Metabolic Syndrome in people treated with Antipsychotics (RISKMet): A multimethod study protocol investigating genetic, behavioural, and environmental risk factors.

INTRODUCTION: The RISKMet project aims to: (1) identify risk factors for metabolic syndrome (MetS) by comparing patients with and without MetS; (2) characterise patients treated with second-generation antipsychotics (SGAs) about MetS diagnosis; (3) study behavioural patterns, including physical activity (PA) and dietary habits, in patients and healthy individuals using a prospective cohort design. METHOD: The RISKMet project investigates MetS in individuals treated with SGAs, focusing on both adult and paediatric populations. The study utilizes a case-control design to examine potential risk factors for MetS, categorizing participants as MetS+ considered as "Cases" and MetS- considered as "Controls" matched by sex and age. The evaluation of factors such as MetS, lifestyle habits, and environmental influences is conducted at two time points, T0 and T3, after 3 months. Subsequently, the project aims to assess body parameters, including physical examinations, and blood, and stool sample collection, to evaluate metabolic markers and the impact of SGAs. The analysis includes pharmacological treatment data and genetic variability. Behavioural markers related to lifestyle, eating behaviour, PA, and mood are assessed at both T0 and T3 using interviews, accelerometers, and a mobile app. The study aims to improve mental and physical well-being in SGA-treated individuals, establish a biobank for MetS research, build an evidence base for physical health programs, and develop preventive strategies for SGA-related comorbidities. CONCLUSIONS: This project innovates MetS monitoring in psychiatry by using intensive digital phenotyping, identifying biochemical markers, assessing familial risks, and including genetically similar healthy controls. STUDY REGISTRATION NUMBER: ISRCTN18419418 at www.isrctn.com.

Induction of diabetes by Tacrolimus in a phenotypic model of obesity and metabolic syndrome.

Introduction: The pathogenesis of Post-Transplant Diabetes Mellitus (PTDM) is complex and multifactorial and it resembles that of Type-2 Diabetes Mellitus (T2DM). One risk factor specific to PTDM differentiates both entities: the use of immunosuppressive therapy. Specifically, Tacrolimus interacts with obesity and insulin resistance (IR) in accelerating the onset of PTDM. In a genotypic model of IR, the obese Zucker rats, Tacrolimus is highly diabetogenic by promoting the same changes in beta-cell already modified by IR. Nevertheless, genotypic animal models have their limitations and may not resemble the real pathophysiology of diabetes. In this study, we have evaluated the interaction between beta-cell damage and Tacrolimus in a non-genotypic animal model of obesity and metabolic syndrome. Methods: Sprague Dawley rats were fed a high-fat enriched diet during 45 days to induce obesity and metabolic dysregulation. On top of this established obesity, the administration of Tacrolimus (1mg/kg/day) during 15 days induced severe hyperglycaemia and changes in morphological and structural characteristics of the pancreas. Results: Obese animals administered with Tacrolimus showed increased size of islets of Langerhans and reduced beta-cell proliferation without changes in apoptosis. There were also changes in beta-cell nuclear factors such as a decrease in nuclear expression of MafA and a nuclear overexpression of FoxO1A, PDX-1 and NeuroD1. These animals also showed increased levels of pancreatic insulin and glucagon. Discussion: This model could be evidence of the relationship between the T2DM and PTDM physiopathology and, eventually, the model may be instrumental to study the pathogenesis of T2DM.

Prenatal Exposure to Chemical Mixtures and Metabolic Syndrome Risk in Children.

Importance: Prenatal exposure to ubiquitous endocrine-disrupting chemicals (EDCs) may increase the risk of metabolic syndrome (MetS) in children, but few studies have studied chemical mixtures or explored underlying protein and metabolic signatures. Objective: To investigate associations of prenatal exposure to EDC mixtures with MetS risk score in children and identify associated proteins and metabolites. Design, Setting, and Participants: This population-based, birth cohort study used data collected between April 1, 2003, and February 26, 2016, from the Human Early Life Exposome cohort based in France, Greece, Lithuania, Norway, Spain, and the UK. Eligible participants included mother-child pairs with measured prenatal EDC exposures and complete data on childhood MetS risk factors, proteins, and metabolites. Data were analyzed between October 2022 and July 2023. Exposures: Nine metals, 3 organochlorine pesticides, 5 polychlorinated biphenyls, 2 polybrominated diphenyl ethers (PBDEs), 5 perfluoroalkyl substances (PFAS), 10 phthalate metabolites, 3 phenols, 4 parabens, and 4 organophosphate pesticide metabolites measured in urine and blood samples collected during pregnancy. Main Outcomes and Measures: At 6 to 11 years of age, a composite MetS risk score was constructed using z scores of waist circumference, systolic and diastolic blood pressures, triglycerides, high-density lipoprotein cholesterol, and insulin levels. Childhood levels of 44 urinary metabolites, 177 serum metabolites, and 35 plasma proteins were quantified using targeted methods. Associations were assessed using bayesian weighted quantile sum regressions applied to mixtures for each chemical group. Results: The study included 1134 mothers (mean [SD] age at birth, 30.7 [4.9] years) and their children (mean [SD] age, 7.8 [1.5] years; 617 male children [54.4%] and 517 female children [45.6%]; mean [SD] MetS risk score, -0.1 [2.3]). MetS score increased per 1-quartile increase of the mixture for metals (ß = 0.44; 95% credible interval [CrI], 0.30 to 0.59), organochlorine pesticides (ß = 0.22; 95% CrI, 0.15 to 0.29), PBDEs (ß = 0.17; 95% CrI, 0.06 to 0.27), and PFAS (ß = 0.19; 95% CrI, 0.14 to 0.24). High-molecular weight phthalate mixtures (ß = -0.07; 95% CrI, -0.10 to -0.04) and low-molecular weight phthalate mixtures (ß = -0.13; 95% CrI, -0.18 to -0.08) were associated with a decreased MetS score. Most EDC mixtures were associated with elevated proinflammatory proteins, amino acids, and altered glycerophospholipids, which in turn were associated with increased MetS score. Conclusions and Relevance: This cohort study suggests that prenatal exposure to EDC mixtures may be associated with adverse metabolic health in children. Given the pervasive nature of EDCs and the increase in MetS, these findings hold substantial public health implications.

The relationship between heavy metals and metabolic syndrome using machine learning.

Background: Exposure to high levels of heavy metals has been widely recognized as an important risk factor for metabolic syndrome (MetS). The main purpose of this study is to assess the associations between the level of heavy metal exposure and Mets using machine learning (ML) method. Methods: The data used in this study are from the national health and nutrition examination survey 2003-2018. According to the demographic information and heavy metal exposure level of participants, a total of 22 variables were included. Lasso was used to screen out the key variables, and 9 commonly used ML models were selected to establish the associations with the 5-fold cross validation method. Finally, we choose the SHapley Additive exPlanations (SHAP) method to explain the prediction results of Adaboost model. Results: 11,667 eligible individuals were randomly divided into two groups to train and verify the prediction model. Through lasso, characteristic variables were selected from 24 variables as predictors. The AUC (area under curve) of the models selected in this study were all greater than 0.7, and AdaBoost was the best model. The AUC value of AdaBoost was 0.807, the accuracy was 0.720, and the sensitivity was 0.792. It is noteworthy that higher levels of cadmium, body mass index, cesium, being female, and increasing age were associated with an increased probability of MetS. Conversely, lower levels of cobalt and molybdenum were linked to a decrease in the estimated probability of MetS. Conclusion: Our study highlights the AdaBoost model proved to be highly effective, precise, and resilient in detecting a correlation between exposure to heavy metals and MetS. Through the use of interpretable methods, we identified cadmium, molybdenum, cobalt, cesium, uranium, and barium as prominent contributors within the predictive model.

Association between endocrine-disrupting chemical mixtures and non-alcoholic fatty liver disease with metabolic syndrome as a mediator among adults: A population-based study in Korea.

Endocrine-disrupting chemicals (EDCs) may play a role in non-alcoholic fatty liver disease (NAFLD); however, studies on the combined effects of EDC mixtures on NAFLD development are limited. Here, we explored the association between exposure to EDC mixtures and NAFLD and investigated the potential mediating role of metabolic syndrome (MetS). We included participants from the Korean National Environmental Health Survey Cycle 4 (2018-2020) and quantified the urinary concentrations of various EDCs-eight phthalate metabolites, three phenols, one antibacterial compound, four parabens, four polycyclic aromatic hydrocarbons, and one pyrethroid pesticide metabolite-as well as serum concentrations of five perfluorinated compounds (PFCs). NAFLD was defined as a hepatic steatosis index (HSI) ≥36 or a fatty liver index (FLI) ≥60. Weighted quantile sum (WQS) regression was employed to evaluate the associations between EDC mixtures and the risk of MetS or NAFLD. Causal mediation analysis was conducted to explore the potential mediating effect of MetS on the association between mixtures of EDCs and NAFLD risk. All estimates were adjusted for age, sex, educational level, physical activity, smoking status, involuntary smoking, and drinking habits. A total of 2942 adults were included in the analysis. Moderate-to-high positive correlations were identified between phthalate metabolites and PFCs. Higher WQS scores were associated with an elevated risk of MetS and NAFLD. The sex-stratified WQS regression model showed that the interactions between the WQS index and sex were significant for MetS and NAFLD. According to the causal mediation analysis, both the direct and indirect effects of EDC mixtures on NAFLD, with MetS as a mediator, were significant in females. Collectively, these findings highlight the need for interventions that could address both EDC mixture exposure and metabolic status to effectively reduce the risks associated with NAFLD and its related complications.

Associations of bisphenol A exposure with metabolic syndrome and its components: A systematic review and meta-analysis.

Mounting evidence shows that bisphenol A (BPA) is associated with metabolic risk factors. The aim of this study was to review related epidemiologic studies and conduct a meta-analysis to quantitatively estimate the association between BPA and metabolic syndrome. Four electronic databases were systematically searched to identify suitable articles. A total of 47 published studies were finally included. Two studies involved metabolic syndrome. Of the 17, 17, 14, and 13 studies on the relationship between BPA with abdominal obesity, blood pressure, fasting plasma glucose, and dyslipidemia, 10, 6, 3, and 4 studies were included in the meta-analysis, respectively. The results showed that the risk of abdominal obesity increased with the increase of BPA exposure, especially in the group with higher BPA exposure levels (Quartile 2 vs. Quartile 1, pooled OR = 1.16, 95%CI: 1.01, 1.33; Q3 vs. Q1, pooled OR = 1.31, 95%CI: 1.13, 1.51; Q4 vs. Q1, pooled OR = 1.40, 95%CI: 1.21, 1.61). However, there was no significant correlation between BPA exposure and metabolic syndrome components including hypertension, abnormal fasting plasma glucose, and dyslipidemia. The present study found that BPA exposure is significantly associated with a higher risk of abdominal obesity. However, the relationship between BPA with metabolic syndrome and its other components needs further longitudinal studies to verify.

Metabolic syndrome and its relation to antipsychotic polypharmacy in schizophrenia, schizoaffective and bipolar disorders.

The risk of metabolic syndrome (MetS) has been attributed to antipsychotic use in psychiatric patients. To date, there is limited data on the relationship between antipsychotic polypharmacy and MetS in patients with schizophrenia, schizoaffective disorder and bipolar disorder. Therefore, we aimed to investigate the rate of MetS in patients with these disorders receiving antipsychotic monotherapy and polypharmacy. We conducted a cross-sectional study on patients seen between January 2017 and December 2020, collecting data on the class, type, route of administration and number of antipsychotics received. We used the American Association of Clinical Endocrinology criteria to diagnose MetS. We included 833 subjects of whom 573 (68.8%) received antipsychotic monotherapy and 260 (31.2%) received polypharmacy. Overall, 28.6% ( N  = 238) had MetS with no statistical difference between the two groups. Diastolic blood pressure and receiving olanzapine were significant predictors for developing MetS. In conclusion, our study found no significant difference in the rate of MetS between antipsychotic monotherapy and polypharmacy. A number of variables were significant predictors for MetS. Our findings were consistent with other studies and warrant the need for careful choice of antipsychotics and regular screening and management of abnormal metabolic parameters.

Aprepitant boasted a protective effect against olanzapine-induced metabolic syndrome and its subsequent hepatic, renal, and ovarian dysfunction; Role of IGF1/p-AKT/FOXO1 and NFκB/IL-1ß/TNF-α signaling pathways in female Wistar albino rats.

Olanzapine-induced metabolic syndrome (MS) is a primary risk factor for insulin resistance, hepatorenal damage, and polycystic ovarian syndrome. The objective of the current study was to assess the protective effects of aprepitant (AP) against MS caused by olanzapine and the associated ovarian, renal, and liver dysfunction via modulation of IGF1/p-AKT/FOXO1 and NFκB/IL-1ß/TNF-α signaling pathways. AP mitigated all biochemical and histopathological abnormalities induced by olanzapine and resulted in a significant reduction of serum HOMA-IR, lipid profile parameters, and a substantial decrease in hepatic, renal, and ovarian MDA, IL-6, IL-1ß, TNF-α, NFκB, and caspase 3. Serum AST, ALT, urea, creatinine, FSH, LH, and testosterone also decreased significantly by AP administration. The FOXO 1 signaling pathway was downregulated in the AP-treated group, while GSH, SOD, and HDL cholesterol levels were elevated.

Association of Nilotinib With Cardiovascular Diseases in Patients With Chronic Myelogenous Leukemia: A National Population-Based Cohort Study.

BACKGROUND: Tyrosine kinase inhibitor (TKI) treatment has been identified to be a risk factor for metabolic syndrome and cardiovascular diseases (CVDs) in patients diagnosed with chronic myeloid leukemia (CML). However, the specific contribution of post-TKI metabolic syndrome and the individual TKIs, including imatinib, nilotinib, and dasatinib, contribute to the development of CVDs remains unclear. METHODS: We conducted a nationwide database to investigate the incidence of post-TKI metabolic syndrome, including diabetes, hyperlipidemia, and hypertension, as well as their association with CVDs. To compare the risk of post-TKI comorbidities and CVDs among TKIs, we utilized the incidence rate ratio (IRR), and subdistribution hazard ratio (SHR) calculated from multiple Fine-Gray models. RESULTS: A total of 1211 patients without diabetes, 1235 patients without hyperlipidemia, and 1074 patients without hypertension were enrolled in the study. The incidence rate of post-TKI diabetes and hyperlipidemia was the highest in patients treated with nilotinib compared to imatinib and dasatinib (IRRs ≥ 3.15, Ps ≤ .047). After adjusting for confounders, nilotinib remained a significant risk factor for post-TKI diabetes and hyperlipidemia at an SHR of 3.83 (P < .001) and 5.15 (P < .001), respectively. Regarding the occurrence of CVDs, patients treated with nilotinib were more likely to develop CVDs than those treated with imatinib in non-hyperlipidemic group (IRR = 3.21, P = .020). Pre-existing and post-TKI hyperlipidemia were found to have a stronger association with CVDs, with SHR values of 5.81 (P = .034) and 13.21 (P = .001), respectively. CONCLUSION: The findings of this study indicate that nilotinib treatment is associated with increased risks of diabetes and hyperlipidemia, with hyperlipidemia being the most significant risk for CVDs. Therefore, we recommend that CML patients receiving nilotinib should undergo screening for diabetes and hyperlipidemia prior to initiating TKI treatment. Additionally, regular monitoring of lipid profiles during TKI therapy and implementing effective management strategies to control hyperlipidemia are crucial.

Weight Gain After Antiretroviral Therapy Initiation and Subsequent Risk of Metabolic and Cardiovascular Disease.

BACKGROUND: Weight gain following initiation of antiretroviral therapy (ART) is common. We assessed the impact of changes in weight in the year following ART initiation with subsequent cardiometabolic disease among AIDS Clinical Trials Group (ACTG) participants. METHODS: Linear regression models were fit to examine the association between change in weight/waist circumference (WC) in weeks 0-48 and change in metabolic parameters in weeks 0-48 and 48-96. Cox proportional hazard models were fit to examine the association between changes in weight/WC in weeks 0-48 and diabetes mellitus (DM), metabolic syndrome, or cardiometabolic and cardiovascular events after week 48. RESULTS: Participants (N = 2624) were primarily male (81%) and non-White (60%). Mean weight gain from 0-48 weeks was 3.6 kg (SD 7.3); 130 participants developed DM; 360 metabolic syndrome; 424 any cardiometabolic event; 28 any cardiovascular event, over 480 weeks of follow-up. In adjusted models, total cholesterol increased by 0.63 mg/dL (95% confidence interval [CI] [.38, .089]) and LDL by 0.39 mg/dL (0.19, 0.59) per 1 kg increase in weight from weeks 0 to48. Participants who experienced >10% weight gain (vs -5% to 5%) had an increased risk of DM (hazard ratio [HR] 2.01, 95% CI [1.30, 3.08]), metabolic syndrome (HR 2.24, 95% CI [1.55, 2.62]), and cardiometabolic outcomes (HR 1.54, 95% CI [1.22, 1.95]). Participants who lost more than 5% of their baseline weight had a lower risk of incident metabolic syndrome (HR 0.67, 95% CI [0.42, 1.07]). Trends for WC were similar. CONCLUSIONS: Weight and body composition changes in the first year following ART initiation are associated with contemporaneous changes in metabolic parameters and subsequent cardiometabolic disease.

Umbrella Review: Association Between Antipsychotic Drugs and Metabolic Syndrome Hallmarks in Children and Adolescents.

OBJECTIVE: To summarize the available evidence on metabolic parameters indicating metabolic adverse effects and risk of metabolic syndrome in children and adolescents treated with antipsychotics, following a pre-specified protocol (PROSPERO ID 252336). METHOD: We searched PubMed, Embase and PsycINFO until May 14, 2021, to identify systematic reviews (SR), meta-analyses (MA) and network meta-analyses (NMA) examining symptoms associated to metabolic syndrome in patients <18 years of age who required treatment with oral antipsychotic drugs. Evidence from quantitative analyses for all outcomes related to anthropometric, glyco-metabolic, and blood pressure parameters (measured from baseline to intervention-end and/or follow-up, in subjects exposed to antipsychotics and placebo) was reported on the basis of their metrics (median difference [medianD], mean difference [MD], standardized mean difference [SMD], odds ratio [OR], risk ratio ([RR]). A qualitative synthesis was also made. A formal quality assessment of the included studies was carried out by using the AMSTAR 2. We also provided a hierarchical stratification of the evidence from meta-analyses based on the class of evidence. RESULTS: A total of 23 articles (13 MA, 4 NMA and 6 SR) were included for review. As compared with placebo, an increase in triglyceride levels was associated with olanzapine (medianD [95% CI]: 37 [12.27, 61.74] mg/dL; MD [95% CI]: 38.57 [21.44, 55.77] mg/dL) and quetiapine (medianD [95% CI]: 21.58 [95% CI]: 4.27, 38.31 mg/dL; MD [95% CI]: 34.87 [20.08, 49.67] mg/dL; SMD [95% CI]: 0.37 [0.06, 0.068]), whereas decreased triglyceride levels were found for lurasidone. Increased total cholesterol level was associated with asenapine (medianD [95% CI]: 9.1 [1.73, 16.44] mg/dL), quetiapine (medianD [95% CI]: 15.60 [7.30, 24.05] mg/dL; olanzapine (MD [95% CI] from 3.67 [1.43, 5.92] mg/dL to 20.47 [13.97, 26.94] mg/dL]; and lurasidone (medianD [95% CI]: 8.94 [1.27, 16.90] mg/dL). Change in glucose levels did not differ among antipsychotics or placebo. Lurasidone, molindone, and ziprasidone were the best tolerated in terms of weight gain. According to the AMSTAR 2 scoring system, 13 (56.5%) reviews were rated as very low quality. According to classes of evidence, most MA were level 4, especially because of their limited total sample size. CONCLUSION: By collating meta-analyses assessing biochemical markers of metabolic syndrome in antipsychotic-treated children, we conclude that olanzapine should not be the antipsychotic of choice in patients at risk for hypertriglyceridemia or hypercholesterolemia. Aripiprazole and lurasidone appear to be better tolerated in terms of metabolic adverse events. Insufficient meta-analytic data are available to provide a precise risk estimate of metabolic syndrome, and, overall, the quality of evidence is low. STUDY REGISTRATION INFORMATION: Association between the use of antipsychotic drugs and alterations of the parameters defining the Metabolic Syndrome (MetS) in children and adolescents: an umbrella review; https://www.crd.york.ac.uk/prospero/; CRD42021252336.

Associated factors with liver fibrosis in rheumatoid arthritis patients treated with methotrexate.

INTRODUCTION: There are conflicting findings on the link between liver fibrosis and cumulative methotrexate dosages. We aimed to determine the frequency of liver fibrosis in rheumatoid arthritis patients treated with methotrexate and to identify its associated factors. METHODS: We conducted a cross-sectional study over 9 months (April-December 2021), including rheumatoid arthritis patients treated with methotrexate. Demographic and clinical data were collected. Liver stiffness was assessed by FibroScan. Fibrosis and significant liver fibrosis were defined as liver stiffness higher than 6 and 7.2 kPa, respectively. Liver tests, albuminemia, lipid profile, and blood glycemia were measured. Metabolic syndrome was also evaluated. Statistical analyses were performed using SPSS. RESULTS: We included 21 men and 47 women. The mean age was 51.60 ± 1.82 years. The mean disease duration was 8.29 ± 6.48 years. The mean weekly intake of methotrexate was 13.76 ± 3.91 mg. The mean methotrexate duration was 4.67 ± 4.24 years. The mean cumulative dose was 3508.87 ± 3390.48 mg. Hypoalbuminemia and metabolic syndrome were found in 34% and 25% of cases. We noted increased alkaline phosphatase levels in four cases. The mean liver stiffness was 4.50 ± 1.53 kPa. Nine patients had liver fibrosis, and four had significant fibrosis. Associated factors with liver fibrosis were as follows: age ≥ 60 years (OR:22.703; 95%CI [1.238-416.487]; p = 0.035), cumulated dose of methotrexate ≥ 3 g (OR: 76.501; 95%CI [2.383-2456.070]; p = 0.014), metabolic syndrome (OR: 42.743; 95%CI [1.728-1057.273]; p = 0.022), elevated alkaline phosphatase levels (OR: 28.252; 95%CI [1.306-611.007]; p = 0.033), and hypoalbuminemia (OR: 59.302; 95%CI [2.361-1489.718]; p = 0.013). CONCLUSION: Cumulating more than 3 g of methotrexate was associated with liver fibrosis in rheumatoid arthritis patients. Having a metabolic syndrome, higher age, hypoalbuminemia, and elevated alkaline phosphatase levels were also likely to be independently associated with liver fibrosis. Key points • Rheumatoid arthritis patients require monitoring hepatic fibrosis when the cumulated dose of methotrexate is above 3 g. • Metabolic syndrome is a risk factor for liver fibrosis, suggesting that its management is necessary to prevent this complication. • Hypoalbuminemia and elevated alkaline phosphatase levels (twice the upper limit) in rheumatoid arthritis patients treated with methotrexate were associated with liver fibrosis.

An adenosine derivative prevents the alterations observed in metabolic syndrome in a rat model induced by a rich high-fat diet and sucrose supplementation.

Metabolic syndrome is a multifactorial disease with high prevalence worldwide. It is related to cardiovascular disease, diabetes, and obesity. Approximately 80% of patients with metabolic syndrome have some degree of fatty liver disease. An adenosine derivative (IFC-305) has been shown to exert protective effects in models of liver damage as well as on elements involved in central metabolism; therefore, here, we evaluated the effect of IFC-305 in an experimental model of metabolic syndrome in rats induced by a high-fat diet and 10% sucrose in drinking water for 18 weeks. We also determined changes in fatty acid uptake in the Huh-7 cell line. In the experimental model, increases in body mass, serum triglycerides and proinflammatory cytokines were induced in rats, and the adenosine derivative significantly prevented these changes. Interestingly, IFC-305 prevented alterations in glucose and insulin tolerance, enabling the regulation of glucose levels in the same way as in the control group. Histologically, the alterations, including mitochondrial morphological changes, observed in response to the high-fat diet were prevented by administration of the adenosine derivative. This compound exerted protective effects against metabolic syndrome, likely due to its action in metabolic regulation, such as in the regulation of glucose blood levels and hepatocyte fatty acid uptake.

Nurse-led lifestyle intervention in a cohort of schizophrenia patients treated with clozapine.

Patients diagnosed with schizophrenia are characterized by early mortality compared to the general population. The main cause of this premature death reflects medical complications linked to metabolic syndrome (MetS). The use of antipsychotics such as clozapine is associated with weight gain and metabolic disturbances in certain predisposed individuals. Non-pharmacological interventions for weight control have become a key element for secondary prevention in the health of patients diagnosed with schizophrenia. Here, we aim to evaluate the physical health effects of a nurse-led non-pharmacological intervention program in patients with a diagnosis of schizophrenia treated with clozapine. Thirty-one outpatients from the outpatient clinical facility of Hospital Clinic in Barcelona, Spain diagnosed with schizophrenia and other psychotic disorders receiving clozapine treatment were enrolled in a prospective interventional study, comprising an 8-week group program of therapeutic education in a healthy lifestyle. MetS factors, physical activity, diet, and lifestyle were evaluated at baseline, post-intervention (8 weeks), and 3 months after the program. Weight, body mass index, high-density lipoprotein cholesterol, and diet patterns displayed significant differences post-intervention and after 3 months, while only waist, hip perimeter, and lifestyle improved post-intervention. Our results suggest the effectiveness of the lifestyle intervention in patients under clozapine treatment despite its long-time differential effect. Strategies to prevent weight gain and metabolic decline will help prevent premature cardiometabolic disease in this vulnerable population.

Cross-sectional associations between phthalates, phenols, and parabens with metabolic syndrome risk during early-to-mid adolescence among a cohort of Mexican youth.

BACKGROUND: Epidemiological studies on children and adults have linked toxicants from plastics and personal care products to metabolic disruption. Yet, the impact of endocrine-disrupting chemicals (EDCs) on adolescent metabolic syndrome (MetS) risk during early and mid-adolescence is unclear. METHODS: To examine the links between exposure to EDCs and MetS risk and its components, cross-sectional data from 344 Mexican youth in early-to-mid adolescence (10-17 years) were analyzed. Urinary biomarker concentrations of phthalates, phenol, and paraben analytes were measured from a single spot urine sample collected in 2015; study personnel obtained anthropometric and metabolic measures. We examined associations between summary phthalates and metabolites, phenol, and paraben analytes with MetS risk z-scores using linear regression, adjusted for specific gravity, sex, age, pubertal status, smoking, alcohol intake, physical activity level, and screen time. As a secondary aim, mediation analysis was conducted to evaluate the role of hormones in the association between summary phthalates with lipids and MetS risk z-scores. RESULTS: The mean (SD) age was 13.2 (1.9) years, and 50.9% were female. Sex-stratified analyses revealed associations between summary phthalates and lipids ratio z-scores, including Σ DEHP [ß = 0.21 (95% CI: 0.04, 0.37; p < 0.01)], phthalates from plastic sources (Σ Plastic) [ß = 0.22 (95% CI: 0.05, 0.39; p < 0.01)], anti-androgenic phthalates (Σ AA) [ß = 0.22 (95% CI: 0.05, 0.39; p < 0.01)], and individual phthalate metabolites (MEHHP, MEOHP, and MECPP) among males. Among females, BPA [ß = 0.24 (95% CI: 0.03, 0.44; p < 0.05)] was positively associated with lipids ratio z-score and one phenol (2,5 DCP) [ß = 0.09 (95% CI: 0.01, 0.18); p < 0.05)] was associated with increased waist circumference z-score. Results showed no evidence of mediation by hormone concentrations in the association between summary phthalates with lipids ratio or MetS risk z-scores. CONCLUSION: Higher EDC exposure was positively associated with serum lipids during adolescence, particularly among males.

Understanding the Perspective of Youths on Undergoing Metabolic Monitoring While on Second-Generation Antipsychotics: Challenges, Insight, and Implications.

Introduction: Prescription of second-generation antipsychotics (SGAs) in youths is rapidly increasing globally, despite the potential for significant adverse effects and long-term health consequences. A known adverse reaction resulting from SGAs is metabolic syndrome (MS). Youths exposed to antipsychotics are at higher risk than adults for adverse drug reactions, including adverse events such as MS (with weight gain as the most significant adverse outcome) and other long-term endocrinological abnormalities. This study aimed to explore the experiences of young patients on factors impacting barriers to metabolic monitoring of SGAs and the strategies to address those barriers thereby providing further guidance on policy and service delivery. Methods: Semi-structured interviews were conducted with patients (youths who were prescribed SGAs) who attended Child and Youth Mental Health Services. The interviews focused on barriers to monitoring and strategies to enhance rates of monitoring that could be customized across study sites. Results: Young patients revealed that none of them had any concerns or objections to receiving anthropometric metabolic measurements. However, they seemed concerned to undergo blood tests as part of the metabolic monitoring process. Specifically, youths cited their fear of the needles as barrier to undergo the required blood tests. Youths have also reported that their dislike to healthy foods and exercise being the most common challenge they face while trying to engage in a healthy lifestyle to manage the SGAs resulted weight gain. Conclusion: Prescribers are recommended to actively engage young patients about the expected SGAs-induced adverse effects, the importance of conducting metabolic monitoring, and how to prevent and minimize the expected adverse effects from the start of initiating SGAs. This could be a vital step toward a successful treatment as the insight of youths into the details of the chosen treatment can play a significant role into treatment adherence and recovery.

Effect of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and benzo[a]pyrene exposure on the development of metabolic syndrome in mice.

AIM: The prevalence of metabolic syndrome (MetS), a cluster of serious medical conditions that raise the risk of lung cancer, has increased worldwide. Tobacco smoking (TS) potentially increases the risk of developing MetS. Despite the potential association of MetS with lung cancer, preclinical models that mimic human diseases, including TS-induced MetS, are limited. Here we evaluated the impact of exposure to tobacco smoke condensate (TSC) and two representative tobacco carcinogens, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNK) and benzo[a]pyrene (BaP), on MetS development in mice. MATERIALS AND METHODS: FVB/N or C57BL/6 mice were exposed to vehicle, TSC, or NNK and BaP (NB) twice weekly for 5 months. The serum levels of total cholesterol (TCHO), triglycerides, high-density lipoprotein (HDL), blood glucose, and metabolites, along with glucose tolerance and body weight, were measured. KEY FINDINGS: Compared with those of vehicle-treated mice, mice with TSC or NB exposure displayed major phenotypes associated with MetS, including increased serum levels of TCHO, triglycerides, and fasting and basal blood glucose and decreased glucose tolerance, and serum levels of HDL. These MetS-associated changes were found in both FVB/N and C57BL/6 mice that were susceptible or resistant to carcinogen-induced tumorigenesis, respectively, indicating that tumor formation is not involved in the TSC- or NB-mediated MetS. Moreover, oleic acid and palmitoleic acid, which are known to be associated with MetS, were significantly upregulated in the serum of TSC- or NB-treated mice compared with those in vehicle-treated mice. SIGNIFICANCE: Both TSC and NB caused detrimental health problems, leading to the development of MetS in experimental mice.

Co-administration of rimonabant prevents glucose intolerance in Sprague-Dawley rats treated chronically with lopinavir/ritonavir and zidovudine: an experimental study design.

Introduction: treatment of HIV infection with Protease Inhibitors (PIs) and Nucleoside Reverse Transcriptase Inhibitors (NRTIs) can lead to insulin resistance and changes in body fat distribution. Overactivity of the endogenous cannabinoid system produces similar disturbances in metabolic syndrome within the general population. However, Cannabinoid receptor type 1 antagonism, in both human and animal studies, reverses many of these biochemical and physical derangements observed in the metabolic syndrome. Methods: using an experimental study design, fifteen adult male Sprague-Dawley rats housed under standard conditions were randomized into three groups; Control, combined Anti-Retroviral Therapy (cART) only and cART + rimonabant. Drugs were administered daily by oral gavage for four weeks. After four weeks, insulin tolerance tests were conducted, the rats were euthanised and fat depots were excised and weighed. Experimental data were analysed using STATA 16.0 with the significance level set at p<0.05. The Shapiro-Wilk test determined normalcy. In cases of significance, post hoc analysis was performed by either the Dunn test or the Tukey HSD test. Results: Sprague Dawley rats treated with cART + rimonabant demonstrated better insulin sensitivity (p = 0.0239) and lower body weight (p = 0.044) than rats treated with cART alone. They had leaner body composition with 58% less adiposity than cART-only rats. Conclusion: the study results suggest a role for the endogenous cannabinoid system in cART induced metabolic derangements and physical changes. Future studies can directly assay ECS activity in cART associated metabolic syndrome.

Long-term air pollution exposure and markers of cardiometabolic health in the National Longitudinal Study of Adolescent to Adult Health (Add Health).

BACKGROUND: Air pollution exposure is associated with cardiovascular morbidity and mortality. Although exposure to air pollution early in life may represent a critical window for development of cardiovascular disease risk factors, few studies have examined associations of long-term air pollution exposure with markers of cardiovascular and metabolic health in young adults. OBJECTIVES: By combining health data from the National Longitudinal Study of Adolescent to Adult Health (Add Health) with air pollution data from the Fused Air Quality Surface using Downscaling (FAQSD) archive, we: (1) calculated multi-year estimates of exposure to ozone (O3) and particulate matter with an aerodynamic diameter ≤ 2.5 µm (PM2.5) for Add Health participants; and (2) estimated associations between air pollution exposures and multiple markers of cardiometabolic health. METHODS: Add Health is a nationally representative longitudinal cohort study of over 20,000 adolescents aged 12-19 in the United States (US) in 1994-95 (Wave I). Participants have been followed through adolescence and into adulthood with five in-home interviews. Estimated daily concentrations of O3 and PM2.5 at census tracts were obtained from the FAQSD archive and used to generate tract-level annual averages of O3 and PM2.5 concentrations. We estimated associations between average O3 and PM2.5 exposures from 2002 to 2007 and markers of cardiometabolic health measured at Wave IV (2008-09), including hypertension, hyperlipidemia, body mass index (BMI), diabetes, C-reactive protein, and metabolic syndrome. RESULTS: The final sample size was 11,259 individual participants. The average age of participants at Wave IV was 28.4 years (range: 24-34 years). In models adjusting for age, race/ethnicity, and sex, long-term O3 exposure (2002-07) was associated with elevated odds of hypertension, with an odds ratio (OR) of 1.015 (95% confidence interval [CI]: 1.011, 1.029); obesity (1.022 [1.004, 1.040]); diabetes (1.032 [1.009,1.054]); and metabolic syndrome (1.028 [1.014, 1.041]); PM2.5 exposure (2002-07) was associated with elevated odds of hypertension (1.022 [1.001, 1.045]). CONCLUSION: Findings suggest that long-term ambient air pollution exposure, particularly O3 exposure, is associated with cardiometabolic health in early adulthood.

The effect of exenatide (a GLP-1 analogue) and sitagliptin (a DPP-4 inhibitor) on asymmetric dimethylarginine (ADMA) metabolism and selected biomarkers of cardiac fibrosis in rats with fructose-induced metabolic syndrome.

Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthesis, is a risk factor for endothelial dysfunction, a common pathophysiological denominator for both atherogenesis and cardiac fibrosis. We aimed to investigate whether the cardioprotective and antifibrotic effects of incretin drugs, exenatide and sitagliptin, may be associated with their ability to affect circulating and cardiac ADMA metabolism. Normal and fructose-fed rats were treated with sitagliptin (5.0/10 mg/kg) or exenatide (5/10 µg/kg) for 4 weeks. The following methods were used: LC-MS/MS, ELISA, Real-Time-PCR, colorimetry, IHC and H&E staining, PCA and OPLS-DA projections. Eight-week fructose feeding resulted in an increase in plasma ADMA and a decrease in NO concentration. Exenatide administration into fructose-fed rats reduced the plasma ADMA level and increased NO level. In the heart of these animals exenatide administration increased NO and PRMT1 level, reduced TGF-ß1, α-SMA levels and COL1A1 expression. In the exenatide treated rats renal DDAH activity positively correlated with plasma NO level and negatively with plasma ADMA level and cardiac α-SMA concentration. Sitagliptin treatment of fructose-fed rats increased plasma NO concentration, reduced circulating SDMA level, increased renal DDAH activity and reduced myocardial DDAH activity. Both drugs attenuated the myocardial immunoexpression of Smad2/3/P and perivascular fibrosis. In the metabolic syndrome condition both sitagliptin and exenatide positively modulated cardiac fibrotic remodeling and circulating level of endogenous NOS inhibitors but had no effects on ADMA levels in the myocardium.