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Plasma metabolites and lipids predict insulin sensitivity improvement in obese, nondiabetic individuals after a 2-phase dietary intervention.
Meyer, A, Montastier, E, Hager, J, Saris, WHM, Astrup, A, Viguerie, N, Valsesia, A
The American journal of clinical nutrition. 2018;(1):13-23
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Abstract
BACKGROUND Weight loss in obese individuals aims to reduce the risk of type 2 diabetes by improving glycemic control. Yet, significant intersubject variability is observed and the outcomes remain poorly predictable. OBJECTIVE The aim of the study was to predict whether an individual will show improvements in insulin sensitivity above or below the median population change at 6 mo after a low-calorie-diet (LCD) intervention. DESIGN With the use of plasma lipidomics and metabolomics for 433 subjects from the Diet, Obesity, and Genes (DiOGenes) Study, we attempted to predict good or poor Matsuda index improvements 6 mo after an 8-wk LCD intervention (800 kcal/d). Three independent analysis groups were defined: "training" (n = 119) for model construction, "testing" (n = 162) for model comparison, and "validation" (n = 152) to validate the final model. RESULTS Initial modeling with baseline clinical variables (body mass index, Matsuda index, total lipid concentrations, sex, age) showed limited performance [area under the curve (AUC) on the "testing dataset" = 0.69; 95% CI: 0.61, 0.77]. Significantly better performance was achieved with an omics model based on 27 variables (AUC = 0.77; 95% CI: 0.70, 0.85; P = 0.0297). This model could be greatly simplified while keeping the same performance. The simplified model relied on baseline Matsuda index, proline, and phosphatidylcholine 0-34:1. It successfully replicated on the validation set (AUC = 0.75; 95% CI: 0.67, 0.83) with the following characteristics: specificity = 0.73, sensitivity = 0.68, negative predictive value = 0.60, and positive predictive value = 0.80. Marginally lower performance was obtained when replacing the Matsuda index with homeostasis model assessment of insulin resistance (AUC = 0.72; 95% CI: 0.64, 0.80; P = 0.08). CONCLUSIONS Our study proposes a model to predict insulin sensitivity improvements, 6 mo after LCD completion in a large population of overweight or obese nondiabetic subjects. It relies on baseline information from 3 variables, accessible from blood samples. This model may help clinicians assessing the large variability in dietary interventions and predict outcomes before an intervention. This trial was registered at www.clinicaltrials.gov as NCT00390637.
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A multicentre weight loss study using a low-calorie diet over 8 weeks: regional differences in efficacy across eight European cities.
Papadaki, A, Linardakis, M, Plada, M, Larsen, TM, van Baak, MA, Lindroos, AK, Pfeiffer, AF, Martinez, JA, Handjieva-Darlenska, T, Kunešová, M, et al
Swiss medical weekly. 2013;:w13721
Abstract
PRINCIPLES The efficacy of low-calorie diets (LCDs) has not been investigated in large-scale studies or among people from different regions, who are perhaps unaccustomed to such methods of losing weight. The aim of the present study was to investigate changes in obesity measures among overweight/obese adults from eight European cities (from Northern, Central and Southern Europe) during the 8-week LCD phase of the DiOGenes study (2006-2007), a family-based, randomised, controlled dietary intervention. METHODS 938 overweight/obese adults completed baseline examinations and underwent an 8-week LCD, providing 3.3-4.2 MJ/day to replace all meals. Anthropometric measurements and body composition were assessed at baseline and post-LCD. RESULTS 773 (82.4%) adults (mean age, 43.1 y) completed the LCD successfully. The highest drop-out rate was observed in Southern (24.9%) and the lowest in Northern (13.3%) European cities. Overall, the LCD induced favourable changes in all outcomes, including an approximate 11.0% reduction in body weight and body fat percentage. Changes in outcomes differed significantly between regions, with North- and Central-European cities generally achieving higher percentage reductions in most anthropometric measurements assessed. Nonetheless, participants in Southern Europe reduced their body fat percentage significantly more than participants in Northern Europe (-11.8 vs. -9.5%, P = 0.017). CONCLUSIONS The LCD significantly improved anthropometric and body composition measurements in all cities participating in DiOGenes.
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The effect of tesofensine on appetite sensations.
Gilbert, JA, Gasteyger, C, Raben, A, Meier, DH, Astrup, A, Sjödin, A
Obesity (Silver Spring, Md.). 2012;(3):553-61
Abstract
Tesofensine (TE), an inhibitor of monoamine presynaptic reuptake, has produced twice the weight loss seen with currently marketed drugs. However, its long term effect on appetite in humans has not been studied. A multicentre phase II trial was divided into two parts (24 weeks each). Part 1 had a randomized, double-blind, placebo-controlled design and Part 2, an open-labeled, single-group, uncontrolled design. A drug-free period (12 ± 3 weeks) separated them. In Part 1, participants (n = 158) were assigned to 0.25, 0.5 or 1.0 mg TE, or placebo. Completers of Part 1 were invited to participate in Part 2 (n = 113), during which they all received 0.5 or 1.0 mg TE. Appetite sensations and a composite satiety score (CSS = satiety + fullness + (100 - hunger) + (100 - prospective food consumption) were assessed. In Part 1 TE induced a dose-dependent increase in CSS at week 12 that correlated with weight loss during the 24 weeks (r = 0.36, P < 0.0001). However, CSS diminished over time as weight loss progressed (e.g., for 1.0 mg; 52 ± 17 mm; 64 ± 13 mm; 55 ± 13 mm at baseline, week 12 and week 24, respectively). After drug withdrawal CSS returned to baseline values (50 ± 17 mm, in the whole sample.), despite the participants' reduced-weight state (-7.2 ± 6.7 kg, P < 0.0001). The reintroduction of TE in Part 2 increased CSS again (56 ± 17 mm at week 60), regardless of initial treatment/weight loss. We postulate that enhanced satiety is involved in early weight loss. Whether the attenuated effect on appetite seen after 24 weeks is due to a counteracting effect in the weight reduced state or whether the appetite suppressing effect of TE per se diminishes over time is, however, still unclear.
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Randomized controlled trials of the D1/D5 antagonist ecopipam for weight loss in obese subjects.
Astrup, A, Greenway, FL, Ling, W, Pedicone, L, Lachowicz, J, Strader, CD, Kwan, R, ,
Obesity (Silver Spring, Md.). 2007;(7):1717-31
Abstract
OBJECTIVE To evaluate the efficacy and safety of the selective dopamine D1/D5 antagonist ecopipam for the treatment of obesity. RESEARCH METHODS AND PROCEDURES Four randomized, double-blind, multicenter trials compared ecopipam (n=1667) and placebo (n=1118) in obese subjects including type 2 diabetic subjects. Subjects received oral ecopipam 10, 30, or 100 mg daily for 12 weeks (Phase 2) or 50 or 100 mg daily for 52 weeks (Phase 3) combined with a weight loss program. Primary efficacy variables were the proportion of subjects with>or=5% weight loss from baseline at 12 weeks (Phase 2) or the distribution of percentage weight loss from baseline at 52 weeks (Phase 3). RESULTS In the Phase 2 study, 26% of subjects administered ecopipam 100 mg vs. 6% of placebo subjects achieved>or=5% weight loss after 12 weeks (p<0.01). In the Phase 3 studies, ecopipam 100 mg produced a 3.1% to 4.3% greater weight loss than placebo at 52 weeks. More subjects administered ecopipam vs. placebo achieved a 5% to 10% or >10% weight loss in two non-diabetic phase 3 trials. Ecopipam-treated subjects also maintained more weight loss compared with placebo subjects at 52 weeks. Phase 3 studies were discontinued because of unexpected psychiatric adverse events (ecopipam 31% vs. placebo 15%), including depression, anxiety, and suicidal ideation. DISCUSSION Ecopipam was effective for achieving and maintaining weight loss in obese subjects, including type 2 diabetic subjects; however, the adverse effects on mood observed in the Phase 3 studies exclude its projected use in weight management.
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Micronutrient intake in overweight subjects is not deficient on an ad libitum fat-reduced, high-simple carbohydrate diet.
Vasilaras, TH, Astrup, A, Raben, A
European journal of clinical nutrition. 2004;(2):326-36
Abstract
OBJECTIVE To investigate whether subjects consuming a fat-reduced, high-simple carbohydrate diet (SCHO) are at greater risk of micronutrient inadequacy than subjects consuming a fat-reduced, high-complex carbohydrate (CCHO) or a normal-fat diet (control, CD). DESIGN A 6-month randomised controlled dietary intervention trial with a parallel design. METHODS In total, 46 overweight (BMI: 24.4-36.3 kg/m(2)) subjects (19 males, 27 females) aged 21-54 y consumed one of three ad libitum diets: SCHO, CCHO, or CD. Nutrient intake was assessed by a 7-day weighed food record. RESULTS Self-reported energy intake did not differ between diet groups. The lowest intake of vitamin B(12) was found in the SCHO group vs CCHO (P=0.025) and vs. CD (P=0.012). In men, zinc intake was lower on the SCHO diet compared to the CD diet (P=0.018). The recommendations for zinc and vitamin B(12) were, however, met by all the diet groups. No other diet differences were observed. Intake of several micronutrients were insufficient in all three diet groups, although in most cases comparable to average Danish intakes. CONCLUSION Zinc intake in men and vitamin B(12) intake in the combined gender groups were lower on a fat-reduced, simple carbohydrate-rich diet compared to a habitual, normal-fat diet, but not below recommended levels.
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Effect of protein intake on bone mineralization during weight loss: a 6-month trial.
Skov, AR, Haulrik, N, Toubro, S, Mølgaard, C, Astrup, A
Obesity research. 2002;(6):432-8
Abstract
OBJECTIVE The long-term effect of dietary protein on bone mineralization is not well understood. RESEARCH METHODS AND PROCEDURES Sixty-five overweight (body mass index, 25 to 29.9 kg/m(2)) or obese (> or =30 kg/m(2)) subjects were enrolled in a randomized, placebo-controlled, 6-month dietary-intervention study comparing two controlled ad libitum diets with matched fat contents: high protein (HP) or low protein (LP). Body composition was assessed by DXA. RESULTS In the HP group, dietary-protein intake increased from 91.4 g/d to a 6-month intervention mean of 107.8 g/d (p < 0.05) and decreased in the LP group from 91.1 g/d to 70.4 g/d (p < 0.05). Total weight loss after 6 months was 8.9 kg in the HP group, 5.1 kg in the LP group, and none in the control group. After 6 months, bone mineral content (BMC) had declined by 111 +/- 13 g (4%) in the HP group and by 85 +/- 13 g (3%) in the LP group (not significant). Loss of BMC was more positively correlated with loss of body fat mass (r = 0.83; p < 0.0001) than with loss of body weight. Six-month BMC loss, adjusted for differences in fat loss, was greater in the LP group than in the HP group [difference in LP vs. HP, 44.8 g (95% confidence interval, 16 to 73.8 g); p < 0.05]. Independent of change in body weight and composition during the intervention, highprotein intake was associated with a diminished loss of BMC (p < 0.01). DISCUSSION Body-fat loss was the major determinant of loss of BMC, and we found no adverse effects of 6 months of high-protein intake on BMC.
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Effect of a 28-d treatment with L-796568, a novel beta(3)-adrenergic receptor agonist, on energy expenditure and body composition in obese men.
Larsen, TM, Toubro, S, van Baak, MA, Gottesdiener, KM, Larson, P, Saris, WH, Astrup, A
The American journal of clinical nutrition. 2002;(4):780-8
Abstract
BACKGROUND Stimulation of energy expenditure (EE) with selective thermogenic beta-adrenergic agonists may be a promising approach for treating obesity. OBJECTIVE We analyzed the effects of the highly selective human beta(3)-adrenergic agonist L-796568 on 24-h EE, substrate oxidation, and body composition in obese, weight-stable men. DESIGN In this 2-center, double-blind, randomized, parallel-group study, we measured 24-h EE before and after 28 d of treatment with L-796568 (375 mg/d) or placebo during weight maintenance (ie, without dietary intervention) in nondiabetic, nonsmoking men aged 25-49 y with body mass index (in kg/m(2)) of 28-35 (n = 10 subjects per treatment group). RESULTS The mean change in 24-h EE from before to after treatment did not differ significantly between groups (92 +/- 586 and 86 +/- 512 kJ/24 h for the L-796568 and placebo groups, respectively). The change in 24-h nonprotein respiratory quotient from before to after treatment did not differ significantly between groups (0.009 +/- 0.021 and 0.009 +/- 0.029, respectively). No changes in glucose tolerance were observed, but triacylglycerol concentrations decreased significantly with L-796568 treatment compared with placebo (-0.76 +/- 0.76 and 0.42 +/- 0.31 mmol/L, respectively; P < 0.002). Overall, treatment-related changes in body composition were not observed, but higher plasma L-796568 concentrations in the L-796568 group were associated with greater decreases in fat mass (r = -0.69, P < 0.03). CONCLUSIONS Treatment with L-796568 for 28 d had no major lipolytic or thermogenic effect but it lowered triacylglycerol concentrations. This lack of chronic effect on energy balance is likely explained by insufficient recruitment of beta(3)-responsive tissues in humans, down-regulation of the beta(3)-adrenergic receptor-mediated effects with chronic dosing, or both.
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Effect of protein and methionine intakes on plasma homocysteine concentrations: a 6-mo randomized controlled trial in overweight subjects.
Haulrik, N, Toubro, S, Dyerberg, J, Stender, S, Skov, AR, Astrup, A
The American journal of clinical nutrition. 2002;(6):1202-6
Abstract
BACKGROUND A high plasma homocysteine concentration is an independent risk factor for cardiovascular disease. Homocysteine concentrations are thought to be raised by high protein and methionine intakes. OBJECTIVE Our goal was to investigate the effects of high and low protein and methionine intakes on homocysteine in overweight subjects. DESIGN Sixty-five overweight subjects were randomly assigned to a 6-mo intervention with a low-protein, low-methionine diet (LP: 12% of total energy, 1.4 g methionine/d; n = 25); a high-protein, high-methionine diet (HP: 22% of total energy, 2.7 g methionine/d; n = 25), both of which had similar fat contents (30% of total energy); or a control diet with an intermediate protein content (n = 15). All food was self-selected at a shop at the department. Protein intake was increased in the HP group mainly through lean meat and low-fat dairy products. Dietary compliance was evaluated by urinary nitrogen excretion. RESULTS Homocysteine concentrations did not change significantly in the LP or control groups but were 25% lower in the HP group (NS). Homocysteine concentrations after the 3-mo intervention were inversely associated with vitamin B-12 intake and with weight change (by multivariate analysis performed for all subjects), but not with methionine or protein intake. Sixty-nine percent of the variation could be explained by baseline homocysteine (P < 0.001), 2% by vitamin B-12 (P = 0.02), and another 2% by weight change (P = 0.06). The plasma homocysteine concentration after 6 mo was associated only with baseline homocysteine (P < 0.001). CONCLUSION A high-protein, high-methionine diet does not raise homocysteine concentrations compared with a low-protein, low-methionine diet in overweight subjects.
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Predictors of weight loss and maintenance during 2 years of treatment by sibutramine in obesity. Results from the European multi-centre STORM trial. Sibutramine Trial of Obesity Reduction and Maintenance.
Hansen, D, Astrup, A, Toubro, S, Finer, N, Kopelman, P, Hilsted, J, Rössner, S, Saris, W, Van Gaal, L, James, W, et al
International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity. 2001;(4):496-501
Abstract
BACKGROUND In this report we assess pre-treatment determinants of weight loss and maintenance outcome in The Sibutramine Trial of Obesity Reduction and Maintenance (STORM), a 2 y randomized, double-blind, placebo-controlled, European multicenter study examining the effect of sibutramine (Sib) on inducing and maintaining weight loss in obese subjects. MATERIAL A total of 605 obese patients (BMI: 30-45 kg/m2) of both gender were included from eight European centers and treated for 24 months. The patients were treated for the initial 6 months by Sib (10 mg/day) and a low-fat low-energy, individualized diet (600 kcal/day deficit). The 467 patients who achieved >5% weight loss after 6 months were randomized 3∶1 to Sib (10 mg/day) (Sib/Sib) and placebo (Sib/Pla) for weight maintenance over a further 18 months. MAIN OUTCOME AND ANALYSES Pre-treatment individual characteristics were assessed as predictors of 6 months weight loss (kg) and 24 months weight maintenance using simple and multivariate correlation and regression analyses. RESULTS In univariate analyses, the 6 month weight loss (n=505) was positively associated with pre-treatment body weight (r=0.27), height (r=0.18), fat-free mass (r=0.21) (all P<0.001), fat mass (r=0.13, P<0.03), and resting metabolic rate (r=0.13, P<0.003). However, no relation was found with age, gender, smoking status, age at onset of obesity, or number of previous slimming attempts. The same predictors were found for weight change to endpoint in the Sib/Sib group (n=350), while no predictors were identified in the Sib/Pla (n=114). In the multivariate regression analysis only pre-treatment body weight predicted weight loss at 6 months (P<0.001). Weight change (kg) to 24 month was predicted by: 4.34+0.07*body weight (kg)-4*treatment (Sib=1, Pla=0)-0.06*age (y), (r2=8%, P<0.001). CONCLUSION Only pre-treatment body weight seems to be an important independent predictor of 6 months weight loss and 24 month weight maintenance in this study on diet and Sib. As only 8% of the variation in 24 months weight change could be explained by the predictors, the clinical value of this information is limited.
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Effect of 8 week intake of probiotic milk products on risk factors for cardiovascular diseases.
Agerholm-Larsen, L, Raben, A, Haulrik, N, Hansen, AS, Manders, M, Astrup, A
European journal of clinical nutrition. 2000;(4):288-97
Abstract
OBJECTIVE To investigate the effect of a probiotic milk product containing the culture CAUSIDO(R) and of two alternative products on risk factors for cardiovascular disease in overweight and obese subjects. DESIGN An 8 week randomized, double-blind, placebo- and compliance-controlled, parallel study. SUBJECTS Seventy healthy, weight-stable, overweight and obese (25.0 INTERVENTION Four groups consumed 450 ml fermented milk products (yoghurt) daily. Group 1: a yoghurt fermented with two strains of Streptococcus thermophilus and two strains of Lactobacillus acidophilus (StLa). Group 2: a placebo yoghurt fermented with delta-acid-lactone (PY). Group 3: a yoghurt fermented with two strains of Streptococcus thermophilus and one strain of Lactobacillus rhamnosus (StLr). Group 4: a yoghurt fermented with one strain of Enterococcus faecium and two strains of Streptococcus thermophilus (CAUSIDO(R) culture), GAIO(R) (G). The dietary composition of the yoghurt was otherwise similar. The fifth group was given two placebo pills (PP) daily. RESULTS When comparing all five treatment groups, unadjusted for changes in body weight, no statistical effects were observed in week 8 in the G-group on low density lipoproteins (LDL)-cholesterol (P=0.29). After adjustment for small changes in body weight, LDL-cholesterol decreased by 8.4% (0.26+/-0.10 mmol/l; P<0.05) and fibrinogen increased (0.74+/-0.32 mmol/l; P<0.05) after 8 weeks in the G-group. This was significantly different from the group consuming chemically fermented yoghurt and the group consuming placebo pills (P<0.05). After 8 weeks, systolic blood pressure was significantly more reduced in the StLa and G-group compared to StLr. No other differences were found. CONCLUSION The CAUSIDO(R) culture reduced LDL-cholesterol and increased fibrinogen in the overweight subjects at a 450 ml consumption daily for 8 weeks. The effect on LDL-cholesterol confirms previous studies. An immunostimulation by one of the strains in the product might explain the effect on fibrinogen in the G-group. SPONSORSHIP MD Foods A/S, Denmark.