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Adverse intrauterine environments can cause persistent changes in epigenetic profiles of stem cells, increasing susceptibility of the offspring to developing metabolic diseases later in life. Effective approaches to restore the epigenetic landscape and function of stem cells remain to be determined. Here we investigated the effects of pharmaceutical activation of AMPK, an essential regulator of energy metabolism, on mitochondrial programming of Wharton's Jelly mesenchymal stem cells (WJ-MSCs) from women with diabetes during pregnancy. Induction of myogenic differentiation of WJ-MSCs was associated with increased PGC-1α expression and mitochondrial DNA abundance. Inhibition of DNA methylation by 5 Azacytidine significantly increased PGC-1α expression and mitochondrial DNA abundance in WJ-MSCs, which were abolished by AMPK inhibitor Compound C (CC), suggesting an AMPK-dependent role of DNA demethylation in regulating mitochondrial biogenesis in WJ-MSCs. Further, activation of AMPK in diabetic WJ-MSCs by AICAR or metformin decreased the level of PGC-1α promoter methylation and increased PGC-1α expression. Notably, decreased PGC-1α promoter methylation by transient treatment of AMPK activators persisted following myogenic differentiation. This was associated with enhanced myogenic differentiation capacity of human WJ-MSCs and increased mitochondrial function. Taken together, our findings revealed an important role for AMPK activators in epigenetic regulation of mitochondrial biogenesis and myogenesis in WJ-MSCs, which could lead to potential therapeutics for preventing fetal mitochondrial programming and long-term adverse outcome in offspring of women with diabetes during pregnancy.

BACKGROUND AND AIMS: Soluble adhesion molecules are associated with cardiovascular disease and increased in individuals with diabetes. This study assesses the impact of diabetes exposure in utero on the abundance of circulating adhesion molecules in cord serum and soluble adhesion molecules released from human umbilical vein endothelial cells (HUVEC) exposed to high glucose concentrations. METHODS AND RESULTS: Women with and without diabetes were recruited. DM was diagnosed based on the American Diabetes Association criteria. Primary cultures of HUVEC were cultured in 5mM and 25mM glucose with 25mM mannitol osmotic control. The soluble adhesion molecules, intracellular adhesion molecule (ICAM), vascular cell adhesion molecule (VCAM) and E-selectin were measured by ELISA in the cord blood serum and conditioned HUVEC media. The mothers with DM were older with higher BMI (p=0.027 and 0.008, respectively). In a fully adjusted model, VCAM was significantly increased in the cord serum of infants born to mothers with diabetes (p=0.046), but ICAM and E-selectin were not different. ICAM was also significantly correlated with maternal HbA1c (r(2)=0.16, p=0.004) and cord serum non-esterified fatty acids (r(2)=0.08, p=0.013). From the HUVEC media, the abundance of adhesion molecules was not different based on DM or high glucose exposure; however, VCAM abundance in the HUVEC supernatant was significantly correlated with ICAM (r(2)=0.27, p=0.010) and cord serum c-peptide (R(2)=0.19, p=0.043). CONCLUSIONS: Alterations in soluble adhesion molecule abundance in infants exposed to the diabetic milieu of pregnancy may reflect early alterations in vascular function predicting future cardiovascular disease.

The perinatal period is a time of substantial bone mass accrual with many factors affecting long-term bone mineralization. Currently it is unclear what effect maternal gestational/type 2 diabetes has on infant bone mass accrual. This is a prospective study of offspring of Native American and Hispanic mothers with normoglycemia (n = 94) and gestational diabetes or type 2 diabetes (n = 64). Infant anthropometrics were measured at birth, 1, and 6 months of age. Cord blood leptin, high-molecular weight adiponectin (HMWA), pigment epithelium-derived factor (PEDF), vascular epithelium growth factor (VEGF), endoglin, and C-peptide were measured by ELISA. Infants had bone mineral density measurement at 1 month or/and 6 months of age using dual-energy x-ray absorptiometry scan. Mothers with diabetes were older (31 ± 6 years vs 25 ± 4 years) and had higher pre-pregnancy BMI (32.6 ± 5.8 vs 27.2 ± 6.4 kg/m(2)) than control mothers. Mean HbA1C of mothers with diabetes was 5.9 ± 1.0% compared to 5.1 ± 0.3% in controls early in pregnancy. Infants born to mothers with diabetes (DM-O) were born at a slightly lower gestational age compared to infants born to control mothers (Con-O). There was no difference in total body less head bone mineral content (BMC) or bone mineral density (BMD) between DM-O and Con-O. For both groups together, bone area, BMD, and BMC tracked over the first 6 months of life (r: 0.56, 0.38, and 0.48, respectively). Percent fat was strongly and positively correlated with BMC at 1 month of age (r = 0.44; p < 0.001) and BMC at both 1 and 6 months of age correlated strongly with birth weight. There were no associations between infant bone mass and cord blood leptin, PEDF, or VEGF, while C-peptide had a significant correlation with BMC at 1 and 6 months only in DM-O (p = 0.01 and 0.03, respectively). Infants born to mothers with well-controlled gestational/type 2 diabetes have normal bone mass accrual. Bone mineral content during this time is highly correlated with indices of infant growth and the association of bone mineral indices with percent body fat suggests that bone-fat crosstalk is operative early in life.

Exposure to diabetes in utero influences future metabolic health of the offspring. MicroRNAs (miRNA) are small noncoding RNAs that may contribute mechanistically to the effects on offspring imparted by diabetes mellitus (DM) during pregnancy. We hypothesized that exposure to DM during pregnancy influences select miRNAs in fetal circulation, in human umbilical vein endothelial cells (HUVEC), and placenta.miRNA abundance was quantified using real-time PCR from RNA isolated from umbilical cord serum exosomes, HUVEC, and placenta exposed to diabetes or normoglycemia during pregnancy. The abundance of each of these miRNAs was determined by comparison to a known standard and the relative expression assessed using the 2miR-126-3p was highly abundant in fetal circulation, HUVEC, and placenta. Diabetes exposure during pregnancy resulted in lower expression of miR-148a-3p and miR-29a-3p in the HUVEC. In the placenta, for miR-126-3p, there was a differential effect of DM by birth weight between DM versus control group, expression being lower at the lower birth weight, however not different at the higher birth weight.Exposure to DM during pregnancy alters miRNA expression in the offspring in a tissue-specific manner.miRNAs are differentially expressed in fetal tissues from offspring exposed to in utero diabetes mellitus compared to those who were not exposed. miRNA expression differs among tissue types (human umbilical vein endothelial cells, placenta and circulation exosomes) and response to diabetes exposure varies according to tissue of origin. miRNA expression is also affected by maternal and infant characteristics such as infant birth weight, infant sex, maternal age, and maternal BMI. miRNAs might be one of the potential mechanisms by which offspring's future metabolic status may be influenced by maternal diabetes mellitus.

Adverse maternal environments, such as diabetes and obesity, impair placental mitochondrial function, which affects fetal development and offspring long-term health. The underlying mechanisms and effective interventions to abrogate such effect remain unclear. Our previous studies demonstrated impaired mitochondrial biogenesis in male human placenta of diabetic mothers. In the present studies, epigenetic marks possibly related to mitochondrial biogenesis in placentae of women with diabetes (n = 23) and controls (n = 23) were analyzed. Effects of metformin were examined in human placental explants from a subgroup of diabetic women and in a mouse model of maternal high fat diet feeding. We found that maternal diabetes was associated with epigenetic regulation of mitochondrial biogenesis in human placenta in a fetal sex-dependent manner, including decreased histone acetylation (H3K27 acetylation) and increased promoter methylation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). In male placenta, the levels of H3K27 acetylation and PGC-1α promoter methylation correlated significantly with the activity of AMP-activated protein kinase (AMPK). Metformin treatment on male diabetic placental explant activated AMPK and stimulated PGC-1α expression, concomitant with increased H3K27 acetylation and decreased PGC-1α promoter methylation. In vivo, we show that maternal metformin treatment along with maternal high fat diet significantly increased mouse placental abundance of PGC-1α expression and downstream mitochondrial transcription factor A (TFAM) and inhibited maternal high fat diet-impaired placental efficiency and glucose tolerance in offspring. Together, these findings suggest the capability of metformin to stimulate placental mitochondrial biogenesis and inhibit the aberrant epigenetic alterations occurring in maternal diabetes during pregnancy, conferring protective effects on offspring.

Objective This study aimed to investigate cellular sources of microRNAs (miRNA) within adipose tissue and the impact of obesity on miRNA expression, as well as to examine targets of miRNAs. Methods miRNA expression by quantitative polymerase chain reaction was examined in adipocytes, adipose tissue macrophages (ATM), and peripheral blood mononuclear cells from and individuals with normal weight and with obesity. Differentiated 3T3-L1 adipocytes were cocultured with macrophages, and 3T3-L1 and differentiated human mesenchymal stem cells were transfected with miR-155, with peroxisome proliferator-activated receptor gamma (PPAR-γ) and solute carrier family 2 member 4 (GLUT4) abundance measured via Western blot analysis. Results Abundance of miR-155 and miR-210 was increased in ATM of participants with obesity by 6.7-fold and 2.9-fold (P = 0.002 and P = 0.013, respectively). miR-130b expression was increased 1.8-fold in ATM and 4.3-fold in adipocytes from participants with obesity (P = 0.007 and P = 0.02, respectively). PPARG mRNA expression decreased 32% (P = 0.044) in adipocytes from individuals with obesity. In 3T3-L1 cells exposed to macrophages, PPARG expression decreased 99.4% (P = 0.02). PPAR-γ protein content declined 75% (P = 0.001) in 3T3-L1 cells transfected with miR-155. GLUT4 protein levels were reduced by 55% (P = 0.021) in differentiated human mesenchymal stem cells exposed to miR-155. Conclusions Adipose tissue miRNAs are influenced in a cell type-specific fashion by obesity, with macrophage miR-155 potentially impacting neighboring adipocytes.

Soluble adhesion molecules are associated with cardiovascular disease and increased in individuals with diabetes. The current study assesses the impact of diabetes exposure in utero on the abundance of circulating adhesion molecules in cord serum as well as soluble adhesion molecules released from human umbilical vein endothelial cells (HUVEC) upon exposure to high levels of glucose. Women with and without diabetes (DM; gestational or type 2) were recruited at delivery. DM was diagnosed based on the criteria by the American Diabetes Association. Primary cultures of HUVEC were established in M199 medium with growth supplements. For the high glucose treatment, medium was adjusted to a final glucose concentration of 25mM with media collected 48 hours post treatment. The soluble adhesion molecules intracellular adhesion molecule (ICAM), vascular cell adhesion molecule (VCAM) and E-selectin were measured by ELISA in the cord blood serum and the conditioned HUVEC media. Serum adhesion molecules were measured in 42 infants born to mothers with normal glycemia and 35 infants of mothers with DM. The mothers with DM were older with higher BMI (p=0.027 and 0.008, respectively). In a fully adjusted model, VCAM was significantly increased in the cord serum of infants born to mothers with diabetes (p=0.046), but ICAM and E-selectin were not different. ICAM was significantly correlated with E-selectin (r2=0.25, p Disclosure S. B. Landreth: None. A. M. Teague: None. M. Jensen: None. S. Gulati: None. J. B. Tryggestad: None. Funding National Institutes of Health (1K23DK106533)

Type 1 diabetes (T1D) is associated with increased arterial stiffness and cardiac autonomic neuropathy. We tested whether those variables are acutely affected by a high fat meal (HFM).Responses to a HFM were measured in adolescents with T1D (N = 14) or without T1D (Control, N = 21). Heart rate variability (HRV), arterial stiffness, blood pressure (BP), and energy expenditure (EE) were measured before (baseline) and four times over 180 min postprandially.T1D had higher blood glucose and insulin, but the suppression of fatty acids (~40%) and rise in triglycerides (~60%) were similar between groups. T1D had 9% higher EE, but postprandial increase in EE was similar to Controls. T1D had ~7 to 24% lower baseline HRV but a similar postprandial decline of ~8 to 25% as Controls. Both groups had a similar 2 to 5% increase in BP after the meal. Rate pressure product increased postprandially in both groups and was higher in T1D. Pulsewave velocity and augmentation index did not differ between groups or change postprandially.Adolescents with T1D have evidence of cardiac autonomic dysfunction and increased EE, but those variables, along with arterial stiffness, are not acutely made worse by a HFM.

BACKGROUND The nitrone compound OKN-007 is a novel anti-cancer agent. In glioblastoma xenografts, OKN-007 reduces cell proliferation and angiogenesis, and increases apoptosis. Here we report on the safety, efficacy, and pharmacokinetics (PK) of OKN-007 in adults with recurrent glioma. METHODS NCT01672463 is a phase 1b trial of OKN-007 in adults with recurrent gliomas previously treated with standard therapy. OKN-007 was administered by IV. The study comprised a 3 + 3 dose escalation design followed by an expansion cohort at the maximum tolerated dose (MTD). The dose escalation drug levels were 20 (n = 3), 40 (n = 3), and 60 mg/kg (n = 3), treating on a schedule of thrice weekly for 4 weeks, then twice weekly for 4 weeks, then once weekly until progression. Drug PK was determined in the dose escalation cohorts. The expansion cohort was treated with 60 mg/kg thrice weekly for 12 weeks, then twice weekly for 12 weeks, then once weekly until progression (n = 6). Kaplan-Meier analysis was used to determine progression-free (PFS) and overall survival (OS). RESULTS Median age was 51 years (range, 25–62). No dose-limiting toxicities were observed. The expansion dose was 60 mg/kg. Of 123 adverse events (AEs), 34 were deemed probably (1.6%) or possibly (26%) treatment-emergent (TEAE). The most commonly-occurring TEAEs were fatigue (4.1%) and headache (3.3%). Grade 3 TEAEs included headache, urinary tract infection, and increased prothrombin time (0.8% each). Two grade 1 AEs, hypokalemia and dizziness, were considered probably attributable to OKN-007. In patients receiving 60 mg OKN-007/kg, median PFS was 1.4 months and OS was 21 months (log rank p = 0.08 for comparison across doses). Systemic PK exposure was dose proportional. The average half-life of OKN-007 is 2.8 hours. CONCLUSIONS OKN-007 appears safe and, compared to standard therapy, may prolong OS in recurrent glioma.

MicroRNA (miRNA) are small non-coding RNAs that impact translation via degrading or repressing mRNA. From animal models, circulation abundance of miRNA is impacted by feeding. The goal of this project was to compare levels of specific circulating miRNAs between youth with T1DM and controls and the impact of a high fat meal on miRNA abundance. Fourteen youth (6 females, 8 males) with T1DM and 29 normal weight control youth (14 females, 15 males) ingested a milkshake with 830 kcal; 36% carbohydrate, 54% fat (31 grams of saturated fat), and 10% protein. Circulating miRNAs (miR-122, 126, and 130b) at baseline and 150 minutes post-ingestion were measured by qPCR. The group with T1DM had a median A1c of 8.4% (7.4, 8.9) with an average duration of 7 years. At baseline, miR-126 tended to be higher in the youth with T1DM (47%, p=0.072). In pooled groups, all three miRNAs decreased at 150 min (miR-122: -21%, p=0.036; miR-126: -37%, p=0.001; and miR-130b: -33%, p=0.023). Within the control group, miR-122 and miR-126 decreased 26% and 28% from baseline (p=0.037 and p=0.035, respectively). Within the T1DM group, miR-126 and miR-130b decreased 49% and 50% from baseline (p=0.007 and p=0.011, respectively). The decrease in miR-122 from baseline was correlated with the total energy expenditure for the meal (r=0.-0.379, p=0.017) and insulin under the curve (r=0.350, p=0.029). The decrease in miR-126 and miR-130b were negatively correlated with glucose area under the curve (r=-0.369 and -0.358, p=0.021 and 0.025, respectively), and the decrease in miR-130b was negatively correlated with baseline NEFA (r= -0.328, p=0.042). miR-122 and 130b both target AMPK, which could alter lipid metabolism, thus explaining the associations with NEFA and energy expenditure. miR-126 is known to target both IRS1 and PI3K in the insulin signaling pathway, potentially explaining the association with glucose. It is clear that the circulating abundance of these miRNAs is reduced following a high fat meal, and that response may be modified by the presence of T1DM. Disclosure J.B. Tryggestad: None. A.M. Teague: None. K.R. Short: None. Funding Harold Hamm Diabetes Center; Ardmore Institute of Health

We measured the effect of an aerobic exercise session on postprandial glucose control in adolescents with habitually low-physical activity. The goal was to determine if the acute or residual response of exercise was altered in people who are overweight/obese (OW/Ob). Eleven normal weight, body mass index (NW, BMI = 48 ± 13 percentile) and 12 OW/Ob (BMI = 91 ± 5 percentile) participants completed 3 trials. In the no exercise (No Ex) trial, participants rested quietly before and after consuming a test meal. In the other 2 trials, a 45-minute aerobic exercise session was performed either 17-hour (Prior Day Ex) or 40 minutes (Same Day Ex) before the test meal. On all trials, the OW/Ob group had higher fasting glucose (~6%) and insulin (~66%), and lower insulin sensitivity (~9%) than the NW group. The Same Day Ex and Prior Day Ex trials resulted in reduced area under the curve for glucose (6% on both trials, P < .01) and insulin (15% and 13%, respectively, P < .03), and increased insulin sensitivity (8% and 6%, respectively, P < .01). The magnitudes of those effects did not differ between the NW and OW/Ob groups. Plasma fatty acids declined and carbohydrate oxidation increased after the meal, but did not differ among trials or groups. The results demonstrate that moderate intensity aerobic exercise increases insulin sensitivity in NW and OW/Ob adolescents and that the beneficial effects of exercise last up to 17 hours. The acute impact of exercise on metabolic health in adolescents is not impaired in overweight/obese participants.

Objective The goal of this study was to examine the associations of maternal weight status before, during, and after pregnancy with breast milk C-reactive protein (CRP) and interleukin 6 (IL-6), two bioactive markers of inflammation, measured at 1 and 3 months post partum. Methods Participants were 134 exclusively breastfeeding mother-infant dyads taking part in the Mothers and Infants Linked for Health (MILK) study, who provided breast milk samples. Pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) were assessed by chart abstraction; postpartum weight loss was measured at the 1- and 3-month study visits. Linear regression was used to examine the associations of maternal weight status with repeated measures of breast milk CRP and IL-6 at 1 and 3 months, after adjustment for potential confounders. Results Pre-pregnancy BMI and excessive GWG, but not total GWG or postpartum weight loss, were independently associated with breast milk CRP after adjustment (β = 0.49, P

Spexin is a novel peptide that has been reported to be down regulated in obese adults and children and in normoglycemic adults following glucose ingestion. Spexin may therefore have a role in metabolic regulation. The purpose of the current study was to determine the effect of obesity and type 2 diabetes (T2DM), and the effect of glucose ingestion on circulating spexin concentration in adolescents. Boys and girls (mean age 16 years old) classified as healthy normal weight (NW, n = 22), obese (Ob, n = 10), or obese with T2DM (n = 12) completed measurements of body composition, blood pressure, cardiorespiratory fitness, and blood concentrations of glucose, insulin, and lipids. The median fasting serum spexin concentration did not differ between groups (NW: 0.35; Ob: 0.38, T2DM: 0.34 ng/mL, respectively). In 10 NW participants who completed a standard oral glucose tolerance test, spexin concentration was unchanged at 30 and 120 minutes relative to the fasting baseline. Finally, spexin was not significantly correlated with any of the body composition, fitness, or blood biochemical measurements. These data do not support the proposed role of spexin as a metabolic regulator or biomarker of glucose control in adolescents.

SummaryBackground Much is to be learnt about human breast milk (HBM). Objectives The purpose of this study is to extend our knowledge of HBM by investigating the role of maternal body mass index (BMI), sex and stage of lactation (month 1 vs. 6) on HBM insulin, glucose, leptin, IL-6 and TNF-α and their associations with infant body composition. Methods Thirty-seven exclusively breastfeeding infants (n = 37; 16♀, 21♂), and their mothers (19–47 kg m−2) were studied at 1 and 6 months of lactation. Infants had body composition measured (using dual-energy X-ray absorptiometry) and HBM collected. Results A significant interaction between maternal BMI and infant sex on insulin levels (p = 0.0322) was observed such that insulin was 229% higher in obese mothers nursing female infants than in normal weight mothers nursing female infants and 179% higher than obese mothers nursing male infants. For leptin, a significant association with BMI category was observed (p

Objective: Postpartum weight retention increases the risk of future obesity and cardiovascular disease. Although exclusive breastfeeding (EBF) has been promoted as an effective means to lose gestational weight gain, previous studies report mixed findings for the relationship between duration of EBF and maternal postpartum weight loss (PPWL). This study evaluates whether meeting the recommended 6-months of EBF is associated with greater PPWL by 6-months than a shorter duration of EBF. Methods: The Mothers and Infants LinKed for Health (MILK) study is an ongoing prospective cohort of non-diabetic, non-smoking mother-infant dyads, all of whom were exclusively breastfeeding at 1-month postpartum. Breastfeeding exclusivity was subsequently self-reported by mothers at 3 and 6-months postpartum. Maternal pre-pregnancy weight and weight at delivery were abstracted from medical records. PPWL was calculated as maternal weight measured at 1, 3 and 6-months minus maternal weight at delivery. Mixed effects linear regression models were used to test the association of duration of EBF with repeated measures of PPWL after adjustment for covariates including maternal pre-pregnancy weight, gestational weight gain, parity, physical activity and infant sex. Results: Among 315 mothers who were exclusively breastfeeding at 1-month, 93% and 75% continued EBF to 3 and 6-months, respectively. By 6-months postpartum, weight loss (least square means ± standard error) was -8.55 ± 1.31 kg among EBF to 1-month, -10.60 ± 0.82 kg among EBF to 3-months and -11.73 ± 0.37 kg among EBF to 6-months (Figure). EBF to 6-months was associated with greater PPWL by 6-months postpartum than EBF to 1 or 3-months (p Conclusion: EBF to 6-months postpartum was associated with greater maternal PPWL than shorter EBF durations. Interventions may promote prolonged EBF as a means of increasing maternal weight loss by 6-months postpartum, but additional research is needed to explore whether these differences persist after weaning.

Maternal pregnancy nutrition influences fetal growth. Evidence is limited, however, on the relationship of maternal diet during pregnancy and lactation on infant postnatal growth and adiposity. Our purpose was to examine associations between maternal diet quality during pregnancy and lactation with offspring growth and body composition from birth to six months. Maternal diet quality was serially assessed in pregnancy and at one and three months postpartum, using the Healthy Eating Index&ndash, 2015 in a cohort of 354 fully breastfeeding mother&ndash, infant dyads. Infant length-for-age (LAZ), weight-for-age (WAZ), and weight-for-length (WLZ) Z-scores were assessed at birth, one, three, and six months. Infant body fat percent (BF%), fat mass (FM), and fat-free mass (FFM) were measured at six months using dual-energy X-ray absorptiometry. Higher maternal diet quality from pregnancy through three months postpartum was associated with lower infant WLZ from birth to six months (p = 0.02) and BF% at six months (p &le, 0.05). Higher maternal diet quality at one and three months postpartum was also associated with lower infant FM at six months (p &lt, 0.01). In summary, maternal diet quality during pregnancy and lactation was inversely associated with infant relative weight and adiposity in early postnatal life. Additional research is needed to explore whether associations persist across the life course.

We aimed to identify miRNAs whose expression levels in fetal tissues are altered by exposure to a diabetic milieu and elucidate the impact on target protein expression. Gestational diabetes mellitus (GDM) affects both immediate and future disease risk in the offspring. We hypothesized that GDM alters miRNA expression in human umbilical vein endothelial cells (HUVECs) that may influence metabolic processes. A cross-sectional design compared differences in miRNA expression in HUVECs and target protein abundance in placentae between infants of women with GDM (IGDM) and infants born to normoglycaemic controls. miRNAs were identified using microarray profiling and literature review and validated by quantitative PCR (qPCR). In vitro transfection studies explored the impact of the miRNA on target protein expression. Expression of seven miRNA species, miR-30c-5p, miR-452-5p, miR-126-3p, miR-130b-3p, miR-148a-3p, miR-let-7a-5p and miR-let-7g-5p, was higher in the HUVECs of IGDM. Abundance of the catalytic subunit of AMP-activated protein kinase α1 (AMPKα1) was decreased in the HUVECs and BeWo cells (transformed trophoblast cell line) transfected with miR-130b and miR-148a mimics. AMPKα1 expression was also decreased in placental tissues of IGDM. The expression of several miRNAs were altered by in utero exposure to DM in infants of women whose dysglycaemia was very well controlled by current standards. Decreased expression of AMPKα1 as a result of increased levels of miR-130b and miR-148a may potentially explain the decrease in fat oxidation we reported in infants at 1 month of age and, if persistent, may predispose offspring to future metabolic disease.

BACKGROUND Temozolomide (TMZ) is the standard of care chemotherapy agent for glioblastoma. Unfortunately, intrinsic or acquired resistance eventually renders TMZ ineffective. The novel anti-cancer agent OKN-007 plus TMZ increased survival in glioma-bearing mice compared to TMZ alone. Furthermore, OKN-007 increased TMZ sensitivity in both TMZ-sensitive and TMZ-resistant cell lines. Therefore, we initiated a clinical trial (NCT03587038) of OKN-007 in combination with TMZ and radiation therapy (RT). Here we report the safety and tolerability findings of this trial in-progress. METHODS Adults with newly-diagnosed and resected GBM are eligible. OKN-007 is administered by IV at 60 mg/kg. There are three treatment phases: Concomitant, Pre-Maintenance, and Maintenance. In the Concomitant Phase, patients receive OKN-007 three times per week (Cohort 1) or five times per week (Cohort 2); all patients receive TMZ at 75 mg/m2 daily and RT at 60 Gy over 30 fractions. In the 28-day Pre-Maintenance Phase, all patients receive OKN-007 thrice weekly. In the Maintenance Phase (MP), comprising up to eighteen 28-day cycles, TMZ is dosed at 150–200 mg/m2 on days 1–5 of each cycle for six cycles. OKN-007 is administered thrice weekly for six cycles, then twice weekly for three cycles, then once weekly for nine cycles. An expansion cohort of up to 25 patients will use the highest tolerated dosing protocol. RESULTS To date, five patients have been enrolled. Three patients in Cohort 1 and one in Cohort 2 advanced to the MP, and no dose-limiting toxicities (DLTs) occurred. One patient in Cohort 2 was removed due to a DLT (grade 3 neutropenic fever). CONCLUSIONS The treatment plan in Cohort 1 appears safe and well-tolerated. Recruitment for Cohort 2 is ongoing and will be expanded to further evaluate safety. Once the outcome of Cohort 2 is known, the regimen for the expansion cohort will be determined.

2538 Background: Despite therapeutic advances, the median overall survival for patients with recurrent, high-grade gliomas remains poor. Thus, there is an urgent need for efficacious new therapies. The nitrone compound, OKN-007 (disodium 4-[(tert-butyl-imino) methyl] benzene-1,3-disulfonate N-oxide) is a promising novel anti-cancer agent. In orthotopic glioblastoma xenografts, OKN-007 reduces cell proliferation and angiogenesis, and increases apoptosis. Here we report on the safety, efficacy, and pharmacokinetics (PK) of OKN-007 in adults with recurrent glioma. Methods: NCT01672463 is a phase Ib trial of OKN-007 in adults with recurrent gliomas previously treated with standard therapy. Patients with recurrence, adequate performance status and organ function, receiving clinically appropriate doses of steroids, with a life expectancy greater than 8 weeks were eligible. OKN-007 was administered by IV. The study comprised a 3+3 dose escalation design followed by an expansion cohort at the maximum tolerated dose (MTD). The dose escalation drug levels were 20 (n = 3), 40 (n = 3), and 60 mg/kg (n = 3), treating on a schedule of thrice weekly for 4 weeks, then twice weekly for 4 weeks, then once weekly until progression. Drug PK was determined in the dose escalation cohorts. The expansion cohort was treated with 60 mg/kg thrice weekly for 12 weeks, then twice weekly for 12 weeks, then once weekly until recurrence (n = 6). Kaplan-Meier analysis was used to determine progression-free (PFS) and overall survival (OS). Results: Median age was 51 years (range, 25-62). No dose-limiting toxicities were observed and 60 mg/kg was chosen for the expansion dose. Of 123 adverse events (AE), 34 were deemed probably (1.6%) or possibly (26%) treatment-emergent (TEAE). The most commonly-occurring TEAE were fatigue (4.1%) and headache (3.3%). No drug-attributable grade 4 or 5 AE were observed. Grade 3 TEAE included headache, urinary tract infection, and increased prothrombin time (0.8% each). Only two grade 1 AE, hypokalemia and dizziness, were considered probably attributable to OKN-007. In patients receiving 60 mg OKN-007/kg, median PFS was 1.4 months and OS was 21 months (log rank p = 0.08 for comparison across doses). Systemic PK exposure was dose proportional. The average half-life of OKN-007 is 2.8 hours. Conclusions: OKN-007 appears safe for patients with recurrent glioma. The MTD was not reached. Our data suggest that, compared to standard therapy, OKN-007 may prolong OS in recurrent glioma. Based on new data, a trial of OKN-007 plus temozolomide is underway in patients with newly diagnosed glioblastoma (NCT03587038). Clinical trial information: NCT01672463 .

Objective To examine the associations of maternal weight status before, during, and after pregnancy with breast milk C-Reactive Protein (CRP) and Interleukin-6 (IL-6), two bioactive markers of inflammation, measured at one and three months postpartum. Methods Participants were 134 exclusively breastfeeding mother-infant dyads taking part in the Mothers and Infants LinKed for Health (MILK) study, who provided breast milk samples. Pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) were assessed by chart abstraction; postpartum weight loss was measured at the one and three month study visits. Linear regression was used to examine the associations of maternal weight status with repeated measures of breast milk CRP and IL-6 at one and three months, after adjustment for potential confounders. Results Pre-pregnancy BMI and excessive GWG, but not total GWG or postpartum weight loss, were independently associated with breast milk CRP after adjustment (β=0.49, p

Exposure to diabetes in utero has been shown to program offspring toward cardiometabolic disease and diabetes (DM). Alteration of fetal microRNA expression is a potential mechanism that mediates the effects of maternal conditions on the fetus. In previous work, we have shown that miRNA-126 expression is increased in umbilical vein endothelial cells (HUVEC) and in cord blood from infants born to mothers with DM. In this study we evaluated the capacity of miRNA-126 to target IRS1 mRNA by binding to a complementary sequence in the 3’UTR. A commercially available plasmid (SwitchGear Genomics) containing the 3’UTR of IRS1 with a luciferase reporter was co-transfected along with miRNA-126 into HEK-293A cells. Luciferase expression was reduced by 1.5-fold with the addition of miR-126 as compared to the controls (Figure 1). As confirmation, the sequence predicted to target miR-126 was cloned from HUVEC into the pmirGLO vector (Promega) also containing luciferase reporter. With the addition of miR-126, luciferase expression was reduced by 2.2-fold. The data suggest that IRS1 is a target for miR-126. As miR-126 is increased in HUVEC of infants born to mothers with DM, we postulate that IRS1 protein will be decreased, potentially impacting downstream signaling within the cell, as well as endothelial function. Future studies are planned to evaluate the impact of miR-126 on endothelial function. Disclosure J.B. Tryggestad: None. A.M. Teague: None. S. Chernausek: Advisory Panel; Self; Novo Nordisk Inc..

Diabetes during pregnancy affects placental function, which impacts fetal development and the long-term health of offspring. Resistin is a peptide hormone originally discovered in mice as an adipocyte-derived factor that induced insulin resistance. Unlike rodent, human resistin is primarily secreted by monocytes or macrophages. Resistin may act differently in humans, which remains unclear. The present study examined the effects of maternal diabetes on fetal resistin levels and the actions of human resistin in placenta mitochondrial biogenesis pathway. Concentrations of human resistin in cord sera were higher in diabetic pregnancies (67 ng/ml, n=42) compared to healthy controls (50 ng/ml, n=81, P< 0.05), and correlated (r=0.4, P=0.002) with a measure of maternal glycemia (glucose concentration 2 h post challenge). Resistin mRNA was abundant in cord blood mononuclear cells (CBMCs). Secretion of resistin from cultured CBMCs was increased in response to high glucose (25 mM) treatment. Exposing placental trophoblastic cells (BeWo cells) or human placental explant to resistin decreased expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), as well as the abundance of mitochondria transcription factor A (TFAM). In human term placentae, the levels of PGC-1α promotor methylation were positively correlated with cord blood resistin concentrations (r= 0.45, p=0.04, n=16). In summary, we have shown that resistin is increased in the fetal circulation during diabetic pregnancy and that this potentially reflects the response of monocytes/macrophages to hyperglycemia and metabolic stresses associated with diabetic pregnancy. In addition, human resistin has the capacity to decrease mitochondrial biogenesis by affecting the epigenetic regulation of PGC-1α expression. Thus, increased exposure to resistin may contribute to mitochondrial dysfunction and long-term aberrant energy metabolism characteristic of the offspring of diabetic pregnancies. Disclosure S. Jiang: None. A.M. Teague: None. J.B. Tryggestad: None. T. Lyons: None. S. Chernausek: Advisory Panel; Self; Novo Nordisk Inc..

OBJECTIVE The aim of this study was to test associations of prepregnancy BMI, gestational weight gain, oral glucose challenge test results, and postpartum weight loss as predictors of breast milk leptin, insulin, and adiponectin concentrations and whether these relationships vary over time. METHODS Milk was collected at 1 and 3 months from 135 exclusively breastfeeding women from the longitudinal Mothers and Infants Linked for Healthy Growth (MILk) study. Hormones were assayed in skimmed samples using ELISA. Mixed-effects linear regression models were employed to assess main effects and effect-by-time interactions on hormone concentrations. RESULTS In adjusted models, BMI was positively associated with milk leptin (P

OBJECTIVE: Obesity and type 2 diabetes mellitus (T2DM) are associated with oxidative stress. Oxidative damage of high-density lipoprotein (oxHDL) leads to a dysfunctional molecule, potentially a mediator and/or marker of cardiometabolic disease. We tested the hypothesis that circulating concentration of oxHDL is higher in obese (Ob) or T2DM adolescents compared to normal-weight (NW) peers. METHODS: In 37 NW, 38 Ob, and 42 T2DM adolescents, ages 11–18 y, fasting concentrations of HDL and LDL cholesterol, oxHDL, oxidized low-density lipoprotein (oxLDL), and myeloperoxidase (MPO) were measured. RESULTS: Compared to the NW group, oxHDL in the Ob group was not different, but was 65% higher (p < 0.01) in the T2DM group. Within the T2DM group oxHDL was higher in boys than in girls but this sex difference was not evident in NW or Ob groups. OxLDL was 23% higher in Ob (p =0.02), and 56% higher in T2DM (p < 0.01) versus NW and did not differ between boys and girls. MPO was not different between NW and Ob but was 88% (p < 0.02) higher in T2DM compared to NW. Contrary to our hypothesis MPO and insulin resistance (HOMA-IR) were not correlated with oxHDL. OxHDL was positively associated with oxLDL and lean body mass while oxLDL was positively associated with apolipoprotein B, triglycerides, HOMA-IR and trunk fat. CONCLUSIONS: The higher concentrations of oxHDL and oxLDL, along with higher MPO in children with T2DM reflect higher oxidative stress compared with obesity alone and potentially increased cardiovascular disease risk in youth with T2DM.

AIMS/HYPOTHESIS We hypothesized that diabetes during pregnancy (DDP) alters genome-wide DNA methylation in placenta resulting in differentially methylated loci of metabolically relevant genes and downstream changes in RNA and protein expression. METHODS We mapped genome-wide DNA methylation with the Infinium 450K Human Methylation Bead Chip in term fetal placentae from Native American and Hispanic women with DDP using a nested case-control design (n = 17 pairs). RNA expression and protein levels were assayed via RNA-Seq and Western Blot. RESULTS Genome-wide DNA methylation analysis revealed 465 CpG sites with significant changes for male offspring, 247 for female offspring, and 277 for offspring of both sexes (p

Diabetes during pregnancy is associated with abnormal placenta mitochondrial function and increased oxidative stress, which affect fetal development and offspring long-term health. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a master regulator of mitochondrial biogenesis and energy metabolism. The molecular mechanisms underlying the regulation of PGC-1α in placenta in the context of diabetes remain unclear. The present study examined the role of microRNA 130b (miR-130b-3p) in regulating PGC-1α expression and oxidative stress in a placental trophoblastic cell line (BeWo). Prolonged exposure of BeWo cells to high glucose mimicking hyperglycemia resulted in decreased protein abundance of PGC-1α and its downstream factor, mitochondrial transcription factor A (TFAM). High glucose treatment increased the expression of miR-130b-3p in BeWo cells, as well as exosomal secretion of miR-130b-3p. Transfection of BeWo cells with miR-130b-3p mimic reduced the abundance of PGC-1α, whereas inhibition of miR-130b-3p increased PGC-1α expression in response to high glucose, suggesting a role for miR-130b-3p in mediating high glucose-induced down regulation of PGC-1α expression. In addition, miR-130b-3p anti-sense inhibitor increased TFAM expression and reduced 4-hydroxynonenal (4-HNE)-induced production of reactive oxygen species (ROS). Taken together, these findings reveal that miR-130b-3p down-regulates PGC-1α expression in placental trophoblasts, and inhibition of miR-130b-3p appears to improve mitochondrial biogenesis signaling and protect placental trophoblast cells from oxidative stress.

Abnormal placental function in maternal diabetes affects fetal health and can predispose offspring to metabolic diseases in later life. There are fetal sex-specific differences in placenta structure and gene expression, which may affect placental responses to maternal diabetes. The present study examined the effects of maternal diabetes on indices of mitochondrial biogenesis in placentae from male and female offspring. Mitochondrial DNA (mtDNA) copy number and expression of key regulators of mitochondrial biogenesis were assessed in placentae from 19 diabetic and 23 non-diabetic women. The abundance of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and mitochondria transcription factor A (TFAM) were lower in female placentae compared to males, but not mtDNA content. In male offspring, maternal diabetes was associated with decreased placental PGC-1α and TFAM, and mitochondrial DNA (mtDNA) content. Male placental TFAM levels were highly correlated with PGC-1α and mtDNA content. However, despite decreased PGC-1α, concomitant changes in TFAM and mtDNA content by diabetes were not observed in females. In addition, TFAM abundance in female placentae was not correlated with PGC-1α or mtDNA content. In summary, placental PGC-1α/TFAM/mitochondrial biogenesis pathway is affected by maternal diabetes and offspring sex. Decreased PGC-1α in response to maternal diabetes plausibly contributes to impaired mitochondrial biogenesis in placentae of male offspring, which may affect long-term health and explain some of enhanced risk of future metabolic diseases in males.

Full breastfeeding (FBF) is promoted as effective for losing pregnancy weight during the postpartum period. This study evaluated whether longer FBF is associated with lower maternal postpartum weight retention (PPWR) as compared to a shorter FBF duration. The MILK (Mothers and Infants Linked for Healthy Growth) study is an ongoing prospective cohort of 370 mother&ndash, infant dyads, all of whom fully breastfed their infants for at least 1 month. Breastfeeding status was subsequently self-reported by mothers at 3 and 6 months postpartum. Maternal PPWR was calculated as maternal weight measured at 1, 3, and 6 months postpartum minus maternal prepregnancy weight. Using linear mixed effects models, by 6 months postpartum, adjusted means &plusmn, standard errors for weight retention among mothers who fully breastfed for 1&ndash, 3 (3.40 &plusmn, 1.16 kg), 3&ndash, 6 (1.41 &plusmn, 0.69 kg), and &ge, 6 months (0.97 &plusmn, 0.32 kg) were estimated. Compared to mothers who reported FBF for 1&ndash, 3 months, those who reported FBF for 3&ndash, 6 months and &ge, 6 months both had lower PPWR over the period from 1 to 6 months postpartum (p = 0.04 and p &lt, 0.01, respectively). However, PPWR from 3 to 6 months was not significantly different among those who reported FBF for 3&ndash, 6 versus &ge, 6 months (p &gt, 0.05). Interventions to promote FBF past 3 months may increase the likelihood of postpartum return to prepregnancy weight.

SummaryBackground Detailed measures of infant body composition are needed for understanding the impact of genes and environment on growth early in life. Objective The purpose of this study was to compare the accuracy and bias of body composition in infants. Methods Dual energy X-ray absorptiometry (DXA) and magnetic resonance imaging (MRI) were used to determine body composition and the trunk depot. The depots measured were total fat mass (FM), total fat-free mass (FFM) and trunk FM and FFM using DXA and MRI in 14 infants. Results None of the regression lines between DXA and MRI significantly deviate from the line of identity for any of the depots studied. However, Bland–Altman analyses revealed bias for trunk FM and trunk FFM. Conclusion Our data showed DXA to be accurate (regression not significantly deviating from the line of identity), with high agreement (indicated by high R2) and without bias (non-significant Bland–Altman) when estimating total FM and FFM. This could not be said for trunk estimates.

We determined the association between daily ambulatory activity and markers of inflammation and oxidative stress in patients with peripheral artery disease (PAD) and claudication. Patients with PAD (n = 134) limited by claudication were studied. Patients took 3275 ± 1743 daily strides for 273 ± 112 minutes each day, and their average daily cadence was 11.7 ± 2.7 strides/min. High-sensitivity C-reactive protein was significantly and negatively associated with the total number of daily strides ( P < .001), total daily ambulatory time ( P < .01), peak activity index ( P < .01), daily average cadence ( P < .05), and the maximum cadences for 60 minutes ( P < .05), 30 minutes ( P < .05), 20 minutes ( P < .05), and 5 minutes ( P < .01). Oxidized low-density lipoprotein and soluble vascular cell adhesion molecule 1 were not significantly associated with any of the ambulatory measures ( P > .05). We conclude that higher levels of community-based, daily ambulatory activity are associated with lower levels of inflammation but are not associated with markers of oxidative stress.

Spexin is a novel peptide that has been reported to be down regulated in obese adults and children and in normoglycemic adults following glucose ingestion. Spexin may therefore have a role in metabolic regulation. The purpose of the current study was to determine the effect of obesity and type 2 diabetes (T2DM), and the effect of glucose ingestion on circulating spexin concentration in adolescents. Boys and girls (mean age 16 years old) classified as healthy normal weight (NW, n = 22), obese (Ob, n = 10), or obese with T2DM (n = 12) completed measurements of body composition, blood pressure, cardiorespiratory fitness, and blood concentrations of glucose, insulin, and lipids. The median fasting serum spexin concentration did not differ between groups (NW: 0.35; Ob: 0.38, T2DM: 0.34 ng/mL, respectively). In 10 NW participants who completed a standard oral glucose tolerance test, spexin concentration was unchanged at 30 and 120 minutes relative to the fasting baseline. Finally, spexin was not significantly correlated with any of the body composition, fitness, or blood biochemical measurements. These data do not support the proposed role of spexin as a metabolic regulator or biomarker of glucose control in adolescents.

Context: Pigment epithelium-derived factor (PEDF) was recently implicated as a metabolic regulatory protein because plasma concentration was increased in obese or insulin resistant adults. To our knowledge, circulating PEDF values in children have not been reported. Because PEDF is a predictor of metabolic health in adults, it may have a similar impact on metabolic profiles in children. Objective: The objective of the study was to determine whether PEDF in normal-weight (NW) and overweight/obese (OW) children and young adults varies with age, sex, or body composition or is associated with clinical markers of metabolic disease. Setting: Volunteers were tested at the University of Oklahoma Health Sciences Center. Participants: Ninety-one NW (8–30 yr old) and 105 OW (8–35 yr old) males and females participated in the study. Main Outcome Measures: Body composition, blood pressure, arterial compliance, fasting plasma PEDF, glucose, insulin, (used for homeostasis model assessment of insulin resistance), triglycerides, cholesterol (total, low density lipoprotein, and high density lipoprotein), and C-reactive protein. Results: PEDF was 60% higher in the OW vs. NW participants but did not differ between males and females. PEDF was positively correlated with body mass, body mass index, fat and lean mass, fasting insulin, and homeostasis model assessment of insulin resistance in both the NW and OW groups. Multiple regression models revealed that fat and lean mass were significant predictors of circulating PEDF levels independent of age, sex, and body mass index category. Conclusions: Plasma PEDF is elevated in OW youth and is positively associated with insulin resistance. These findings suggest that PEDF may play a role in the development of cardiometabolic dysfunction in youth.

The purpose of this study was to determine the acute and residual impact of a single exercise bout on meal glucose control in adolescents with habitually low physical activity. Twelve adolescents (seven females/five males, 14 ± 2 yr) completed three trials. One trial [No Exercise (No Ex)] was completed after refraining from vigorous activity for ≥ 3 d. On the other two trials, a 45-min aerobic exercise bout at 75% peak heart rate was performed either 17-h Prior Day Exercise (Prior Day Ex) trial or 1-h Same Day Exercise (Same Day Ex) trial before consuming the test meal (2803 kJ, 45/40/15% energy as carbohydrate/fat/protein, respectively). Compared to No Ex, insulin sensitivity (SI) (minimal model analysis) was increased by 45% (p < 0.03) and 78% (p < 0.01) on the Prior Day Ex and Same Day Ex trials, respectively. This improvement in glucose control was supported by corresponding reductions in the net area under the curve for glucose, insulin, and c-peptide, although there was no change in postprandial suppression of fatty acids. These results show that SI is improved with a single bout of moderate intensity exercise in adolescents with habitually low physical activity and that the residual beneficial effect of exercise lasts at least 17 h. This finding highlights the plasticity of exercise responses in youth and the importance of daily exercise for metabolic health.

Taurine has been demonstrated to be a conditionally indispensable nutrient for several carnivorous fish species. Currently, trout feeds contain reduced levels of fishmeal which had been the primary source of dietary taurine. The reduction of fishmeal in the diet, and thus dietary taurine, may limit growth. A 12-week feeding trial was conducted using a factorial treatment design with taurine supplementation (3 levels) and methionine supplementation (3 levels) as the main effects. The diets were formulated to be fishmeal free, containing only plant proteins. Taurine was supplemented at 0, 5, and 10 g/kg dry diet and methionine was supplemented at 0, 5, and 10 g/kg dry diet in a 3 × 3 factorial design. All diets were formulated to contain 43.8% crude protein from intact protein and 20% lipid. Fifteen fish with a mean initial weight of approximately 18.4 g per fish were stocked in each of 27 tanks. The unsupplemented diet had 3.6 g of taurine/kg diet and 11.5 g total sulfur amino acids (met + cys)/kg diet. Supplementation with taurine improved growth ( p = 0.096, g gain per fish), and with 5 g/kg diet an increase in feed consumption ( p = 0.095) was observed. Methionine supplementation reduced growth ( p = 0.010, g gain per fish) and feed consumption ( p = 0.055). Neither taurine nor methionine supplementation had an effect on protein retention efficiency, energy retention efficiency or feed conversion ratio. Increased methionine intakes resulted in decreased ( p = 0.009) intraperitoneal fat deposition, whereas taurine levels had no effect. Plasma GH levels were not affected by either methionine or taurine supplementation, but decreased plasma IGF-I concentrations ( p = 0.009) were associated with methionine supplementation (5 g/kg diet). In conclusion, dietary taurine inclusion does appear beneficial for trout fed all-plant protein diets, and supplementation of methionine above the requirement does not appear to spare taurine.

We used continuous glucose monitoring to test the hypothesis that mean amplitude of glycemic excursions (MAGE) is associated with circulating markers of oxidative and vascular stress in adolescents with habitually low physical activity classified as healthy weight, healthy obese, or obese with type 2 diabetes mellitus (T2DM).A group of 13- to 21-year-olds (healthy weight = 12, healthy obese = 10, T2DM = 12) wore a continuous glucose monitor and step activity monitor for 5 days.Physical activity was similar among groups (6551 ± 401 steps/d), but aerobic fitness (peak rate of oxygen consumption) was lower (P .05) in T2DM (15.6 ± 1.8 mL/kg/min) than either healthy weight (26.2 ± 2.2) or healthy obese (24.4 ± 2.5). MAGE (mg/dL) was higher (P .01) in T2DM (82 ± 10) vs healthy obese (33 ± 3) and healthy weight (30 ± 3). Average glucose followed a similar pattern as MAGE. Oxidized low density lipoprotein was higher (P .05) in T2DM (70.3 ± 5.0 U/L) and healthy obese (58.1 ± 3.8) than healthy weight (48.4 ± 2) and positively correlated with MAGE (r = 0.77). Other stress markers that were both elevated in T2DM and correlated with MAGE included E-selectin (r = 0.50), intercellular adhesion molecule 1 (r = 0.35), and C-reactive protein (r = 0.52); soluble receptor for advanced glycosylation end product was lower in T2DM and inversely correlated with MAGE (r = -0.38).MAGE is highest in obese youth with T2DM. The associations between MAGE and oxidative stress markers support the proposed contribution of glycemic variability to risk for future cardiovascular disease.

BACKGROUND: Offspring of women with diabetes mellitus (DM) during pregnancy have a risk of developing metabolic disease in adulthood greater than that conferred by genetics alone. The mechanisms responsible are unknown, but likely involve fetal exposure to the in utero milieu, including glucose and circulating adipokines. The purpose of this study was to assess the impact of maternal DM on fetal adipokines and anthropometry in infants of Hispanic and Native American women.METHODS: We conducted a prospective study of offspring of mothers with normoglycemia (Con-O; n = 79) or type 2 or gestational DM (DM-O; n = 45) pregnancies. Infant anthropometrics were measured at birth and 1-month of age. Cord leptin, high-molecular-weight adiponectin (HMWA), pigment epithelium-derived factor (PEDF) and C-peptide were measured by ELISA. Differences between groups were assessed using the Generalized Linear Model framework. Correlations were calculated as standardized regression coefficients and adjusted for significant covariates.RESULTS: DM-O were heavier at birth than Con-O (3.7 ± 0.6 vs. 3.4 ± 0.4 kg, p = 0.024), but sum of skinfolds (SSF) were not different. At 1-month, there was no difference in weight, SSF or % body fat or postnatal growth between groups. Leptin was higher in DM-O (20.1 ± 14.9 vs. 9.5 ± 9.9 ng/ml in Con-O, p CONCLUSIONS: Maternal DM results in fetal hyperleptinemia independent of adiposity. HMWA appears to influence postnatal growth. Thus, in utero exposure to DM imparts hormonal differences on infants even without aberrant growth.

Taurine has been demonstrated to be conditionally indispensable for several carnivorous fish species. Current trends in trout production include decreasing levels of fish-meal content in feeds, along with faster growing strains of fish. Taurine may be a limiting nutrient in support of elevated planes of growth for rainbow trout. A 9-wk feeding trial was conducted using a factorial treat- ment design with protein source (fish meal or plant) and taurine supplementation (four levels) as the main effects. The fish-meal diet series included 23% herring meal and contained 1.76% total sulfur amino acids (TSAA). The plant diet series did not contain any animal proteins and substituted protein from soy protein concentrate in place of the herring-meal protein and contained 1.5% TSAA. Taurine was supplemented at 0, 5, 10, and 15 g/kg dry diet to each of the diets in the plant series and the fish-meal series of diets. All diets were formulated to contain 43.8% crude protein and 20% lipid with an estimated physiological fuel value of 4.2 kcal/g. Fifteen fish were stocked in each of 24 tanks with a mean initial weight of approximately 26.8 g per fish. The un- supplemented fish-meal diet contained 2 g/kg tau- rine, and the unsupplemented plant diet had taurine levels below the detection limit of 0.1 g/kg diet. Taurine supplementation improved growth, feed conversion ratios, protein retention efficiencies, and energy retention efficiencies of fish fed the plant protein diets. No effects of taurine supplementation were observed for these response factors in fish fed the fish-meal series diets. This study demonstrates that taurine supplementation may be necessary for rainbow trout fed plant-protein- based feeds. The removal offishmeal from the diet of rain- bow trout and other carnivorous fish species has had wide interest globally. Current diet formula- tions often utilize a variety of protein sources to replace all but a small portion of fish meal. Substituting the last portion of fish-meal protein with plant-derived products often results in reduced growth rates. Animal renderings from industry, including meat and bone meals, poul- try meals, feather meals, and blood products, have been widely evaluated as substitutes for fish meal, but these products also have limits based on nutrient profiles and nutrient digest

To determine whether exposure to diabetes in utero affects resting energy expenditure (REE) and fuel oxidation in infants.At 35 ± 5 days after birth, body composition and REE were measured in full-term offspring of Native American and Hispanic women with either well-controlled diabetes (13 girls, 11 boys) or normal healthy pregnancies (18 girls, 17 boys).Control of dysglycemia during gestation in the women with diabetes mellitus met current clinical standards, shown by average glycated hemoglobin (5.9 ± 0.2%; 40.6 ± 2.3 mmol/mol). Infant body mass (offspring of women with diabetes: 4.78 ± 0.13, control offspring: 4.56 ± 0.08 kg) and body fatness (offspring of women with diabetes: 25.2 ± 0.6, control offspring: 24.2 ± 0.5 %) did not differ between groups. REE, adjusted for lean body mass, was 14% lower in offspring of women with diabetes (41.7 ± 2.3 kJ/h) than control offspring (48.6 ± 2.0, P = .025). Fat oxidation was 26% lower in offspring of women with diabetes (0.54 ± 0.05 g/h) than control offspring (0.76 ± 0.04, P.01) but carbohydrate oxidation did not differ. Thus, fat oxidation accounted for a lower fraction of REE in the offspring of women with diabetes (49 ± 4%) than control offspring (60 ± 3%, P = .022). Mothers with diabetes were older and had higher prepregnancy body mass index than control mothers.Well-controlled maternal diabetes did not significantly affect body mass or composition of offspring at 1-month old. However, infants with mothers with diabetes had reduced REE and fat oxidation, which could contribute to adiposity and future disease risk. Further studies are needed to assess the impact differences in age and higher prepregnancy body mass index.

Assessing dietary biotin content, biotin bioavailability, and resulting biotin status are crucial in determining whether biotin deficiency is teratogenic in humans. Accuracy in estimating dietary biotin is limited both by data gaps in food composition tables and by inaccuracies in published data. The present study applied sensitive and specific analytical techniques to determine values for biotin content in a select group of foods. Total biotin content of 87 foods was determined using acid hydrolysis and the HPLC/avidin-binding assay. These values are consistent with published values in that meat, fish, poultry, egg, dairy, and some vegetables are relatively rich sources of biotin. However, these biotin values disagreed substantially with published values for many foods. Assay values varied between 247 times greater than published values for a given food to as much as 36% less than the published biotin value. Among 51 foods assayed for which published values were available, only seven agreed within analytical variability (720%). We conclude that published values for biotin content of foods are likely to be inaccurate.

Background: Smoking accelerates the degradation of many nutrients, including lipids, antioxidants, and certain B vitamins. Accelerated biotin catabolism is of concern in women because marginal biotin deficiency is teratogenic in mammals. Objective: The objective was to assess the effect of smoking on the biotin status of women. Design: A preliminary study of 7 women and 3 men examined the urinary concentrations of biotin and its metabolites biotin sulfoxide and bisnorbiotin in smokers. The interpretation of the results of this study was limited by the lack of a contemporaneous control group; consequently, we conducted a cohort-controlled study. Smoking women (n = 8) and nonsmoking control subjects (n = 15) provided 24-h urine samples; excretion rates of biotin, the biotin metabolites, and 3-hydroxyisovaleric acid were determined. Increased urinary excretion of 3-hydroxyisovaleric acid, which reflects a reduced activity of the biotin-dependent enzyme 3-methylcrotonyl-Co A carboxylase, is a sensitive indicator of biotin depletion at the tissue level. Results: Compared with control subjects from previous studies, the smoking women in the preliminary study excreted significantly less urinary biotin (P = 0.02). Moreover, the ratio of urinary biotin sulfoxide to biotin increased (P = 0.04) in these women. In the cohort-controlled study, the urinary excretion of biotin decreased by 30% (P = 0.04), and the ratios of urinary bisnorbiotin and biotin sulfoxide to biotin increased significantly, which indicated accelerated catabolism in smokers. Moreover, the urinary excretion of 3-hydroxyisovaleric acid was greater in the smokers than in the control subjects (P = 0.04), which indicated biotin depletion in the smokers at the tissue level. Conclusion: These data provide evidence of accelerated biotin metabolism in smoking women, which results in marginal biotin deficiency.