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BACKGROUND/OBJECTIVES: The objective of this study was to develop approaches to expressing resting energy expenditure (REE) and lean body mass (LM) phenotypes of metabolic disorders in terms of Z- scores relative to their predicted healthy values. SUBJECTS/METHODS: Body composition and REE were measured in 135 healthy participants. Prediction equations for LM and REE were obtained from linear regression and the range of normality by the standard deviation of residuals. Application is demonstrated in patients from three metabolic disorder groups (lipodystrophy, n = 7; thyrotoxicosis, n = 16; and resistance to thyroid hormone (RTH), n = 46) in which altered REE and/or LM were characterised by departure from the predicted healthy values, expressed as a Z-score. RESULTS: REE (kJ/min) = -0.010 x age (years) + 0.016 x FM (kg) + 0.054 x fat- free mass (kg) + 1.736 ([R.sup.2] = 0.732, RSD = 0.36kJ/min). LM (kg) = 5.30 x bone mineral content (kg) + 10.66 x [height.sup.2] (m) + 6.40 (male). LM (kg) = 0.20 x fat (kg) + 14.08 x [height.sup.2] (m) - 2.93 (female). (male [R.sup.2] = 0.55, RSD = 3.90 kg; female [R.sup.2] = 0.59, RSD = 3.85 kg). We found average Z-scores for REE and LM of 1.77 kJ/min and -0.17 kg in the RTH group, 5.82 kJ/min and -1.23 kg in the thyrotoxic group and 2.97 kJ/min and 4.20 kg in the LD group. CONCLUSION: This approach enables comparison of data from individuals with metabolic disorders with those of healthy individuals, describing their departure from the healthy mean by a Z-score. European Journal of Clinical Nutrition (2014) 68, 234-240; doi: 10.1038/ejcn.2013.237; published online 27 November 2013 Keywords: resting energy expenditure; lean mass; body composition; Z-score; metabolic disease, INTRODUCTION Many metabolic disorders such as thyroid disease or lipodystrophy (LD) are associated with changes in body composition, energy expenditure or both. (1,2) In describing the phenotypes of such conditions, [...]

Objectives:To measure uptake and disposal kinetics and absolute absorption of vitamin K1 using two stable isotope-labelled forms of vitamin K1.Subjects:Ten subjects (nine women and one man) aged between 22 and 31 years, with a mean (±standard deviation) body mass index of 22.5±2.4 kg/m2. Subjects took capsules containing 3 μg of methyl-13C vitamin K1, three times a day for six days to reach a steady state for plasma vitamin K1 isotopic enrichment. On day seven, subjects were given an intravenous dose of Konakion MM to measure disposal kinetics and at the same time, a capsule containing 4 μg of ring-D4 vitamin K1 to measure absorption. Plasma vitamin K1 concentration was measured by high-performance liquid chromatography and isotopic composition by gas chromatography mass spectrometry.Results:The disposal kinetics of the intravenous dose of vitamin K1 were resolved into two exponentials with half-times of 0.22 (±0.14) and 2.66 (±1.69) h. Absorption of oral, deuterated vitamin K1 was 13 (±9) %.Conclusions:Two-compartmental kinetic parameters observed in this study are similar to those obtained previously using radioactive tracers, but there may be additional slow-turnover body pools acting as stores of vitamin K1. The kinetic parameters determined from the intravenous dose allowed determination of the absolute absorption of vitamin K1 from a bolus oral dose.European Journal of Clinical Nutrition (2008) 62, 1273–1281; doi:10.1038/sj.ejcn.1602859; published online 1 August 2007 [ABSTRACT FROM AUTHOR]

Background: Little is known about population levels of energy expenditure, as national surveillance systems typically employ only crude measures. The National Diet and Nutrition Survey (NDNS) in the UK measured energy expenditure in a 10% subsample by gold-standard doubly labelled water (DLW)., Methods: DLW-subsample participants from the NDNS (383 males, 387 females) aged 4-91 years were recruited between 2008 and 2015 (rolling programme). Height and weight were measured and body-fat percentage estimated by deuterium dilution., Results: Absolute total energy expenditure (TEE) increased steadily throughout childhood, ranging from 6.2 and 7.2 MJ/day in 4- to 7-year-olds to 9.7 and 11.7 MJ/day for 14- to 16-year-old girls and boys, respectively. TEE peaked in 17- to 27-year-old women (10.7 MJ/day) and 28- to 43-year-old men (14.4 MJ/day), before decreasing gradually in old age. Physical-activity energy expenditure (PAEE) declined steadily with age from childhood (87 kJ/day/kg in 4- to 7-year-olds) through to old age (38 kJ/day/kg in 71- to 91-year-olds). No differences were observed by time, region and macronutrient composition. Body-fat percentage was strongly inversely associated with PAEE throughout life, irrespective of expressing PAEE relative to body mass or fat-free mass. Compared with females with <30% body fat, females with >40% recorded 29 kJ/day/kg body mass and 18 kJ/day/kg fat-free mass less PAEE in analyses adjusted for age, geographical region and time of assessment. Similarly, compared with males with <25% body fat, males with >35% recorded 26 kJ/day/kg body mass and 10 kJ/day/kg fat-free mass less PAEE., Conclusions: This first nationally representative study reports levels of human-energy expenditure as measured by gold-standard methodology; values may serve as a reference for other population studies. Age, sex and body composition are the main determinants of energy expenditure. Key Messages This is the first nationally representative study of human energy expenditure, covering the UK in the period 2008-2015. Total energy expenditure (MJ/day) increases steadily with age throughout childhood and adolescence, peaks in the 3rd decade of life in women and 4th decade of life in men, before decreasing gradually in old age. Physical activity energy expenditure (kJ/day/kg or kJ/day/kg fat-free mass) declines steadily with age from childhood to old age, more steeply so in males. Body-fat percentage is strongly inversely associated with physical activity energy expenditure. We found little evidence that energy expenditure varied by geographical region, over time, or by dietary macronutrient composition., (© The Author(s) 2020. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Rationale: We describe a novel method for preparing milk samples and profiling their triglyceride (TG) fractions. This method was used to explore how the TG profile of milk modulates as lactation progresses and how the TG profile differs between breasts., Methods: Fresh milk was spotted onto Whatman filter paper and air-dried. Liquid Extraction Surface Analysis coupled to Fourier Transform Mass Spectrometry (LESA-MS) was adapted for molecular profiling. Collision-Induced Dissociation (CID) was used to profile fatty acid residues., Results: LESA-MS produced the relative abundances of all isobaric TGs described and showed that mammary glands within one individual can produce a different profile of TGs. CID was used to uncover the configuration of isobaric triglycerides, indicating the relative amounts of the fatty acids contributing to that triglyceride's mass. This also indicated the presence of very long chain fatty acids (C26:0 and C26:1) that have not been reported before in human breast milk., Conclusions: We conclude that spotting on paper and the use of LESA-MS and CID on milk spots is not only a means for analysing milk in unprecedented detail for this preparation time, but is also amenable to conditions in which collecting and storing fresh milk samples for detailed profiling is prohibitively difficult., (© 2019 The Authors Rapid Communications in Mass Spectrometry Published by John Wiley & Sons, Ltd.)

Background: Low bioavailability of nitric oxide (NO) is implicated in the pathophysiology of sickle cell disease (SCD). We designed a nested pilot study to be conducted within a clinical trial testing the effects of a daily ready-to-use supplementary food (RUSF) fortified with arginine (Arg) and citrulline (Citr) vs. non-fortified RUSF in children with SCD. The pilot study evaluated 1) the feasibility of a non-invasive stable isotope method to measure whole-body NO production and 2) whether Arg+Citr supplementation was associated with increased whole-body NO production., Subjects: Twenty-nine children (70% male, 9-11years, weight 16.3-31.3 kg) with SCD., Methods: Sixteen children received RUSF+Arg/Citr (Arg, 0.2  g/kg/day; Citr, 0.1  g/kg/day) in combination with daily chloroquine (50 mg) and thirteen received the base RUSF in combination with weekly chloroquine (150 mg). Plasma amino acids were assessed using ion-exchange elution (Biochrom-30, Biochrom, UK) and whole-body NO production was measured using a non-invasive stable isotopic method., Results: The RUSF+Arg/Citr intervention increased plasma arginine (P = .02) and ornithine (P = .003) and decreased the ratio of asymmetric dimethylarginine to arginine (P = .01), compared to the base RUSF. A significant increase in whole-body NO production was observed in the RUSF-Arg/Citr group compared to baseline (weight-adjusted systemic NO synthesis 3.38 ± 2.29 μmol/kg/hr vs 2.35 ± 1.13 μmol/kg/hr, P = .04). No significant changes were detected in the base RUSF group (weight-adjusted systemic NO synthesis 2.64 ± 1.14 μmol/kg/hr vs 2.53 ± 1.12 μmol/kg/hr, P = .80)., Conclusions: The non-invasive stable isotopic method was acceptable and the results provided supporting evidence that Arg/Citr supplementation may increase systemic NO synthesis in children with SCD., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims/hypothesis: Being born small for gestational age (SGA) is associated with an increased risk of type 2 diabetes in an affluent society, but could confer an improved chance of survival during sparse living conditions. We studied whether insulin action and other metabolic responses to prolonged fasting differed between 21 young adults born SGA and 18 matched controls born appropriate for gestational age (AGA)., Methods: A frequently sampled IVGTT and indirect calorimetry measurements were performed after a 36 h fast. Endogenous glucose production, insulin sensitivity (SI), first-phase insulin secretion and glucose effectiveness were estimated by stable isotope tracer techniques and minimal modelling. Muscle and fat biopsies were obtained after 35 h of fasting., Results: During fasting, SGA individuals experienced a more pronounced decrease in serum insulin and lower plasma triacylglycerol levels compared with AGA individuals. In addition, energy expenditure decreased in SGA but increased in AGA individuals. After fasting, SGA individuals displayed lower fat oxidation than AGA individuals. SG was reduced in SGA compared with AGA individuals, whereas hepatic or whole body insulin action (SI) did not differ between groups. SGA individuals had increased muscle PPARGC1A DNA methylation. We found no differences in adipose tissue PPARGC1A DNA methylation, muscle and adipose tissue PPARGC1A mRNA expression, or muscle glycogen levels between the groups., Conclusion: Compared with AGA individuals, SGA individuals displayed a more energy-conserving and potentially beneficial [corrected] cardiometabolic response to 36 h fasting. The role of increased muscle PPARGC1A DNA methylation in mediating this response requires further study.

Objective: First, to evaluate the ability of a short dietary questionnaire (SDQ) to estimate energy intake (EI) on group and individual levels compared with total energy expenditure (TEE) measured by the doubly labelled water method. Second, to compare the SDQ's performance in estimating energy, nutrient and food intakes with a sixty-six-item FFQ used in large-scale Swedish epidemiological research., Design: Cross-sectional., Setting: Umeå, Sweden., Subjects: In total, sixty-five non-pregnant women, of whom thirty-one were overweight or obese, and twenty-five pregnant, normal-weight women completed the protocol., Results: On average, the SDQ captured 78 % and 79 % of absolute TEE in the non-pregnant and pregnant normal-weight women, respectively. Furthermore, the SDQ captured an average of 57 % of TEE in the overweight/obese non-pregnant women. The Spearman correlation of EI and TEE was significant in the overweight and obese women only (ρ = 0·37, 95 % CI 0·02, 0·64). There was no significant difference between the SDQ and the more extensive FFQ in the ability to assess EI when compared with TEE. Intakes of most nutrients and foods were significantly higher when assessed with the SDQ compared with the FFQ., Conclusions: A new short dietary questionnaire with an alternative design underestimated EI of non-pregnant and pregnant, overweight and obese women on a group level but was able to rank the overweight/obese women according to EI. Furthermore, the short questionnaire captured as much or more of the energy, nutrient and food intakes of non-pregnant normal-weight and overweight/obese women on the group level as a traditional, more extensive FFQ.

Context: Low serum IGF-1 levels have been linked to increased risk for development of type 2 diabetes. However, the physiological role of IGF-1 in glucose metabolism is not well characterized., Objective: Our objective was to explore glucose and lipid metabolism associated with variations in serum IGF-1 levels., Design, Setting and Participants: IGF-1 levels were measured in healthy, nonobese male volunteers aged 18 to 50 years from a biobank (n = 275) to select 24 subjects (age 34.8 ± 8.9 years), 12 each in the lowest (low-IGF) and highest (high-IGF) quartiles of age-specific IGF-1 SD scores. Evaluations were undertaken after a 24-hour fast and included glucose and glycerol turnover rates using tracers, iv glucose tolerance test to estimate peripheral insulin sensitivity (IS) and acute insulin and C-peptide responses (indices of insulin secretion), magnetic resonance spectroscopy to measure intramyocellular lipids (IMCLs), calorimetry, and gene expression studies in a muscle biopsy., Main Outcome Measures: Acute insulin and C-peptide responses, IS, and glucose and glycerol rate of appearance (Ra) were evaluated., Results: Fasting insulin and C-peptide levels and glucose Ra were reduced (all P < .05) in low-IGF compared with high-IGF subjects, indicating increased hepatic IS. Acute insulin and C-peptide responses were lower (both P < .05), but similar peripheral IS resulted in reduced insulin secretion adjusted for IS in low-IGF subjects (P = 0.044). Low-IGF subjects had higher overnight levels of free fatty acids (P = .028) and β-hydroxybutyrate (P = .014), increased accumulation of IMCLs in tibialis anterior muscle (P = .008), and a tendency for elevated fat oxidation rates (P = .058); however, glycerol Ra values were similar. Gene expression of the fatty acid metabolism pathway (P = .0014) was upregulated, whereas the GLUT1 gene was downregulated (P = .005) in the skeletal muscle in low-IGF subjects., Conclusions: These data suggest that serum IGF-1 levels could be an important marker of β-cell function and glucose as well as lipid metabolic responses during fasting.

Methods of determining insulin sensitivity that use an oral challenge of glucose are preferred to those using intravenous administration since the measurement is made in conditions more akin to normal physiology. One previously reported protocol (ODILE) studies glucose uptake in isolation from absorption and endogenous production by the intravenous administration of tracer approximately forty-five minutes after the oral dose is given. However, this methodology has not been validated against other accredited procedures. This study utilizes the euglycemic hyperinsulinemic clamp in order to validate the ODILE method.

Objective: We sought to assess the association between maternal gestational physical activity and insulin action and body composition in early infancy., Research Design and Methods: At 28-32 weeks' gestation, pregnant women participating in an observational study in Sweden underwent assessments of height, weight, and body composition, an oral glucose tolerance test, and 10 days of objective physical activity assessment. Thirty mothers and infants returned at 11-19 weeks postpartum. Infants underwent assessments of weight, length, and body composition., Results: Early insulin response was correlated with total physical activity (r = -0.47; P = 0.007). Early insulin response (r = -0.36; P = 0.045) and total physical activity (r = 0.52; P = 0.037) were also correlated with infant fat-free mass. No maternal variable was significantly correlated with infant adiposity., Conclusions: The relationships between maternal physical activity, insulin response, and infant fat-free mass suggest that physical activity during pregnancy may affect metabolic outcomes in the mother and her offspring.

Some women in rural Pakistan are chronically undernourished, and consequently underweight. Concerns have been expressed that the degree of undernourishment might be sufficiently severe to affect lactation performance. We have obtained data on maternal body composition and infant breast milk intake using stable isotope methods in a group of thirty three mother and infant pairs at approximately six months of age. The maternal body mass index ranged from 16.6 to 29.1 kg·m(-2). In this population we found that exclusive breast-feeding tended to be associated with lower maternal body fat, and that there was no evidence for compromised lactational performance due to malnourishment. Finally we note that when our data is combined with that from other studies there may be a generalised negative correlation between breast milk intake and maternal body fat.

Stable isotopic methods are considered the "gold standard" for the measurement of rates of in vivo NO production. However, values reported for healthy human individuals differ by more than 1 order of magnitude. The reason for the apparent variability in NO production is unclear. The primary aim of this review was to evaluate and compare the rates of in vivo NO production in health and disease using stable isotope methods. Articles were retrieved using the PubMed electronic database. Information on concentrations, isotopic enrichments of fluxes, and conversion rates of molecules involved in the NO metabolic pathway was extracted from selected articles; 35 articles were included in the final analysis. Three protocols were identified, including the arginine-citrulline, the arginine-nitrate, and the oxygen-nitrate protocols. The arginine-citrulline protocol showed a wider variability compared to the arginine-nitrate and oxygen-nitrate protocols. The direction of the association between disease state and rate of NO production was essentially determined by the etiopathogenesis of the disorder (inflammatory, metabolic, vascular). Considerable variation in methodologies used to assess whole-body NO synthesis in humans exists. The precision of several aspects of the techniques and the validity of some assumptions made remain unknown, and there is a paucity of information about physiological rates of NO production from childhood over adolescence to old age., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Overweight and obesity during pregnancy raise the risk of gestational diabetes and birth complications. Lifestyle factors like physical activity may decrease these risks through beneficial effects on glucose homeostasis. Here we examined physical activity patterns and their relationships with measures of glucose homeostasis in late pregnancy compared to non-pregnant women., Methods: Normal weight and overweight women without diabetes (N = 108; aged 25-35 years) were studied; 35 were pregnant (in gestational weeks 28-32) and 73 were non-pregnant.Insulin sensitivity and β-cell response were estimated from an oral glucose tolerance test. Physical activity was measured during 10-days of free-living using a combined heart rate sensor and accelerometer. Total (TEE), resting (REE), and physical activity (PAEE) energy expenditure were measured using doubly-labeled water and expired gas indirect calorimetry., Results: Total activity was associated with reduced first-phase insulin response in both pregnant (Regression r2 = 0.11; Spearman r = -0.47; p = 0.007) and non-pregnant women (Regression r2 = 0.11 Spearman; r = -0.36; p = 0.002). Relative to non-pregnant women, pregnant women were estimated to have secreted 67% more insulin and had 10% lower fasting glucose than non-pregnant women. Pregnant women spent 13% more time sedentary, 71% less time in moderate-to-vigorous intensity activity, had 44% lower objectively measured total activity, and 12% lower PAEE than non-pregnant women. Correlations did not differ significantly for any comparison between physical activity subcomponents and measures of insulin sensitivity or secretion., Conclusions: Our findings suggest that physical activity conveys similar benefits on glucose homeostasis in pregnant and non-pregnant women, despite differences in subcomponents of physical activity.

Background: Few studies have compared the validity of objective measures of physical activity energy expenditure (PAEE) in pregnant and non-pregnant women. PAEE is commonly estimated with accelerometers attached to the hip or waist, but little is known about the validity and participant acceptability of wrist attachment. The objectives of the current study were to assess the validity of a simple summary measure derived from a wrist-worn accelerometer (GENEA, Unilever Discover, UK) to estimate PAEE in pregnant and non-pregnant women, and to evaluate participant acceptability., Methods: Non-pregnant (N = 73) and pregnant (N = 35) Swedish women (aged 20-35 yrs) wore the accelerometer on their wrist for 10 days during which total energy expenditure (TEE) was assessed using doubly-labelled water. PAEE was calculated as 0.9×TEE-REE. British participants (N = 99; aged 22-65 yrs) wore accelerometers on their non-dominant wrist and hip for seven days and were asked to score the acceptability of monitor placement (scored 1 [least] through 10 [most] acceptable)., Results: There was no significant correlation between body weight and PAEE. In non-pregnant women, acceleration explained 24% of the variation in PAEE, which decreased to 19% in leave-one-out cross-validation. In pregnant women, acceleration explained 11% of the variation in PAEE, which was not significant in leave-one-out cross-validation. Median (IQR) acceptability of wrist and hip placement was 9(8-10) and 9(7-10), respectively; there was a within-individual difference of 0.47 (p<.001)., Conclusions: A simple summary measure derived from a wrist-worn tri-axial accelerometer adds significantly to the prediction of energy expenditure in non-pregnant women and is scored acceptable by participants.

In the third instalment of this tutorial, the authors explain the determination of the isotopic composition of a sample from a mass spectrometric measurement, and the methods of calculation as well as the units used. This tutorial outlines the practices in common usage, so that researchers new to this field can obtain a good understanding of the fundamentals involved.