Adverse Metabolic Effects Research Articles

Role of D2 receptor (–141 C Ins/Del) genetic polymorphism on olanzapine-induced adverse drug reaction in schizophrenic patients

Olanzapine is commonly prescribed for the management of schizophrenia and is associated with many adverse effects like weight gain, hyperglycemia, and hyperprolactinemia, which may increase the risk of other diseases like diabetes mellitus and cardiovascular diseases. Genetic polymorphism of the D2 receptor may be responsible for the incidence of such adverse effects. This study aimed to assess the role of D2 receptor–141 C Ins/Del (rs1799732) genetic polymorphism and olanzapine-induced adverse effects in Iraqi schizophrenic patients. The case-control study was performed from October 2022 to April 2023 in Al-Hassan Al-Mojtaba Hospital. A total of 100 schizophrenic patients consisting of both genders, aged between 20 and 65 years, were recruited from the Psychiatry Outpatient Department, and 50 apparently healthy without any disease comprising both genders aged 20 to 63 years, served as a control group and were also enrolled in this study. Plasma level of FBS, HbA1c, lipid profile, and prolactin were measured, and genotyping of D2 Receptor–141 C Ins/Del (rs1799732) Polymorphisms was detected using the RFLP method. The heterozygous (Ins/Del) and mutant (Del/Del) alleles of D2 receptor–141 C Ins/Del (rs1799732) was significantly predominated in schizophrenic patient and absent in healthy volunteers. Schizophrenic patients with the deletion allele of D2 receptor–141 C Ins/Del and who were administered olanzapine (rs1799732) exhibited notably higher susceptibility to metabolic adverse effects induced by olanzapine, such as weight gain, hyperglycemia, dyslipidemia, and hyperprolactinemia. In conclusion, the genetic polymorphism of D2 receptor–141 C Ins/Del (rs1799732) was significantly associated with olanzapine induce metabolic adverse effects in Iraqi schizophrenic patients.

Is Physical Activity an Efficient Strategy to Control the Adverse Effects of Persistent Organic Pollutants in the Context of Obesity? A Narrative Review.

Obesity affects nearly 660 million adults worldwide and is known for its many comorbidities. Although the phenomenon of obesity is not fully understood, science regularly reveals new determinants of this pathology. Among them, persistent organic pollutants (POPs) have been recently highlighted. Mainly lipophilic, POPs are normally stored in adipose tissue and can lead to adverse metabolic effects when released into the bloodstream. The main objective of this narrative review is to discuss the different pathways by which physical activity may counteract POPs' adverse effects. The research that we carried out seems to indicate that physical activity could positively influence several pathways negatively influenced by POPs, such as insulin resistance, inflammation, lipid accumulation, adipogenesis, and gut microbiota dysbiosis, that are associated with the development of obesity. This review also indicates how, through the controlled mobilization of POPs, physical activity could be a valuable approach to reduce the concentration of POPs in the bloodstream. These findings suggest that physical activity should be used to counteract the adverse effects of POPs. However, future studies should accurately assess its impact in specific situations such as bariatric surgery, where weight loss promotes POPs' blood release.

Patients With Autoimmune Hepatitis and Nonalcoholic Fatty Liver Disease: Characteristics, Treatment, and Outcomes.

The objective of this study was to characterize an autoimmune hepatitis (AIH)/nonalcoholic fatty liver disease (NAFLD) overlap cohort, determine if they received standard of care treatment, and delineate their outcomes in comparison with patients with AIH or NAFLD alone. AIH is a relatively rare and heterogeneously presenting liver disease of unknown etiology. NAFLD is a leading cause of liver disease worldwide. AIH treatment includes steroids, which have adverse metabolic effects that can worsen NAFLD. No treatment guidelines are available to mitigate this side on AIH/NAFLD overlap patients. Few studies to date have examined these patients' characteristics, management practices, and outcomes. A single-center, retrospective chart review study examining biopsy-proven AIH/NAFLD, AIH, and NAFLD patients. Characteristics, treatment, and 1- and 3-year outcomes (all-cause mortality, need for liver transplantation, or decompensated cirrhosis) were evaluated. A total of 72 patients (36.1% AIH/NAFLD, 34.7% AIH, and 29.2% NAFLD) were included. AIH/NAFLD patients were found to be more often Hispanic/Latino, female, and with lower liver aminotransaminases, immunoglobulin G, and anti-smooth muscle antibody positivity. AIH/NAFLD patients were less likely to receive standard of care treatment. No significant differences in outcomes were seen between AIH/NAFLD and either AIH or NAFLD. Our study demonstrated that AIH/NAFLD patients have unique characteristics and are less likely to receive standard of care treatment compared with patients with AIH alone. Despite this, no difference in outcomes (all-cause mortality, need for liver transplantation, or decompensated cirrhosis) was seen. Given NAFLD's rising prevalence, AIH/NAFLD cases will likely increase, and may benefit from alternative treatment guidelines to prevent worsening of NAFLD.

Modulation of Leucine Sensors to Mitigate Antipsychotics-Induced Metabolic Syndrome: A New Vista.

Second-generation antipsychotics (SGAs) are currently the mainstay in the pharmacotherapy of some psychiatric disorders, which have improved the quality of life of millions of patients globally. A broad spectrum of activity and diminished liabilities of extrapyramidal side effects have made SGAs better alternatives compared to first-generation antipsychotics. Nevertheless, they display a complex profile of activity by affecting an array of biological targets and, as a result, are associated with a constellation of metabolic abnormalities such as hyperglycemia, dyslipidemia, weight gain, and cardiovascular problems. The SGAs-induced metabolic syndrome's exact mechanism has remained nebulous, but some evidence points the finger at mTOR signaling. In this viewpoint, we propose potential strategies to prevent or alleviate the SGA-induced metabolic adverse effects by modulating the activity of the leucine sensors, Sestrins.

Perinatal triphenyl phosphate exposure induces metabolic dysfunctions through the EGFR/ERK/AKT signaling pathway: Mechanistic in vitro and in vivo studies

Triphenyl phosphate (TPhP), a widely used organophosphate-flame retardant, is ubiquitously found in household environments and may adversely affect human health. Evidence indicates that TPhP exposure causes metabolic dysfunctions in vivo; however, the underlying mechanism of such adverse effects has not been comprehensively investigated. Herein, we utilized two in vitro models including mouse and human preadipocytes to delineate adipogenic mechanisms of TPhP. The results revealed that both mouse and human preadipocytes exposed to TPhP concentration-dependently accumulated more fat through a significant upregulation of epidermal growth factor receptor (EGFR). We demonstrated that TPhP significantly promoted adipogenesis through the activation of EGFR/ERK/AKT signaling pathway as evident by a drastic reduction in adipogenesis of preadipocytes cotreated with inhibitors of EGFR and its major effectors. Furthermore, we confirmed the mechanism of TPhP-induced metabolic dysfunctions in vivo. We observed that male mice perinatally exposed to TPhP had a significant increase in adiposity, hepatic triglycerides, insulin resistance, plasma insulin levels, hypotension, and phosphorylated EGFR in gonadal fat. Interestingly, an administration of a potent and selective EGFR inhibitor significantly ameliorated the adverse metabolic effects caused by TPhP. Our findings uncovered a potential mechanism of TPhP-induced metabolic dysfunctions and provided implications on toxic metabolic effects posed by environmental chemicals.

Evaluation of antipsychotic monitoring in a community health center during the COVID‐19 pandemic

AbstractBackgroundThe coronavirus disease 2019 (COVID‐19) pandemic complicated providers' ability to appropriately monitor patients on antipsychotic medications, as visits moved to telehealth. Adverse metabolic and movement effects can be difficult to assess virtually, reducing adherence to national antipsychotic guidelines. This review was conducted to evaluate provider adherence to antipsychotic medication monitoring during the COVID‐19 pandemic, educate providers on the proper antipsychotic monitoring methods, and then reassess adherence to guidelines.MethodsThis was a retrospective chart review of patients receiving antipsychotics from mental health (MH) and primary care (PC) providers consisting of three phases. Providers prescribing antipsychotics between June 1, 2021, and June 1, 2022, were included in phase one. Patients were reviewed for relevant data including demographics, antipsychotic(s) prescribed, glucose, hemoglobin A1c, total cholesterol, low‐density lipoprotein (LDL), high‐density lipoprotein (HDL), triglycerides, weight/ body mass index (BMI), waist circumference, Abnormal Involuntary Movement Scale (AIMS), and other movement disorder assessments. Providers were then given an educational flyer outlining proper antipsychotic monitoring in October 2022 as phase two. During phase three, providers prescribing antipsychotics between October 1, 2022, and February 23, 2023, were included for review. Monitoring rates were compared to national antipsychotic guidelines, and adherence rates were calculated for each monitoring parameter. Comparisons between phase one and phase three were performed using Chi‐squares to determine statistically significant differences (p < 0.05).ResultsUnfortunately, most monitoring rates decreased from baseline to follow‐up. All metabolic parameters were statistically significantly lower in the follow‐up sample compared to the baseline sample. These differences were seen when comparing the overall sample as well as the MH and PC provider groups across time points. Movement disorder monitoring showed no statistically significant differences between timepoints, with one exception. Among PC providers, the rate of AIMS monitoring was significantly increased from baseline (0%) to follow‐up (11.1%, p = 0.000).ConclusionPharmacist passive education of clinicians alone did not provide a significant change in provider's adherence to antipsychotic monitoring.

Systemic lupus erythematosus patients have unique changes in serum metabolic profiles across age associated with cardiometabolic risk.

Cardiovascular disease through accelerated atherosclerosis is a leading cause of mortality for patients with systemic lupus erythematosus (SLE), likely due to increased chronic inflammation and cardiometabolic defects over age. We investigated age-associated changes in metabolomic profiles of SLE patients and healthy controls (HCs). Serum NMR metabolomic profiles from female SLE patients (n = 164, age = 14-76) and HCs (n = 123, age = 13-72) were assessed across age by linear regression and by age group between patients/HCs (Group 1, age ≤ 25, n = 62/46; Group 2, age = 26-49, n = 50/46; Group 3, age ≥ 50, n = 52/31) using multiple t tests. The impact of inflammation, disease activity and treatments were assessed, and UK Biobank disease-wide association analysis of metabolites was performed. Age-specific metabolomic profiles were identified in SLE patients vs HCs, including reduced amino acids (Group 1), increased very-low-density lipoproteins (Group 2), and increased low-density lipoproteins (Group 3). Twenty-five metabolites were significantly altered in all SLE age groups, dominated by decreased atheroprotective high-density lipoprotein (HDL) subsets, HDL-bound apolipoprotein (Apo)A1 and increased glycoprotein acetyls (GlycA). Furthermore, ApoA1 and GlycA were differentially associated with disease activity and serological measures, as well as atherosclerosis incidence and myocardial infarction mortality risk through disease-wide association. Separately, glycolysis pathway metabolites (acetone/citrate/creatinine/glycerol/lactate/pyruvate) uniquely increased with age in SLE, significantly influenced by prednisolone (increased pyruvate/lactate) and hydroxychloroquine (decreased citrate/creatinine) treatment and associated with type 1 and type 2 diabetes by disease-wide association. Increasing HDL (ApoA1) levels through therapeutic/nutritional intervention, whilst maintaining low disease activity, in SLE patients from a young age could improve cardiometabolic disease outcomes. Biomarkers from the glycolytic pathway could indicate adverse metabolic effects of current therapies.

CerS6-dependent ceramide synthesis in hypothalamic neurons promotes ER/mitochondrial stress and impairs glucose homeostasis in obese mice

Dysregulation of hypothalamic ceramides has been associated with disrupted neuronal pathways in control of energy and glucose homeostasis. However, the specific ceramide species promoting neuronal lipotoxicity in obesity have remained obscure. Here, we find increased expression of the C16:0 ceramide-producing ceramide synthase (CerS)6 in cultured hypothalamic neurons exposed to palmitate in vitro and in the hypothalamus of obese mice. Conditional deletion of CerS6 in hypothalamic neurons attenuates high-fat diet (HFD)-dependent weight gain and improves glucose metabolism. Specifically, CerS6 deficiency in neurons expressing pro-opiomelanocortin (POMC) or steroidogenic factor 1 (SF-1) alters feeding behavior and alleviates the adverse metabolic effects of HFD feeding on insulin sensitivity and glucose tolerance. POMC-expressing cell-selective deletion of CerS6 prevents the diet-induced alterations of mitochondrial morphology and improves cellular leptin sensitivity. Our experiments reveal functions of CerS6-derived ceramides in hypothalamic lipotoxicity, altered mitochondrial dynamics, and ER/mitochondrial stress in the deregulation of food intake and glucose metabolism in obesity.

Cardiometabolic outcomes in Kronos Early Estrogen Prevention Study continuation: 14-year follow-up of a hormone therapy trial.

This study aimed to determine long-term cardiometabolic effects of hormone therapies initiated within 3 years of onset of menopause after a 14-year follow-up study of participants of the Kronos Early Estrogen Prevention Study (KEEPS). KEEPS was a multisite clinical trial that recruited recently menopausal women with good cardiovascular health for randomization to oral conjugated equine estrogens (Premarin, 0.45 mg/d) or transdermal 17β-estradiol (Climara, 50 μg/d) both with micronized progesterone (Prometrium, 200 mg/d) for 12 d/mo, or placebo pills and patch for 4 years. KEEPS continuation recontacted KEEPS participants 14 years after randomization and 10 years after the completion of the 4-year clinical trial to attend in-person clinic visits. Participants of KEEPS continuation (n = 299 of the 727 KEEPS participants; 41%) had an average age of 67 years (range, 58-73 y). Measurements of systolic and diastolic blood pressures, waist-to-hip ratio, fasting levels of glucose, insulin, lipid profiles, and homeostasis model assessment of insulin resistance were not different among the treatment groups at either KEEPS baseline or at KEEPS continuation visits, or for change between these two visits. The frequency of self-reported diabetes ( P = 0.007) and use of diabetes medications was higher in the placebo than the oral conjugated equine estrogens ( P = 0.045) or transdermal 17β-estradiol ( P = 0.02) groups, but these differences were not supported by the laboratory measurements of glycemia or insulin resistance. There was no evidence of cardiovascular and/or metabolic benefits or adverse effects associated with 4 years use of oral or transdermal forms of hormone therapy by recently menopausal women with good cardiovascular health after 10 years.

Tigecycline and Hypoglycemia, When and How?

Objective: To describe the clinical characteristics of hypoglycemia that develop with tigecycline therapy and to review and summarize the current evidence of this uncommonly occurring metabolic adverse effect of tigecycline therapy. Underlying risk factors and potential mechanisms are also discussed. Data source: A 3-phase literature search was performed. In phase 1, the Cochrane Central Register of Controlled Trials (CENTRAL) Library, MEDLINE, and Embase electronic databases were searched for hypoglycemia and tigecycline, published from inception until August 2023. In phase 2, MEDLINE was searched for tigecycline randomized controlled trials and results were manually screened for hypoglycemia. In phase 3, the US Food and Drug Administration Adverse Event Reporting System public dashboard was searched for reports on tigecycline and hypoglycemia from June 2005 until July 2023. Study selection and data extraction: Relevant English-language citations and those conducted in humans were considered. Relevance to patient care and clinical practice: Hypoglycemia of various causes is an independent mortality risk. This review raises awareness among clinicians about the possibility of hypoglycemia with tigecycline therapy. Conclusion: Data on tigecycline-related hypoglycemia are scarce. Hypoglycemia may occur at any time during tigecycline therapy and can be severe and persist for days after tigecycline cessation. Renal dysfunction or renal replacement therapy may predispose to severe hypoglycemia during tigecycline therapy. Tigecycline-related hypoglycemia may develop in patients with or without diabetes mellitus and appears independent of insulin or antidiabetic agents. Intravenous dextrose showed efficacy in the restoration of euglycemia. Studies are needed to determine whether tigecycline-related hypoglycemia is iatrogenic or spontaneous.

E47 as a novel glucocorticoid-dependent gene mediating lipid metabolism in patients with endogenous glucocorticoid excess.

E47 has been identified as a modulating transcription factor of glucocorticoid receptor target genes, its loss protecting mice from metabolic adverse effects of glucocorticoids. We aimed to analyze the role of E47 in patients with endogenous glucocorticoid excess [Cushing's syndrome (CS)] and its association with disorders of lipid and glucose metabolism. This is a prospective cohort study including 120 female patients with CS (ACTH-dependent = 79; ACTH-independent = 41) and 26 healthy female controls. Morning whole blood samples after an overnight fast were used to determine E47 mRNA expression levels in patients with overt CS before and 6-12 months after curative surgery. Expression levels were correlated with the clinical phenotype of the patients. Control subjects underwent ACTH stimulation tests and dexamethasone suppression tests to analyze short-term regulation of E47. E47 gene expression showed significant differences in patient cohorts with overt CS vs. patients in remission (p = 0.0474) and in direct intraindividual comparisons pre- vs. post-surgery (p = 0.0353). ACTH stimulation of controls resulted in a significant decrease of E47 mRNA expression 30min after i.v. injection compared to baseline measurements. Administration of 1 mg of dexamethasone overnight in controls did not change E47 mRNA expression. E47 gene expression showed a positive correlation with total serum cholesterol (p = 0.0036), low-density lipoprotein cholesterol (p = 0.0157), and waist-arm ratio (p = 0.0138) in patients with CS in remission. E47 is a GC-dependent gene that is upregulated in GC excess potentially aiming at reducing metabolic glucocorticoid side effects such asdyslipidemia.

The genetics of falling susceptibility and identification of causal risk factors

Falls represent a huge health and economic burden. Whilst many factors are associated with fall risk (e.g. obesity and physical inactivity) there is limited evidence for the causal role of these risk factors. Here, we used hospital and general practitioner records in UK Biobank, deriving a balance specific fall phenotype in 20,789 cases and 180,658 controls, performed a Genome Wide Association Study (GWAS) and used Mendelian Randomisation (MR) to test causal pathways. GWAS indicated a small but significant SNP-based heritability (4.4%), identifying one variant (rs429358) in APOE at genome-wide significance (P < 5e-8). MR provided evidence for a causal role of higher BMI on higher fall risk even in the absence of adverse metabolic consequences. Depression and neuroticism predicted higher risk of falling, whilst higher hand grip strength and physical activity were protective. Our findings suggest promoting lower BMI, higher physical activity as well as psychological health is likely to reduce falls.

Cardiometabolic Effects of Antipsychotics in Challenging Behavior and Neuropsychiatric Symptoms in Patients With Intellectual Disability.

Introduction Despite the well-established association between antipsychotics and metabolic adverse effects in psychiatric disorders, the variable influence of long-term and off-label antipsychotic medication on behavioral disorders has not been investigated in detail. Objective To clarify the impact of antipsychotic use on challenging behavior (CB) and neuropsychiatric symptoms (NPS), we evaluated the clinical findings and cardiometabolic effects in individuals with intellectual disability (ID) hospitalized in our residential facility for profoundly disabled patients. Patients and methods A total of 130 individuals hospitalized in our residential facility were retrospectively investigated and divided into two groups - individuals with and without CB and NPS. Antipsychotics (first- and second-generation antipsychotics) are prescribed to all individuals in the CB and NPS-positive ID group. Conversely, antipsychotics were not prescribed to any individuals in the CB- and NPS-negative ID groups. To investigate the cardiometabolic effects of antipsychotics, the following metabolic parameters were measured: body weight (BW), total calorie intake per day, body mass index (BMI), blood pressure, serum lipid levels (total cholesterol, high-density lipoprotein cholesterol, and triglyceride), and corrected QT interval (QTc) of electrocardiogram (ECG). The etiology of disabilities, level of ID, severity of motor disability, and presence or absence of epilepsy were also examined. Results Two main results were derived: (1) Autism spectrum disorder was the most predominant etiology in individuals with CB and NPS who were prescribed antipsychotics, and (2) the mean values of metabolic parameters were all normal in both medicated and nonmedicated individuals, but the total calorie intake was significantly higher in individuals who were prescribed antipsychotics. Conclusions Our investigation demonstrated that in individuals with an adequate energy intake, most metabolic parameters can be maintained within normal limits. We suggest that body weight control is the primary step in avoiding the cardiometabolic adverse effects of antipsychotics in intellectually disabled individuals with CB and NPS.

Effect of Hermetia illucens Fat, Compared with That of Soybean Oil and Palm Oil, on Hepatic Lipid Metabolism and Plasma Metabolome in Healthy Rats.

Palm oil (PO) is currently the most widely used fat source for food production, but insect fat from Hermetia illucens larvae (HF) might be a suitable alternative fat source, because its production is less harmful to the environment. The present study investigated the effect of HF, as compared to PO and soybean oil (SO), on the hepatic lipid metabolism and the plasma metabolome of healthy rats, which were randomly assigned to three groups (n = 10 rats/group), and fed three different semi-synthetic diets containing either SO, PO, or HF as the main fat source for 4 weeks. Feed intake, body weight gain, liver and plasma lipid concentrations, and the hepatic mRNA levels of genes involved in lipid metabolism and inflammation did not differ between groups. Targeted plasma metabolomics revealed 294 out of 630 metabolites analyzed to be different between groups. Principal component analysis showed a clear separation of the plasma metabolomes of the SO group and the other two groups, but no separation of those of the PO and the HF groups. The present study shows that HF exerts no adverse metabolic effects in healthy rats, compared to PO or SO, indicating that HF is a safe alternative fat source to PO for food production.

Clozapine suppresses NADPH oxidase activation, counteracts cytosolic H2O2, and triggers early onset mitochondrial dysfunction during adipogenesis of human liposarcoma SW872 cells

Long-term treatment of schizophrenia with clozapine (CLZ), an atypical antipsychotic drug, is associated with an increased incidence of metabolic disorders mediated by poorly understood mechanisms. We herein report that CLZ, while slowing down the morphological changes and lipid accumulation occurring during SW872 cell adipogenesis, also causes an early (day 3) inhibition of the expression/nuclear translocation of CAAT/enhancer-binding protein β and peroxisome proliferator-activated receptor γ. Under the same conditions, CLZ blunts NADPH oxidase-derived reactive oxygen species (ROS) by a dual mechanism involving enzyme inhibition and ROS scavenging. These effects were accompanied by hampered activation of the nuclear factor (erythroid-derived2)-like 2 (Nrf2)-dependent antioxidant responses compared to controls, and by an aggravated formation of mitochondrial superoxide. CLZ failed to exert ROS scavenging activities in the mitochondrial compartment but appeared to actively scavenge cytosolic H2O2 derived from mitochondrial superoxide. The early formation of mitochondrial ROS promoted by CLZ was also associated with signs of mitochondrial dysfunction. Some of the above findings were recapitulated using mouse embryonic fibroblasts.We conclude that the NADPH oxidase inhibitory and cytosolic ROS scavenging activities of CLZ slow down SW872 cell adipogenesis and suppress their Nrf2 activation, an event apparently connected with increased mitochondrial ROS formation, which is associated with insulin resistance and metabolic syndrome. Thus, the cellular events characterised herein may help to shed light on the more detailed molecular mechanisms explaining some of the adverse metabolic effects of CLZ.

THU298 Effect Of SGLT2 Inhibition On Metabolic, Cardiac And Renal Outcomes In Heart Transplant Recipients (EMPA-HTx study): Protocol And Study Design

Abstract Disclosure: L.M. Raven: None. C.A. Muir: None. C. Kessler Iglesias: None. E. Kotlyar: None. K. Muthiah: None. N.K. Bart: Advisory Board Member; Self; Bristol-Myers Squibb. Grant Recipient; Self; Pfizer, Inc. Speaker; Self; Pfizer, Inc. P.S. Macdonald: Speaker; Self; Boehringer Ingelheim, AstraZeneca. C.S. Hayward: None. A. Jabbour: None. J.R. Greenfield: Speaker; Self; Boehringer Ingelheim, AstraZeneca. Background: Heart transplantation (HTx) is standard of care for treatment of end-stage heart failure. Immunosuppression medication, required to prevent rejection, can result in adverse metabolic and renal effects. Clinically significant post-transplant complications include metabolic (diabetes, weight gain), renal impairment and cardiac disease, such as allograft vasculopathy and myocardial fibrosis. Sodium glucose co-transporter 2 inhibitors (SGLT2i) may have positive effects on all of these post-transplant complications. SGLT2i have been observed to improve metabolic parameters in patients with type 2 diabetes following cardiac and renal transplantation, but their benefit and safety in HTx has not been evaluated in randomised prospective studies. Aims: The overall aim of this project is to study the safety and efficacy of empagliflozin in HTx recipients. The primary end point will be improvement in glycaemic control assessed by change in glycosylated hemoglobin (HbA1c) and/or fructosamine, with secondary endpoints of cardiac fibrosis assessed by cardiac magnetic resonance, and renal function assessed by serum creatinine. Methods: Randomised, placebo-controlled trial of empagliflozin 10 mg daily versus placebo in recent HTx recipients. One hundred participants will be randomised 1:1. They will commence the study medication within 6-8 weeks of transplantation. Follow up will be 12 months after transplantation. Results from routine pre-HTx assessment will be reviewed to assess for pre-HTx diagnosis of diabetes. Routine laboratory tests, including full blood count, biochemistry, glucose, lipids and liver function as well as HbA1c, fructosamine, beta-hydroxybutyrate and urine albumin creatinine ratio, will be measured at baseline prior to receipt of study drug or placebo. Patients will be reviewed monthly during the study until 12 months post-HTx and data will be collected for each patient at each study visit. Cardiovascular magnetic resonance will be measured at baseline and 12 months after HTx. This study has been approved by St Vincent’s Hospital Human Research Ethics Committee (2021/ETH12184). Trial registration: ACTRN12622000978763. Discussion: This study will, for the first time, determine the efficacy and safety of SGLT2i in HTx recipients. Presentation: Thursday, June 15, 2023

FRI025 Succinate Receptor Activation Increases Respiration In Human But Not Murine Brown Adipocytes

Abstract Disclosure: B.T. McNeill: None. A. Kelman: None. L.E. Ramage: None. K.J. Suchacki: None. S.J. Wakelin: None. N.M. Morton: None. R.H. Stimson: None. Brown adipose tissue (BAT) is a thermogenic tissue that generates heat to maintain body temperature. BAT activation is a potential therapeutic target for treating obesity-related cardiometabolic disease. We performed RNA sequencing of human primary brown and white adipocytes and identified SUCNR1, which encodes the succinate receptor, as highly differentially expressed (20-fold) in brown versus white adipocytes. Succinate is known to increase BAT thermogenesis, while SUCNR1 activation inhibits lipolysis in white adipose tissue (WAT). We hypothesized that SUCNR1 activation increases BAT thermogenesis in humans and in mice. To test this, we investigated the effect of succinate and the selective SUCNR1 agonist cis-epoxysuccinic acid (C-ESA) in human and murine primary brown/ beige adipocytes. In addition, we determined the metabolic effects of disruption of Sucnr1 in mice either fed control or a high fat (HFD) for 12 weeks and measured energy expenditure when housed at standard room temperature (21°C) and during cold exposure (4°C). In human brown and white adipocytes, succinate increased basal and noradrenaline-stimulated respiration, while C-ESA increased basal respiration only in human brown adipocytes without altering UCP1 mRNA levels. SUCNR1 activation reduced glycerol release only in human white adipocytes. Male (but not female) Sucnr1-/- mice exhibited impaired glucose tolerance versus Sucnr1+/+ littermates after 2 weeks of HFD, and greater fat mass was also observed in the Sucnr1-/- mice following chronic HFD. However, energy expenditure, locomotor activity and tail vein temperature were unchanged in male Sucnr1-/- mice either at 21°C or 4°C. In addition, expression of Ucp1 and Pgc1α in BAT and inguinal WAT were similar between genotypes. Sucnr1 deletion had no effect on fat mass or glucose tolerance in mice fed a control diet. In vitro, differentiated brown adipocytes from Sucnr1-/- mice demonstrated comparable cellular respiration and Ucp1 mRNA levels both basally and during noradrenaline stimulation to Sucnr1+/+ adipocytes. Succinate and C-ESA did not stimulate respiration in murine brown or white adipocytes. These data reveal that SUCNR1 activation enhances brown adipocyte respiration in human but not murine brown adipocytes, highlighting a novel pathway regulating BAT function in addition to differences between species. These data also reveal novel sex-specific differences in the metabolic effects of SUCNR1, although the mechanisms through which female mice are protected from the adverse metabolic effects of Sucnr1 deletion are unclear. SUCNR1 activation may be a novel therapeutic target to treat obesity and associated metabolic disease, but requires further research in humans to determine the specific mechanisms through which SUCNR1 regulates BAT thermogenesis. Presentation: Friday, June 16, 2023

FRI032 Cellular Insights Into Metabolically Healthy And Unhealthy Obesity

Abstract Disclosure: M.C. Petersen: None. G.I. Smith: None. J. Yu: None. R.A. Barve: Other; Self; Royalties; PercayAI. J. Yoshino: None. G.I. Shulman: None. S. Klein: Advisory Board Member; Self; Merck, Altimmune. Some people with obesity are resistant to the adverse metabolic effects of excess adiposity and are considered to have “metabolically healthy obesity” (MHO). However, the mechanisms responsible for MHO are not clear. We evaluated whole-body insulin sensitivity (glucose infusion rate/plasma insulin during a hyperinsulinemic-euglycemic clamp) and several putative factors that regulate insulin action, including skeletal muscle diacylglycerol (DAG) and ceramide content and transcriptomic profiles in abdominal subcutaneous adipose tissue (ASAT) and muscle, in three groups separated by adiposity and metabolic function: i) 20 adults with MHO (BMI = 38.6 ± 1.2 kg/m2, normal fasting glucose, oral glucose tolerance, hemoglobin A1c, and intrahepatic triglyceride content); ii) 20 adults with MUO (BMI= 39.5 ± 1.1 kg/m2, prediabetes and hepatic steatosis); and iii) 15 adults who were metabolically-healthy and lean (MHL, BMI= 22.7 ± 0.4 kg/m2). Insulin sensitivity progressively decreased from MHL to MHO to MUO [109 ± 7 to 72 ± 7 to 30 ± 2 (μg glucose/kg FFM/min)/(μU/mL), respectively]. Muscle plasma membrane and total cellular sn-1,2-DAG contents were greater in the MHO and MUO groups compared with the MHL group, with no difference between MHO and MUO groups. In contrast, muscle ceramide content in multiple compartments progressively increased from MHL to MHO to MUO and were inversely correlated with insulin sensitivity among all subjects (plasma membrane, r = -0.61; mitochondria, r = -0.56; endoplasmic reticulum, r = -0.51, all P &amp;lt; 0.001). In ASAT, the expression of genes involved in extracellular matrix (ECM) remodeling and inflammation were greater in MUO than MHO, whereas the expression of genes involved in lipogenesis was greater in MHO than MUO. Sparse partial least-squares discriminant analysis, a classification algorithm, was used to identify the features that best discriminated the MHO and MUO groups. Of 125 variables, fasting plasma C-peptide concentration and skeletal muscle mitochondrial ceramide content were the best discriminants of MHO and MUO. Muscle mitochondrial ceramide content was negatively correlated with muscle transcripts involved in mitochondrial structure/function (e.g., ATP5MG [r = -0.69, P &amp;lt; 0.0001] and MPC1 [r = -0.67, P &amp;lt; 0.0001]) and PAQR4 (r = -0.71, P &amp;lt; 0.0001), which encodes a ceramidase in the adiponectin receptor family. In addition, the muscle transcripts that positively correlated with muscle mitochondrial ceramide content were strongly enriched for ECM and TGFβ-related pathways. Conclusions: Greater whole-body insulin sensitivity in people with MHO than MUO is associated with alterations in adipose tissue and skeletal muscle biology, namely decreased markers of ASAT ECM remodeling and inflammation, decreased skeletal muscle ceramide content, and increased skeletal muscle expression of PAQR4 and genes associated with mitochondrial content/function. Presentation: Friday, June 16, 2023

SAT121 Challenging Health Disparities In Mental Illness: Addressing Diabetes And Metabolic Disease

Abstract Disclosure: R. Chen: Speaker; Self; Boehringer Ingelheim, Novo Nordisk, AstraZeneca, Eli Lilly &amp; Company. C. Finneran: None. D. Higgins: None. C. Lum: None. J. Allen: None. Introduction: Having a severe mental illness such as schizophrenia confers a substantial increase in the prevalence of diabetes, obesity and premature cardiovascular disease. These health disparities, particularly in diabetes care, have led to a life expectancy in this vulnerable group which is up to 25-30 years less than that of the general population. There are several potential causes for these health disparities. These include poor health literacy, poor recognition by clinicians of the relationship between mental illness and diabetes, the persistent separation of mental and physical health care as well as the adverse metabolic effects of antipsychotics. Despite numerous national and international guidelines, patients frequently have difficulties in accessing appropriate metabolic health care and negotiating health pathways. There is little evidence that these health disparities are being addressed in a systematic way. We sought to challenge the traditional separation of mental and physical health care and to address these health disparities. Aims: To establish an integrated multidisciplinary service to manage metabolic health in this vulnerable population. Methods: A collaborative pilot program between diabetes and mental health units has a clinical team of exercise physiologist, dietitian, endocrinologist, diabetes educator and mental health nurse. A model of care has been developed where all patients assessed by the mental-health unit are routinely screened with a tool which assesses anthropometry (including weight, height, BMI) and biochemistry (including HbA1c. lipids and renal function). Patients are managed in weekly multidisciplinary clinics based in the mental health unit, with defined referral criteria (type 2 diabetes, metabolic syndrome, pre-diabetes, dyslipidaemia, hypertension and weight-gain). Results: From June 2020 to September 2022, we assessed 194 patients with 421 occasions of service. 49 patients (25%) had diabetes, 18 had pre-diabetes and 31 had newly-diagnosed diabetes. 91 had metabolic syndrome, 94 were smokers, 123 had dyslipidaemia and 17 were of first nations background. We have also provided education to mental health staff to upskill knowledge on diabetes. Conclusions: Collaboration between mental health and diabetes clinicians has been essential to coordinate a patient-centred service whereby all patients meeting the referral criteria are assessed. New diagnoses of diabetes would potentially have been missed and patients with established diabetes have been assessed whilst they would not have received any diabetes care without the establishment of this clinic. These diabetes health disparities are particularly startling in light of the benefits of early multifactorial intervention in preventing diabetes related complications. Presentation: Saturday, June 17, 2023

Adherence to Recommended Metabolic Monitoring of Children and Adolescents Taking Second-Generation Antipsychotics.

Clinical guidelines recommend periodic monitoring for adverse metabolic effects associated with second-generation antipsychotic medications. The authors sought to evaluate adherence to the guideline-recommended metabolic monitoring schedule for children and adolescents prescribed second-generation antipsychotics. The authors used a national electronic medical records database for a retrospective study of children and adolescents ages 1-17 years (N=9,620) who were prescribed second-generation antipsychotics in January 2010-December 2018. Adherence to guideline-recommended monitoring of body mass index (BMI), blood glucose, and cholesterol was categorized as full, partial, and no monitoring. Full monitoring of patients was defined as strict metabolic monitoring, following the guideline-recommended schedule. Patients who received any monitoring, but not meeting the full monitoring criteria, were considered partially monitored. Three multinomial logistic regression models were fitted for each metabolic parameter to identify predictors associated with monitoring status. BMI was the metabolic parameter with the highest adherence to guideline-recommended monitoring (full monitoring, 4.7% of patients; partial monitoring, 44.8%), followed by blood glucose (full monitoring, 6.5%; partial monitoring, 29.4%) and cholesterol (full monitoring, 0.8%; partial monitoring, 22.4%). Being Black (vs. non-Black), having a comorbid mood disorder (vs. none), receiving olanzapine as the index second-generation antipsychotic (vs. aripiprazole), and receiving an antidepressant as a concurrent medication (vs. none) were associated with a higher likelihood of receiving both full and partial monitoring of all three metabolic parameters. Both full and partial adherence to guideline-recommended monitoring of children and adolescents prescribed second-generation antipsychotics were poor. However, children and adolescents at increased metabolic risk tended to be more closely monitored.