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Objective: The objective of this study was to study how acid accumulation (lower plasma bicarbonate and higher anion gap [AG] and corrected anion gap [CAG]) correlates with metabolic parameters, food intake, and 24‐h energy expenditure (EE). Methods: Acid accumulation was measured in 286 healthy adults with estimated glomerular filtration rate > 60 mL/min/1.73 m2. Measurements included body composition by dual‐energy x‐ray absorptiometry scan, ad libitum energy intake by a vending machine paradigm over 3 days, and 24‐h EE in a whole‐room indirect calorimeter. Results: Lower bicarbonate, higher AG, and higher CAG were correlated with higher waist and thigh circumferences, body fat (percentage), fat mass, triglycerides, and lower high‐density lipoprotein cholesterol. Acid accumulation markers were correlated with higher total energy (CAG partial r = 0.17; p = 0.02), fat (CAG partial r = 0.17; p = 0.02), protein intake (CAG partial r = 0.20; p = 0.006), and 24‐h EE (CAG partial r = 0.24; p = 0.0007). A mediation analysis of CAG and total energy intake found that 24‐h EE was a partial mediator (40%), but the association remained significant (β = 0.15; p < 0.0001). Conclusions: In healthy individuals, acid accumulation was associated with an unfavorable metabolic phenotype; higher 24‐h EE; and increased total energy, fat, and protein intake. Acid accumulation markers, as putative markers of higher dietary acid load (e.g., from protein), may affect energy balance physiology promoting weight gain. [ABSTRACT FROM AUTHOR]

Genetic determinants of interindividual differences in energy expenditure (EE) are largely unknown. Sphingolipids, such as ceramides, have been implicated in the regulation of human EE via mitochondrial uncoupling. In this study, we investigated whether genetic variants within enzymes involved in sphingolipid synthesis and degradation affect EE and insulin-related traits in a cohort of American Indians informative for 24-h EE and glucose disposal rates during a hyperinsulinemic-euglycemic clamp. Association analysis of 10,084 genetic variants within 28 genes involved in sphingolipid pathways identified a missense variant (rs267738, A>C, E115A) in exon 4 of CERS2 that was associated with higher sleeping EE (116 kcal/day) and increased rates of endogenous glucose production during basal (5%) and insulin-stimulated (43%) conditions, both indicators of hepatic insulin resistance. The rs267738 variant did not affect ceramide synthesis in HepG2 cells but resulted in a 30% decrease in basal mitochondrial respiration. In conclusion, we provide evidence that the CERS2 rs267738 missense variant may influence hepatic glucose production and postabsorptive sleeping metabolic rate. Article Highlights: The genetic determinants of interindividual differences in energy expenditure (EE) are not well established. Sphingolipids have been proposed to influence EE by altering mitochondrial function. Association analysis of genetic variants in genes involved in sphingolipid pathways identified a missense variant (rs267738, A>C, E115A) in CERS2 associated with higher sleeping EE assessed by whole-room indirect calorimetry. The rs267738 variant was associated with increased glucose production under basal and insulin-stimulated conditions and with decreased basal mitochondrial respiration. The rs267738 missense variant may affect the expression of key gluconeogenic genes G6PC1 and PCK1. [ABSTRACT FROM AUTHOR]

Background/Objective: To identify predictors of incident type 2 diabetes using a mixed meal tolerance test (MMTT). Methods: Adult Indigenous Americans without diabetes (n = 501) from a longitudinal cohort underwent at baseline a 4-h MMTT, measures of body composition, an oral glucose tolerance test, an intravenous glucose tolerance test for acute insulin response (AIR), and a hyperinsulinemic-euglycemic clamp for insulin action (M). Plasma glucose responses from the MMTT were quantified by the total and incremental area under the curve (AUC/iAUC). Results: At follow-up (median time 9.6 [inter-quartile range: 5.6–13.5] years), 169 participants were diagnosed with diabetes. Unadjusted Cox proportional hazards models, glucose AUC180-min (HR: 1.98, 95% CI: 1.67, 2.34, p < 0.0001), AUC240-min (HR: 1.93, 95% CI: 1.62, 2.31, p < 0.0001), and iAUC180-min (HR: 1.43, 95% CI: 1.20, 1.71, p < 0.0001) were associated with an increased risk of diabetes. After adjustment for covariates (age, sex, body fat percentage, M, AIR, Indigenous American heritage) in three subsequent models, AUC180-min (HR: 1.44, 95% CI: 1.10, 1.88, p = 0.007) and AUC240-min (HR: 1.41, 95% CI: 1.09, 1.84, p < 0.01) remained associated with increased risk of diabetes. Conclusions: Glucose responses to a mixed meal predicted the development of type 2 diabetes. This indicates that a mixed nutritional challenge provides important information on disease risk. Clinical Trial Registry: ClinicalTrials.gov identifier : NCT00340132, NCT00339482 [ABSTRACT FROM AUTHOR]

Aim: Reduced renal insulin signalling is implicated in the pathogenesis of albuminuria. We sought to investigate whether insulin action and secretion, measured before diabetes onset, are associated with the development of albuminuria after diabetes onset. Materials and Methods: Baseline body composition, insulin sensitivity by hyperinsulinaemic‐euglycaemic clamp at submaximal and maximal insulin stimulation (240 and 2400 pmol/m2/min; M‐low and M‐high), and insulin secretion by intravenous glucose tolerance test [acute insulin response (AIR)] were measured in 170 Southwestern Indigenous American adults who subsequently developed diabetes. After diabetes onset and during the median follow‐up of 13.6 years, 81 participants (48%) developed albuminuria (urine albumin‐to‐creatinine ratio ≥30 mg/g). Separate associations of M‐low, M‐high and AIR (per 1‐SD change) with the risk of albuminuria were assessed by Cox regression models adjusted for age, sex and body fat (%). Results: Participants who developed albuminuria were of similar age (26.4 ± 5.4 vs. 27.5 ± 6.1 years), sex (46% vs. 48% male), body fat (36.4 ± 7.5 vs. 35.7 ± 7.9%) and AIR [2.3 ± 0.3 vs. 2.3 ± 0.3, pmol/L (log)] as those who did not develop albuminuria but had lower insulin sensitivity [M‐low: 0.33 ± 0.08 vs. 0.36 ± 0.12, p =.03; M‐high: 0.87 ± 0.11 vs. 0.91 ± 0.12, p =.02; mg/kg‐metabolic body size/min (log)]. In separate adjusted models, lower M‐low and M‐high were both associated with an increased risk for albuminuria [hazard ratio (HR) 1.51, 95% confidence interval (CI) 1.14, 2.00, p =.004; HR 1.31, 95% CI 1.06, 1.63, p =.01), whereas AIR was not (HR 1.15, 95% CI 0.87, 1.56, p =.3). Conclusions: Lower insulin sensitivity is associated with the development of albuminuria, suggesting a role for insulin signalling in the pathogenesis of proteinuria. [ABSTRACT FROM AUTHOR]

Objective: We investigated how changes in 24‐h respiratory exchange ratio (RER) and substrate oxidation during fasting versus an energy balance condition influence subsequent ad libitum food intake. Methods: Forty‐four healthy, weight‐stable volunteers (30 male and 14 female; mean [SD], age 39.3 [11.0] years; BMI 31.7 [8.3] kg/m2) underwent 24‐h energy expenditure measurements in a respiratory chamber during energy balance (50% carbohydrate, 30% fat, and 20% protein) and 24‐h fasting. Immediately after each chamber stay, participants were allowed 24‐h ad libitum food intake from computerized vending machines. Results: Twenty‐four‐hour RER decreased by 9.4% (95% CI: −10.4% to −8.5%; p < 0.0001) during fasting compared to energy balance, reflecting a decrease in carbohydrate oxidation (mean [SD], −2.6 [0.8] MJ/day; p < 0.0001) and an increase in lipid oxidation (2.3 [0.9] MJ/day; p < 0.0001). Changes in 24‐h RER and carbohydrate oxidation in response to fasting were correlated with the subsequent energy intake such that smaller decreases in fasting 24‐h RER and carbohydrate oxidation, but not lipid oxidation, were associated with greater energy intake after fasting (r = 0.31, p = 0.04; r = 0.40, p = 0.007; and r = −0.27, p = 0.07, respectively). Conclusions: Impaired metabolic flexibility to fasting, reflected by an inability to transition away from carbohydrate oxidation, is linked with increased energy intake. [ABSTRACT FROM AUTHOR]

Objective: Adipose tissue (AT) contains a bimodal population of large and small adipocytes. Changes in fat cell size (FCS) distribution and AT caloric density (kcal/g) with weight loss are unclear. We aimed to evaluate changes in FCS and AT calories in weight loss and determine associations with anthropometrics. Materials and methods: Healthy adults (6 men/4 women; age 33 ± 11 years; BMI 35 ± 6 kg/m2) underwent DXA and subcutaneous abdominal/thigh fat biopsies, before and after 6 weeks of caloric restriction. AT calories (bomb calorimetry) and hormones (adiponectin, leptin, FGF21) were measured. Results: Abdominal large cell diameter (LCD; Δ = −13.2 μm, p = 0.01) and nadir (Δ = −7.3 μm, p = 0.03) decreased. In repeated measures correlations (rrm), abdominal and thigh LCD and nadir were associated with fat mass (FM) loss (rrm = 0.68; rrm = 0.63; rrm = 0.66; rrm = 0.62, p's < 0.05, respectively) and waist circumference decrease (rrm = 0.70; rrm = 0.60, p's ≤ 0.05). Small cell percentage did not change and was not associated with FM changes. Abdominal AT calories were unchanged with weight loss. Change in leptin was associated with change in abdominal LCD (rrm = 0.77, p = 0.01). Conclusions: Caloric restriction reduces adipocyte LCD and nadir. These changes are associated with FM loss. Larger fat cells should be considered as phenotypic targets for weight loss. Clinical Trials Registration: clinicaltrials.gov identifier: NCT00687115, May 29, 2008 [ABSTRACT FROM AUTHOR]

OBJECTIVE: We examined longitudinal associations between emotional distress (specifically, depressive symptoms and diabetes distress) and medication adherence in Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE), a large randomized controlled trial comparing four glucose-lowering medications added to metformin in adults with relatively recent-onset type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: The Emotional Distress Substudy assessed medication adherence, depressive symptoms, and diabetes distress in 1,739 GRADE participants via self-completed questionnaires administered biannually up to 3 years. We examined baseline depressive symptoms and diabetes distress as predictors of medication adherence over 36 months. Bidirectional visit-to-visit relationships were also examined. Treatment satisfaction, beliefs about medication, diabetes care self-efficacy, and perceived control over diabetes were evaluated as mediators of longitudinal associations. RESULTS: At baseline, mean ± SD age of participants (56% of whom were White, 17% Hispanic/Latino, 18% Black, and 66% male) was 58.0 ± 10.2 years, diabetes duration 4.2 ± 2.8 years, HbA1c 7.5% ± 0.5%, and medication adherence 89.9% ± 11.1%. Higher baseline depressive symptoms and diabetes distress were independently associated with lower adherence over 36 months (P < 0.001). Higher depressive symptoms and diabetes distress at one visit predicted lower adherence at the subsequent 6-month visit (P < 0.0001) but not vice versa. Treatment assignment did not moderate relationships. Patient-reported concerns about diabetes medications mediated the largest percentage (11.9%–15.5%) of the longitudinal link between emotional distress and adherence. CONCLUSIONS: Depressive symptoms and diabetes distress both predict lower adherence to glucose-lowering medications over time among adults with T2DM. Addressing emotional distress and concerns about anticipated negative effects of taking these treatments may be important to support diabetes treatment adherence. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To describe the individual and joint associations of baseline factors with glycemia, and also with differential effectiveness of medications added to metformin. RESEARCH DESIGN AND METHODS: Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) participants (with type 2 diabetes diagnosed for <10 years, on metformin, and with HbA1c 6.8–8.5%; N = 5,047) were randomly assigned to a basal insulin (glargine), sulfonylurea (glimepiride), glucagon-like peptide 1 agonist (liraglutide), or dipeptidyl peptidase 4 inhibitor (sitagliptin). The glycemic outcome was HbA1c ≥7.0%, subsequently confirmed. Univariate and multivariate regression and classification and regression tree (CART) analyses were used to assess the association of baseline factors with the glycemic outcome at years 1 and 4. RESULTS: In univariate analyses at baseline, younger age (<58 years), Hispanic ethnicity, higher HbA1c, fasting glucose, and triglyceride levels, lower insulin secretion, and relatively greater insulin resistance were associated with the glycemic outcome at years 1 and/or 4. No factors were associated with differential effectiveness of the medications by year 4. In multivariate analyses, treatment group, younger age, and higher baseline HbA1c and fasting glucose were jointly associated with the glycemic outcome by year 4. The superiority of glargine and liraglutide at year 4 persisted after multiple baseline factors were controlled for. CART analyses indicated that failure to maintain HbA1c <7% by year 4 was more likely for younger participants and those with baseline HbA1c ≥7.4%. CONCLUSIONS: Several baseline factors were associated with the glycemic outcome but not with differential effectiveness of the four medications. Failure to maintain HbA1c <7% was largely driven by younger age and higher HbA1c at baseline. Factors that predict earlier glycemic deterioration could help in targeting patients for more aggressive management. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To compare the effects of insulin sensitivity and β-cell function over time on HbA1c and durability of glycemic control in response to dual therapy. RESEARCH DESIGN AND METHODS: GRADE participants were randomized to glimepiride (n = 1,254), liraglutide (n = 1,262), or sitagliptin (n = 1,268) added to baseline metformin and followed for mean ± SD 5.0 ± 1.3 years, with HbA1c assessed quarterly and oral glucose tolerance tests at baseline, 1, 3, and 5 years. We related time-varying insulin sensitivity (HOMA 2 of insulin sensitivity [HOMA2-%S]) and early (0–30 min) and total (0–120 min) C-peptide (CP) responses to changes in HbA1c and glycemic failure (primary outcome HbA1c ≥7% [53 mmol/mol] and secondary outcome HbA1c >7.5% [58 mmol/mol]) and examined differential treatment responses. RESULTS: Higher HOMA2-%S was associated with greater initial HbA1c lowering (3 months) but not subsequent HbA1c rise. Greater CP responses were associated with a greater initial treatment response and slower subsequent HbA1c rise. Higher HOMA2-%S and CP responses were each associated with lower risk of primary and secondary outcomes. These associations differed by treatment. In the sitagliptin group, HOMA2-%S and CP responses had greater impact on initial HbA1c reduction (test of heterogeneity, P = 0.009 HOMA2-%S, P = 0.018 early CP, P = 0.001 total CP) and risk of primary outcome (P = 0.005 HOMA2-%S, P = 0.11 early CP, P = 0.025 total CP) but lesser impact on HbA1c rise (P = 0.175 HOMA2-%S, P = 0.006 early CP, P < 0.001 total CP) in comparisons with the glimepiride and liraglutide groups. There were no differential treatment effects on secondary outcome. CONCLUSIONS: Insulin sensitivity and β-cell function affected treatment outcomes irrespective of drug assignment, with greater impact in the sitagliptin group on initial (short-term) HbA1c response in comparison with the glimepiride and liraglutide groups. [ABSTRACT FROM AUTHOR]

Accurately measuring dietary sugars intake in large-scale epidemiological studies is necessary to understand dietary sugars' true impact on health. Researchers have developed a biomarker that can be used to assess total sugars intake. Our objective is to test this biomarker in diverse populations using an ad libitum intake protocol. Healthy adult participants (n = 63; 58% Indigenous Americans/Alaska Natives; 60% male; BMI (mean ± SD) = 30.6 ± 7.6 kg.m2) were admitted for a 10-day inpatient stay. On day 2, body composition was measured by DXA, and over the last 3 days, ad libitum dietary intake was measured using a validated vending machine paradigm. Over the same days, participants collected daily 24 h urine used to measure sucrose and fructose. The 24 h urinary sucrose and fructose biomarker (24hruSF) (mg/d) represents the sum of 24 h urinary sucrose and fructose excretion levels. The association between the 3-day mean total sugars intake and log 24uSF level was assessed using the Pearson correlation. A linear mixed model regressing log-biomarker on total sugars intake was used to investigate further the association between biomarker, diet, and other covariates. Mean (S.D.) total sugars intake for the group was 197.7 g/d (78.9). Log 24uSF biomarker was moderately correlated with total sugars intake (r = 0.33, p = 0.01). In stratified analyses, the correlation was strongest in females (r = 0.45, p = 0.028), the 18–30 age group (r = 0.44, p = 0.079), Indigenous Americans (r = 0.51, p = 0.0023), and the normal BMI category (r = 0.66, p = 0.027). The model adjusted for sex, age, body fat percent, and race/ethnicity demonstrated a statistically significant association between 24uSF and total sugars intake (β = 0.0027, p < 0.0001) and explained 31% of 24uSF variance (marginal R2 = 0.31). Our results demonstrated a significant relationship between total sugars intake and the 24uSF biomarker in this diverse population. However, the results were not as strong as those of controlled feeding studies that investigated this biomarker. [ABSTRACT FROM AUTHOR]

We examined whether perceived stress, anhedonia, and food insecurity were associated with dietary adherence during a 6-week intervention. Sixty participants (23 m; 53 ± 14 y) completed psychosocial measures and were provided with full meals. Individuals with obesity were randomized to a weight-maintaining energy needs (WMENs) (n = 18; BMI 33 ± 4) or a 35% calorie-reduced diet (n = 19; BMI 38 ± 9); normal-weight individuals (n = 23; BMI 23 ± 2) were assigned to a WMENs diet. Adherence scores were determined via weekly assessments and daily ecological momentary assessments (EMAs) of real-time behavior in a natural environment. Perceived stress and anhedonia were associated with % body fat (all r-values > 0.25, all p-values < 0.05), but food insecurity and adherence were not. Higher perceived stress (r = −0.31, p = 0.02), anhedonia (r = −0.34, p = 0.01), and food insecurity (r = −0.27, p = 0.04) were associated with lower adherence scores, even after adjusting for age, sex, and % body fat. In all adjusted models, % body fat was not associated with adherence. Higher measures of stress, anhedonia, and food insecurity predicted lower adherence independently of body fat, indicating that psychosocial factors are important targets for successful adherence to dietary interventions, regardless of body size. [ABSTRACT FROM AUTHOR]

Objective: The existence of seasonal changes in energy metabolism is uncertain. We investigated the relationship between the seasons and spontaneous physical activity (SPA), energy expenditure (EE), and other components measured in a respiratory chamber. Methods: Between 1985–2005, 671 healthy adults (aged 28.8 ± 7.1 years; 403 men) in Phoenix, Arizona had a 24-hour stay in the respiratory chamber equipped with radar sensors; SPA (expressed as a percentage over the time interval), the energy cost of SPA, EE, and respiratory exchange ratio (RER) were measured. Results: In models adjusted for known covariates, SPA (%) was lower during summer (7.2 ± 2.9, p = 0.0002), spring (7.5 ± 2.9, p = 0.025), and fall (7.6 ± 3, p = 0.038) compared to winter (8.3 ± 3.5, reference). Conversely, energy cost of SPA (kcal/h/%) was higher during summer (2.18 ± 0.83, p = 0.0008), spring (2.186 ± 0.83, p = 0.017), and fall (2.146 ± 0.75, p = 0.038) compared to winter (2.006 ± 0.76). Protein (292 ± 117 kcal/day, β = −21.2, p = 0.08) oxidation rates was lower in the summer compared to winter. Carbohydrate and lipid oxidation rates (kcal/day) did not differ across seasons. RER and 24-h EE did not differ by season. Conclusion: SPA, representing fidgeting-like behavior in the chamber, demonstrated a winter peak and summer nadir in humans living in a desert climate. These findings indicate that the physiological propensity for movement may be affected by seasonal factors. Clinical trial registration: ClinicalTrials.gov identifiers: NCT00340132, NCT00342732 [ABSTRACT FROM AUTHOR]

Obesity is a chronic disease that affects more than 650 million adults worldwide. Obesity not only is a significant health concern on its own, but predisposes to cardiometabolic comorbidities, including coronary heart disease, dyslipidemia, hypertension, type 2 diabetes, and some cancers. Lifestyle interventions effectively promote weight loss of 5% to 10%, and pharmacological and surgical interventions even more, with some novel approved drugs inducing up to an average of 25% weight loss. Yet, maintaining weight loss over the long‐term remains extremely challenging, and subsequent weight gain is typical. The mechanisms underlying weight regain remain to be fully elucidated. The purpose of this Pennington Biomedical Scientific Symposium was to review and highlight the complex interplay between the physiological, behavioral, and environmental systems controlling energy intake and expenditure. Each of these contributions were further discussed in the context of weight‐loss maintenance, and systems‐level viewpoints were highlighted to interpret gaps in current approaches. The invited speakers built upon the science of obesity and weight loss to collectively propose future research directions that will aid in revealing the complicated mechanisms involved in the weight‐reduced state. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to test proportional‐integral‐derivative (PID) control of air inflow rate in a whole‐room indirect calorimeter to improve accuracy in measuring oxygen (O2) consumption (V̇O2) and carbon dioxide (CO2) production (V̇CO2). Methods: A precision gas blender infused nitrogen (N2) and CO2 into the calorimeter over 24 hours based on static and dynamic infusion profiles mimicking V̇O2 and V̇CO2 patterns during resting and non‐resting conditions. Constant (60 L/min) versus time‐variant flow set by a PID controller based on the CO2 concentration was compared based on errors between measured versus expected values for V̇O2,V̇CO2, respiratory exchange ratio, and metabolic rate. Results: Compared with constant inflow, the PID controller allowed both a faster rise time and long‐term maintenance of a stable CO2 concentration inside the calorimeter, resulting in more accurate V̇CO2 estimates (mean hourly error, PID: −0.9%, 60 L/min = −2.3%, p < 0.05) during static infusions. During dynamic infusions mimicking exercise sessions, the PID controller achieved smaller errors for V̇CO2 (mean: −0.6% vs. −2.7%, p = 0.02) and respiratory exchange ratio (mean: 0.5% vs. −3.1%, p = 0.02) compared with constant inflow conditions, with similar V̇O2 (p = 0.97) and metabolic rate (p = 0.76) errors. Conclusions: PID control in a whole‐room indirect calorimeter system leads to more accurate measurements of substrate oxidation during dynamic metabolic studies. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to assess the reproducibility and physiological determinants of mixed‐meal tolerance tests (MMTTs) on glucose and insulin responses. Methods: While inpatients on a weight‐maintaining diet, 894 individuals (574 with normal and 267 with impaired glucose regulation and 53 with type 2 diabetes [T2D]) underwent 9‐hour MMTTs (breakfast and lunch; 30% weight‐maintaining diet each; 40% carbohydrate, 40% fat, and 20% protein). Total/incremental areas under the curve (AUC/iAUC) were calculated from MMTT plasma glucose/insulin concentrations. Acute insulin response (AIR) was quantified by intravenous glucose tolerance test and insulin action (M) via hyperinsulinemic‐euglycemic clamp. A subset had repeat MMTTs (median follow‐up = 1.4 years). Results: In individuals without T2D, for breakfast‐versus‐lunch reproducibility of glucose, AUCs were moderate (intraclass correlation coefficients [ICCs]: 0.44‐0.61), and iAUCs were poor (ICCs < 0.15). For repeated MMTTs, reproducibility of AUC/iAUCs was low (ICCs: 0.11‐0.36). For insulin, AUC reproducibility was high (ICCs > 0.70), and iAUCs were moderate (ICCs: 0.64‐0.71). For repeated MMTTs, ICC AUC/iAUCs were 0.34 to 0.54. In those with T2D, ICC glucose AUC/iAUCs were >0.80 and >0.50, respectively, and for insulin were <0.40. For repeated MMTTs, ICC glucose/insulin AUC/iAUCs were moderate. Glucose AUCs associated with M/AIR (partial Rs < −0.25), and insulin AUCs negatively/positively associated with M/AIR (partial Rs = −0.51/0.24). Conclusions: Reproducibility of glucose/insulin responses to MMTTs varied by subtraction of fasting values, glucose status, and time. Insulin secretion and action explained ~20% of MMTT responses. The substantial variability in MMTT response requires consideration in studies using MMTT outcomes. [ABSTRACT FROM AUTHOR]

Objective: This study investigated whether interindividual variance in diet‐induced metabolic flexibility is explained by differences in gut hormone concentrations. Methods: A total of 69 healthy volunteers with normal glucose regulation underwent 24‐hour assessments of respiratory quotient (RQ) in a whole‐room indirect calorimeter during eucaloric feeding (EBL; 50% carbohydrate, 30% fat) and then, in a crossover design, during 24‐hour fasting and three normal‐protein (20%) overfeeding diets (200% energy requirements). Metabolic flexibility was defined as the change in 24‐hour RQ from EBL during standard (50% carbohydrate), high‐fat (60%), and high‐carbohydrate (75%) overfeeding diets. Plasma concentrations of glucagon‐like peptide‐1 (GLP‐1) and peptide YY (PYY) after an overnight fast were measured prior to and after each diet. Results: Compared with EBL, on average, 24‐hour RQ decreased by ~4% during high‐fat overfeeding, whereas it increased by ~4% during standard overfeeding and by ~9% during high‐carbohydrate overfeeding. During high‐carbohydrate overfeeding, but not during any other overfeeding diet or fasting, increased GLP‐1 concentration was associated with increased RQ (r = 0.44, p < 0.001), higher/lower carbohydrate/lipid oxidation rates (r = 0.34 and r = −0.51, both p < 0.01), respectively, and increased plasma insulin concentration (r = 0.38, p = 0.02). Conclusions: Increased GLP‐1 concentration following high‐carbohydrate overfeeding associated with a greater shift to carbohydrate oxidation, suggesting that GLP‐1 may be implicated in diet‐induced metabolic flexibility to carbohydrate overload. [ABSTRACT FROM AUTHOR]

Background Molecular stable isotope ratios are a novel type of dietary biomarker with high sensitivity and specificity for certain foods. Among these, fatty acid carbon isotope ratios (CIRs) have strong potential but have not been investigated as dietary biomarkers. Objectives We evaluated whether fatty acid CIRs and mass proportions were associated with meat, fish, and sugar-sweetened beverage (SSB) intake. Methods Thirty-two men [aged 46.2 ± 10.5 y; BMI (kg/m2): 27.2 ± 4.0] underwent a 12-wk inpatient dietary intervention at the National Institute of Diabetes and Digestive and Kidney Diseases in Phoenix, Arizona. Men were randomly assigned to 1 of 8 dietary treatments varying the presence/absence of dietary meat, fish, and SSBs in all combinations. Fatty acid CIRs and mass proportions were measured in fasting blood samples and adipose tissue biopsies that were collected pre- and postintervention. Dietary effects were analyzed using multivariable regression and receiver operating characteristic AUCs were calculated using logistic regression. Results CIRs of the several abundant SFAs, MUFAs and arachidonic acid (20:4n-6) in plasma were strongly associated with meat, as were a subset of these fatty acids in RBCs. Effect sizes in plasma ranged from 1.01‰ to 1.93‰ and were similar but attenuated in RBCs. Mass proportions of those fatty acids were not associated with diet. CIRs of plasma dihomo-γ-linolenic acid (20:3n–6) and adipose palmitic acid (16:0) were weakly associated with SSBs. Mass proportions of plasma odd-chain fatty acids were associated with meat, and mass proportions of plasma EPA and DHA (20:5n–3 and 22:6n–3) were associated with fish. Conclusions CIRs of plasma and RBC fatty acids show promise as sensitive and specific measures of dietary meat. These provide different information from that provided by fatty acid mass proportions, and are informative where mass proportion is not. This trial is registered at www.clinicaltrials.gov as NCT01237093. [ABSTRACT FROM AUTHOR]

Objective: Reduced dorsolateral prefrontal cortex (dlPFC) activity and inhibitory control may contribute to obesity. The study objective was to assess effects of repeated transcranial direct current stimulation (tDCS) on food Go/No-Go (GNG), food Stroop performance, and snack food intake.Methods: Twenty-nine individuals with obesity (12 male; mean [SD], age 42 [11] years; BMI 39 [8]) participated in a combined inpatient/outpatient randomized parallel-design trial and received 15 sessions of anodal or sham tDCS to the left dlPFC. Food-related inhibitory control (GNG), attentional bias (Stroop), and snack food intake were assessed at baseline, completion of inpatient sessions (day 7), and follow-up (day 31).Results: GNG performance improved in the anodal group by day 31, compared with sham (p = 0.01), but Stroop scores did not differ by intervention. Greater snack food intake was associated with lower GNG scores (p = 0.01), driven by the sham group (p < 0.001) and higher food and palatable bias scores on the Stroop (all p = 0.02) across both groups. Changes on tasks were not associated with changes in intake.Conclusions: Anodal tDCS to the left dlPFC improved performance on a food-related inhibitory control task, providing evidence of potential for therapeutic benefit of neuromodulation in areas controlling executive function. Results showed that tDCS to the dlPFC reduced snack food intake and hunger; however, underlying neurocognitive mechanisms remain uncertain. [ABSTRACT FROM AUTHOR]

Context: A greater decrease in 24-hour energy expenditure (24hEE) during short-term fasting is indicative of a thrifty phenotype. Objective: As ghrelin and the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis are implicated in the regulation of energy intake and metabolism, we investigated whether ghrelin, GH, and IGF-1 concentrations mediate the fasting-induced decrease in 24hEE that characterizes thriftiness. Methods: In 47 healthy individuals, 24hEE was measured in a whole-room indirect calorimeter both during 24-hour eucaloric and fasting conditions. Plasma total ghrelin, GH, and IGF-1 concentrations were measured by enzyme-linked immunosorbent assay after an overnight fast the morning before and after each 24-hour session. Results: During 24-hour fasting, on average 24hEE decreased by 8.0% (P < .001), GH increased by ~5-fold (P < .001), whereas ghrelin (mean +23 pg/mL) and IGF-1 were unchanged (both P ≥ .19) despite a large interindividual variability in ghrelin change (SD 150 pg/mL). Greater fasting-induced increase in ghrelin was associated with a greater decrease in 24hEE during 24-hour fasting (r = –0.42, P = .003), such that individuals who increased ghrelin by 200 pg/mL showed an average decrease in 24hEE by 55 kcal/day. Conclusion: Short-term fasting induced selective changes in the ghrelin/GH/IGF-1 axis, specifically a ghrelin-independent GH hypersecretion that did not translate into increased IGF-1 concentrations. Greater increase in ghrelin after 24-hour fasting was associated with greater decrease in 24hEE, indicating ghrelin as a novel biomarker of increased energy efficiency of the thrifty phenotype. [ABSTRACT FROM AUTHOR]

Objective: Physiological systems responsible for water homeostasis and energy metabolism are interconnected. This study hypothesized altered responses to dehydration including thirst, ad libitum water intake, and copeptin in men with obesity.Methods: Forty-two men (22 lean and 20 with obesity) were stimulated by a 2-hour hypertonic saline infusion and a 24-hour water deprivation. In each dehydrating condition, thirst, ad libitum water intake after dehydration, and urinary and hormonal responses including copeptin were assessed.Results: After each dehydration condition, ad libitum water intake was similar between both groups (p > 0.05); however, those with obesity reported feeling less thirsty (p < 0.05) and had decreased copeptin response and higher urinary sodium concentrations when stressed (p < 0.05). Angiotensin II, aldosterone, atrial and brain natriuretic peptides, and apelin concentrations did not differ by adiposity group and did not explain the different thirst or copeptin responses in men with obesity. However, leptin was associated with copeptin response in lean individuals during the hypertonic saline infusion (p < 0.05), but the relationship was diminished in those with obesity.Conclusions: Diminished thirst and copeptin responses are part of the obesity phenotype and may be influenced by leptin. Adiposity may impact pathways regulating thirst and vasopressin release, warranting further investigation. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to evaluate the agreement of commonly reported energy metabolism measurements obtained from two different whole-room indirect calorimeters (WRICs).Methods: Nine healthy adult volunteers were evaluated over four separate 24-hour periods in a crossover design, twice in two different WRICs of different sizes, each operated according to the Room Indirect Calorimetry Operating and Reporting Standards published in 2020. The reproducibility of repeated measurements was quantified by the coefficient of variation (CV) and intraclass correlation coefficient (ICC).Results: The CVs between and within each WRIC for average 24-hour carbon dioxide production rate (VCO2 ) and oxygen consumption rate (VO2 ), 24-hour energy expenditure (EE), and respiratory exchange ratio ranged from 1.5% to 3.6%, whereas sleep EE ranged from 3.1% to 5.5%. CVs for macronutrient oxidation rates and spontaneous physical activity were higher, ranging from 9.2% to 38.1%. ICCs of VCO2 , VO2 , 24-hour EE, and energy expenditure at zero activity were >0.95, indicating excellent reproducibility, whereas ICCs for lipid oxidation, awake and fed thermogenesis, and sleep EE ranged from 0.55 to 0.92, indicating moderate to high reproducibility. ICCs for respiratory exchange ratio and carbohydrate and protein oxidation rates were lower (<0.70). Spontaneous physical activity showed high reproducibility within chambers (ICC = 0.88) but differed substantially between chambers (ICC = 0.23).Conclusions: Cross-chamber reproducibility is high for common outcome measures assessed in the respiratory chamber. The results support efforts to promote standardization across WRICs to allow multicenter studies. [ABSTRACT FROM AUTHOR]

Background: The natural abundance nitrogen stable isotope ratio (NIR) of whole tissue correlates with animal protein intakes, including meat and fish. Amino acid (AA) NIRs (NIRAAs) are more variable than the whole-tissue NIRs and may thus better differentiate among foods.Objectives: We evaluated whether NIRAAs were associated with intakes of fish and meat and whether these dietary associations were larger than with whole-tissue NIRs.Methods: Men were recruited at the National Institute of Diabetes and Digestive and Kidney Diseases in Phoenix, Arizona, and randomly assigned to one of eight 12-wk inpatient dietary interventions, which varied the presence/absence of fish, meat, and sugar-sweetened beverages (SSBs) in all possible combinations. Fasting blood was drawn pre- and postintervention and plasma and RBC NIRAAs (free and protein-bound) were measured as secondary outcomes in 32 participants. Multivariable regression was used to determine responses of postintervention NIRAAs to dietary variables, and logistic regression was used to calculate receiver operating characteristic AUCs.Results: Most plasma NIRAAs increased with fish and meat intakes, but to a greater extent with fish intake. The largest increase in response to fish intake was plasma NIRLeucine (β = 2.19, SE = 0.26). The NIRThreonine decreased with both fish and meat intakes. Fewer RBC NIRAAs increased with fish intake, and only RBC NIRProline increased with meat intake. No plasma or RBC NIRAA responded to SSB intake. We identified fish intake with a high degree of accuracy using plasma NIRLeucine (corrected AUC, cAUC = 0.96) and NIRGlutamic acid/glutamine (cAUC = 0.93), and meat intake to a lower degree using plasma NIRProline (cAUC = 0.80) and RBC NIRProline (cAUC = 0.85).Conclusions: Plasma and RBC NIRAAs were associated with fish and meat intakes but were not superior to whole-tissue stable isotope biomarkers in identifying these intakes in a US diet. This trial is registered at www.clinicaltrials.gov as NCT01237093. [ABSTRACT FROM AUTHOR]

Objective: Food insecurity is known to be associated with obesity, but its association with physiological measures is unclear. Therefore, it was hypothesized that, compared with food-secure individuals, those with food insecurity would have higher 24-hour energy expenditure (EE [kilocalories per day]) and 24-hour respiratory quotient (RQ [ratio]). Subsequently, hormones involved in appetite regulation, substrate oxidation, and EE were explored.Methods: A total of 113 healthy participants without diabetes (75 men; mean [SD], age 40 [12] years; BMI 30 [8] kg/m2 ) were included in this analysis. Participants completed the Food Security Short Form, underwent a dual-energy x-ray absorptiometry scan, and spent 24 hours in a human respiratory chamber following a weight-maintaining diet.Results: Compared with individuals with food security, participants with food insecurity had no difference in 24-hour EE. However, they had higher carbohydrate oxidation rates (p = 0.03) and lower lipid oxidation rates (p = 0.02), resulting in higher 24-hour RQ (p < 0.01). They also had lower fasting glucagon-like peptide 1 (p = 0.03) concentrations.Conclusions: Food insecurity is associated with higher 24-hour RQ and lower fasting glucagon-like peptide 1 concentrations, metabolic and hormonal differences previously shown to drive greater calorie intake in the setting of unrestricted food availability. These findings therefore provide new insight into the paradoxical link between restricted food access and increased adiposity. [ABSTRACT FROM AUTHOR]

Objective: Fidgeting, a type of spontaneous physical activity (SPA), has substantial thermogenic potential. This research aims to examine secular trends in SPA and energy expenditure (EE) inside a respiratory chamber. Methods: From 1985 to 2005, healthy adults (n = 678; mean age: 28.8 years; men: 60%; 522 Indigenous American, 129 White, and 27 Black) had a 24‐hour stay in the respiratory chamber equipped with radar sensors. Body composition, glucose tolerance, fasting insulin, insulin action (hyperinsulinemic‐euglycemic clamp), and insulin secretion (intravenous glucose tolerance test) were measured as covariates. Results: SPA, adjusted for age, sex, race, and body composition, declined (r = −0.30, p < 0.0001), with a concomitant rise in the energy cost of SPA (r = 0.30, p < 0.0001). The 24‐hour EE adjusted for covariates increased (r = 0.31, p < 0.0001), which was reflected in increases in EE during sleep (r = 0.18, p < 0.0001) and during the awake, fed condition (r = 0.28, p < 0.0001). The secular trends in SPA or 24‐hour EE were unchanged with adjustment for measures related to glucose metabolism. Conclusions: Secular trend analyses showed a decline in fidgeting. However, this decline in SPA was partially counterbalanced by an increase in energy cost of this activity and a rise in EE. Nevertheless, our results support public health efforts to promote small but sustained changes in these behaviors. [ABSTRACT FROM AUTHOR]

Objective: Weight change is a dynamic function of whole‐body energy balance resulting from the interplay between energy intake and energy expenditure (EE). Recent reports have provided evidence for the existence of a causal effect of EE on energy intake, suggesting that increased EE may drive overeating, thereby promoting future weight gain. This study investigated the relationships between ad libitum energy intake and 24‐hour EE (24‐h EE) in sedentary conditions versus long‐term, free‐living weight change using a mediation analysis framework. Methods: Native American individuals (n = 61, body fat by dual‐energy x‐ray absorptiometry: 39.7% [SD 9.5%]) were admitted to the clinical inpatient unit and had baseline measurements as follows: 1) 24‐h EE accurately measured in a whole‐room indirect calorimeter during energy balance and weight stability; and 2) ad libitum energy intake objectively assessed for 3 days using computerized vending machines. Free‐living weight change was assessed after a median follow‐up time of 1.7 years (interquartile range: 1.2‐2.9). Results: The total effect of 24‐h EE on weight change (−0.23 kg per 100‐kcal/d difference in EE at baseline) could be partitioned into the following two independent and counterbalanced effects: higher EE protective against weight gain (−0.46 kg per 100‐kcal/d difference in EE at baseline) and an orexigenic effect promoting overeating, thereby favoring weight gain (+0.23 kg per 100‐kcal/d difference in EE at baseline). Conclusions: The overall impact of EE on body weight regulation should be evaluated by also considering its collateral effect on energy intake. Any weight loss intervention aimed to induce energy deficits by increasing EE should take into account any potential orexigenic effects that promote compensatory overeating, thereby limiting the efficacy of these obesity therapies. [ABSTRACT FROM AUTHOR]

Objective: Negative affect and food insecurity have been proposed to impede adherence to weight loss interventions. Therefore, this study examined the role of these variables on dietary adherence using Ecological Momentary Assessment.Methods: A total of 50 participants (19 male participants; age = 49 [SD 14] years) participated in an outpatient dietary study. Lean participants (n = 22; BMI ≤ 25 kg/m2 ) received a weight-maintaining energy needs (WMEN) diet, and participants with obesity (BMI ≥ 30) were randomized to receive either a WMEN diet (n = 14) or a 35% calorie-reduced diet (n = 14). Food insecurity was measured, and, twice daily, Ecological Momentary Assessment captured real-time affect ratings and adherence. Between-person (trait-level) and lagged within-person (state-level) scores were calculated.Results: Greater food insecurity and trait-level negative affect were associated with reduced adherence (p = 0.0015, p = 0.0002, respectively), whereas higher trait-level positive affect was associated with greater adherence (p < 0.0001). Significant interactions between affect and food insecurity revealed an association between higher trait positive affect and increased adherence at lower levels of food insecurity. Higher trait negative affect was more strongly associated with decreased adherence in participants with greater levels of food insecurity (-1 SD: B = -0.21, p = 0.22; mean: B = -0.46, SE = 0.13, p = 0.0004; +1 SD: B = -0.71, SE = 0.17, p < 0.0001).Conclusions: Trait-level affect may be crucial in predicting dietary adherence, especially in those with greater food insecurity. [ABSTRACT FROM AUTHOR]

Background The hepatokine fibroblast growth factor 21 (FGF21) influences eating behavior and sugar consumption in rodent models. However, whether circulating FGF21 concentration is associated with food and soda intake in humans is still unclear. Objective We investigated whether fasting plasma FGF21 concentration is associated with objective measures of ad libitum food intake and soda consumption. Methods Healthy individuals [ n  = 109; 69 men, aged 34 ± 10 y; BMI (kg/m2): 30.4 ± 7.7; body fat by DXA: 30.5% ± 8.9%] with available plasma for hormonal measurements participated in an inpatient cohort study to objectively quantify ad libitum food and soda intake for 3 d using an automated and reproducible vending machine paradigm. Fasting plasma FGF21 concentration was measured by ELISA prior to ad libitum feeding. Results Fasting FGF21 concentration was inversely associated with daily soda intake (R = −0.22, P  = 0.02 adjusted for demographics and anthropometrics), such that an interindividual difference of 200 pg/mL was associated with an average lower soda consumption by 68 kcal/d. Conversely, no associations were observed with total daily energy intake or macronutrient intake (all P  > 0.17). Conclusions Higher plasma fasting FGF21 concentration is associated with lower ad libitum soda intake. Although this inverse correlation does not imply causation, the present results support the putative role of FGF21 in the reward pathways regulating sugar consumption in humans. This trial was registered at www.clinicaltrials.gov as NCT00342732. [ABSTRACT FROM AUTHOR]

Background The human thrifty phenotype is characterized by a greater decrease in 24-h energy expenditure (24EE) during fasting due to relatively higher eucaloric 24EE in sedentary conditions, both of which are indicative of greater propensity to weight gain. Thriftiness is also associated with a smaller increase in 24EE (i.e. reduced adaptive thermogenesis) during overfeeding. Objectives We investigated whether short-term measures of adaptive thermogenesis during overfeeding with low/normal/high protein content characterize thriftiness. Methods In this secondary cross-sectional analysis of a single-arm crossover study, 24EE was measured using whole-room indirect calorimetry during energy balance, fasting, and different overfeeding conditions (low/3% protein, high/30% protein, and 3 normal/20% protein diets) with 200% of eucaloric requirements in 77 healthy individuals [63 men; BMI (in kg/m2): 26.4 ± 4.3; body fat by DXA: 27.7% ± 9.4%, mean ± SD] with normal glucose regulation. Relations between the 24EE during energy balance (adjusted for body composition) and 24EE during each overfeeding diet were analyzed using separate linear regression models. Participants were arbitrarily categorized as thrifty / spendthrift based on the median value (−177 kcal/d) of the difference in 24EE between fasting and energy balance conditions. Results Differences in 24EE during low/high-protein overfeeding diets (regression line slope = 0.76 and 0.68, respectively, both P  < 0.05 compared with slope = 1) but not during the normal-protein overfeeding diets (all P  > 0.05 compared with slope = 1) were dependent on baseline 24EE during energy balance. Specifically, individuals with higher eucaloric 24EE (thriftier phenotype) showed smaller increases in 24EE during protein-imbalanced overfeeding. Analyzed by group, thrifty individuals had smaller increases in 24EE by 42 and 237 kcal/d during low- and high-protein overfeeding, respectively, compared with spendthrift individuals who showed greater increases in 24EE by 100 and 302 kcal/d (P  ≤ 0.03 compared with thrifty group). Conclusions During acute overfeeding conditions with low/high-protein content, thrifty participants have limited capacity to increase 24EE, indicating that impaired adaptive thermogenesis during protein-imbalanced diets further characterizes the thrifty phenotype and its susceptibility to weight gain. This trial was registered at clinicalTrials.gov as NCT00523627. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to evaluate whether a 12-week, weight-maintaining, macronutrient-stable dietary intervention that varies only by meat, fish, or soda consumption alters 24-hour energy expenditure (24hrEE) and substrate oxidation.Methods: Healthy males were recruited to participate in a 12-week inpatient study and were randomized to a weight-maintaining dietary intervention that contained varying combinations of meat (0% or 19%), fish (0% or 6%), or soda (0% or 14%) in a factorial design. Macronutrient composition across dietary intervention groups was as follows: 50% of energy from carbohydrates, 30% of energy from fat, and 20% of energy from protein. Whole-room indirect calorimetry at baseline and week 12 were used to measure 24hrEE and substrate oxidation.Results: Twenty-six males (mean [SEM], age: 46.6 [10.4] years; BMI: 26.9 [4.1] kg/m2 ) completed all measurements. Fish consumption resulted in higher 24hrEE by 126 (55) kcal/d compared with no fish consumption (P = 0.03), whereas 24hrEE for soda consumption was 132 (56) kcal/d (P = 0.03) lower. Approximately 80% of the decrease in 24hrEE with soda consumption was due to lower awake-inactive energy expenditure (EE; P = 0.001). No specific EE component accounted for the differences observed with fish consumption.Conclusions: The data indicate that dietary sources of protein and carbohydrates appear to influence 24hrEE and inactive EE. [ABSTRACT FROM AUTHOR]

Background The carbon isotope ratios (CIRs) of individual amino acids (AAs) may provide more sensitive and specific biomarkers of sugar-sweetened beverages (SSBs) than total tissue CIR. Because CIRs turn over slowly, long-term controlled-feeding studies are needed in their evaluation. Objective We assessed the responses of plasma and RBC CIRAA's to SSB and meat intake in a 12-wk inpatient feeding study. Methods Thirty-two men (aged 46.2 ± 10.5 y) completed the feeding study at the National Institute of Diabetes and Digestive and Kidney Diseases in Phoenix, Arizona. The effects of SSB, meat, and fish intake on plasma and RBC CIRAA's were evaluated in a balanced factorial design with each dietary variable either present or absent in a common weight-maintaining, macronutrient-balanced diet. Fasting blood samples were collected biweekly from baseline. Dietary effects on the postfeeding CIR of 5 nonessential AAs (CIRNEAA's) and 4 essential AAs (CIREAA's) were analyzed using multivariable regression. Results In plasma, 4 of 5 CIRNEAA's increased with SSB intake. Of these, the CIRAla was the most sensitive (β = 2.81, SE = 0.38) to SSB intake and was not affected by meat or fish intake. In RBCs, all 5 CIRNEAA's increased with SSBs but had smaller effect sizes than in plasma. All plasma CIREAA's increased with meat intake (but not SSB or fish intake), and the CIRLeu was the most sensitive (β = 1.26, SE = 0.23). CIRs of leucine and valine also increased with meat intake in RBCs. Estimates of turnover suggest that CIRAA's in plasma, but not RBCs, were in equilibrium with the diets by the end of the study. Conclusions The results of this study in men support CIRNEAA's as potential biomarkers of SSB intake and suggest CIREAA's as potential biomarkers of meat intake in US diets. This trial was registered at clinicaltrials.gov/ct2/show/NCT01237093 as NCT01237093. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Impaired insulin clearance is implicated in the pathogenesis of type 2 diabetes, but prospective evidence remains limited. Therefore, we sought to identify factors associated with the metabolic clearance rate of insulin (MCRI) and to investigate whether lower MCRI is associated with increased risk of incident type 2 diabetes. Methods: From a longitudinal cohort, 570 adult Native Americans without diabetes living in the Southwestern United States were characterised at baseline and 448 participants were monitored over a median follow-up period of 7.9 years with 146 (32%) incident cases of diabetes identified (fasting plasma glucose ≥7.0 mmol/l, 2 h plasma glucose [2-h PG] ≥11.1 mmol/l, or clinical diagnosis). At baseline, participants underwent dual-energy x-ray absorptiometry or hydrodensitometry to assess body composition, a 75 g OGTT, an IVGTT to assess acute insulin response (AIR), and a hyperinsulinaemic–euglycaemic clamp to assess MCRI and insulin action (M). Results: In adjusted linear models, MCRI was inversely associated with body fat percentage (r = −0.35), fasting plasma insulin (r = −0.55) and AIR (r = −0.22), and positively associated with M (r = 0.17; all p < 0.0001). In multivariable Cox proportional hazard models, lower MCRI was associated with an increased risk of diabetes after adjustment for age, sex, heritage, body fat percentage, AIR, M, fasting plasma glucose, 2-h PG, and fasting plasma insulin (HR per one-SD difference in MCRI: 0.77; 95% CI 0.61, 0.98; p = 0.03). Conclusions/interpretation: Lower MCRI is associated with an unfavourable metabolic phenotype and is associated with incident type 2 diabetes independent of established risk factors. Clinical trial registration numbers: ClinicalTrials.gov NCT00339482; NCT00340132 [ABSTRACT FROM AUTHOR]

Objective: Circulating albumin is negatively associated with adiposity but whether it is associated with increased energy intake, lower energy expenditure or weight gain has not been examined. Methods: In study 1 (n=238; 146 men), we evaluated whether fasting albumin concentration was associated with 24-h energy expenditure and ad libitum energy intake. In study 2 (n=325;167 men), we evaluated the association between plasma albumin and change in weight and body composition. Results: After adjustment for known determinants of energy intake lower plasma albumin concentration was associated with greater total daily energy intake (β= 89.8 kcal/day per 0.1 g/dl difference in plasma albumin, p=0.0047). No associations were observed between plasma albumin concentrations and 24-h energy expenditure or 24-h respiratory quotient (p>0.2). Over 6 years, volunteers gained on average 7.5 ± 11.7 kg (p<0.0001). Lower albumin concentrations were associated with greater weight [β=3.53 kg, p=0.039 (adjusted for age, sex, follow up time), CI 0.16 to 6.21 per 1 g/dl difference albumin concentration] and fat mass (β=2.3 kg, p=0.022), respectively, but not with changes in fat free mass (p=0.06). Conclusions: Lower albumin concentrations were associated with increased ad libitum food intake and weight gain, indicating albumin as a marker of energy intake regulation. Clinical Trial Registration: ClinicalTrials.gov, identifiers NCT00340132, NCT00342732. [ABSTRACT FROM AUTHOR]

Objective: With the upsurge in interest in the gut microbiome, complete and accurate measurement of ingested calories and calories lost through excreted stool is crucial for assessing the effect of the microbiota on nutrient absorption. Methods: Measurement of ingested and excreted calories was conducted over 3 days. Meals were made in duplicate: one was given to the participant, and one was used for the measurement of calories. Stool was marked by nonabsorbable dye ingested prior to and at the end of each 3‐day diet period and was collected for caloric assessment from the appearance of the first dye marker until the appearance of the second dye marker. Results: Stool calories per gram for pellets were 4.91 ± 0.06 kcal/g. The mean stool calorie loss as a percentage of ingested calories was 7.3% ± 1.6% (range, 6.6%‐8.5%). The stool measurement of kilocalories per gram was not associated with the total measured stool calories or with stool weight (P = 0.2 and P = 0.2, respectively) over the 3‐day period. However, the weight of stool samples during each dietary intervention was positively associated with the calorie loss in stool (r = 0.58, P < 0.0001). Conclusions: Our methods provide a direct measure of ingested calories and stool calories needed to accurately assess relative stool calorie loss as a measure of nutrient absorption. The weight of stool samples across the marked diet period is crucial to determining total stool calories. [ABSTRACT FROM AUTHOR]

Background/objectives: Nighttime eating (NE) behavior has a genetic component and predicts weight gain. We hypothesized that some genetic variants, which affect NE would also show an effect on body mass index (BMI). We aimed to determine which known BMI variants associate with NE in Southwestern American Indians (SWAIs), who are at elevated risk for obesity.Methods: Known BMI variants from the GIANT-UK Biobank meta-analysis (N = 700,000) were analysed in SWAIs characterized for NE during an inpatient 3-day protocol. Variants were analysed for association with NE using whole-genome sequence data from 50 SWAIs (23 cases and 27 controls) and selected variants were genotyped in an additional 32 SWAIs (13 NE cases and 19 controls). Variants associated with NE in a meta-analysis of the two SWAI samples were further analysed for association with nightly caloric intake and functionality in hypothalamus, pituitary, and adrenal tissues.Results: Variants were identified where the allele that associated with increased BMI in the GIANT-UK Biobank meta-analysis (P ≤ 1 × 10-8) also had a P < 0.01 for increased NE in the SWAI meta-analysis. These variants were captured by six tagSNPs. Comparison of the nightly calorie intake by genotype and eQTL data from relevant tissues highlighted rs3753612 upstream of HCRTR1.Conclusions: Our strategy led to the HCRTR1 locus, which has previously been linked to sleep regulation and feeding. Although this is an intriguing candidate gene for NE, further studies in larger samples and different populations are required to validate the role of HCRTR1 in NE. [ABSTRACT FROM AUTHOR]

Background: Obesity and energy expenditure (EE) are heritable and genetic variants influencing EE may contribute to the development of obesity. We sought to identify genetic variants that affect EE in American Indians, an ethnic group with high prevalence of obesity.Methods: Whole-exome sequencing was performed in 373 healthy Pima Indians informative for 24-hour EE during energy balance. Genetic association analyses of all high-quality exonic variants (≥5 carriers) was performed, and those predicted to be damaging were prioritized.Results: Rs752074397 introduces a premature stop codon (Cys264Ter) in DAO and demonstrated the strongest association for 24-hour EE, where the Ter allele associated with substantially lower 24-hour EE (mean lower by 268 kcal/d) and sleeping EE (by 135 kcal/d). The Ter allele has a frequency = 0.5% in Pima Indians, whereas is extremely rare in most other ethnic groups (frequency < 0.01%). In vitro functional analysis showed reduced protein levels for the truncated form of DAO consistent with increased protein degradation. DAO encodes D-amino acid oxidase, which is involved in dopamine synthesis which might explain its role in modulating EE.Conclusion: Our results indicate that a nonsense mutation in DAO may influence EE in American Indians. Identification of variants that influence energy metabolism may lead to new pathways to treat human obesity.Clinical Trial Registration Number: NCT00340132. [ABSTRACT FROM AUTHOR]

Objective: Weight stigma is associated with poor dietary adherence, yet adherence is essential for weight loss and maintenance. This study aimed to determine differences in dietary adherence and perceived hunger between lean individuals and two groups of individuals with obesity.Methods: In a 6-week outpatient dietary intervention (23 males; aged 48  [SD 14] years), lean participants (n = 23; BMI 23  [SD 2] kg/m2 ) received a weight-maintaining energy needs (WMEN) diet, and participants with obesity (BMI 36  [SD 7]) were randomized to either WMEN (n = 18) or a 35% calorie-reduced (CR) diet (n = 19). All food was provided, and multiple adherence and hunger ratings were assessed daily and weekly on an outpatient basis and in person at twice-weekly visits (e.g., 24-hour recall, diaries).Results: Weight decreased more in the group of CR individuals with obesity (β = -0.301 kg/wk, P = 0.02) compared with the group of lean individuals and the group of WMEN individuals with obesity. However, total percent adherence did not differ between groups (P = 0.60), and hunger scores did not change across groups over time (P = 0.08).Conclusions: Results indicate that there are no differences in dietary adherence between lean individuals and individuals with obesity and adherence is not associated with adiposity or hunger. Thus, the belief that nonadherence (e.g., lack of willpower) is unique to obesity is untrue and may perpetuate weight bias and stigma. [ABSTRACT FROM AUTHOR]

Whole-room indirect calorimeters have been used to study human metabolism for more than a century. These studies have contributed substantial knowledge to the assessment of nutritional needs and the regulation of energy expenditure and substrate oxidation in humans. However, comparing results from studies conducted at different sites is challenging because of a lack of consistency in reporting technical performance, study design, and results. In May 2019, an expert panel was convened to consider minimal requirements for conducting and reporting the results of human whole-room indirect calorimeter studies. We propose Room Indirect Calorimetry Operating and Reporting Standards, version 1.0 (RICORS 1.0) to provide guidance to ensure consistency and facilitate meaningful comparisons of human energy metabolism studies across publications, laboratories, and clinical sites. [ABSTRACT FROM AUTHOR]

A greater decrease in 24-h energy expenditure (24 EE) during 24-h fasting defines a "thriftier" metabolic phenotype prone to weight gain during overfeeding and resistant to weight loss during caloric restriction. As the thermogenic response to mild cold exposure (COLD) may similarly characterize this human phenotype identified by acute fasting conditions, we analyzed changes in 24 EE and sleeping metabolic rate (SLEEP) in a whole-room indirect calorimeter during 24-h fasting at thermoneutrality (24°C) and during energy balance both at thermoneutrality (24°C) and mild cold (19°C) in 20 healthy volunteers (80% male; aged 36.6 ± 11.4 years; percentage body fat 34.8 ± 10.5%). Greater decrease in 24 EE during fasting (thriftier phenotype) was associated with less increase in 24 EE during COLD (i.e., less cold-induced thermogenesis). Greater decreases in plasma fibroblast growth factor 21 (FGF21) after 24-h fasting and after COLD were highly correlated and associated with greater decreases in SLEEP in both conditions. We conclude that the metabolic responses to short-term fasting and COLD are associated with and mediated by the liver-derived hormone FGF21. Thus, the 24 EE response to COLD further identifies the "thrifty" versus "spendthrift" phenotype, providing an additional setting to investigate the physiological mechanisms underlying the human metabolic phenotype and characterizing the individual susceptibility to weight change. [ABSTRACT FROM AUTHOR]

Objective: The relationship between adipocyte size and ad libitum energy intake has not been previously examined. This study hypothesized an inverse relationship between adipocyte size and daily energy intake (DEI).Methods: Seventy healthy adults (39 men and 31 women; BMI 30.0  [SD 6.3]) underwent dual-energy x-ray absorptiometry and subcutaneous fat biopsies from the abdomen and thigh. Osmium-fixed adipocytes were sized with a Coulter counter. Volunteers self-selected food from a vending machine paradigm as the only source of energy intake over 3 days as inpatients. Volunteers also had 24-hour respiratory quotient (RQ) measured in a whole-room indirect calorimeter.Results: In women, the large cell peak diameter of the thigh depot was greater than that of the abdominal depot (Δ = +15.8 μm; P < 0.0001). In women, thigh peak diameter was inversely associated with DEI (β = -264.7 kcal/d per 10-μm difference; P = 0.03) after adjusting for demographics and body composition. The thigh peak diameter in women was associated with 24-hour RQ (r = -0.47, P = 0.04) after adjusting for demographics, body composition, and 24-hour energy balance. These associations did not extend to men or the abdominal depot.Conclusions: In women, thigh adipocyte size was associated with reduced DEI and 24-hour RQ, indicating a special role for thigh fat in women. This depot-specific sexual dimorphism indicates common regulation of energy intake and adipocyte size in the thigh region of women. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to assess the relationship between dopamine, a neurotransmitter involved in feeding behavior, and ad libitum energy intake in humans.Methods: Healthy individuals (n = 158; 72 Native American, 50 white, 18 black, and 18 Hispanic participants; BMI: 33 [SD 9] kg/m2 ; body fat: 33% [SD 9%]) were admitted for two inpatient studies investigating the determinants of ad libitum energy intake and assessed for 3 days using a highly reproducible, computerized vending machine paradigm. Urine was collected for 24 hours during eucaloric conditions prior to the ad libitum feeding period, and urinary dopamine excretion rate was quantified by high-performance liquid chromatography.Results: Urinary dopamine excretion rate was on average 346 ± 106 μg over 24 hours and was positively correlated with BMI (r = 0.28, P < 0.0001). Higher dopamine concentrations were associated with lower cognitive restraint (ρ = -0.25, P = 0.005) and greater total ad libitum energy intake (r = 0.29, P = 0.0002). However, after adjustment for anthropometrics, in black and white cohorts, higher dopamine concentrations were associated with greater total ad libitum energy intake (r = 0.70, P = 0.001 and r = 0.33, P = 0.02, respectively), whereas no associations were observed in Native American or Hispanic cohorts (all P > 0.3).Conclusions: Higher urinary dopamine concentrations are associated with greater ad libitum energy intake, indicating a role for dopamine in the reward pathway regulating human feeding behavior. [ABSTRACT FROM AUTHOR]

Objective: We evaluated the effect of optimizing metformin dosing on glycemia and body weight in type 2 diabetes.Research Design and Methods: This was a prespecified analysis of 6,823 participants in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) taking metformin as the sole glucose-lowering drug who completed a 4- to 14-week (mean ± SD 7.9 ± 2.4) run-in in which metformin was adjusted to 2,000 mg/day or a maximally tolerated lower dose. Participants had type 2 diabetes for <10 years and an HbA1c ≥6.8% (51 mmol/mol) while taking ≥500 mg of metformin/day. Participants also received diet and exercise counseling. The primary outcome was the change in HbA1c during run-in.Results: Adjusted for duration of run-in, the mean ± SD change in HbA1c was -0.65 ± 0.02% (-7.1 ± 0.2 mmol/mol) when the dose was increased by ≥1,000 mg/day, -0.48 ± 0.02% (-5.2 ± 0.2 mmol/mol) when the dose was unchanged, and -0.23 ± 0.07% (-2.5 ± 0.8 mmol/mol) when the dose was decreased (n = 2,169, 3,548, and 192, respectively). Higher HbA1c at entry predicted greater reduction in HbA1c (P < 0.001) in univariate and multivariate analyses. Weight loss adjusted for duration of run-in averaged 0.91 ± 0.05 kg in participants who increased metformin by ≥1,000 mg/day (n = 1,894).Conclusions: Optimizing metformin to 2,000 mg/day or a maximally tolerated lower dose combined with emphasis on medication adherence and lifestyle can improve glycemia in type 2 diabetes and HbA1c values ≥6.8% (51 mmol/mol). These findings may help guide efforts to optimize metformin therapy among persons with type 2 diabetes and suboptimal glycemic control. [ABSTRACT FROM AUTHOR]

The ability to switch fuels for oxidation in response to changes in macronutrient composition of diet (metabolic flexibility) may be informative of individuals' susceptibility to weight gain. Seventy-nine healthy, weight-stable participants underwent 24-h assessments of energy expenditure and respiratory quotient (RQ) in a whole-room calorimeter during energy balance (EBL) (50% carbohydrate, 30% fat) and then during 24-h fasting and three 200% overfeeding diets in a crossover design. Metabolic flexibility was defined as the change in 24-h RQ from EBL during fasting and standard overfeeding (STOF) (50% carbohydrate, 30% fat), high-fat overfeeding (HFOF) (60% fat, 20% carbohydrate), and high-carbohydrate overfeeding (HCOF) (75% carbohydrate, 5% fat) diets. Free-living weight change was assessed after 6 and 12 months. Compared with EBL, RQ decreased on average by 9% during fasting and by 4% during HFOF but increased by 4% during STOF and by 8% during HCOF. A smaller decrease in RQ, reflecting a smaller increase in lipid oxidation rate, during HFOF but not during the other diets predicted greater weight gain at both 6 and 12 months. An impaired metabolic flexibility to acute HFOF can identify individuals prone to weight gain, indicating that an individual's capacity to oxidize dietary fat is a metabolic determinant of weight change. [ABSTRACT FROM AUTHOR]

Background/objective: Evidence from non-human species indicate that hydration and arginine vasopressin (AVP) influence fuel selection, energy expenditure (EE), and food intake, but these relationships are unclear in humans. We sought to assess whether hydration biomarkers [24-h urine volume (UVol) and urine urea nitrogen concentration (UUN)] and copeptin (a surrogate for AVP) are associated with 24-h EE, respiratory quotient (RQ), and daily energy intake (DEI).Subjects/methods: In a secondary analysis of collected data, we selected healthy adults (Group 1, n = 177) who had 24-h whole-room indirect calorimetry measurements in energy balance with 24-h urine collection and fasting copeptin measurements (n = 117), followed by 3 days ad libitum food intake. A separate group (Group 2, n = 284) with hydration markers and calorimetry measurements was also studied. The main outcome measures were 24-h RQ, 24-h EE, DEI, substrate oxidation.Results: In Group 1, lower 24-h UVol and higher 24-h UUN, indicating lower hydration, were correlated with lower 24-h RQ (r = 0.35, p < 0.0001, and r = -0.29, p = 0.0001, respectively; results similar in Group 2) and predicted subsequent reduced DEI (r = 0.20, p = 0.01, and r = -0.27, p = 0.0003, respectively), adjusted for confounders. Copeptin was independently associated with 24-h lipid oxidation (r = -0.23, p = 0.01). In Group 2, lower hydration was associated with reduced 24-h EE (24-h UVol: r = 0.29, p < 0.0001; 24-h UUN: r = -0.25, p < 0.0001).Conclusions: Hydration biomarkers were associated with metabolic differences characterized by altered food intake, fuel selection, and possibly EE. Independently, copeptin was associated with higher lipid oxidation. [ABSTRACT FROM AUTHOR]

Background Naturally occurring carbon and nitrogen stable isotope ratios [13C/12C (CIR) and 15N/14N (NIR)] are promising dietary biomarkers. As these candidate biomarkers have long tissue residence times, long-term feeding studies are needed for their evaluation. Objective Our aim was to evaluate plasma, RBCs, and hair CIR and NIR as biomarkers of fish, meat, and sugar-sweetened beverage (SSB) intake in a 12-wk dietary intervention. Methods Thirty-two men (aged 46.2 ± 10.5 y; BMI: 27.2 ± 4.0 kg/m2) underwent a 12-wk inpatient dietary intervention at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in Phoenix, Arizona. The effects of fish, meat, and SSB intake on CIR and NIR were evaluated using a balanced factorial design, with each intake factor at 2 levels (present/absent) in a common, background diet (50% carbohydrate, 30% fat, 20% protein). Fasting blood samples were taken biweekly from baseline, and hair samples were collected at baseline and postintervention. Data were analyzed using multivariable regression. Results The postintervention CIR of plasma was elevated when diets included meat (β = 0.89, 95% CI: 0.73,1.05) and SSBs (β = 0.48, 95% CI: 0.32, 0.64). The postintervention NIR of plasma was elevated when diets included fish (β = 0.85, 95% CI: 0.64, 1.05) and meat (β = 0.61, 95% CI: 0.42, 0.8). Results were similar for RBCs and hair. Postintervention RBC CIR and NIR had strong associations with baseline, suggesting that turnover to the intervention diets was incomplete after 12 wk. Estimates of isotopic turnover rate further confirmed incomplete turnover of RBCs. Conclusions CIR was associated with meat and SSBs, and more strongly with meat. NIR was associated with fish and meat, and more strongly with fish. Overall, CIR and NIR discriminated between dietary fish and meat, and to a lesser extent SSBs, indicating their potential utility as biomarkers of intake in US diets. Approaches to make these biomarkers more specific are needed. This trial was registered at clinicaltrials.gov as NCT01237093. [ABSTRACT FROM AUTHOR]

Background Greater increase in 24-h energy expenditure (24EE) during overfeeding and smaller decrease in 24EE during fasting ("spendthrift" metabolic phenotype) are associated with more weight loss during sustained caloric restriction in overweight subjects. Objectives The aim of this study was to investigate whether these acute metabolic responses can also predict weight gain during sustained overfeeding in lean individuals. Methods Seven lean men participated in this study. Prior to overfeeding, 24EE responses to fasting and 200% normal-protein overfeeding were measured in a whole-room indirect calorimeter. Volunteers underwent 6 wk of 150% low-protein (2%) overfeeding followed by another wk of weight-maintaining diet, during which 24EE was revaluated. Body composition, 24EE, and various hormone concentrations, including fibroblast growth factor 21 (FGF21), were assessed at baseline, at wk 1, 3, and 6 of the overfeeding period, and 1 wk following overfeeding through the use of dual-energy X-ray absorptiometry, indirect calorimetry, and ELISA. Cumulative energy surplus was calculated from 24EE, daily physical activity, and direct measurements of calories of nutrient intake, feces, and urine by bomb calorimetry. Results The average weight gain during 6 wk of low-protein overfeeding was 3.8 kg (6.1%, min: +2.5%, max: +8.0%). During 24-h fasting at baseline, 24EE decreased on average (mean ± SD) by 158 ± 81 kcal/d (P  = 0.007). Subjects with less 24EE decrease during fasting (more metabolically spendthrift individuals) gained less weight (r  = −0.84, P  = 0.03), less fat mass (r  = −0.81, P  = 0.049), and stored less calories (r  = −0.91, P  = 0.03) during overfeeding. Following overfeeding, increased 24EE above requirements for achieved body size was associated with less weight and fat mass gain (r  = −0.78, P  = 0.04) and with the increase in 24EE during 200% normal-protein overfeeding measured at baseline (r  = 0.91, P  = 0.005). Serum FGF21 concentrations increased up to 44-fold during overfeeding (P  <  0.0001). Conclusions Low-protein overfeeding may be an important tool to identify metabolic phenotypes (spendthrift compared with thrifty) that characterize susceptibility to weight gain. This trial was registered at clinicaltrials.gov as NCT00687115. [ABSTRACT FROM AUTHOR]

Background: A greater decrease in 24-hour energy expenditure (EE) during fasting and a smaller increase in 24-hour EE during low-protein overfeeding (metabolic "thrifty" phenotype) predict weight gain. As thyroid hormones (TH) are implicated in energy intake and metabolism, we assessed whether: (i) TH concentrations are altered by 24-hour fasting or overfeeding diets with varying protein content and (ii) diet-related changes in TH correlate with concomitant changes in EE. Methods: Fifty-eight euthyroid healthy subjects with normal glucose regulation underwent 24-hour dietary interventions including fasting, eucaloric feeding, and five overfeeding diets in a crossover design within a whole-room indirect calorimeter to measure the 24-hour EE. Overfeeding diets (200% of energy requirements) included three diets with 20% protein, one diet with 3% protein (low-protein overfeeding diet [LPF]: 46% fat), and one diet with 30% protein (high-protein overfeeding diet [HPF]: 44% fat, n = 51). Plasma free thyroxine (fT4), free triiodothyronine (fT3), and fibroblast growth factor 21 (FGF21) concentrations were measured after overnight fast the morning of and after each diet. Results: On average, fT4 increased by 8% (+0.10 ng/dL, 95% confidence interval [CI 0.07–0.13], p < 0.0001) and fT3 decreased by 6% (−0.17 pg/mL [CI −0.27 to −0.07], p = 0.001) after 24-hour fasting, whereas both fT4 and fT3 decreased by 5% (−0.07 ng/dL [CI −0.11 to −0.04], p < 0.0001) and 4% (−0.14 pg/mL [CI −0.24 to −0.04], p = 0.008) following HPF, respectively. Greater decreases in fT3 after HPF are associated with larger decreases in FGF21 (r = 0.40, p = 0.005). Following LPF, the mean fT3 increased by 6% (+0.14 pg/mL [CI 0.05–0.2], p = 0.003) with no change in fT4 (p = 0.7). No changes in TH were observed after normal-protein overfeeding diets (all p > 0.1). No associations were observed between TH concentrations and diet-related changes in 24-hour EE during any diet (all p > 0.07). Conclusions: Acute (200%) short-term (24 hours) changes in food intake induce small changes in TH concentrations only after diets with low (0% fasting and 3% protein overfeeding) or high (30% protein overfeeding) protein content. The fT3-FGF21 association after high-protein overfeeding suggests a role for TH in inhibiting FGF21 secretion by the liver during protein excess. These results indicate that TH are involved in protein metabolism; however, they do not mediate the short-term EE response to diets that characterize the metabolic phenotypes and determine the individual susceptibility to weight gain. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor 21 (FGF21) regulates energy expenditure (EE) and influences weight change during low-protein overfeeding in rodent models. The change in EE after a low-protein overfeeding diet is a predictor of weight change in humans and a feature of the "thrifty" metabolic phenotype. However, there are no studies showing an association between circulating FGF21 and diet-related EE in humans. We assessed the changes in plasma FGF21 concentrations after 24 h of seven dietary interventions with different macronutrient content while in a whole-room indirect calorimeter in 64 healthy subjects with normal glucose regulation. Plasma FGF21 concentration consistently increased by threefold only after the two low-protein (3%) overfeeding diets, one high in carbohydrate (75%) and the other high in fat (46%), with larger increases in FGF21 being associated with greater increases in 24-h EE. Subjects with smaller increases in FGF21 after the low-protein high-fat diet gained more weight after 6 months in free-living conditions. Therefore, the individual predisposition to weight gain over time can be assessed by 24-h overfeeding a low-protein diet and measurements of plasma FGF21 concentrations. Individuals with a blunted FGF21 response to a low-protein diet have a thrifty metabolism and are at risk for future weight gain. [ABSTRACT FROM AUTHOR]

Context Surrogate indices of muscle and hepatic insulin sensitivity derived from an oral glucose tolerance test (OGTT) are frequently used in clinical studies. However, the predictive accuracy of these indices has not been validated. Design In this cross-sectional study, hyperinsulinemic-euglycemic glucose clamp with tritiated glucose infusion and a 75-g OGTT were performed in individuals (n = 659, aged 18 to 49 years, body mass index of 16 to 64 kg/m2) with varying degrees of glucose tolerance. A calibration model was used to assess the ability of OGTT-derived, tissue-specific surrogate indices [hepatic insulin resistance index (HIRI) and muscle insulin sensitivity index (MISI)] to predict insulin sensitivity/resistance indices derived from the reference glucose clamp [Hepatic-IRbasal, a product of fasting plasma insulin and hepatic glucose production (HGP), Hepatic-IRclamp, reciprocal of the percent suppression of HGP during the insulin clamp corrected for plasma insulin concentration, and Muscle-ISclamp, a measure of peripheral glucose disposal]. Predictive accuracy was assessed by root mean squared error of prediction and leave-one-out, cross-validation-type square root of the mean squared error of prediction. Results HIRI and MISI were correlated with their respective clamp-derived indices. HIRI was negatively related to Muscle-ISclamp (r = –0.62, P < 0.0001) and MISI correlated with Hepatic-IR derived from the clamp (Hepatic-IRbasal: r = –0.48, P < 0.0001 and Hepatic-IRclamp: r = –0.41, P < 0.0001). However, the accuracy of HIRI and MISI to predict Hepatic-IR (basal or during clamp) was not significantly different. Likewise, the ability of HIRI and MISI to predict Muscle-ISclamp was also similar. Conclusion Our findings indicate that the surrogate indices derived from an OGTT are accurate in predicting insulin sensitivity but are not tissue specific. [ABSTRACT FROM AUTHOR]

Objective: The association between food insecurity and obesity may be partially explained by overeating in response to unpredictable food availability cycles. The aim of this study was to measure objective food intake in food-insecure individuals.Methods: Eighty-two volunteers (53 m; BMI 29 ± 7; 38 ± 12 years) were admitted to our inpatient Clinical Research Unit and completed the Food Security Short Form, Three-Factor Eating Questionnaire, Gormally Binge Eating Scale, and body composition assessment (dual-energy x-ray absorptiometry). After 5 days of a weight-maintaining diet, participants self-selected food from an ad libitum vending machine paradigm for 3 days. Mean daily intake (kilocalories), macronutrient intake, and percentage of weight-maintaining energy needs (%WMEN) were calculated.Results: Based on Food Security Short Form cutoffs, food-insecure participants (n = 46; 56%) had higher body weight (P = 0.04), fat-free mass (P = 0.05), disinhibition (P = 0.008), hunger (P = 0.02), and binge-eating scores (P = 0.02) but not cognitive restraint (P = 0.37) compared with food-secure individuals. They overate more kilocalories (P = 0.001), %WMEN (P = 0.003), fat (P = 0.003), and carbohydrates (P = 0.004) during the vending machine paradigm, continued to increase their hourly rate of kilocalories (group × time; β = 37.7 cumulative kcal/h; P < 0.0001), and ate more total kilocalories across the 72 hours (β = 47.09 kcal/h; P = 0.003).Conclusions: Food insecurity may amplify susceptibility to weight gain via overeating during times of unlimited food access. [ABSTRACT FROM AUTHOR]