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Abstract Background and Hypotheses Weight gain and adverse cardiometabolic effects often limit the clinical utility of olanzapine. In ENLIGHTEN-2, combining olanzapine with the opioid receptor antagonist samidorphan (OLZ/SAM) mitigated olanzapine-associated weight gain. These analyses tested the hypothesis that OLZ/SAM would be associated with reduced adverse cardiometabolic effects compared with olanzapine. Study Design This phase 3 double-blind study randomized adults with schizophrenia to OLZ/SAM or olanzapine for 24 weeks. Post hoc analyses assessed changes from baseline to week 24 in cardiometabolic risk parameters, including body mass index (BMI), risk of developing obesity (BMI ≥30 kg/m2) or metabolic syndrome, waist circumference, along with mean and potentially clinically significant changes in blood pressure, glucose, and lipids. Results After 24 weeks’ treatment, compared with olanzapine, OLZ/SAM was associated with smaller least-squares mean (LSM) changes from baseline in systolic blood pressure (LSM difference, −2.63 mm Hg; 95% CI: −4.78, −0.47), diastolic blood pressure (LSM difference, −0.75 mm Hg; 95% CI: −2.31, 0.80), and BMI (LSM difference, −0.65 kg/m2; 95% CI: −1.01, −0.28). OLZ/SAM treatment was also associated with reduced risk of shifting from normal blood pressure to stage 1/2 hypertension (odds ratio [OR], 0.48; 95% CI: 0.24, 0.96), becoming obese (OR, 0.52; 95% CI: 0.32, 0.82), and developing metabolic syndrome (OR, 0.55; 95% CI: 0.31, 0.99) compared with olanzapine. No treatment group differences were noted for risk of hyperglycemia or hyperlipidemia. Conclusions OLZ/SAM treatment was associated with lower risk of worsening cardiometabolic risk factors related to obesity, hypertension, and metabolic syndrome relative to olanzapine. NCT02694328, https://clinicaltrials.gov/ct2/show/NCT02694328.

Background: Excessive fructose intake causes metabolic syndrome in animals and can be partially prevented by lowering the uric acid level. We tested the hypothesis that fructose might induce features of metabolic syndrome in adult men and whether this is protected by allopurinol. Methods: A randomized, controlled trial of 74 adult men who were administered 200 g fructose daily for 2 weeks with or without allopurinol. Primary measures included changes in ambulatory blood pressure (BP), fasting lipids, glucose and insulin, homeostatic model assessment (HOMA) index, body mass index and criteria for metabolic syndrome. Results: The ingestion of fructose resulted in an increase in ambulatory BP (7±2 and 5±2 mm Hg for systolic (SBP) and diastolic BP (DBP), P<0.004 and P<0.007, respectively). Mean fasting triglycerides increased by 0.62±0.23 mmol l−1 (55±20 mg per 100 ml), whereas high-density lipoprotein cholesterol decreased by 0.06±0.02 mmol l−1 (2.5±0.7 mg per 100 ml), P<0.002 and P<0.001, respectively. Fasting insulin and HOMA indices increased significantly, whereas plasma glucose level did not change. All liver function tests showed an increase in values. The metabolic syndrome increased by 25–33% depending on the criteria. Allopurinol lowered the serum uric acid level (P<0.0001) and prevented the increase in 24-h ambulatory DBP and daytime SBP and DBP. Allopurinol treatment did not reduce HOMA or fasting plasma triglyceride levels, but lowered low-density lipoprotein cholesterol relative to control (P<0.02) and also prevented the increase in newly diagnosed metabolic syndrome (0–2%, P=0.009). Conclusions: High doses of fructose raise the BP and cause the features of metabolic syndrome. Lowering the uric acid level prevents the increase in mean arterial blood pressure. Excessive intake of fructose may have a role in the current epidemics of obesity and diabetes.

Obesity, is a state of chronic inflammation, characterized by elevated lipids, insulin resistance and relative hypogonadotropic hypogonadism. We have defined the accompanying decreased Luteinizing Hormone (LH), Follicle-Stimulating Hormone (FSH), ovarian steroids and reduced pituitary response to Gonadotropin-releasing Hormone (GnRH) as Reprometabolic syndrome, a phenotype that can be induced in healthy normal weight women (NWW) by acute infusion of free fatty acids and insulin. To identify potential mediators of insulin and lipid-related reproductive endocrine dysfunction. Secondary analysis of crossover study of eumenorrheic reproductive aged women of normal Body Mass Index (BMI) (<25 kg/m2) at an academic medical center. Participants underwent 6-hour infusions of either saline/heparin or insulin plus fatty acids (Intralipid plus heparin), in the early follicular phase of sequential menstrual cycles, in random order. Euglycemia was maintained by glucose infusion. Frequent blood samples were obtained. Pooled serum from each woman was analyzed for cytokines, interleukins, chemokines, adipokines, Fibroblast Growth Factor-21 (FGF-21) and markers of endoplasmic reticulum (ER) stress (CHOP and GRP78). Wilcoxon signed-rank tests were used to compare results across experimental conditions. Except for Macrophage Inflammatory Protein-1β (MIP-1β), no significant differences were observed in serum levels of any of the inflammatory signaling or ER stress markers tested. Acute infusion of lipid and insulin, to mimic the metabolic syndrome of obesity, was not associated with an increase in inflammatory markers. These results imply that the endocrine disruption and adverse reproductive outcomes of obesity are not a consequence of the ambient inflammatory environment but may be mediated by direct lipotoxic effects on the hypothalamic-pituitary-ovarian (HPO) axis.

PurposeThe objective of this study was to test a low-carbohydrate diet (LCD) plus walking to reduce androgen deprivation therapy (ADT)-induced metabolic disturbances.Materials and methodsThis randomized multi-center trial of prostate cancer (PCa) patients initiating ADT was designed to compare an LCD (≤20g carbohydrate/day) plus walking (≥30 min for ≥5 days/week) intervention vs. control advised to maintain usual diet and exercise patterns. Primary outcome was change in insulin resistance by homeostatic model assessment at 6 months. To detect 20% reduction in insulin resistance, 100 men were required. The study was stopped early after randomizing 42 men due to slow accrual. Secondary outcomes included weight, body composition, lipids, and prostate-specific antigen (PSA). Changes from baseline were compared between arms using rank-sum tests.ResultsAt 6 months, LCD/walking reduced insulin resistance by 4% vs. 36% increase in control (p = 0.13). At 3 months, vs. control, LCD/walking arm significantly lost weight (7.8kg; p<0.001), improved insulin resistance (↑36%; p = 0.015), hemoglobin A1c (↓3.3%; p = 0.01), high-density lipoprotein (HDL) (↑13%; p = 0.004), and triglyceride (↓37%; p = 0.036). At 6 months, weight loss (10.6kg; p<0.001) and HDL (↑27%; p = 0.003) remained significant. LCD/walking preserved total body bone mineral count (p = 0.025), reduced fat mass (p = 0.002), lean mass (p = 0.036), and percent body fat (p = 0.004). There were no differences in PSA. Limitations include the effect of LCD, weight loss vs. walking instruction are indistinguishable, and small sample size.ConclusionsIn an underpowered study, LCD/walking did not improve insulin sensitivity at 6 months. Given most secondary outcomes were improved at 3 months with some remaining improved at 6 months and a secondary analysis showed that LCD/walking reduced insulin resistance over the study, supporting future larger studies of LCD/walking intervention to reduce ADT-induced disturbances.

Background Fructose intake, mainly as table sugar or high fructose corn syrup, has increased in recent decades and is associated with increased risk for kidney stones. We hypothesized that fructose intake alters serum and urinary components involved in stone formation. Methods We analyzed a previously published randomized controlled study that included 33 healthy male adults (40–65 years of age) who ingested 200 g of fructose (supplied in a 2-L volume of 10% fructose in water) daily for 2 weeks. Participants were evaluated at the Unit of Nephrology of the Mateo Orfila Hospital in Menorca. Changes in serum levels of magnesium, calcium, uric acid, phosphorus, vitamin D, and intact PTH levels were evaluated. Urine magnesium, calcium, uric acid, phosphorus, citrate, oxalate, sodium, potassium, as well as urinary pH, were measured. Results Ingestion of fructose was associated with an increased serum level of uric acid ( p  < 0.001), a decrease in serum ionized calcium ( p  = 0.003) with a mild increase in PTH ( p  < 0.05) and a drop in urinary pH ( p  = 0.02), an increase in urine oxalate ( p  = 0.016) and decrease in urinary magnesium ( p  = 0.003). Conclusions Fructose appears to increase urinary stone formation in part via effects on urate metabolism and urinary pH, and also via effects on oxalate. Fructose may be a contributing factor for the development of kidney stones in subjects with metabolic syndrome and those suffering from heat stress. Trial registration ClinicalTrials.gov NCT00639756 March 20, 2008.

Although dexamethasone is highly effective in the treatment of pediatric acute lymphoblastic leukemia (ALL), it can cause serious metabolic side effects. Because studies regarding the effects of dexamethasone are limited by their small scale, we prospectively studied the direct effects of treating pediatric ALL with dexamethasone administration with respect to activation of components of metabolic syndrome (MetS); in addition, we investigated whether these side effects were correlated with the level of dexamethasone. Fifty pediatric patients (3-16 years of age) with ALL were studied during a 5-day dexamethasone course during the maintenance phase of the Dutch Childhood Oncology Group ALL-10 and ALL-11 protocols. Fasting insulin, glucose, total cholesterol, HDL, LDL, and triglycerides levels were measured at baseline (before the start of dexamethasone; T1) and on the fifth day of treatment (T2). Dexamethasone trough levels were measured at T2. We found that dexamethasone treatment significantly increased the following fasting serum levels (P<0.05): HDL, LDL, total cholesterol, triglycerides, glucose, and insulin. In addition, dexamethasone increased insulin resistance (HOMA-IR>3.4) from 8% to 85% (P<0.01). Dexamethasone treatment also significantly increased the diastolic and systolic blood pressure. Lastly, dexamethasone trough levels (N = 24) were directly correlated with high glucose levels at T2, but not with other parameters. These results indicate that dexamethasone treatment acutely induces three components of the MetS. Together with the weight gain typically associated with dexamethasone treatment, these factors may contribute to the higher prevalence of MetS and cardiovascular risk among survivors of childhood leukemia who received dexamethasone treatment.

Objective: Second-generation antipsychotics (SGAs) cause weight gain and cardiometabolic abnormalities in children and adolescents. Less well-investigated is the outcome of these adverse events following SGA discontinuation, which we examined. Methods: Medically healthy 7 to 17-year-old patients treated with risperidone for ≥6 months were enrolled and returned for follow-up, 1.5 years later. Treatment history was extracted from the medical and pharmacy records. Anthropometric and laboratory measurements were obtained at each research visit. Multivariable linear regression analysis and Fisher's exact test were used to compare participants who remained on risperidone at follow-up (Risp Cont Group) with those who had discontinued SGA treatment (SGA Disc Group) and those who had switched to another SGA (SGA Cont Group). Correlational analyses examined the association between change in age-sex specific body mass index (BMI) z score between study entry and follow-up and change in cardiometabolic outcomes. Results: The sample consisted of 101 participants (93% male) with a mean age of 11.7±2.6 years at study entry. The majority had an externalizing disorder and received 0.03±0.02 mg/kg/day of risperidone, for 2.5±1.6 years. At follow-up, 18% (n=18) were in the SGA Disc Group and 9% (n=9) were in the SGA Cont Group. BMI z score decreased in the SGA Disc Group, remained unchanged in the Risp Cont Group (n=74), and increased in the SGA Cont Group. Importantly, the change in BMI z score between study entry and follow-up was significantly correlated with the change in systolic and diastolic blood pressure z scores, heart rate, waist circumference, percent body fat, inflammatory markers, fasting total insulin, homeostatic model assessment insulin resistance index (HOMA-IR), C-peptide, total, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol, triglycerides, triglycerides/HDL ratio, and leptin. Conclusions: Following several years of treatment, risperidone discontinuation is associated with a reversal of the excessive weight gain, mediated by a negative energy balance, and a corresponding improvement in cardiometabolic parameters.

Glucose and lipid metabolism dysfunction is a significant side effect associated with antipsychotics. Although there are many studies about the linkages between drugs and metabolic dysfunction, most of these studies have compared the effects of two antipsychotics on only one metabolic measure: either glucose or lipid metabolism. The present study aimed to investigate the effects of clozapine, olanzapine, risperidone, and sulpiride on glucose and lipid metabolism in first-episode schizophrenia. One hundred twelve schizophrenics were assigned randomly to receive clozapine, olanzapine, risperidone, or sulpiride for 8 weeks. Planned assessments included body mass index (BMI), waist-to-hip ratio, fasting glucose, insulin, C-peptide, insulin resistance index (IRI), cholesterol, and triglyceride. All measures were collected at baseline and at the end of the 8-week treatment. After treatment, insulin, C-peptide, and IRI were significantly increased in the four groups, but not fasting glucose levels. Cholesterol and triglyceride levels were significantly increased in the clozapine and olanzapine groups. Patients treated with clozapine and olanzapine had higher fasting insulin, C-peptide, and IRI levels than those treated with risperidone and sulpiride. Among the four antipsychotics, the increases of mean BMI from high to low were as follows: clozapine, olanzapine, sulpiride, and risperidone. This study confirmed that the four antipsychotic drugs were associated with an increase of insulin, C-peptide, and IRI. It was found that clozapine and olanzapine were associated with an increase in cholesterol and triglyceride levels. The effects of clozapine and olanzapine on the glucose and lipid metabolism outweighed those of risperidone and sulpiride.

Purpose Alterations in one-carbon metabolism (OCM) have been repeatedly reported in schizophrenia. However, there is a scarcity of studies addressing the effects of antipsychotics on selected OCM markers in schizophrenia and provided results are inconsistent. Methods We recruited 39 first-episode schizophrenia (FES) patients and determined serum profile of total homocysteine (tHcy), folate, vitamin B12, lipoproteins and glucose at baseline and after 12 weeks of treatment with second-generation antipsychotics (SGA) including olanzapine and risperidone in monotherapy. Results After 12 weeks of treatment, all patients had significantly higher body mass index (BMI), serum levels of total cholesterol (TC), low-density lipoproteins (LDL), triglycerides (TG) and tHcy together with significantly lower levels of folate and vitamin B12. The analysis of differences between SGA revealed the same biochemical alterations in patients treated with olanzapine as in the whole group, while those receiving risperidone had no statistically significant changes in serum folate, vitamin B12 and TG. There was a significantly higher increase in BMI and TC in patients treated with olanzapine in comparison with those treated with risperidone. Patients receiving olanzapine had a higher decrease in vitamin B12 than those assigned to the treatment with risperidone. Changes in folate, vitamin B12, tHcy and TC levels were significant only in males, even after Bonferroni correction. Multiple regression analysis revealed that changes in tHcy levels are associated with gender and baseline metabolic parameters (BMI, glucose, TC, LDL and HDL) but not with selected SGA. Conclusions These results indicate that SGA may influence OCM, especially in first-episode schizophrenia (FES) males.

IntroductionProstate cancer survivors (PCS) receiving androgen deprivation therapy (ADT) experience deleterious side effects such as unfavourable changes in cardiometabolic factors that lead to sarcopenic obesity and metabolic syndrome (MetS). While loss of lean body mass (LBM) compromises muscular strength and quality of life, MetS increases the risk of cardiovascular disease and may influence cancer recurrence. Exercise can improve LBM and strength, and may serve as an alternative to the pharmacological management of MetS in PCS on ADT. Prior exercise interventions in PCS on ADT have been effective at enhancing strength, but only marginally effective at enhancing body composition and ameliorating cardiometabolic risk factors. This pilot trial aims to improve on existing interventions by employing periodised resistance training (RT) to counter sarcopenic obesity in PCS on ADT. Secondary aims compare intervention effects on cardiometabolic, physical function, quality of life and molecular skeletal muscle changes. An exploratory aim examines if protein supplementation (PS) in combination with RT elicits greater changes in these outcomes.Methods and analysisA 2×2 experimental design is used in 32 PCS on ADT across a 12-week intervention period. Participants are randomised to resistance training and protein supplementation (RTPS), RT, PS or control. RT and RTPS groups perform supervised RT three times per week for 12 weeks, while PS and RTPS groups receive 50 g whey protein per day. This pilot intervention applies a multilayered approach to ameliorate detrimental cardiometabolic effects of ADT while investigating molecular mechanisms underlying skeletal muscle changes in PCS.Ethics and disseminationThis trial was approved by the University of Southern California Institutional Review Board (HS-13–00315). Results from this trial will be communicated in peer-reviewed publications and scientific presentations.Trial registration numberNCT01909440; Pre-results.