho on admission may be secondary to low IGF-1 levels and may contribute to the clinical manifestations of AN. The role of klotho in the pathophysiology of AN and as a novel marker of disease severity should be further explored. (C) 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.