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Background: No medications are currently approved for the treatment of nonmonogenic, nonsyndromic obesity in children younger than 12 years of age. Although the use of liraglutide has been shown to induce weight loss in adults and adolescents with obesity, its safety and efficacy have not been established in children., Methods: In this phase 3a trial, which consisted of a 56-week treatment period and a 26-week follow-up period, we randomly assigned children (6 to <12 years of age) with obesity, in a 2:1 ratio, to receive either once-daily subcutaneous liraglutide at a dose of 3.0 mg (or the maximum tolerated dose) or placebo, plus lifestyle interventions. The primary end point was the percentage change in the body-mass index (BMI; the weight in kilograms divided by the square of the height in meters). The confirmatory secondary end points were the percentage change in body weight and a reduction in BMI of at least 5%., Results: A total of 82 participants underwent randomization; 56 were assigned to the liraglutide group and 26 to the placebo group. At week 56, the mean percentage change from baseline in BMI was -5.8% with liraglutide and 1.6% with placebo, representing an estimated difference of -7.4 percentage points (95% confidence interval [CI], -11.6 to -3.2; P<0.001). The mean percentage change in body weight was 1.6% with liraglutide and 10.0% with placebo, representing an estimated difference of -8.4 percentage points (95% CI, -13.4 to -3.3; P = 0.001), and a reduction in BMI of at least 5% occurred in 46% of participants in the liraglutide group and in 9% of participants in the placebo group (adjusted odds ratio, 6.3 [95% CI, 1.4 to 28.8]; P = 0.02). Adverse events occurred in 89% and 88% of participants in the liraglutide and placebo groups, respectively. Gastrointestinal adverse events were more common in the liraglutide group (80% vs. 54%); serious adverse events were reported in 12% and 8% of participants in the liraglutide and placebo groups, respectively., Conclusions: Among children (6 to <12 years of age) with obesity, treatment with liraglutide for 56 weeks plus lifestyle interventions resulted in a greater reduction in BMI than placebo plus lifestyle interventions. (Funded by Novo Nordisk; SCALE Kids ClinicalTrials.gov number, NCT04775082.)., (Copyright © 2024 Massachusetts Medical Society.)

Aims: To examine associations between weight loss/gain and risk of developing 13 obesity-related complications (ORCs), stratified by baseline body mass index (BMI)., Materials and Methods: In this retrospective cohort study, we included adults with obesity (>30 kg/m 2 ) from the UK Clinical Practice Research Datalink GOLD database with weight change (-50% to +50%) between Years 1 and 4 (N = 418 774 [median follow-up: 7 years]). Associations between weight change, baseline BMI and risk of developing ORCs during follow-up were assessed using Cox proportional hazard models., Results: The impact of weight change on ORCs was generally dependent on baseline BMI. Four clear patterns were seen across the 13 outcomes. Pattern 1 showed greatest weight loss benefit for people with low baseline BMI (type 2 diabetes, sleep apnoea, hypertension and dyslipidaemia); Pattern 2 showed most weight loss benefit at lower baseline BMI but no significant weight loss effect at higher baseline BMI (asthma, hip/knee osteoarthritis and polycystic ovary syndrome); Pattern 3 showed benefit in most cardiovascular diseases with weight loss (chronic kidney disease, heart failure, atrial fibrillation and venous thromboembolism), but no additional benefit with >10% weight loss; Pattern 4 showed no clear relationship between weight change and unstable angina/myocardial infarction and depression. We found similar but opposite patterns for weight gain., Conclusions: Weight loss benefit is dependent on weight loss magnitude and initial BMI, and weight gain is associated with a similar risk increase. Four patterns of association were identified between degree of weight change, baseline BMI and 13 ORCs., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: As childhood obesity prevalence increases, determining which patients respond to anti-obesity medications would strengthen personalized approaches to obesity treatment. In the SCALE Teens trial among pubertal adolescents with obesity (NCT02918279), liraglutide 3.0 mg (or maximum tolerated dose) significantly reduced body mass index (BMI) standard deviation score on average versus placebo. That said, liraglutide effects on BMI reduction varied greatly among adolescents, similar to adults., Objectives: To identify post hoc characteristics predictive of achieving ≥5% and ≥10% BMI reductions at 56 weeks with liraglutide versus placebo in adolescents from the SCALE Teens trial., Methods: Logistic regression analysis was performed in 251 adolescents treated with liraglutide (n = 125) or placebo (n = 126) for 56 weeks. Baseline characteristics (selected a priori) included sex, race, ethnicity, age, Tanner (pubertal) stage, glycemic status (hyperglycemia [type 2 diabetes/prediabetes] vs. normoglycemia), obesity category (Class II/III vs. I), severity of depression symptoms (Patient Health Questionnaire-9), and weight variability (weight fluctuations over time). The effects of early responder status (≥4% BMI reduction at week 16) on week 56 response were assessed using descriptive statistics., Results: Baseline characteristics did not affect achievement of ≥5% and ≥10% BMI reductions at week 56 in adolescents treated with liraglutide. Further, there was no association between weight variability and BMI reduction. Early liraglutide responders appeared to have greater BMI and body weight reductions at week 56 compared with early non-responders., Conclusions: This secondary analysis suggests that adolescents with obesity may experience significant BMI reductions after 56 weeks of liraglutide treatment, regardless of their sex, race, ethnicity, age, pubertal stage, glycemic status, obesity category, severity of depression symptoms, or weight variability. Early response may predict greater week 56 response., (© 2023 The Authors. Pediatric Obesity published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Purpose: This study aimed to determine whether minimum recommended moderate-to-vigorous physical activity (MVPA; 30-min bout of continuous moderate-intensity walking) is sufficient to counteract the detrimental effects of prolonged sitting on postprandial metabolism and if there are any effects of breaking up sitting with intermittent standing when achieving minimum recommended MVPA., Methods: Fourteen (n = 14) physically inactive healthy adult males underwent four intrahospital 27-h interventions: 9-h continuous sitting (SIT), 15-min standing bouts every 30 min during the 9-h sitting (STAND), 30-min moderate-intensity walking bout followed by 8.5 h of sitting (MVPA), and 30-min moderate-intensity walking bout followed by 15-min standing bouts every 30 min during 8.5 h of sitting (MVPA + STAND). Three standardized meals on intervention day (day 1) and breakfast the following day (day 2) were served., Results: Cumulative postprandial glucose response (incremental area under the curve) was lower in STAND versus SIT (↓27%, P = 0.04, effect size [ES] = -0.7) because of decreases in postprandial glucose after breakfast on day 1 (STAND vs SIT: ↓40%, P = 0.01, ES = -0.7) and day 2 (STAND vs SIT: ↓33%, P = 0.06, ES = -0.6). STAND did not affect postprandial insulin responses. Cumulative postprandial insulin response was lower in MVPA versus SIT (↓18%, P = 0.03, ES = -0.3) and MVPA + STAND versus SIT (↓26%, P = 0.02, ES = -0.4) because of expected exercise-induced decreases in postprandial insulin after breakfast on day 1 only (MVPA vs SIT: ↓36%, P = 0.003, ES = -0.7; MVPA + STAND vs SIT: ↓43%, P = 0.0001, ES = -0.8)., Conclusion: Breaking up prolonged sitting with nonambulatory standing across 9 h acutely reduced postprandial glycemic response during and the day after the intervention independent of insulin levels, whereas a 30-min MVPA bout did not.

Objectives: There has been a parallel increase in the incidence of obesity and diabetes as well as the number of daily meals. However, evidence is lacking regarding the role of intermittent fasting. The aim of this study was to determine the effects of a Ramadan model of intermittent fasting (RIF; 14 h of daytime abstinence from food and drinking) for 28 d on body composition, glucose metabolism, and cognitive function., Methods: Ten healthy, lean men were included in a nonrandomized, crossover, intervention study. Testing was performed before a control period of 28 d, as well as before and after 28 d of RIF. Whole-body dual-energy x-ray absorptiometry, magnetic resonance imaging of the abdomen, fitness test, oral glucose tolerance test, and cognitive function tests were performed. As secondary outcome, the participants' physical activity and 72-h glycemic responses were monitored 6 d within each of the periods. Dietary intake, appetite, and mood questionnaires also were assessed., Results: Comparing Δ differences from testing days; body mass index changes from the control period (Δ mean: 0.2 kg/m 2 , 95% confidence interval [CI], -2 to 0.5) and the RIF period (Δ mean: -0.3 kg/m 2 , 95% CI, -0.6 to -0.1) were significantly different (P < 0.05). Secondary outcomes within the RIF period showed an increased area under curve (AUC) for hunger accompanied by a reduced AUC for satiety (both, P < 0.05), less mean steps per day (P < 0.05), and less positive feelings in the afternoon (P < 0.01) compared with the control period. No changes were observed in any of the other evaluated parameters., Conclusions: Free-living participants were able to comply with 14 h of daily daytime abstinence from food and drinking for 28 d with only a minor effect on body mass index and without any effects on body composition, glucose metabolism, and cognitive function., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Physical activity and alternate-day fasting/caloric restriction may both ameliorate aspects of the metabolic syndrome, such as insulin resistance, visceral fat mass accumulation, and cognitive impairment by overlapping mechanisms. The purpose of this study was to test the hypothesis that alternate-day caloric restriction (ADCR) with overall energy balance would reduce insulin resistance and accumulation of visceral fat, in addition to improving cognitive functions, after 8 consecutive days in bed. Healthy, lean men (n = 20) were randomized to 1) 8 days of bed rest with three daily isoenergetic meals (control group, n = 10); and 2) 8 days of bed rest with 25% of total energy requirements every other day and 175% of total energy requirements every other day (ADCR group). Oral glucose tolerance testing, dual-energy X-ray absorptiometry (DXA) scans, magnetic resonance imaging of the abdomen and brain, V̇o 2max , and tests for cognitive function were performed before and after bed rest. In addition, daily fasting blood samples and 24-h glucose profiles by continuous glucose monitoring system were assessed during the 8 days of bed rest period. Bed rest induced insulin resistance, visceral fat accumulation, and worsening of mood. No positive effects emerged from ADCR on these negative health outcomes. Compared with the control group, ADCR was associated with improved and steadier glycemic control on fasting days and higher glycemic fluctuation and indexes of insulin resistance on overeating days. In contrast to our hypothesis, the metabolic impairment induced by 8 days of bed rest was not counteracted by ADCR with overall energy balance., New & Noteworthy: Alternate-day caloric restriction without overall energy reduction does not ameliorate the metabolic impairment induced in lean men by 8 days of bed rest., (Copyright © 2017 the American Physiological Society.)

Bed rest and physical inactivity are the consequences of hospital admission for many patients. Physical inactivity induces changes in glucose metabolism, but its effect on the incretin effect, which is reduced in, e.g., Type 2 diabetes, is unknown. To investigate how 8 days of strict bed rest affects the incretin effect, 10 healthy nonobese male volunteers underwent 8 days of strict bed rest. Before and after the intervention, all volunteers underwent an oral glucose tolerance test (OGTT) followed by an intravenous glucose infusion (IVGI) on the following day to mimic the blood glucose profile from the OGTT. Blood glucose, serum insulin, serum C-peptide, plasma incretin hormones [glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic peptide (GIP)], and serum glucagon were measured serially during both the OGTT and the IVGI. The incretin effect is calculated as the relative difference between the area under the curve for the insulin response during the OGTT and that of the corresponding IVGI, respectively. Concentrations of glucose, insulin, C-peptide, and GIP measured during the OGTT were higher after the bed rest intervention (all P < 0.05), whereas there was no difference in the levels of GLP-1 and Glucagon. Bed rest led to a mean loss of 2.4 kg of fat-free mass, and induced insulin resistance evaluated by the Matsuda index, but did not affect the incretin effect (P = 0.6). In conclusion, 8 days of bed rest induces insulin resistance, but we did not see evidence of an associated change in the incretin effect., (Copyright © 2016 the American Physiological Society.)

Background: Obesity amongst children is a growing problem worldwide. In contrast to adults, little is known on the effects of controlled weight loss on components of the metabolic syndrome in children. The primary aim of the study was to evaluate the effects of a 20-week exercise and diet guidance intervention on body mass index (BMI) in a group of overweight children. Our hypothesis was an observed reduction in BMI and secondarily in body fat content, insulin insensitivity, and other components of the metabolic syndrome in the intervention group., Methods: School children from Copenhagen were randomly allocated to an intervention group (n = 19) or a control group (n = 19). Anthropometric assessment, whole body dual-energy X-ray absorptiometry scan, two hours oral glucose tolerance test, steps measured by pedometer, and fitness tests were measured at baseline and at 20 weeks., Results: Thirty-seven children (30 girls) participated at baseline, aged 8.7 ± 0.9 years with a BMI of 21.8 ± 3.7 kg/m2 (mean ± SD), and 36 children completed the study. The intervention group decreased their BMI (the intervention effect is the difference in change between the groups adjusted for the respective baseline values (DELTA) = -2.0 kg/m2, 95% CI: -2.5; -1.5, P <0.001), total body mass (DELTA = -4.0 kg, 95% CI: -4.9; -3.0, P <0.001), and fat mass (DELTA = -3.3 kg, 95% CI: -4.2; -2.7, P <0.001) compared to the control group after the intervention. The intervention group displayed decreased waist, hip and waist-to-height ratio (WHtR) (all three variables; P <0.001), area under curve for plasma insulin (P <0.05), and increased mean and minimum steps/day (P <0.05 and P <0.01, respectively)., Conclusions: The multicomponent intervention had significant favorable effects on BMI, weight, WHtR, mean and minimum steps/day, and fat mass. In addition, similar beneficial metabolic effects were found in the children as shown in adults, e.g. increase in peripheral insulin sensitivity., Trial Registration: Clinicaltrials.gov Identifier number NCT01660789.

Elevated interleukin-6 (IL-6) levels are associated with type 2 diabetes, but its role in glucose metabolism is controversial. We investigated the effect of IL-6 on insulin-stimulated glucose metabolism in type 2 diabetes patients and hypothesized that an acute, moderate IL-6 elevation would increase the insulin-mediated glucose uptake. Men with type 2 diabetes not treated with insulin [n = 9, age 54.9 ± 9.7 (mean ± SD) yr, body mass index 34.8 ± 6.1 kg/m(2), HbA1c 7.0 ± 1.0%] received continuous intravenous infusion with either recombinant human IL-6 (rhIL-6) or placebo. After 1 h with placebo or rhIL-6, a 3-h hyperinsulinemic-isoglycemic clamp was initiated. Whole body glucose metabolism was measured using stable isotope-labeled tracers. Signal transducer and activator of transcription 3 (STAT3) phosphorylation and suppressor of cytokine signaling 3 (SOCS3) expression were measured in muscle biopsies. Whole body energy expenditure was measured using indirect calorimetry. In response to the infusion of rhIL-6, circulating levels of IL-6 (P < 0.001), neutrophils (P < 0.001), and cortisol (P < 0.001) increased while lymphocytes decreased (P < 0.01). However, IL-6 infusion did not change glucose infusion rate, rate of appearance, or rate of disappearance during the clamp. While IL-6 enhanced phosphorylation of STAT3 in skeletal muscle (P = 0.041), the expression of SOCS3 remained unchanged. Whole body oxygen uptake (P < 0.01) and expired carbon dioxide (P < 0.01) increased during rhIL-6 infusion. In summary, although IL-6 induced local and systemic responses, the insulin-stimulated glucose uptake was not affected. While different contributing factors may be involved, our results are in contrast to our hypothesis and previous findings in young, healthy men.

Recent years have seen an increase in the frequency of extreme rainfall and subsequent flooding across the world. Climate change models predict that such flooding will become more common, triggering sewer overflows, potentially with increased risks to human health. In August 2010, a triathlon sports competition was held in Copenhagen, Denmark, shortly after an extreme rainfall. The authors took advantage of this event to investigate disease risks in two comparable cohorts of physically fit, long distance swimmers competing in the sea next to a large urban area. An established model of bacterial concentration in the water was used to examine the level of pollution in a spatio-temporal manner. Symptoms and exposures among athletes were examined with a questionnaire using a retrospective cohort design and the questionnaire investigation was repeated after a triathlon competition held in non-polluted seawater in 2011. Diagnostic information was collected from microbiological laboratories. The results showed that the 3.8 kilometer open water swimming competition coincided with the peak of post-flooding bacterial contamination in 2010, with average concentrations of 1.5x10(4) E. coli per 100 ml water. The attack rate of disease among 838 swimmers in 2010 was 42% compared to 8% among 931 swimmers in the 2011 competition (relative risk (RR) 5.0; 95% CI: 4.0-6.39). In 2010, illness was associated with having unintentionally swallowed contaminated water (RR 2.5; 95% CI: 1.8-3.4); and the risk increased with the number of mouthfuls of water swallowed. Confirmed aetiologies of infection included Campylobacter, Giardia lamblia and diarrhoeagenic E. coli. The study demonstrated a considerable risk of illness from water intake when swimming in contaminated seawater in 2010, and a small but measureable risk from non-polluted water in 2011. This suggests a significant risk of disease in people ingesting small amounts of flood water following extreme rainfall in urban areas.

The purpose of this study was to examine if fat oxidation was affected by menopausal status and to investigate if this could be related to the oxidative capacity of skeletal muscle. Forty-one healthy women were enrolled in this cross-sectional study [premenopausal (n = 19), perimenopausal (n = 8), and postmenopausal (n = 14)]. Estimated insulin sensitivity was obtained from an oral glucose tolerance test. Body composition was measured by dual-energy X-ray absorptiometry and magnetic resonance imaging. Fat oxidation and energy expenditure were measured during an acute exercise bout of 45 min of ergometer biking at 50% of maximal oxygen consumption (Vo2 max). Muscle biopsies from the vastus lateralis of the quadriceps muscle were obtained before and immediately after the exercise bout. Postmenopausal women had 33% [confidence interval (CI) 95%: 12-55] lower whole body fat oxidation (P = 0.005) and 19% (CI 95%: 9-22) lower energy expenditure (P = 0.02) during exercise, as well as 4.28 kg lower lean body mass (LBM) than premenopausal women. Correction for LBM reduced differences in fat oxidation to 23% (P = 0.05), whereas differences in energy expenditure disappeared (P = 0.22). No differences between groups were found in mRNA [carnitine palmitoyltransferase I, β-hydroxyacyl-CoA dehydrogenase (β-HAD), peroxisome proliferator-activated receptor-α, citrate synthase (CS), pyruvate dehydrogenase kinase 4, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α)], protein [phosphorylated AMP-activated protein kinase (AMPK), vascular endothelial growth factor, pyruvate dehydrogenase-1Eα, cytochrome oxidase I], or enzyme activities (β-HAD, CS) in resting skeletal muscle, except for an increased protein level of cytochrome c in the post- and perimenopausal women relative to premenopausal women. Postmenopausal women demonstrated a trend to a blunted exercise-induced increase in phosphorylation of AMPK compared with premenopausal women (P = 0.06). We conclude that reduced whole body fat oxidation after menopause is associated with reduced LBM.