Maximizing information from space data resources: a case for expanding integration across research disciplines.

Regulatory systems are affected in space by exposure to weightlessness, high-energy radiation or other spaceflight-induced changes. The impact of spaceflight occurs across multiple scales and systems. Exploring such interactions and interdependencies via an integrative approach provides new opportunities for elucidating these complex responses. This paper argues the case for increased emphasis on integration, systematically archiving, and the coordination of past, present and future space and ground-based analogue experiments. We also discuss possible mechanisms for such integration across disciplines and missions. This article then introduces several discipline-specific reviews that show how such integration can be implemented. Areas explored include: adaptation of the central nervous system to space; cerebral autoregulation and weightlessness; modelling of the cardiovascular system in space exploration; human metabolic response to spaceflight; and exercise, artificial gravity, and physiologic countermeasures for spaceflight. In summary, spaceflight physiology research needs a conceptual framework that extends problem solving beyond disciplinary barriers. Administrative commitment and a high degree of cooperation among investigators are needed to further such a process. Well-designed interdisciplinary research can expand opportunities for broad interpretation of results across multiple physiological systems, which may have applications on Earth.

Bisphenol-A and phthalate metabolism in children with neurodevelopmental disorders.

BACKGROUND: The etiology of autism spectrum (ASD) and Attention Deficit/Hyperactivity (ADHD) disorders are multifactorial. Epidemiological studies have shown associations with environmental pollutants, such as plasticizers. This study focused on two of these compounds, the Bisphenol-A (BPA) and Diethylhexyl Phthalate (DEHP). The major pathway for BPA and DEHP excretion is via glucuronidation. Glucuronidation makes insoluble substances more water-soluble allowing for their subsequent elimination in urine. HYPOTHESIS: Detoxification of these two plasticizers is compromised in children with ASD and ADHD. Consequently, their tissues are more exposed to these two plasticizers. METHODS: We measured the efficiency of glucuronidation in three groups of children, ASD (n = 66), ADHD (n = 46) and healthy controls (CTR, n = 37). The children were recruited from the clinics of Rutgers-NJ Medical School. A urine specimen was collected from each child. Multiple mass spectrometric analyses including the complete metabolome were determined and used to derive values for the efficiency of glucuronidation for 12 varied glucuronidation pathways including those for BPA and MEHP. RESULTS: (1) Both fold differences and metabolome analyses showed that the three groups of children were metabolically different from each other. (2) Of the 12 pathways examined, only the BPA and DEHP pathways discriminated between the three groups. (3) Glucuronidation efficiencies for BPA were reduced by 11% for ASD (p = 0.020) and 17% for ADHD (p<0.001) compared to controls. DEHP showed similar, but not significant trends. CONCLUSION: ASD and ADHD are clinically and metabolically different but share a reduction in the efficiency of detoxification for both BPA and DEHP with the reductions for BPA being statistically significant.

Video Didactic Preparation Augments Problem-Based Learning for First Year Medical Students.

Problem-based learning (PBL) utilizes a self-directed strategy. This process relies on group participation to succeed. Students without a background in biology or medicine can feel overwhelmed by the complexity of the subject matter and unable to participate in the group learning process. We incorporated curated educational videos in the PBL curriculum to help address this situation. First year medical students participated in this study in the form of a typical PBL session. They were then assessed on basic and clinical science knowledge and their learning experience. Student basic science and clinical knowledge were similar between the student groups. However, the students given a list of suggested videos scored higher in their learning experience, perception of feeling prepared, and participating in the group PBL experience than students who were not given the video list. Results from this study indicate that videos can be utilized to enhance the PBL process.

Metabolic perturbance in autism spectrum disorders: a metabolomics study.

Autism spectrum disorders (ASD) are a group of biological disorders with associated metabolic derangement. This study aimed to identify a pattern of metabolic perturbance in ASD using metabolomics in urinary specimens from 48 children with ASD and 53 age matched controls. Using a combination of liquid- and gas-chromatography-based mass spectrometry, we detected the levels of 82 metabolites (53 of which were increased) that were significantly altered between the ASD and the control groups using osmolality normalized data. Pattern analysis showed that the levels of several amino acids such as glycine, serine, threonine, alanine, histidine, glutamyl amino acids and the organic acid, taurine were significantly (p≤0.05) lower in ASD children. The levels of antioxidants such as carnosine were also reduced in ASD (p=0.054). Furthermore, several gut bacterial metabolites were significantly altered in ASD children who had gastrointestinal dysfunction. Overall, this study detected abnormal amino acid metabolism, increased oxidative stress, and altered gut microbiomes in ASD. The relationship of altered gut microbial co-metabolism and the disrupted metabolisms requires further investigation.

Resveratrol prevents the wasting disorders of mechanical unloading by acting as a physical exercise mimetic in the rat.

Long-term spaceflight induces hypokinesia and hypodynamia, which, along microgravity per se, result in a number of significant physiological alterations, such as muscle atrophy, force reduction, insulin resistance, substrate use shift from fats to carbohydrates, and bone loss. Each of these adaptations could turn to serious health deterioration during the long-term spaceflight needed for planetary exploration. We hypothesized that resveratrol (RES), a natural polyphenol, could be used as a nutritional countermeasure to prevent muscle metabolic and bone adaptations to 15 d of rat hindlimb unloading. RES treatment maintained a net protein balance, soleus muscle mass, and soleus muscle maximal force contraction. RES also fully maintained soleus mitochondrial capacity to oxidize palmitoyl-carnitine and reversed the decrease of the glutathione vs. glutathione disulfide ratio, a biomarker of oxidative stress. At the molecular level, the protein content of Sirt-1 and COXIV in soleus muscle was also preserved. RES further protected whole-body insulin sensitivity and lipid trafficking and oxidation, and this was likely associated with the maintained expression of FAT/CD36, CPT-1, and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in muscle. Finally, chronic RES supplementation maintained the bone mineral density and strength of the femur. For the first time, we report a simple countermeasure that prevents the deleterious adaptations of the major physiological functions affected by mechanical unloading. RES could thus be envisaged as a nutritional countermeasure for spaceflight but remains to be tested in humans.

Decreased Adiponectin Levels in Early Pregnancy Are Associated with High Risk of Prematurity for African American Women.

The relationship of low maternal serum adiponectin levels with preterm delivery among a multi-ethnic group has not been extensively investigated. We examined ethnic differences in cytokine/adipokine profiles and whether they contribute to several adverse pregnancy outcomes, particularly preterm delivery. Data and samples were from a large prospective observational cohort (n = 1776) of young, generally healthy pregnant women (African American 36.4%, Hispanic 48.0%, Caucasian 15.6%). Serum cytokine/adipokine concentrations were measured at entry (mean gestational age of 16.83 weeks) using the Liminex xMap Technology. Multivariable analyses were performed. A significant difference in adiponectin level was observed among ethnic groups. African Americans had a decreased adiponectin and increased resistin levels compared to Hispanics and Caucasians (p < 0.05 to p < 0.0001 for each). Decreased adiponectin (lowest quartile) was positively associated with preterm delivery independent of usual risk factors (adjusted odds ratio (AOR) 1.46, 95% confidence interval (CI) 1.05, 2.04 for all preterm and AOR 1.84, 95% CI 1.07, 3.17 for early preterm births). The results were unchanged when women with preeclampsia were excluded. Similar results were observed in African Americans. Decreased adiponectin levels were not related to preterm birth in either Hispanics or Caucasians. Lower adiponectin levels were also significantly associated with an increased risk of developing gestational diabetes (AOR 1.72, 95% CI 1.05, 2.84) and preeclampsia (AOR 1.45, 95% CI 1.00, 2.14) in the whole cohort and in Caucasians. We did not find any consistent relationships between the other markers with outcome variables. Dysregulation in maternal adiponectin at early gestation is associated with an increased risk of preterm delivery. An ethnic difference in adiponectin levels may contribute to a higher preterm delivery rate in African American women.

Does protein supplementation prevent muscle disuse atrophy and loss of strength?

Recently there has been much interest in the use of dietary amino acids supplements to decrease the losses in muscle mass and strength observed after space flight or during aging using bed rest analogs. This interest persists even if the results have been mixed. Of the six published amino acid supplementation studies, three showed benefit, three did not. A recent study re-evaluating protein requirements in humans suggests that the official RDA is 41% underestimated. Interestingly, the three studies that showed benefits fed their test subjects a baseline protein level around the old RDA for protein. The three that did not show benefit gave the subjects a baseline protein intake higher than the new RDA. We suggest that the positive effects observed on protein metabolism might just reflect the benefits of adequate protein intake achieved during bed rest rather than a protective effect against bed-rest induced disuse. In conclusion, the efficiency of amino acid countermeasures for preventing the loss in protein mass during space flight or bed rest needs to be seriously questioned. These results extend to clinical situations such as serious illness and progress of aging in which physical inactivity is a significant component of the loss in muscle function.

Maternal diet, C-reactive protein, and the outcome of pregnancy.

OBJECTIVE: To examine the association of high-sensitivity C-reactive protein (hsCRP), a systemic biomarker for the inflammatory process at entry to care, with pregnancy-induced hypertension/preeclampsia, adverse outcomes of pregnancy, and the maternal diet. DESIGN: Random sample (N = 520) with normal glucose tolerance from a large prospective cohort study of urban, low income, minority gravidae. RESULTS: During pregnancy, the highest tertile of hsCRP (range, 7.06-137.41 mg/L) was associated with significantly increased risks for early preterm delivery (<34 weeks). However, after stratification by maternal pregravid body mass index (BMI), risk for early preterm delivery <34 weeks (adjusted odds ratios [AOR] = 3.58, 95% confidence interval [CI] = 1.05-12.27), and pregnancy-induced hypertension (AOR = 2.66, 95% CI = 1.03-6.86) including preeclampsia (AOR = 2.72, 95% CI = 1.08-6.85) was shown to be specific to lean women (BMI <25) with high hsCRP. Increased hsCRP was unrelated to risk among overweight and obese gravidae. We found high hsCRP to be associated with diet. After stratification by BMI, dietary differences (higher intakes of protein and cholesterol with a lower intake of carbohydrate and a higher entry dietary glycemic index) were associated with increased hsCRP only among lean gravidae and not among those who were overweight or obese. CONCLUSIONS: High hsCRP is a diet-related biomarker for serious complications and poor outcome in lean women with normal glucose tolerance.

Weight loss in humans in space.

INTRODUCTION: Bodyweight loss during spaceflight has been observed among astronauts since the early space missions. Considerable mission data has been accumulated, including data from female astronauts, on the many Shuttle and International Space Station missions. The purpose of this study was to investigate the association between observed weight loss during spaceflight and potential covariate factors. METHODS: We performed a statistical analysis of the association between bodyweight change and plausible clinical and mission covariates, using data obtained from the NASA Longitudinal Study of Astronaut Health (LSAH). RESULTS: We confirmed that spaceflight is associated with weight change (-2.1 +/- 0.1%, N = 514). Prospective predictors of weight loss included: being a first-time astronaut, preflight bodyweight and BMI, routinely performing preflight exercise sessions lasting greater than 1 h, and baseline levels of cholesterol, potassium, and chloride. Severe space motion sickness was significantly associated with greater weight loss. Unexpectedly, a higher number of extravehicular activities per mission protected against weight loss. Mission duration had the strongest association with bodyweight change (-2.4 +/- 0.4% per 100 d in space). DISCUSSION: On average, space missions are associated with cumulative loss of bodyweight over time. Unless effective countermeasures are implemented, significant weight loss will be a likely outcome in a subset of astronauts as mission durations increase. New predictors of intra-mission bodyweight changes and other associated factors are identified.

Individual free fatty acids have unique associations with inflammatory biomarkers, insulin resistance and insulin secretion in healthy and gestational diabetic pregnant women.

Objective: We investigated the relationships of maternal circulating individual free fatty acids (FFA) with insulin resistance, insulin secretion and inflammatory biomarkers during mid-pregnancy. Research design and methods: The data were drawn from a prospective cohort of generally healthy pregnant women (n=1368, African-American 36%, Hispanic 48%, Caucasian 16%) in Camden, NJ. We quantitatively determined 11 FFAs, seven cytokine/adipokine, homeostatic model assessment of insulin resistance (HOMA-IR) and C-peptide levels from the fasting blood samples that were collected at 16 weeks of gestation. Multivariate analyses were performed along with separate analyses for each individual FFA. Results: High HOMA-IR (p<0.001) and C-peptide (p<0.0001) levels were positively associated with a twofold to fourfold increased risk for developing gestational diabetes mellitus (GDM). Negative relationships were found with specific FFAs (molecular percentage, palmitoleic, oleic, linolenic, myristic acids) and HOMA-IR and C-peptide levels (p<0.01 to p<0.0001). In contrast, palmitic, stearic, arachidonic, dihomo-γ-linolenic (DGLA) and docosahexaenoic acids were positively associated with HOMA-IR and C-peptide (p<0.01 to p<0.0001). The individual FFAs also predicted cytokine/adipokine levels. For example, women who had elevated DGLA (highest quartile) were twice as (adjusted OR 2.06, 95% CI 1.42 to 2.98) likely to have higher interleukin (IL)-8 (p<0.0001) levels. Conversely, women with high palmitoleic, oleic, and linolenic acid levels had reduced odds (≥2-fold, p<0.01 to p<0.001) for having higher IL-8, IL-6 or tumor necrosis factor-alpha levels. Conclusion: Our results suggest that maternal individual FFAs uniquely affect insulin resistance and secretion. The effects are either direct or indirect via modulation of the inflammatory response. Modifying the composition of FFAs may help in reducing the risk of GDM.

Association of elevated serum ferritin levels and the risk of gestational diabetes mellitus in pregnant women: The Camden study.

OBJECTIVE- We examined the influence of a moderately elevated serum ferritin level at entry to care on the risk of gestational diabetes mellitus (GDM) and a possible mechanism (increased iron stores versus inflammation). RESEARCH DESIGN AND METHODS- In a prospective observational study with 1,456 healthy pregnant women in Camden, New Jersey, serum ferritin and anthropometric measurements were determined. Serum C-reactive protein (CRP) concentration was measured in a nested case-control study of 172 subjects. RESULTS- Women who developed GDM had a higher concentration of serum ferritin than women who did not develop GDM (P < 0.001). Elevated serum ferritin level (highest quintile) was significantly and positively correlated with prepregnant BMI and skinfold measurements. Women in the highest quintile of serum ferritin had a twofold increased risk of developing GDM adjusted for several known risk factors (adjusted odds ratio, 2.02 [95% CI 1.04-3.92], P < 0.05). Similar results were obtained with a nested case-control study, in which women in the highest tertile of serum ferritin (2.35 [1.06-5.22], P < 0.05) or CRP (2.67 [1.16-6.17], P < 0.001) had a greater than twofold increased risk of GDM. However, these effects were modified and became nonstatistically significant after additional adjustment for prepregnant BMI. CONCLUSIONS- Elevated serum ferritin concentrations early in gestation are associated with an increased risk of GDM. The association, at least in part, is mediated by the maternal fat mass and obesity. These data suggest a possible link between elevated serum ferritin and low-grade inflammation.

Vitamin E: maternal concentrations are associated with fetal growth.

BACKGROUND: Few data exist on the effects of the 2 most abundant isomers of vitamin E (alpha- and gamma-tocopherols) on fetal growth. OBJECTIVE: We measured maternal plasma concentrations of alpha- and gamma-tocopherols and examined their relation with measures of fetal growth. We also examined the relation, controlled for associated maternal factors, of diet and supplement use to tocopherol concentrations at week 28 of gestation. DESIGN: A cohort of 1231 gravid women from Camden, NJ, was studied from entry to care (16.0 +/- 0.15 wk gestation); plasma tocopherol concentrations were measured at entry and at week 28. RESULTS: Plasma concentrations of alpha-tocopherol at entry and at week 28 were positively related to increased fetal growth (birth weight for gestation), a decreased risk of small-for-gestational-age births, and an increased risk of large-for-gestational-age births. Concentration of alpha-tocopherol at week 28 was positively related to use of prenatal multivitamins and dietary intake of vitamin E; concentration of gamma-tocopherol was related positively to dietary fat intake and negatively to multivitamin use. CONCLUSION: Early and late circulating concentrations of alpha-tocopherol are positively associated with fetal growth.

Effect of a low-carbohydrate diet on appetite, blood glucose levels, and insulin resistance in obese patients with type 2 diabetes.

BACKGROUND: It is not known how a low-carbohydrate, high-protein, high-fat diet causes weight loss or how it affects blood glucose levels in patients with type 2 diabetes. OBJECTIVE: To determine effects of a strict low-carbohydrate diet on body weight, body water, energy intake and expenditure, glycemic control, insulin sensitivity, and lipid levels in obese patients with type 2 diabetes. DESIGN: Inpatient comparison of 2 diets. SETTING: General clinical research center of a university hospital. PATIENTS: 10 obese patients with type 2 diabetes. INTERVENTION: Usual diets for 7 days followed by a low-carbohydrate diet for 14 days. MEASUREMENTS: Body weight, water, and composition; energy intake and expenditure; diet satisfaction; hemoglobin A1c; insulin sensitivity; 24-hour urinary ketone excretion; and plasma profiles of glucose, insulin, leptin, and ghrelin. RESULTS: On the low-carbohydrate diet, mean energy intake decreased from 3111 kcal/d to 2164 kcal/d. The mean energy deficit of 1027 kcal/d (median, 737 kcal/d) completely accounted for the weight loss of 1.65 kg in 14 days (median, 1.34 kg in 14 days). Mean 24-hour plasma profiles of glucose levels normalized, mean hemoglobin A1c decreased from 7.3% to 6.8%, and insulin sensitivity improved by approximately 75%. Mean plasma triglyceride and cholesterol levels decreased (change, -35% and -10%, respectively). LIMITATIONS: The study was limited by the short duration, small number of participants, and lack of a strict control group. CONCLUSION: In a small group of obese patients with type 2 diabetes, a low-carbohydrate diet followed for 2 weeks resulted in spontaneous reduction in energy intake to a level appropriate to their height; weight loss that was completely accounted for by reduced caloric intake; much improved 24-hour blood glucose profiles, insulin sensitivity, and hemoglobin A1c; and decreased plasma triglyceride and cholesterol levels. The long-term effects of this diet, however, remain uncertain.

Plasma protein synthesis after spaceflight.

INTRODUCTION: Astronauts land in a protein-depleted state. An anabolic phase takes place during the postflight period as muscle regains the lost protein. Yet where dietary intake has been measured after spaceflight, there does not appear to be any significant increase in dietary protein intake relative to preflight to provide additional amino acids to support muscles as they regain protein. We hypothesized that protein synthesis in other tissues is sub-optimal after spaceflight because of substrate competition for amino acids occurring between the muscles needing protein and other tissues. METHODS: We measured selected plasma protein synthesis rates before and after spaceflight on the Shuttle using the 15N glycine-hippuric acid method. The fractional protein synthesis rates (FSR) of four plasma proteins, fibrinogen, complement C-3, ceruloplasmin, and haptoglobin, were measured before and after a 16-d flight on the Space Shuttle. Data was obtained for four subjects. Preflight measurements of plasma protein synthesis rates were made 45 and 7 d before launch. Postflight measurements were done on the day of landing and 6 and 14 d later. RESULTS: Compared with preflight, plasma protein synthesis rates were reduced 6 d after landing. DISCUSSION: Plasma protein synthesis rates are depressed after spaceflight. The observations are consistent with amino acids being the limiting factor due to substrate competition between the muscles needing protein and other tissues.

Towards human exploration of space: The THESEUS review series on nutrition and metabolism research priorities.

Nutrition has multiple roles during space flight from providing sufficient nutrients to meet the metabolic needs of the body and to maintain good health, to the beneficial psychosocial aspects related to the meals. Nutrition is central to the functioning of the body; poor nutrition compromises all the physiological systems. Nutrition is therefore likely to have a key role in counteracting the negative effects of space flight (e.g., radiation, immune deficits, oxidative stress, and bone and muscle loss). As missions increase in duration, any dietary/nutritional deficiencies will become progressively more detrimental. Moreover, it has been recognized that the human diet contains, in addition to essential macronutrients, a complex array of naturally occurring bioactive micronutrients that may confer significant long-term health benefits. It is therefore critical that astronauts be adequately nourished during missions. Problems of nutritional origin are often treatable by simply providing the appropriate nutrients and adequate recommendations. This review highlights six key issues that have been identified as space research priorities in nutrition field: in-flight energy balance; altered feeding behavior; development of metabolic stress; micronutrient deficiency; alteration of gut microflora; and altered fluid and electrolytes balance. For each of these topics, relevance for space exploration, knowledge gaps and proposed investigations are described. Finally, the nutritional questions related to bioastronautics research are very relevant to multiple ground-based-related health issues. The potential spin-offs are both interesting scientifically and potentially of great clinical importance.

Oxidative stress, diet, and the etiology of preeclampsia.

BACKGROUND: A current theory holds that oxidative stress, ie, an imbalance between maternal prooxidants and antioxidants, is a component of preeclampsia. It is uncertain whether such an imbalance occurs before clinical recognition of the syndrome or whether it is related to diet. OBJECTIVE: We measured urinary excretion of the isoprostane 8-iso-prostaglandin F(2alpha), which is an indicator of oxidative damage to lipids, and the total antioxidant power, which is a global measure of antioxidant status, at the entry to prenatal care. We also examined the relation of these indexes to diet during pregnancy. DESIGN: A cohort of 307 gravidae from Camden, NJ, was studied from entry to prenatal care (at 15.0 +/- 0.49 wk gestation). Measures of the maternal diet were obtained by 24-h recall. RESULTS: Risk of preeclampsia was increased 5-fold with higher urinary isoprostane excretion and decreased 3-fold with higher total antioxidant power. Over the course of pregnancy, there were significant trends for an association of higher isoprostane excretion with increased consumption of energy-adjusted fat, polyunsaturated fat, and polyunsaturated fatty acids (n-3, n-6, and linoleic and linolenic fatty acids), whereas total antioxidant power was not related to diet. CONCLUSIONS: Increased urinary excretion of isoprostane and decreased antioxidant production is an imbalance that is consistent with oxidative stress, and it precedes clinical recognition of preeclampsia. The maternal diet is an underlying factor that provides an environment for free radical generation.

Effect of hind limb muscle unloading on liver metabolism of rats.

In response to decreased use, skeletal muscle undergoes an adaptive reductive remodeling. There is a shift in fiber types from slow twitch to fast twitch fiber types. Associated with muscle unloading is an increased reliance on carbohydrate metabolism for energy. The hind limb suspended (HLS) rat model was used as the experimental model to determine whether skeletal muscle unloading had any impact on the liver. We used a combination of actual enzyme assays and microarray mRNA expression to address this question. The GenMAPP program was used to identify altered metabolic pathways. We found that the major changes in the liver with HLS were increases in the expression of genes involved in the generation of energy fuels for export, specifically gluconeogenesis and lipogenesis. The expression of mRNA was increased (P<0.05) for three of the four enzymes involved in the regulation of gluconeogenesis pathway (pyruvate carboxylase (PC), phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (G-6-Pase). Actual assay of enzymatic activity, in micromol . min(-1) . mg protein(-1) showed G-6-Pase (0.14+0.01 vs 0.17+0.01 P<0.05), fructose 1,6, bisphophosphatase (0.048+0.002 vs 0.054+0.002, P<0.07), and PEPCK (0.031+0.002 vs 0.038+0.012 (P<0.05) to be increased. We conclude that 1) atrophied muscle is not the only tissue to be affected by HLS, as there is also a response by the liver; and 2) the major changes in liver substrate metabolism induced by HLS appear to be limited to glucose and triglyceride production. The increase in glycolytic capacity in disused muscle is paralleled by an increase in glucogenic capacity by the liver.

Bisphenol A Exposure in Children With Autism Spectrum Disorders.

The etiology of autism spectrum disorders (ASD) is believed to involve genetic and environmental components. This study focused on the plasticizer, Bisphenol-A (BPA). The major pathway for BPA metabolism and excretion is via glucuronidation. To determine whether there was a relationship between BPA exposure and ASD, urine specimens were collected from 46 children with ASD and 52 controls. Free and total BPA concentrations were determined by mass spectrometry. The fraction glucuronidated was calculated from the difference. A metabolomics study was done to investigate metabolite distribution in the urine. (i) Most of the BPA excreted in the urine was as the glucuronide; (ii) about 20% of the ASD children had BPA levels beyond the 90th percentile (>50 ng/mL) of the frequency distribution for the total sample of 98 children; (iii) Mann-Whitney U tests and multiple regression analyses found significant differences (P < 0.05) between the groups in total and % bound BPA; and (iv) the metabolomics analyses showed the number of absolute partial correlations >|0.30| between metabolite concentrations and total BPA was ∼3 times greater with the ASD group than the controls (P < 0.001), and the number of absolute partial correlations > |0.30| for % bound BPA was ∼15 times higher with ASD (P < 0.001). The results suggest there is an association between BPA and ASD.

Excessive caloric intake acutely causes oxidative stress, GLUT4 carbonylation, and insulin resistance in healthy men.

Obesity-linked insulin resistance greatly increases the risk for type 2 diabetes, hypertension, dyslipidemia, and non-alcoholic fatty liver disease, together known as the metabolic or insulin resistance syndrome. How obesity promotes insulin resistance remains incompletely understood. Plasma concentrations of free fatty acids and proinflammatory cytokines, endoplasmic reticulum ( ER) stress, and oxidative stress are all elevated in obesity and have been shown to induce insulin resistance. However, they may be late events that only develop after chronic excessive nutrient intake. The nature of the initial event that produces insulin resistance at the beginning of excess caloric intake and weight gain remains unknown. We show that feeding healthy men with ~6000 kcal/day of the common U.S. diet [~50% carbohydrate (CHO), ~ 35% fat, and ~15% protein] for 1 week produced a rapid weight gain of 3.5 kg and the rapid onset (after 2 to 3 days) of systemic and adipose tissue insulin resistance and oxidative stress but no inflammatory or ER stress. In adipose tissue, the oxidative stress resulted in extensive oxidation and carbonylation of numerous proteins, including carbonylation of GLUT4 near the glucose transport channel, which likely resulted in loss of GLUT4 activity. These results suggest that the initial event caused by overnutrition may be oxidative stress, which produces insulin resistance, at least in part, via carbonylation and oxidation-induced inactivation of GLUT4.

Association of glutathione peroxidase activity with insulin resistance and dietary fat intake during normal pregnancy.

Glutathione peroxidase (GPx) is one of the most important antioxidant enzymes in humans. We studied the relationship between erythrocyte GPx activity and fasting serum insulin, plasma glucose, and C-peptide, estimates of insulin resistance from the homeostasis model of assessment as well as dietary fat intake in 408 normotensive nondiabetic pregnant women from Camden, NJ. GPx activity and the metabolic parameters were determined at entry to care (16 wk of pregnancy) and during the third trimester. GPx activity and the levels of insulin resistance increased significantly between entry and the third trimester. Statistically significant associations, all positive, were observed between GPx activity and fasting insulin (beta = 0.009, P < 0.001), glucose (beta = 0.975, P < 0.05), C-peptide (beta = 1.537, P < 0.01), and insulin resistance from the homeostasis model of assessment (beta = 0.209, P < 0.01). Dietary intakes of fat and polyunsaturated fatty acids were positively correlated with GPx activity as well. African Americans had significantly higher GPx activity, dietary fat, and polyunsaturated fatty acid intake than Hispanics and Caucasians. In conclusion, we demonstrated that normal pregnancy is associated with increased GPx activity and insulin resistance. There are ethnic differences in antioxidant response and dietary fat intake. Our findings suggest a potential link among antioxidant defenses, insulin resistance, and dietary fat intake.