Healthy Weight Loss Maintenance with Exercise, Liraglutide, or Both Combined.

BACKGROUND: Weight regain after weight loss is a major problem in the treatment of persons with obesity. METHODS: In a randomized, head-to-head, placebo-controlled trial, we enrolled adults with obesity (body-mass index [the weight in kilograms divided by the square of the height in meters], 32 to 43) who did not have diabetes. After an 8-week low-calorie diet, participants were randomly assigned for 1 year to one of four strategies: a moderate-to-vigorous-intensity exercise program plus placebo (exercise group); treatment with liraglutide (3.0 mg per day) plus usual activity (liraglutide group); exercise program plus liraglutide therapy (combination group); or placebo plus usual activity (placebo group). End points with prespecified hypotheses were the change in body weight (primary end point) and the change in body-fat percentage (secondary end point) from randomization to the end of the treatment period in the intention-to-treat population. Prespecified metabolic health-related end points and safety were also assessed. RESULTS: After the 8-week low-calorie diet, 195 participants had a mean decrease in body weight of 13.1 kg. At 1 year, all the active-treatment strategies led to greater weight loss than placebo: difference in the exercise group, -4.1 kg (95% confidence interval [CI], -7.8 to -0.4; P = 0.03); in the liraglutide group, -6.8 kg (95% CI, -10.4 to -3.1; P<0.001); and in the combination group, -9.5 kg (95% CI, -13.1 to -5.9; P<0.001). The combination strategy led to greater weight loss than exercise (difference, -5.4 kg; 95% CI, -9.0 to -1.7; P = 0.004) but not liraglutide (-2.7 kg; 95% CI, -6.3 to 0.8; P = 0.13). The combination strategy decreased body-fat percentage by 3.9 percentage points, which was approximately twice the decrease in the exercise group (-1.7 percentage points; 95% CI, -3.2 to -0.2; P = 0.02) and the liraglutide group (-1.9 percentage points; 95% CI, -3.3 to -0.5; P = 0.009). Only the combination strategy was associated with improvements in the glycated hemoglobin level, insulin sensitivity, and cardiorespiratory fitness. Increased heart rate and cholelithiasis were observed more often in the liraglutide group than in the combination group. CONCLUSIONS: A strategy combining exercise and liraglutide therapy improved healthy weight loss maintenance more than either treatment alone. (Funded by the Novo Nordisk Foundation and others; EudraCT number, 2015-005585-32; ClinicalTrials.gov number, NCT04122716.).

Combination of exercise and GLP-1 receptor agonist treatment reduces severity of metabolic syndrome, abdominal obesity, and inflammation: a randomized controlled trial.

BACKGROUND: Identifying and reducing cardiometabolic risks driven by obesity remains a healthcare challenge. The metabolic syndrome is associated with abdominal obesity and inflammation and is predictive of long-term risk of developing type 2 diabetes and cardiovascular disease in otherwise healthy individuals living with obesity. Therefore, we investigated the effects of adherent exercise, a glucagon-like peptide 1 receptor agonist (GLP-1 RA), or the combination on severity of metabolic syndrome, abdominal obesity, and inflammation following weight loss. METHODS: This was a randomized, double-blinded, placebo-controlled trial. During an 8-week low-calorie diet (800 kcal/day), 195 adults with obesity and without diabetes lost 12% in body weight. Participants were then evenly randomized to four arms of one-year treatment with: placebo, moderate-to-vigorous exercise (minimum of 150 min/week of moderate-intensity or 75 min/week of vigorous-intensity aerobic physical activity or an equivalent combination of both), the GLP-1 RA liraglutide 3.0 mg/day, or a combination (exercise + liraglutide). A total of 166 participants completed the trial. We assessed the prespecified secondary outcome metabolic syndrome severity z-score (MetS-Z), abdominal obesity (estimated as android fat via dual-energy X-ray absorptiometry), and inflammation marker high-sensitivity C-reactive protein (hsCRP). Statistical analysis was performed on 130 participants adherent to the study interventions (per-protocol population) using a mixed linear model. RESULTS: The diet-induced weight loss decreased the severity of MetS-Z from 0.57 to 0.06, which was maintained in the placebo and exercise groups after one year. MetS-Z was further decreased by liraglutide (- 0.37, 95% CI - 0.58 to - 0.16, P < 0.001) and the combination treatment (- 0.48, 95% CI - 0.70 to - 0.25, P < 0.001) compared to placebo. Abdominal fat percentage decreased by 2.6, 2.8, and 6.1 percentage points in the exercise, liraglutide, and combination groups compared to placebo, respectively, and hsCRP decreased only in the combination group compared with placebo (by 43%, P = 0.03). CONCLUSION: The combination of adherent exercise and liraglutide treatment reduced metabolic syndrome severity, abdominal obesity, and inflammation and may therefore reduce cardiometabolic risk more than the individual treatments. Trial registration EudraCT number: 2015-005585-32, ClinicalTrials.gov: NCT04122716.

No effect of multi-strain probiotic supplementation on metabolic and inflammatory markers and newborn body composition in pregnant women with obesity: Results from a randomized, double-blind placebo-controlled study.

BACKGROUND AND AIMS: Modulation of the gut microbiome composition with probiotics may have beneficial metabolic effects in pregnant women with obesity. The aim was to investigate the effect of probiotic supplementation during pregnancy on metabolic and inflammatory markers and the body composition of the offspring. METHODS AND RESULTS: A randomized double-blind trial in 50 pregnant women (pre-pregnancy BMI ≥30 and < 35 kg/m2) comparing multi-strain probiotics (Vivomixx®; 450 billion CFU/d) versus placebo from 14 to 20 weeks of gestation until delivery was carried out. Participants were followed with two predelivery visits at gestational week 27-30 and 36-37 and with one postdelivery visit. All visits included fasting blood samples (C-reactive protein (CRP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), insulin, C-peptide, glucose, glucagon, and glucagon-like peptide-1 (GLP-1)). At delivery, umbilical cord blood samples were collected (GLP-1 and glucagon). At the postdelivery visit, a dual-energy X-ray absorptiometry (DXA) scan of the newborn was performed. Forty-nine of 50 participants completed the study until delivery, and 36 mother-offspring dyads underwent postdelivery examinations including a DXA scan. There were no significant differences in changes in measured biomarkers between the probiotic versus the placebo group. No differences were found in newborn body composition or GLP-1 and glucagon. GLP-1 measured in umbilical blood samples was positively correlated to fat percent in offspring from the probiotic group. CONCLUSION: In this study of pregnant women with obesity and their newborns, there was no effect of probiotic supplementation in mothers or babies on metabolic or inflammatory biomarkers or on body composition of offspring. This study was registered at clinicaltrials.gov as NCT02508844.

Liraglutide changes body composition and lowers added sugar intake in overweight persons with insulin pump-treated type 1 diabetes.

AIMS: To present secondary outcome analyses of liraglutide treatment in overweight adults with insulin pump-treated type 1 diabetes (T1D), focusing on changes in body composition and dimensions, and to evaluate changes in food intake to identify potential dietary drivers of liraglutide-associated weight loss. MATERIALS AND METHODS: A 26-week randomized placebo-controlled study was conducted to investigate the efficacy and safety of liraglutide 1.8 mg daily in 44 overweight adults with insulin pump-treated T1D and glucose levels above target, and demonstrated significant glycated haemoglobin (HbA1c)- and body weight-reducing effects. For secondary outcome analysis, dual X-ray absorptiometry scans were completed at Weeks 0 and 26, and questionnaire-based food frequency recordings were obtained at Weeks 0, 13 and 26 to characterize liraglutide-induced changes in body composition and food intake. RESULTS: Total fat and lean body mass decreased in liraglutide-treated participants (fat mass -4.6 kg [95% confidence interval {CI} -5.7; -3.5], P < 0.001; lean mass -2.5 kg [95% CI -3.2;-1.7], P < 0.001), but remained stable in placebo-treated participants (fat mass -0.3 kg [95% CI -1.3;0.8], P = 0.604; lean mass 0.0 kg [95% CI -0.7;0.7]; P = 0.965 [between-group P values <0.001]). Participants reduced their energy intake numerically more in the liraglutide arm (-1.1 MJ [95% CI -2.0;-0.02], P = 0.02) than in the placebo arm (-0.9 MJ [95% CI -2.0;0.1], P = 0.22), but the between-group difference was statistically insignificant (P = 0.42). However, energy derived from added sugars decreased by 27% in the liraglutide arm compared with an increase of 14% in the placebo arm (P = 0.004). CONCLUSIONS: Liraglutide lowered fat and lean body mass compared with placebo. Further, liraglutide reduced intake of added sugars. However, no significant difference in total daily energy intake was detected between liraglutide- and placebo-treated participants.

Low versus high carbohydrate diet in type 1 diabetes: A 12-week randomized open-label crossover study.

AIMS: To compare the effects of a low carbohydrate diet (LCD < 100 g carbohydrate/d) and a high carbohydrate diet (HCD > 250 g carbohydrate/d) on glycaemic control and cardiovascular risk factors in adults with type 1 diabetes. MATERIALS AND METHODS: In a randomized crossover study with two 12-week intervention arms separated by a 12-week washout, 14 participants using sensor-augmented insulin pumps were included. Individual meal plans meeting the carbohydrate criteria were made for each study participant. Actual carbohydrate intake was entered into the insulin pumps throughout the study. RESULTS: Ten participants completed the study. Daily carbohydrate intake during the two intervention periods was (mean ± standard deviation) 98 ± 11 g and 246 ± 34 g, respectively. Time spent in the range 3.9-10.0 mmol/L (primary outcome) did not differ between groups (LCD 68.6 ± 8.9% vs. HCD 65.3 ± 6.5%, P = 0.316). However, time spent <3.9 mmol/L was less (1.9 vs. 3.6%, P < 0.001) and glycaemic variability (assessed by coefficient of variation) was lower (32.7 vs. 37.5%, P = 0.013) during LCD. No events of severe hypoglycaemia were reported. Participants lost 2.0 ± 2.1 kg during LCD and gained 2.6 ± 1.8 kg during HCD (P = 0.001). No other cardiovascular risk factors, including fasting levels of lipids and inflammatory markers, were significantly affected. CONCLUSIONS: Compared with an intake of 250 g of carbohydrate per day, restriction of carbohydrate intake to 100 g per day in adults with type 1 diabetes reduced time spent in hypoglycaemia, glycaemic variability and weight with no effect on cardiovascular risk factors.

Vitamin D insufficiency, preterm delivery and preeclampsia in women with type 1 diabetes - an observational study.

INTRODUCTION: The aim of this study was to evaluate whether vitamin D insufficiency is associated with preterm delivery and preeclampsia in women with type 1 diabetes. MATERIAL AND METHODS: An observational study of 198 pregnant women with type 1 diabetes. 25-Hydroxy-Vitamin D and HbA1c were measured in blood samples in early (median 8 weeks, range 5-14) and late (34 weeks, range 32-36) pregnancy. Kidney involvement (microalbuminuria or nephropathy) at inclusion, smoking status at inclusion, preterm delivery (<37 weeks) and preeclampsia (blood pressure ≥140/90 mmHg and proteinuria) were registered. Vitamin D supplementation of 10 µg daily was routinely recommended. RESULTS: Thirty-nine (20%) of the 198 women delivered preterm and 16 (8%) developed preeclampsia. Vitamin D insufficiency (<50 nmol/L) was present in 68 women (34%) in early pregnancy and in 73 women (37%) in late pregnancy. Preterm delivery occurred more frequently in women with vitamin D insufficiency in late pregnancy (27% vs. 15%, crude odds ratio 2.1; 95% confidence interval 1.0-4.3, p = 0.04). After adjustment for preexisting kidney involvement, HbA1c in late pregnancy and smoking the association became nonsignificant (adjusted odds ratio 1.8; 95% confidence interval 0.8-3.7). Preeclampsia developed in 11% of women with vitamin D insufficiency vs. 6% of the remaining women (crude odds ratio 1.8; 95% confidence interval 0.9-4.1, p = 0.25). CONCLUSION: In women with type 1 diabetes, preterm delivery was twice as frequent in women with vitamin D insufficiency in late pregnancy in crude analysis, but in this small study, low vitamin D was not independently associated with preterm birth or preeclampsia.

Effect of propranolol on survival in patients with decompensated cirrhosis: a nationwide study based Danish patient registers.

BACKGROUND & AIMS: We assessed the impact of propranolol on death, risk of hepatorenal syndrome and peritonitis in patients with cirrhosis. METHODS: This study was a retrospective observational study and data were retrieved from Danish databases. We used our own criteria to stratify the patients into groups of patients with mildly decompensated cirrhosis or severely decompensated cirrhosis. A subgroup of patients with a history of peritonitis was also analyzed. Follow-up time was limited to 2 years from cohort entry. The reported hazard ratios (HR) with 95% confidence interval (CI) were based on a propensity score matched cohort. RESULTS: Among 3719 patients, we found 3075 patients with mildly and 644 with severely decompensated cirrhosis. Propranolol was used by 20% of the patients. Among the patients with mildly decompensated cirrhosis, propranolol use vs. non-propranolol was related with a HR of 0.7 (95% CI 0.6-0.9) and among the patients with severely decompensated cirrhosis, the HR was 0.6 (95% CI 0.4-0.9). Reduced mortality was found for doses of propranolol lower than 160 mg/day only. Among 361 patients with peritonitis, we found reduced mortality in the propranolol group with a HR of 0.5 (95% CI 0.3-0.8). The use of propranolol was associated with a HR of 0.4 (95% CI 0.2-0.9) for developing peritonitis during follow-up among patients with severely decompensated cirrhosis. CONCLUSIONS: In patients with decompensated cirrhosis, we found an association between propranolol use and reduced mortality risk for doses lower than 160 mg/day.

Glucose tolerance in obese pregnant women determines newborn fat mass.

INTRODUCTION: Offspring of obese women have both short-term and long-term increased morbidities. We investigated the relationship between maternal 2-h plasma glucose level determined by an oral glucose tolerance test, degree of obesity, gestational weight gain and total fat, abdominal fat, and fat-free masses in the offspring of obese mothers. MATERIAL AND METHODS: Obese mother-newborn dyads were recruited and 2-h plasma glucose levels were assessed during gestational weeks 27-30; neonatal body composition was measured by dual-energy X-ray absorptiometry scanning (DXA) within 48 h of birth. RESULTS: Among 264 term, healthy, and singleton infants eligible for inclusion, 248 were included. Of these, 205 (83%) obese mother-newborn dyads had a DXA scan and 2-h plasma glucose measurements. Linear regression analysis showed that birthweight z-scores correlated with 2-h plasma glucose levels (p = 0.002) after adjusting for gestational weight gain, maternal age, education, smoking, prepregnancy degree of obesity, parity, and birth length. Total (p = 0.012) and abdominal (p = 0.039) fat masses correlated with 2-h plasma glucose levels after adjusting for gestational weight gain, maternal age, education, smoking, prepregnancy degree of obesity, parity, gestational age, and newborn sex. There was no association between total (p = 0.88) and abdominal (p = 0.61) fat-free masses and 2-h plasma glucose. CONCLUSION: At 27-30 weeks of gestation, 2-h plasma glucose levels are related to total and abdominal newborn fat masses, but not to fat-free mass. Interventions targeting maternal postprandial glucose levels may induce more appropriate birthweight, thereby reducing the risk of subsequent morbidity.

Low bone turnover phenotype in Rett syndrome: results of biochemical bone marker analysis.

BACKGROUND: Patients with Rett syndrome (RTT) are at risk of having low bone mass and low-energy fractures. METHODS: We characterized bone metabolism by both bone formation and resorption markers in blood in a RTT population of 61 girls and women and 122 well-matched healthy controls. Levels of N-terminal propeptides of collagen type 1 (P1NP), C-terminal telopeptide cross links (CTX), osteocalcin (OC), and bone-specific alkaline phosphatase (B-ALP) were compared between RTT patients and controls in regression models adjusted for BMI, vitamin D status, volumetric bone mineral apparent density of the lumbar spine (vBMAD spine), and femoral neck (vBMAD neck). We examined biochemical bone marker levels overall and stratified to persons younger than age 25 y or equal to or older than age 25 y. RESULTS: The RTT patients had reduced levels of all biochemical bone markers (P < 0.05), which remained significant in persons younger than 25 y (P ≤ 0.001) regarding P1NP, CTX, and OC. Bone marker levels were not significantly associated to methyl-CpG-binding protein 2 (MECP2) mutation group, walking ability, or previous low-energy fractures. CONCLUSION: Our findings of a low bone turnover state in girls with RTT suggest critical attention to medical treatment of low bone mass in young RTT patients.

Prevalence of and Risk Factors for Low Bone Mineral Density Assessed by Quantitative Computed Tomography in People Living With HIV and Uninfected Controls.

BACKGROUND: Low bone mineral density (BMD) has been described in people living with HIV (PLWH). We examined the prevalence of low BMD measured by quantitative computed tomography (QCT), a method that allows 3-dimensional volumetric density measures at the thoracic spine, in well-treated PLWH and uninfected controls and assessed risk factors for reduced BMD. METHODS: Cross-sectional study including 718 PLWH from the Copenhagen Co-Morbidity in HIV infection (COCOMO) study and 718 uninfected controls matched on age and sex from the Copenhagen General Population Study (CGPS). Trabecular BMD was determined by QCT. RESULTS: Median BMD was 144.2 mg/cm in PLWH vs. 146.6 mg/cm in controls (P = 0.580). HIV status was not associated with BMD in univariable or multivariable linear analyses. However, a higher prevalence of very low BMD (T-score ≤ -2.5) was found in PLWH (17.2% vs. 11.0% in controls, P = 0.003). In unadjusted analysis, HIV was associated with very low BMD (odds ratio 1.68 [95% confidence interval: 1.24-2.27], P = 0.001), but this association was not significant after adjusting for age, sex, smoking, alcohol, body mass index, physical activity, and ethnicity. Previous AIDS-defining disease was associated with lower BMD, but no other associations with HIV-specific variables were identified. CONCLUSION: Using QCT, we found a higher prevalence of very low BMD in PLWH than in controls. However, HIV status was not independently associated with BMD indicating that traditional risk factors contribute to the difference in prevalence of very low BMD. Focus on improvement of lifestyle factors, especially in PLWH with previous AIDS-defining disease, may prevent very low BMD in PLWH.

Diurnal, weekly, and long-time variation in serum concentrations of YKL-40 in healthy subjects.

Serum YKL-40 is a potential biomarker of prognosis in cancer patients, but assessment of serum YKL-40 requires knowledge of its normal variation. In this study, we evaluated diurnal, weekly, and long-term variation in serum YKL-40 in healthy subjects using a commercial ELISA. The intra-assay coefficient of variation was

Urokinase plasminogen activator receptor affects bone homeostasis by regulating osteoblast and osteoclast function.

UNLABELLED: The uPAR and its ligand uPA are expressed by both osteoblasts and osteoclasts. Their function in bone remodeling is unknown. We report that uPAR-lacking mice display increased BMD, increased osteogenic potential of osteoblasts, decreased osteoclasts formation, and altered cytoskeletal reorganization in mature osteoclasts. INTRODUCTION: Urokinase receptor (uPAR) is actively involved in the regulation of important cell functions, such as proliferation, adhesion, and migration. It was previously shown that the major players in bone remodeling, osteoblasts and osteoclasts, express uPAR and produce urokinase (uPA). The purpose of this study was to investigate the role of uPAR in bone remodeling. MATERIALS AND METHODS: In vivo studies were performed in uPAR knockout (KO) and wildtype (WT) mice on a C57Bl6/SV129 (75:25) background. Bone mass was analyzed by pQCT. Excised tibias were subjected to mechanical tests. UPAR KO calvaria osteoblasts were characterized by proliferation assays, RT-PCR for important proteins secreted during differentiation, and immunoblot for activator protein 1 (AP-1) family members. In vitro osteoclast formation was tested with uPAR KO bone marrow monocytes in the presence of macrophage-colony stimulating factor (M-CSF) and RANKL. Phalloidin staining in osteoclasts served to study actin ring and podosome formation. RESULTS: pQCT revealed increased bone mass in uPAR-null mice. Mechanical tests showed reduced load-sustaining capability in uPAR KO tibias. uPAR KO osteoblasts showed a proliferative advantage with no difference in apoptosis, higher matrix mineralization, and earlier appearance of alkaline phosphatase (ALP). Surface RANKL expression at different stages of differentiation was not altered. AP-1 components, such as JunB and Fra-1, were upregulated in uPAR KO osteoblasts, along with other osteoblasts markers. On the resorptive side, the number of osteoclasts formed in vitro from uPAR KO monocytes was decreased. Podosome imaging in uPAR KO osteoclasts revealed a defect in actin ring formation. CONCLUSIONS: The defective proliferation and differentiation of bone cells, coincident with both aberrant expression of transcription factors and cytoskeletal organization, are typical uPAR-dependent molecular phenotypes, and we have now shown their function in osteoblasts and osteoclasts function in vivo.

Bone mineral density and bone markers in patients with a recent low-energy fracture: effect of 1 y of treatment with calcium and vitamin D.

BACKGROUND: Low-energy fractures of the hip, forearm, shoulder, and spine are known consequences of osteoporosis. OBJECTIVE: We evaluated the effect of 1 y of treatment with calcium and vitamin D on bone mineral density (BMD) and bone markers in patients with a recent low-energy fracture. DESIGN: In a double-blinded design, patients with fracture of the hip (lower-extremity fracture, or LEF) or upper extremity (UEF) were randomly assigned to receive 3000 mg calcium carbonate + 1400 IU cholecalciferol or placebo (200 IU cholecalciferol). BMD of the hip (HBMD) and lumbar spine (LBMD) were evaluated by dual-energy X-ray absorptiometry, and physical performance was assessed by the timed Up & Go test. Serum concentrations of 25-hydroxycholecalciferol, parathyroid hormone (PTH), telepeptide of type I collagen (ICTP), osteocalcin, and N-terminal propeptide of collagen type I were measured. RESULTS: A total of 122 patients were included (84% women; x +/- SD age: 70 +/- 11 y); 68% completed the study. In an intention-to-treat analysis, LBMD increased in the intervention group and decreased in the placebo group, and the difference between the groups was significant after 12 mo: 0.931 +/- 0.211 compared with 0.848 +/- 0.194 (P<0.05). No significant change was shown for HBMD. The effect of treatment was more pronounced in patients aged <70 y. The intervention decreased bone turnover. PTH was significantly lower in the intervention group (P<0.01) for the LEF patients. ICTP and change in LBMD were significantly related to physical performance. CONCLUSIONS: A 1-y intervention with calcium and vitamin D reduced bone turnover, significantly increased BMD in patients younger than 70 y, and decreased bone loss in older patients. The effect of treatment was related to physical performance.

A high-protein diet during hospitalization is associated with an accelerated decrease in soluble urokinase plasminogen activator receptor levels in acutely ill elderly medical patients with SIRS.

Acute illness and hospitalization in elderly individuals are often accompanied by the systemic inflammatory response syndrome (SIRS) and malnutrition, both associated with wasting and mortality. Nutritional support and resistance training were shown to increase muscle anabolism and reduce inflammation in healthy elderly. We hypothesized that nutritional support and resistance training would accelerate the resolution of inflammation in hospitalized elderly patients with SIRS. Acutely admitted patients aged >65 years with SIRS were randomized to an intervention consisting of a high-protein diet (1.7 g/kg per day) during hospitalization, and daily protein supplement (18.8 g) and 3 weekly resistance training sessions for 12 weeks after discharge (Intervention, n=14), or to standard-care (Control, n=15). Plasma levels of the inflammatory biomarkers soluble urokinase plasminogen activator receptor (suPAR), interleukin-6, C-reactive protein (CRP), and albumin were measured at admission, discharge, and 4 and 13 weeks after discharge. The Intervention group had an earlier decrease in suPAR levels than the Control group: -15.4% vs. +14.5%, P=.007 during hospitalization, and -2.4% vs. -28.6%, P=.007 between discharge and 4 weeks. There were no significant effects of the intervention on the other biomarkers. All biomarkers improved significantly between admission and 13 weeks, although with different kinetics (suPAR: -22%, interleukin-6: -86%, CRP: -89%, albumin: +11%). Nutritional support during hospitalization was associated with an accelerated decrease in suPAR levels, whereas the combined nutrition and resistance training intervention after discharge did not appear to affect the inflammatory state. Our results indicate that improved nutritional care during hospitalization may accelerate recovery in acutely ill elderly medical patients.

The effect of protein intake and resistance training on muscle mass in acutely ill old medical patients - A randomized controlled trial.

BACKGROUND & AIM: Stress metabolism is associated with accelerated loss of muscle that has large consequences for the old medical patient. The aim of this study was to investigate if an intervention combining protein and resistance training was more effective in counteracting loss of muscle than standard care. Secondary outcomes were changes in muscle strength, functional ability and body weight. METHODS: 29 acutely admitted old (>65 years) patients were randomly assigned to the intervention (n = 14) or to standard care (n = 15). The Intervention Group received 1.7 g protein/kg/day during admission and a daily protein supplement (18.8 g protein) and resistance training 3 times per week the 12 weeks following discharge. Muscle mass was assessed by Dual-energy X-ray Absorptiometry. Muscle strength was assessed by Hand Grip Strength and Chair Stand Test. Functional ability was assessed by the de Morton Mobility Index, the Functional Recovery Score and the New Mobility Score. Changes in outcomes from time of admission to three-months after discharge were analysed by linear regression analysis. RESULTS: The intention-to-treat analysis showed no significant effect of the intervention on lean mass (unadjusted: ß-coefficient = -1.28 P = 0.32, adjusted for gender: ß-coefficient = -0.02 P = 0.99, adjusted for baseline lean mass: ß-coefficient = -0.31 P = 0.80). The de Morton Mobility Index significantly increased in the Control Group (ß-coefficient = -11.43 CI: 0.72-22.13, P = 0.04). No other differences were found. CONCLUSION: No significant effect on muscle mass was observed in this group of acutely ill old medical patients. High compliance was achieved with the dietary intervention, but resistance training was challenging. Clinical trials identifier NCT02077491.

The Association between Newborn Regional Body Composition and Cord Blood Concentrations of C-Peptide and Insulin-Like Growth Factor I.

BACKGROUND: Third trimester fetal growth is partially regulated by C-peptide and insulin-like growth factor I (IGF-I). Prenatal exposures including maternal obesity and high gestational weight gain as well as high birth weight have been linked to subsequent metabolic disease. We evaluated the associations between newborn regional body composition and cord blood levels of C-peptide and IGF-I. METHODS: We prospectively included obese and normal-weight mothers and their newborns; cord blood was collected and frozen. Analyses of C-peptide and IGF-I were performed simultaneously, after recruitment was completed. Newborn regional body composition was assessed with dual-energy X-ray absorptiometry scanning (DXA) within 48 hours of birth. RESULTS: Three hundred thirty-six term infants were eligible to participate in the study; of whom 174 (52%) infants had cord blood taken. Total, abdominal and arm and leg fat mass were positively associated with C-peptide (p < 0.001). Arm and leg fat mass was associated with IGF-I concentration: 28 g [95% confidence interval: 4, 53] per doubling of IGF-I. There was no association between total or abdominal fat mass and IGF-I. Fat-free mass was positively associated with both C-peptide (p < 0.001) and IGF-I (p = 0.004). CONCLUSION: Peripheral fat tissue accumulation was associated with cord blood C-peptide and IGF-I. Total and abdominal fat masses were related to C-peptide but not to IGF-I. Thus, newborn adiposity is partially mediated through C-peptide and early linear growth is associated with IGF-I.

Accelerated protein digestion and amino acid absorption after Roux-en-Y gastric bypass.

BACKGROUND: Roux-en-Y gastric bypass (RYGB) involves exclusion of major parts of the stomach and changes in admixture of gastro-pancreatic enzymes, which could have a major impact on protein digestion and amino acid absorption. OBJECTIVE: We investigated the effect of RYGB on amino acid appearance in the systemic circulation from orally ingested protein and from endogenous release. DESIGN: Nine obese glucose-tolerant subjects, with a mean body mass index (in kg/m(2)) of 39.2 (95% CI: 35.2, 43.3) and mean glycated hemoglobin of 5.3% (95% CI: 4.9%, 5.6%), were studied before and 3 mo after RYGB. Leucine and phenylalanine kinetics were determined under basal conditions and during 4 postprandial hours by intravenous infusions of [3,3,3-(2)H3]-leucine and [ring-(2)D5]-phenylalanine combined with ingestion of [1-(13)C]-leucine intrinsically labeled caseinate as the sole protein source of the meal. Changes in body composition were assessed by dual-energy X-ray absorptiometry. RESULTS: After RYGB, basal plasma leucine concentration did not change, but marked changes were seen postprandially with 1.7-fold increased peak concentrations (before­mean: 217 µmol/L; 95% CI: 191, 243 µmol/L; 3 mo­mean: 377 µmol/L; 95% CI: 252, 502 µmol/L; P = 0.012) and 2-fold increased incremental AUC (before-mean: 4.1 mmol ∙ min/L; 95% CI: 2.7, 5.5 mmol ∙ min/L; 3 mo-mean: 9.5 mmol ∙ min/L; 95% CI: 4.9, 14.2 mmol ∙ min/L; P = 0.032). However, the postprandial hyperleucinemia was transient, and concentrations were below basal concentrations in the fourth postprandial hour. These concentration differences were mainly caused by changes in leucine appearance rate from orally ingested caseinate: peak rate increased nearly 3-fold [before­mean: 0.5 µmol/(kg fat-free mass ∙ min); 95% CI: 0.4, 0.5 µmol/(kg fat-free mass ∙ min); 3 mo­mean 1.4 µmol/(kg fat-free mass ∙ min); 95% CI: 0.8, 1.9 µmol/(kg fat-free mass ∙ min); P = 0.002], and time to peak was much shorter (before­mean: 173 min; 95% CI: 137, 209 min; 3 mo­mean: 65 min; 95% CI: 46, 84 min; P < 0.001). Only minor changes were seen in endogenous leucine release after RYGB. CONCLUSIONS: RYGB accelerates caseinate digestion and amino acid absorption, resulting in faster and higher but more transient postprandial elevation of plasma amino acids. Changes are likely mediated by accelerated intestinal nutrient entry and clearly demonstrate that protein digestion is not impaired after RYGB. This trial was registered at clinicaltrials.gov as NCT01559792.

GLP-1 Receptor Agonist Treatment Increases Bone Formation and Prevents Bone Loss in Weight-Reduced Obese Women.

CONTEXT: Recent studies indicate that glucagon-like peptide (GLP)-1 regulates bone turnover, but the effects of GLP-1 receptor agonists (GLP-1 RAs) on bone in obese weight-reduced individuals are unknown. OBJECTIVE: To investigate the role of GLP-1 RAs on bone formation and weight loss-induced bone mass reduction. DESIGN: Randomized control study. SETTING: Outpatient research hospital clinic. PARTICIPANTS: Thirty-seven healthy obese women with body mass index of 34 ± 0.5 kg/m(2) and age 46 ± 2 years. INTERVENTION: After a low-calorie-diet-induced 12% weight loss, participants were randomized to treatment with or without administration of the GLP-1 RA liraglutide (1.2 mg/d) for 52 weeks. In case of weight gain, up to two meals per day could be replaced with a low-calorie-diet product to maintain the weight loss. MAIN OUTCOME MEASURES: Total, pelvic, and arm-leg bone mineral content (BMC) and bone markers [C-terminal telopeptide of type 1 collagen (CTX-1) and N-terminal propeptide of type 1 procollagen (P1NP)] were investigated before and after weight loss and after 52-week weight maintenance. Primary endpoints were changes in BMC and bone markers after 52-week weight maintenance with or without GLP-1 RA treatment. RESULTS: Total, pelvic, and arm-leg BMC decreased during weight maintenance in the control group (P < .0001), but not significantly in the liraglutide group. Thus, total and arm-leg BMC loss was four times greater in the control group compared to the liraglutide group (estimated difference, 27 g; 95% confidence interval, 5-48; P = .01), although the 12% weight loss was maintained in both groups. In the liraglutide group, the bone formation marker P1NP increased by 16% (7 ± 3 µg/L) vs a 2% (-1 ± 4 µg/L) decrease in the control group (P < .05). The bone resorption marker CTX-1 collagen did not change during the weight loss maintenance phase. CONCLUSIONS: Treatment with a long-acting GLP-1 RA increased bone formation by 16% and prevented bone loss after weight loss obtained through a low-calorie diet, supporting its role as a safe weight-lowering agent.

Single-nucleotide polymorphisms in the P2X7 receptor gene are associated with post-menopausal bone loss and vertebral fractures.

The purinergic P2X7 receptor has a major role in the regulation of osteoblast and osteoclast activity and changes in receptor function may therefore affect bone mass in vivo. The aim of this study was to determine the association of non-synonymous single-nucleotide polymorphisms in the P2RX7 gene to bone mass and fracture incidence in post-menopausal women. A total of 1694 women (aged 45-58) participating in the Danish Osteoporosis Prevention Study were genotyped for 12 functional P2X7 receptor variants. Bone mineral density was determined at baseline and after 10 years. In addition, vertebral fracture incidence was documented at 10 years. We found that the rate of bone loss was clearly associated with the Arg307Gln amino acid substitution such that individuals heterozygous for this polymorphism had a 40% increased rate of bone loss. Furthermore, individuals carrying the Ile568Asn variant allele had increased bone loss. In contrast, the Gln460Arg polymorphism was associated with protection against bone loss. The Ala348Thr polymorphism was associated with a lower vertebral fracture incidence 10 years after menopause. Finally, we developed a risk model, which integrated P2RX7 genotypes. Using this model, we found a clear association between the low-risk (high-P2X7 function) alleles and low rate of bone loss. Conversely, high-risk (reduced P2X7 function) alleles were associated with a high rate of bone loss. In conclusion, an association was demonstrated between variants that reduce P2X7 receptor function and increased rate of bone loss. These data support that the P2X7 receptor is important in regulation of bone mass.

ZP2307, a novel, cyclic PTH(1-17) analog that augments bone mass in ovariectomized rats.

Daily injections of human parathyroid hormone (1-34), hPTH(1-34), provide a highly effective treatment option for severe osteoporosis. However, PTH analogs shorter than 28 amino acids do not retain any bone augmenting potential. Here, we present ZP2307 ([Ac5c¹, Aib³, Leu8, Gln¹°, Har¹¹, Ala¹², Trp¹4, Asp¹7]PTH(1-17)-NH2), a novel, chemically modified and cyclized hPTH(1-17) analog, that augments bone mass in ovariectomized, osteopenic rats. Subcutaneous administration of this structurally constrained, K¹³-D¹7 side-chain-to-side-chain cyclized peptide reversed bone loss and increased bone mineral density (BMD) up to or above baseline levels in rat long bones and vertebrae. Highly significant effects of ZP2307 were achieved at doses of 40-320 nmol/kg. Micro-CT and histomorphometric analyses showed that ZP2307 improved quantitative and qualitative parameters of bone structure. Biomechanical testing of rat femora confirmed that ZP2307 dramatically increased bone strength. Over a broad maximally effective dose range (40-160 nmol/kg) ZP2307 did not increase serum concentrations of ionized free calcium above normal levels. Only at the highest dose (320 nmol/kg) ZP2307 induced hypercalcemic calcium levels in the ovariectomized rats. To our knowledge ZP2307 is the smallest PTH peptide analog known to exert augmentation of bone. Our findings suggest that ZP2307 has the potential to effectively augment bone mass over a broad dose range without a concomitant increase in the serum concentration of ionized free calcium above the normal range.