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Direct evidence in humans for the impact of the microbiome on nutrient absorption is lacking. We conducted an extended inpatient study using two interventions that we hypothesized would alter the gut microbiome and nutrient absorption. In each, stool calorie loss, a direct proxy of nutrient absorption, was measured. The first phase was a randomized cross-over dietary intervention in which all participants underwent in random order 3 d of over- and underfeeding. The second was a randomized, double-blind, placebo-controlled pharmacologic intervention using oral vancomycin or matching placebo ( NCT02037295 ). Twenty-seven volunteers (17 men and 10 women, age 35.1 ± 7.3, BMI 32.3 ± 8.0), who were healthy other than having impaired glucose tolerance and obesity, were enrolled and 25 completed the entire trial. The primary endpoints were the effects of dietary and pharmacological intervention on stool calorie loss. We hypothesized that stool calories expressed as percentage of caloric intake would increase with underfeeding compared with overfeeding and increase during oral vancomycin treatment. Both primary endpoints were met. Greater stool calorie loss was observed during underfeeding relative to overfeeding and during vancomycin treatment compared with placebo. Key secondary endpoints were to evaluate the changes in gut microbial community structure as evidenced by amplicon sequencing and metagenomics. We observed only a modest perturbation of gut microbial community structure with under- versus overfeeding but a more widespread change in community structure with reduced diversity with oral vancomycin. Increase in Akkermansia muciniphila was common to both interventions that resulted in greater stool calorie loss. These results indicate that nutrient absorption is sensitive to environmental perturbations and support the translational relevance of preclinical models demonstrating a possible causal role for the gut microbiome in dietary energy harvest. A proof-of-concept clinical study shows that perturbations to the gut microbiome affect nutrient absorption in humans.

Background Plasma albumin is reduced during inflammation. Obesity, a strong risk factor for type 2 diabetes (T2D), is associated with adipose tissue inflammation. However, whether albumin is associated with adipose tissue inflammation and whether it predicts T2D are unclear. Methods Adults (predominantly American Indian) from a longitudinal study were included. Macrophage content and gene expression related to recruitment/activation were measured from subcutaneous adipose tissue (n = 51). The relationship between plasma albumin and adiposity (dual-energy X-ray absorptiometry or hydrodensitometry), glucose (oral glucose tolerance test), insulin action (hyperinsulinemic-euglycemic clamp), and insulin secretion (intravenous glucose tolerance test) were evaluated (n = 422). Progression to T2D was evaluated by Cox regression (median follow-up 8.8 years; 102 progressors). Results Albumin was associated with macrophage markers including C1QB (r = − 0.30, p = 0.04), CSF1R (r = − 0.30, p = 0.03), and CD11b (r = − 0.36, p = 0.01). Albumin was inversely associated with body fat percentage (r = − 0.14, p = 0.003), fasting plasma glucose (r = − 0.17, p = 0.0003), and 2 h plasma glucose (r = − 0.11, p = 0.03), and was reduced in impaired glucose regulation compared with normal glucose regulation (mean ± SD: 39.4 ± 3.6 g/l and 40.1 ± 3.9 g/l, respectively; p = 0.049). Albumin predicted T2D, even after adjustment for confounders (HR, 0.75; 95% CI 0.58–0.96; p = 0.02; per one SD difference in albumin). Conclusions Reduced albumin is associated with an unfavorable metabolic profile, characterized by increased adipose tissue inflammation, adiposity, and glucose, and with an increased risk for T2D.

Abstract Background Interindividual variability in 24-hour energy expenditure (24EE) during energy-balance conditions is mainly determined by differences in body composition and demographic factors. Previous studies suggested that 24EE might also be influenced by sympathetic nervous system activity via catecholamine (norepinephrine, epinephrine) secretion. Therefore, we analyzed the association between catecholamines and energy expenditure in 202 individuals from a heterogeneous population of mixed ethnicities. Methods Participants (n = 202, 33% female, 14% black, 32% white, 41% Native American, 11% Hispanic, age: 36.9 ± 10.3 y [mean ± SD], percentage body fat: 30.3 ± 9.4) resided in a whole-room calorimeter over 24 hours during carefully controlled energy-balance conditions to measure 24EE and its components: sleeping metabolic rate (SMR), awake-fed thermogenesis (AFT), and spontaneous physical activity (SPA). Urine samples were collected, and 24-h urinary epinephrine and norepinephrine excretion rates were assessed by high-performance liquid chromatography. Results Both catecholamines were associated with 24EE and SMR (norepinephrine: +27 and +19 kcal/d per 10 μg/24h; epinephrine: +18 and +10 kcal/d per 1 μg/24h) in separate analyses after adjustment for age, sex, ethnicity, fat mass, fat-free mass, calorimeter room, temperature, and physical activity. In a multivariate model including both norepinephrine and epinephrine, only norepinephrine was independently associated with both 24EE and SMR (both P < .008), whereas epinephrine became insignificant. Neither epinephrine nor norepinephrine were associated with adjusted AFT (both P = .37) but epinephrine was associated with adjusted SPA (+0.5% per 1 μg/24h). Conclusions Our data provide compelling evidence that sympathetic nervous system activity, mediated via norepinephrine, is a determinant of human energy expenditure during nonstressed, eucaloric conditions.

ObjectiveThe 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.MethodsBetween 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.ResultsIn 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.ConclusionSPA, 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 registrationClinicalTrials.gov identifiers: NCT00340132, NCT00342732

Précis:Diet and intrinsic factors influenced fuel preference during 24 hours of fasting and consumption of 4 different overfeeding diets. Higher fasting urinary epinephrine correlated with smaller energy expenditure reductions.AbstractContext:In humans, dietary vs intraindividual determinants of macronutrient oxidation preference and the role of the sympathetic nervous system (SNS) during short-term overfeeding and fasting are unclear.Objective:To understand the influence on metabolic changes of diet and SNS during 24 hours of overfeeding.Design, Setting, Participants, and Interventions:While residing on a clinical research unit, 64 participants with normal glucose regulation were assessed during energy balance, fasting, and four 24-hour overfeeding diets, given in random order. The overfeeding diets contained 200% of energy requirements and varied macronutrient proportions: (1) standard (50% carbohydrate, 20% protein, and 30% fat); (2) 75% carbohydrate; (3) 60% fat; and (4) 3% protein.Main Outcome Measures:Twenty-four–hour energy expenditure (EE) and macronutrient oxidation rates were measured in an indirect calorimeter during the dietary interventions, with concomitant measurement of urinary catecholamines and free cortisol.Results:EE decreased with fasting (−7.7% ± 4.8%; P < 0.0001) and increased with overfeeding. The smallest increase occurred during consumption of the diet with 3% protein (2.7% ± 4.5%; P = 0.001) and the greatest during the diet with 75% carbohydrate (13.8 ± 5.7%; P < 0.0001). Approximately 60% of macronutrient oxidation was determined by diet and 20% by intrinsic factors (P < 0.0001). Only urinary epinephrine differed between fasting and overfeeding diets (Δ = 2.25 ± 2.9 µg/24h; P < 0.0001). During fasting, higher urinary epinephrine concentrations correlated with smaller reductions in EE (ρ = 0.34; P = 0.01).Conclusions:Independent from dietary macronutrient proportions, there is a strong individual contribution to fuel preference that remains consistent across diets. Higher urinary epinephrine levels may reflect the importance of epinephrine in maintaining EE during fasting.

Controlling the molecular transport of nutrients through the gut is an attractive strategy to modulate host metabolism. Herein, a technique of stress‐based evolution of an individual's own microbiota to enhance lipid metabolism is presented, which is based on sequential culture of these bacteria in higher concentrations of lipids. Using this technique, a probiotic formulation of bacterial colonies that exhibit increased lipid metabolism was generated from oral microbiota samples from mice, canine, and human sources. Mice fed a high‐fat diet (HFD) and administered lipid stress evolved (LSE) probiotics excreted increased lipids in stool and reduced triglyceride transport into the blood by three‐fold till 3 h post‐oral gavage of soybean oil, as compared to controls. In addition, these enhanced probiotics prevented weight gain in mice fed a HFD five‐fold better than controls and induced weight loss in mice with diet change three‐fold faster than diet change alone. In these mice, there was a marked change in appearance with a more healthy, less oily coat. Controlled metabolic cage experiments demonstrated that the total movement, food intake, and water intake were not significantly different between mice receiving LSE probiotic versus a control probiotic formulation, suggesting that important health measures are unchanged with LSE probiotic administration. Overall, this facile stress‐based culture technique can be utilized to modulate bacterial metabolism and applied to different industrial processes of probiotic generation and to affect different disease outcomes such as obesity.

Background The COVID-19 pandemic significantly impacted global mental health, leading to increased levels of fear, stress, and anxiety [1]. Previous research has suggested associations between functional fear of detrimental mental health outcomes and psychological stressors which may drive maladaptive eating behaviors. This study explored the associations between COVID-19 fear during later stages of the pandemic, psychological distress (anxiety, depression, and stress), maladaptive eating behaviors (emotional, uncontrolled, binge, and nighttime eating), and self-reported body weight. Methods This was a global cross-sectional survey conducted from February 2022 to February 2024, involving 4390 adults (70% female) from 25 countries. The survey collected information on demographics, psychosocial impact, eating behaviors, and COVID-19 related behaviors. General linear models, multinomial logistic regression modes, and structural equation modeling were used to analyze the data. Results Higher fear of COVID-19 was significantly associated with increased emotional and uncontrolled eating, even after adjusting for psychological distress and other covariates. Specifically, each unit increase in fear of COVID-19 scores was associated with a corresponding increase in emotional eating (β = 0.018) and uncontrolled eating (β = 0.029) behaviors ( p -values < 0.0001). Furthermore, fear of COVID-19 was linked to higher odds of engaging in binge eating (OR = 1.05, 95% CI: 1.03, 1.07, p -value < 0.0001) and nighttime eating behaviors (OR = 1.04, 95% CI: 1.03, 1.06, p -value < 0.0001) in models adjusted for covariates; however, these associations were no longer significant when psychological distress variables were included. Fear of COVID-19 was also associated with body weight (β = 0.18) and BMI (β = 0.08) even with adjustments of covariates and psychological distress variables ( p -values < 0.01). Structural equation modeling showed that fear of COVID-19 was related to current body weight through its impact on psychological distress and maladaptive eating behaviors. Conclusions Maladaptive eating behaviors influenced by the psychological distress experienced during the COVID-19 pandemic have persisted into the later stages of the pandemic. These results underscore an interconnectedness between functional fear and its influence on maladaptive eating behaviors and body weight. Understanding this link is crucial and has the potential to inform the development of public health policies. Trial registration Clinical Trials.gov NCT04896060 Date of Registration: May 21, 2021.

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 AUC 180-min (HR: 1.98, 95% CI: 1.67, 2.34, p  < 0.0001), AUC 240-min (HR: 1.93, 95% CI: 1.62, 2.31, p  < 0.0001), and iAUC 180-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, AUC 180-min (HR: 1.44, 95% CI: 1.10, 1.88, p  = 0.007) and AUC 240-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

Adiponectin is a collagen-like circulating protein secreted by adipocytes that is proposed to mediate obesity-related resistance to insulin. In a case-control series, we assessed the role of adiponectin in later development of type 2 diabetes in 70 patients who later developed type 2 diabetes and 70 controls, matched for body-mass index, age, and sex. Cases and controls were taken from the longitudinal study of health in the Pima Indian population. At baseline, the concentration of adiponectin was lower in cases than in controls (p=0·01) and individuals with high concentrations of this protein were less likely to develop type 2 diabetes than those with low concentrations (incidence rate ratio 0·63 [95% CI 0·43–0·92]; p=0·02).

Childhood Predictors of Young-Onset Type 2 Diabetes Paul W. Franks 1 2 , Robert L. Hanson 1 , William C. Knowler 1 , Carol Moffett 1 , Gleebah Enos 1 , Aniello M. Infante 1 , Jonathan Krakoff 1 and Helen C. Looker 1 1 Diabetes Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona 2 Genetic Epidemiology and Clinical Research Group, Department of Public Health and Clinical Medicine, Division of Medicine, Umeå University Hospital, Umeå, Sweden Address correspondence to Dr. Robert L. Hanson, Diabetes Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, 1550 E. Indian School Rd., Phoenix, AZ 85014. E-mail: rhanson{at}phx.niddk.nih.gov Abstract OBJECTIVE— Optimal prevention of young-onset type 2 diabetes requires identification of the early-life modifiable risk factors. We aimed to do this using longitudinal data in 1,604 5- to 19-year-old initially nondiabetic American Indians. RESEARCH DESIGN AND METHODS— For type 2 diabetes prediction, we derived an optimally weighted, continuously distributed, standardized multivariate score (zMS) comprising commonly measured metabolic, anthropometric, and vascular traits (i.e., fasting and 2-h glucose, A1C, BMI, waist circumference, fasting insulin, HDL cholesterol, triglycerides, and blood pressures) and compared the predictive power for each feature against zMS. RESULTS— In separate Cox proportional hazard models, adjusted for age, sex, and ethnicity, zMS and each of its component risk factors were associated with incident type 2 diabetes. Stepwise proportional hazards models selected fasting glucose, 2-h glucose, HDL cholesterol, and BMI as independent diabetes predictors; individually, these were weaker predictors than zMS ( P < 0.01). However, a parsimonious summary score combining only these variables had predictive power similar to that of zMS ( P = 0.33). Although intrauterine diabetes exposure or parental history of young-onset diabetes increased a child’s absolute risk of developing diabetes, the magnitude of the diabetes-risk relationships for zMS and the parsimonious score were similar irrespective of familial risk factors. CONCLUSIONS— We have determined the relative value of the features of the metabolic syndrome in childhood for the prediction of subsequent type 2 diabetes. Our findings suggest that strategies targeting obesity, dysregulated glucose homeostasis, and low HDL cholesterol during childhood and adolescence may have the most success in preventing diabetes. DBP, diastolic blood pressure IED, intrauterine exposure to diabetes ODP, offspring of a diabetic parent OGTT, oral glucose tolerance test ONDP, offspring of nondiabetic parents ROC, receiver operating characteristic ROC AUC, area under the ROC curve SBP, systolic blood pressure zMS, standardized multivariate score Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 24 August 2007. DOI: 10.2337/db06-1639. Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db06-1639 . The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted August 22, 2007. Received November 22, 2006. DIABETES