MG53 E3 Ligase-dead Mutant Protects Diabetic Hearts from Acute Ischemic/Reperfusion Injury and Ameliorates Diet-induced Cardiometabolic Damage

Cardiometabolic diseases, including diabetes and its cardiovascular complications, are the global leading cause of death, highlighting a major unmet medical need. Over the last decade, MG53, also named TRIM72, has emerged as a powerful agent for myocardial membrane repair and cardioprotection, but its therapeutic value is complicated by its E3 ligase activity that mediates metabolic disorders. Here, we show that an E3 ligase-dead mutant, MG53-C14A, retains its cardioprotective function without causing metabolic side-effects. When administrated in normal animals, both recombinant human wild type MG53 protein (rhMG53-WT) and its E3 ligase-dead mutant (rhMG53-C14A) protect the heart equally from myocardial infarction and ischemia/reperfusion (I/R) injury. However, in diabetic <i>db/db</i> mice, rhMG53-WT treatment markedly aggravates hyperglycemia, cardiac I/R injury and mortality, whereas acute and chronic treatment of rhMG53-C14A still effectively ameliorates I/R-induced myocardial injury and mortality or diabetic cardiomyopathy, respectively, without inflicting metabolic side-effects. Furthermore, knock-in of MG53-C14A protects the mice from high-fat diet-induced metabolic disorders and cardiac damage. Thus, the E3 ligase-dead mutant MG53-C14A not only protects the heart from acute myocardial injury but also counteract metabolic stress, providing a potentially important therapy for the treatment of acute myocardial injuries amidst metabolic disorders, including diabetes and obesity.

MG53 E3 Ligase-dead Mutant Protects Diabetic Hearts from Acute Ischemic/Reperfusion Injury and Ameliorates Diet-induced Cardiometabolic Damage

Cardiometabolic diseases, including diabetes and its cardiovascular complications, are the global leading cause of death, highlighting a major unmet medical need. Over the last decade, MG53, also named TRIM72, has emerged as a powerful agent for myocardial membrane repair and cardioprotection, but its therapeutic value is complicated by its E3 ligase activity that mediates metabolic disorders. Here, we show that an E3 ligase-dead mutant, MG53-C14A, retains its cardioprotective function without causing metabolic side-effects. When administrated in normal animals, both recombinant human wild type MG53 protein (rhMG53-WT) and its E3 ligase-dead mutant (rhMG53-C14A) protect the heart equally from myocardial infarction and ischemia/reperfusion (I/R) injury. However, in diabetic <i>db/db</i> mice, rhMG53-WT treatment markedly aggravates hyperglycemia, cardiac I/R injury and mortality, whereas acute and chronic treatment of rhMG53-C14A still effectively ameliorates I/R-induced myocardial injury and mortality or diabetic cardiomyopathy, respectively, without inflicting metabolic side-effects. Furthermore, knock-in of MG53-C14A protects the mice from high-fat diet-induced metabolic disorders and cardiac damage. Thus, the E3 ligase-dead mutant MG53-C14A not only protects the heart from acute myocardial injury but also counteract metabolic stress, providing a potentially important therapy for the treatment of acute myocardial injuries amidst metabolic disorders, including diabetes and obesity.

Metabolic side effects of antipsychotic drugs in individuals with schizophrenia during medium- to long-term treatment: protocol for a systematic review and network meta-analysis of randomized controlled trials

Background Antipsychotic drugs and especially the newer compounds are known to cause metabolic side effects. However, a comprehensive comparison of the different substances regarding their propensity to cause metabolic side effects in medium- to long-term treatment of schizophrenia is lacking. Methods We will conduct a systematic review and network meta-analysis (NMA). We will include randomized controlled trials (RCTs) in which participants received either placebo or an antipsychotic (i.e. placebo-controlled trials and head-to-head comparisons of drugs). We will include studies in individuals with schizophrenia or related disorders (such as schizophreniform or schizoaffective disorders) at any stage of the disease (acute episode; maintenance phase). We will include studies with a duration of more than 3 months (medium- to long-term treatment). The primary outcome will be the change in body weight. Secondary outcomes will be the further metabolic parameters: fastening glucose, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides. We will search for eligible studies (independent of the publication status) in Cochrane Schizophrenia Group’s Study-Based Register of Trials, which is compiled by regular searches in trial registries and multiple electronic databases from their inception onwards including MEDLINE, EMBASE and PsycINFO. Additionally, we will search previously published systematic reviews and websites of pharmaceutical companies for eligible studies. At least two reviewers will independently conduct the process of study selection and data extraction. We will use the Cochrane Risk of Bias 2 tool to evaluate the risk of bias in studies. We will conduct random-effects NMA within a Bayesian framework to synthesize all evidence for each outcome. We will conduct sensitivity and subgroup analyses to assess the robustness of the findings and to explore heterogeneity. The confidence in the results will be evaluated using the Confidence in Network Meta-Analysis (CINeMA) framework. Discussion This systematic review and network meta-analysis will provide a synthesis of the existing evidence from RCTs how antipsychotic drugs differ in terms of metabolic side effects during medium- to long-term treatment. The findings have the potential to influence the choice of antipsychotic medication made by individuals with schizophrenia and their physicians. Systematic review registration PROSPERO CRD42020175414

Audit on the monitoring of metabolic side effects of antipsychotics in acute inpatient psychiatric units at Fieldhead Hospital

AimsThe current audit aims to assess the compliance with Prescribing Observatory for Mental Health (POMH-UK) guidance on monitoring of metabolic side effects of patients prescribed antipsychotics. Compliance was monitored to ensure that all patients prescribed continuing antipsychotics have their body mass index (BMI), blood pressure, blood glucose and lipids checked within the expected time limits of minimum once per year.BackgroundPatients diagnosed with Schizophrenia rank amongst the worst of chronic medical illnesses in terms of quality of life. This may in part be due to the use of long term antipsychotic medications, in particular the use of atypical antipsychotics which have been increasingly associated with metabolic side effects including hypertension, weight gain, glucose intolerance and dyslipidaemia. These side effects are related to the development of both diabetes mellitus and cardiovascular disease and can lead to increased mortality and morbidity, affecting compliance and engagement to healthcare services. Despite the availability of clinical guidelines, monitoring and screening of metabolic side effects in patients prescribed antipsychotics continues to be suboptimal.MethodThe audit involved a review of electronic records relating to physical health monitoring of patients at two acute inpatient units from January-March 2019. Demographic and clinical variables were collected which included ethnicity, diagnostic grouping as well as current medications. Data were collected on evidence of screening for hypertension, BMI, blood glucose and lipids. Descriptive statistics were applied to study the clinical features of the sample and examine whether performance met clinical practice standard.ResultThe audit overall demonstrated partial compliance with POMH-UK guidelines with a total of 31 patients admitted on long term antipsychotics. Of these patients, 86% were prescribed atypical antipsychotics with 14% prescribed typical antipsychotics. Screening only occurred in 68% of patients for lipid profile with only 71% for BMI and 74% for blood glucose. Blood pressure had the highest compliance rate of 87% of patients being screened.ConclusionEarly identification and monitoring of complications from metabolic syndrome may decrease the risk of more serious health outcomes and improve patients’ quality of life. However in clinical practice, standards are not always met in accordance with best practice recommendations. Requirement of a tailored guideline for physical health monitoring with weekly planned interventions as well as adequate training and awareness of healthcare staff is imperative to drive improvement and increase adherence rates.

Monitoring of metabolic side-effects in children and adolescents prescribed antipsychotic medication: A systematic review

Objectives: Prescribing antipsychotic medications to children and adolescents with severe mental and developmental disorders is common; however, there is a lack of consensus on appropriate metabolic monitoring for this population. This review systematically evaluates studies examining metabolic monitoring of children and adolescents prescribed antipsychotic medication to understand the clinical practice of metabolic monitoring and identify opportunities to improve the safety of antipsychotic prescribing in this population. Methods: A systematic search for original research on metabolic monitoring in children and adolescents prescribed antipsychotics was conducted in six databases (PubMed, EMBASE, PsycINFO, The Cochrane Library [Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, CENTRAL], Cochrane Methodology Register and Web of Science [Science and Social Science Citation Index]) from inception to February 2020 following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies were assessed for quality and findings summarised using narrative synthesis. Results: Fifteen papers were identified. Studies agreed on the need for metabolic monitoring; however, there was a gap between guideline-recommended practice and clinical practice. Variable rates of baseline and subsequent monitoring were reported for both physical and biochemical parameters, with particularly low rates for monitoring requiring venesection. Younger age was also associated with lower monitoring rates. Implementation of quality improvement activities (new guidelines, staff education and checklists) improved monitoring rates although the measurement of biochemical parameters still occurred in only a minority of children. Conclusion: Despite widespread awareness and concern regarding metabolic side-effects, monitoring occurred inconsistently and infrequently, particularly for biochemical parameters requiring venesection. Monitoring of anthropometric measures (weight, body mass index and waist circumference) with escalation to more laboratory testing where metabolic concerns are identified may improve monitoring. Minimising iatrogenic harm, through reduced antipsychotic prescription where possible, is a clinical priority in this population.

A Focused Review of the Metabolic Side-Effects of Clozapine

The second generation antipsychotic drug clozapine represents the most effective pharmacotherapy for treatment-resistant psychosis. It is also associated with low rates of extrapyramidal symptoms and hyperprolactinemia compared to other antipsychotic drugs. However, clozapine tends to be underutilized in clinical practice due to a number of disabling and serious side-effects. These are characterized by a constellation of metabolic side-effects which include dysregulation of glucose, insulin, plasma lipids and body fat. Many patients treated with clozapine go on to develop metabolic syndrome at a higher rate than the general population, which predisposes them for Type 2 diabetes mellitus and cardiovascular disease. Treatments for the metabolic side-effects of clozapine vary in their efficacy. There is also a lack of knowledge about the underlying physiology of how clozapine exerts its metabolic effects in humans. In the current review, we focus on key studies which describe how clozapine affects each of the main symptoms of the metabolic syndrome, and cover some of the treatment options. The clinical data are then discussed in the context of preclinical studies that have been conducted to identify the key biological substrates involved, in order to provide a better integrated overview. Suggestions are provided about key areas for future research to better understand how clozapine causes metabolic dysregulation.

Dietary fiber and probiotics for the treatment of atypical antipsychotic-induced metabolic side effects: study protocol for a randomized, double-blind, placebo-controlled trial

Background Atypical antipsychotic medications, which are effective for the treatment of schizophrenia and bipolar disorder, are associated with features of metabolic syndrome, such as weight gain, hyperglycemia, dyslipidemia, and insulin resistance. Although there are a few studies on the effects of dietary fiber or probiotics on weight loss in obese people, no published trials have reported the efficacy of dietary fiber and probiotics on reducing atypical antipsychotic-induced weight gain. Methods For this 12-week randomized, double-blind, placebo-controlled study, 100 patients with a weight gain of more than 10% after taking atypical antipsychotic medications were recruited. Participants were randomized to four groups as follows: probiotics (840 mg twice daily (bid)) plus dietary fiber (30 g bid), probiotics (840 mg bid) plus placebo, placebo plus dietary fiber (30 g bid), or placebo group. The primary outcome was the change in body weight. Secondary outcomes included changes in metabolic syndrome parameters, appetite score, biomarkers associated with a change in weight, and gut microbiota composition and function. Discussion To date, this is the first randomized, placebo-controlled, double-blinded trial investigating the efficacy of dietary fiber and probiotics alone and in combination to reduce metabolic side effects induced by atypical antipsychotic medications. If effective, it is possible to conclude that dietary fiber and probiotics can reduce atypical antipsychotic-induced metabolic side effects. Trial registration number ClinicalTrials.gov NCT03379597. Registered on 19 November 2017.

Effect of liraglutide on neural and peripheral markers of metabolic function during antipsychotic treatment in rats

Background: Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist that prevents metabolic side effects of the antipsychotic drugs (APDs) olanzapine and clozapine through unknown mechanisms. Aim: This study aimed to investigate the effect of chronic APD and liraglutide co-treatment on key neural and peripheral metabolic signals, and acute liraglutide co-treatment on clozapine-induced hyperglycaemia. Methods: In study 1, rats were administered olanzapine (2 mg/kg), clozapine (12 mg/kg), liraglutide (0.2 mg/kg), olanzapine + liraglutide co-treatment, clozapine + liraglutide co-treatment or vehicle for six weeks. Feeding efficiency was examined weekly. Examination of brain tissue (dorsal vagal complex (DVC) and mediobasal hypothalamus (MBH)), plasma metabolic hormones and peripheral (liver and kidney) cellular metabolism and oxidative stress was conducted. In study 2, rats were administered a single dose of clozapine (12 mg/kg), liraglutide (0.4 mg/kg), clozapine + liraglutide co-treatment or vehicle. Glucose tolerance and plasma hormone levels were assessed. Results: Liraglutide co-treatment prevented the time-dependent increase in feeding efficiency caused by olanzapine, which plateaued by six weeks. There was no effect of chronic treatment on melanocortinergic, GABAergic, glutamatergic or endocannabionoid markers in the MBH or DVC. Peripheral hormones and cellular metabolic markers were unaltered by chronic APD treatment. Acute liraglutide co-treatment was unable to prevent clozapine-induced hyperglycaemia, but it did alter catecholamine levels. Conclusion: The unexpected lack of change to central and peripheral markers following chronic treatment, despite the presence of weight gain, may reflect adaptive mechanisms. Further studies examining alterations across different time points are required to continue to elucidate the mechanisms underlying the benefits of liraglutide on APD-induced metabolic side effects.

A comparison of the metabolic side-effects of the second-generation antipsychotic drugs risperidone and paliperidone in animal models

Background The second generation antipsychotic drugs represent the most common form of pharmacotherapy for schizophrenia disorders. It is now well established that most of the second generation drugs cause metabolic side-effects. Risperidone and its active metabolite paliperidone (9-hydroxyrisperidone) are two commonly used antipsychotic drugs with moderate metabolic liability. However, there is a dearth of preclinical data that directly compares the metabolic effects of these two drugs, using sophisticated experimental procedures. The goal of the present study was to compare metabolic effects for each drug versus control animals. Methods Adult female rats were acutely treated with either risperidone (0.1, 0.5, 1, 2, 6 mg/kg), paliperidone (0.1, 0.5, 1, 2, 6 mg/kg) or vehicle and subjected to the glucose tolerance test; plasma was collected to measure insulin levels to measure insulin resistance with HOMA-IR. Separate groups of rats were treated with either risperidone (1, 6 mg/kg), paliperidone (1, 6 mg/kg) or vehicle, and subjected to the hyperinsulinemic euglycemic clamp. Results Fasting glucose levels were increased by all but the lowest dose of risperidone, but only with the highest dose of paliperidone. HOMA-IR increased for both drugs with all but the lowest dose, while the three highest doses decreased glucose tolerance for both drugs. Risperidone and paliperidone both exhibited dose-dependent decreases in the glucose infusion rate in the clamp, reflecting pronounced insulin resistance. Conclusions In preclinical models, both risperidone and paliperidone exhibited notable metabolic side-effects that were dose-dependent. Differences between the two were modest, and most notable as effects on fasting glucose.