Metabolic Parameters Research Articles

7943 In Obese C57Bl6 Male Mice, Weight Loss due to Caloric Restriction Reduced Bone Morphology but Improved Components of Systemic Metabolism

Abstract Disclosure: C. Chlebek: None. C. McAndrews: None. S.N. Costa: None. C.J. Rosen: None. Obesity and calorie restriction individually alter systemic cellular metabolism and affect musculoskeletal tissue health. Obesity reduces trabecular and cortical bone quality. Clinically, obese patients are advised to lose weight, despite the negative effects of calorie restriction on bone in nonobese preclinical models. Little is known about bone quality following weight loss in obese preclinical models. We hypothesized that in obese models, caloric restriction would further worsen bone quality. To induce obesity, male C57Bl6 mice (8 weeks old) received 60% high fat diet for 12 weeks (high fat feeding phase). Following obesity induction, the HFD-CR group was acclimated to control low fat diet for 2 wks and then underwent 30% caloric restriction for 8 wks (caloric restriction feeding phase). The HFD group received 60% kcal high fat diet from ages 8 to 30 wks. LFD mice received control low fat 10% kcal diet for the study duration. Mice were euthanized at 30 wks of age. Body weight, body composition, and bone mineral density were recorded at baseline and at the end of each diet. Glucose and insulin tolerance were recorded at the end of the high fat and caloric restriction feeding phases. At euthanasia, cortical and trabecular bone morphology (µCT) were assessed.Adverse metabolic parameters worsened with high fat feeding but improved by caloric restriction. Compared to LFD animals, HFD and HFD-CR mice gained body weight, fat mass, and lean mass during the high fat feeding phase. After the caloric restriction feeding phase, body weight, fat mass, and lean mass were reduced in HFD-CR compared to both HFD and LFD controls (p < 0.0001). After 12 weeks of high fat feeding, glucose and insulin tolerance were reduced in HFD and HFD-CR mice compared to LFD (p < 0.0001). Caloric restriction improved both glucose and insulin tolerance in HFD-CR mice compared to both HFD and LFD animals (p < 0.0001). Caloric restriction improved areal bone mineral density, but at euthanasia, HFD-CR mice had worse bone morphology compared to LFD or HFD animals. Although areal bone mineral density (aBMD) was reduced by the high fat feeding phase, HFD-CR and LFD aBMD was not different at the end of the study (p < 0.0001). At euthanasia, HFD-CR mice had reduced cortical area and cortical thickness (p < 0.05). Marrow area and moment of inertia were not different between diets. Compared to LFD, both HFD and HFD-CR mice had reduced tibial bone volume fraction (p < 0.05). HFD-CR animals had smaller trabecular thickness (p < 0.05) and greater trabecular number (p < 0.01) compared to HFD mice. Despite improvements in components of systemic metabolism, caloric restriction in obese preclinical models reduced bone morphology in both trabecular and cortical compartments. This work will improve our understanding of the musculoskeletal system following caloric restriction in obese models and will aid in nutritional counseling for obese patients. Presentation: 6/1/2024

8261 Achievement of Diabetes Treatment Goals in Mexico from 2016 to 2022

Abstract Disclosure: D. Ramirez Garcia: None. C.A. Fermin Martinez: None. P.N. Mendez Labra: None. N.E. Antonio Villa: None. J.A. Seiglie: None. O.Y. Bello-Chavolla: None. Background: Optimal diabetes care involves achieving goals with treatment in key metabolic parameters including HbA1c, blood pressure (BP), low density lipoprotein cholesterol (LDL-C) levels, and smoking cessation. Evaluation of diabetes care in Mexico has been incomplete, with previous studies focusing primarily on glycemic control, but not on a comprehensive analysis of combined treatment targets. Objective: To estimate achievement of diabetes treatment goals (HbA1c [A], BP [B], LDL-C [C], smoking cessation [N], and combined targets [AB, BC, AC, ABC, ABCN]) using data from nationally representative surveys from 2016-2022 among individuals with diagnosed diabetes in Mexico. Methods: We analyzed serial cross-sectional National Health and Nutrition Surveys from 2016-2022. A total of 2,689 adults with diagnosed diabetes ≥20 years were identified amongst 21,248 adults ≥20 years. Weighted prevalence estimates were obtained for glycemic control (HbA1c <7% in those <65 years, and <7.5% in those ≥65 years), BP control (<130/80 mmHg), LDL-C control (<70 mg/dL), smoking cessation, and combined targets. We also fitted logistic regression models to estimate the odds of achieving treatment targets according to age, sex, educational level, indigenous identity, and survey cycle. Results: In 2022, the prevalence of HbA1c, BP, and LDL-C control among individuals with diagnosed diabetes in Mexico was 41.2% (95% CI 30.5-52.0%), 46.0% (95% CI 36.5-55.5%), and 17% (95% CI 10.2-25.2%), respectively. Non-smoking prevalence was 92.4% (95% CI 88.6-96.2%). Combined target achievement was low, with a prevalence of 10.8% (95%CI 6.2-15.5%) for BC and 4% (95% CI 1.7-6.3%) for ABCN. The proportion of goal achievement was relatively stable across 2016-2022 for every parameter analyzed, except for LDL-C. LDL-C had the lowest proportion of control across all cycles, although a gradual increase was observed: 8.1% (95% CI 4-12.3%) in 2016 to 17% (95% CI 10.2-25.2%) in 2022. The increase in LDL-C control coincides with greater prevalence of statin use across survey cycles. Men had lower odds of achieving ABCN combined control (OR 0.49, 95%CI 0.45-0.54) than women. Similarly, compared with individuals <45 years, participants 45-64 years (OR 0.36, 95%CI 0.32-0.40) and ≥65 years (OR 0.41 95%CI 0.35-0.47) had lower odds of achieving composite control. Conclusions: Achievement of diabetes treatment goals in Mexico is suboptimal. Less than half of individuals with diagnosed diabetes achieve HbA1c or BP goals, less than a fifth achieve LDL-C control, and only 1 in 20 individuals achieve ABCN control. Greater efforts are needed to the improve the comprehensive care of individuals with diabetes in Mexico. Presentation: 6/3/2024

8040 Precision-Engineered Activin and GDF Ligand Trap HS235: A Novel Lean Mass-Preserving Treatment for Obesity

Abstract Disclosure: G. Schang: Employee; Self; 35Pharma. M. De Molliens: Employee; Self; 35Pharma. E. Brule: Employee; Self; 35Pharma. C. Chauvet: Employee; Self; 35Pharma. J. Denis: Employee; Self; 35Pharma. A. Sours: Employee; Self; 35Pharma. V. Ganesh: Employee; Self; 35Pharma. G. Tremblay: Employee; Self; 35Pharma. J. Schoelermann: Employee; Self; 35Pharma. M. O'Connor: Employee; Self; 35Pharma. Introduction: Novel anti-obesity medications including incretin mimetics have revolutionized the pharmacotherapy of obesity and type 2 diabetes, leading to unprecedented weight loss and clinically meaningful improvement of glucose metabolism and cardiometabolic health. However, incretins reduce body mass in a non-selective manner; both fat mass and lean mass are lost with incretin treatment. In obese patients treated with incretins, undesirable loss of lean body mass (LBM) can account for up to 40% of overall weight loss. Loss of LBM negatively impacts resting metabolic rate, leading to a weight loss plateau and often unsustainable results. Furthermore, individuals with sarcopenia, characterized by low muscle mass and strength, are at greater risk for heart failure. The preservation, or even increase, of LBM is therefore a desirable treatment goal for obesity pharmacotherapy and overall cardiometabolic health. Activins and growth differentiation factors (GDFs), which are members of the TGF-beta superfamily, are validated targets controlling body composition and metabolism. Specifically, blockade of activins and GDFs has anabolic effects in metabolically active tissues such as skeletal muscle and brown adipose tissue, while reducing white adipose tissue mass. Therefore, specific and selective blockade of activins and GDFs represents a novel anti-obesity treatment strategy which can act orthogonally to current anti-obesity medications. HS235 is an activin receptor ectodomain-based (ActR) Fc-fusion protein that has been rationally designed to attain optimal inhibition of ligands controlling body composition in obesity. Methods: A structure-assisted rational molecular engineering approach coupled with cell-based potency screening was employed to design HS235. To validate the anti-obesogenic potential of HS235, diet-induced obese (DIO) mice were injected with HS235, an incretin mimetic, or a combination of both. Fat mass, LBM, muscle weights, and biomarker readouts were assessed at the end of study. Results: In cell-based assays, HS235 potently and selectively neutralized activins and GDFs implicated in body composition. This translated to complete in vivo target engagement and pharmacodynamic response. In a DIO mouse model, both HS235 and the incretin mimetic significantly improved metabolic parameters and decreased fat mass, but only HS235 increased LBM, while incretin-based treatment led to LBM loss. Importantly, the addition of HS235 to the incretin mimetic lead to a synergistic fat mass loss and prevented loss of LBM. Conclusion: Potent and selective inhibition of activins and GDFs by HS235 represents a novel LBM preserving weight loss strategy orthogonal to incretin mimetics. Collectively, these data support the development of HS235 as a novel anti-obesity agent to complement currently approved incretin-based medications to improve quality of weight loss. Presentation: 6/3/2024

6714 Bone And Radiologic Findings In Congenital Generalized Lipodystrophy: A Systematic Review

Abstract Disclosure: R.M. Tuska: None. M. Brush: None. A.A. Livinski: None. R.J. Brown: None. Congenital Generalized Lipodystrophy (CGL) is characterized by a near-total loss of subcutaneous adipose tissue, leading to severe metabolic and systemic comorbidities. CGL is most commonly caused by mutations in AGPAT2 (CGL1) and BSCL2 (CGL2) genes. Skeletal abnormalities such as diffuse sclerosis, lytic bone lesions, and high bone mineral density (BMD) have been recognized in many patients with CGL, but the radiologic and clinical features of these bone phenotypes remain ill-defined. The aim of this systematic review was to evaluate the bone manifestations and radiologic findings associated with CGL1 and CGL2. We searched 6 databases: CINAHL Plus, Embase, Global Index Medicus (WHO), PubMed, Scopus, and Web of Science: Core. We screened articles utilizing a dual reviewer process in Covidence. Included publications reported primary bone and radiologic findings in patients with CGL1 or CGL2. Exclusions comprised publications without full text, duplicate publications, those lacking bone measures, and review articles. Two reviewers extracted data using RedCap and assessed risk of bias. 270 records were screened and 37 records reporting 179 cases of CGL were included for data extraction. Among the 79 patients assessed for bone cysts, 49 (62%) exhibited lytic appearing lesions. Of these 49, 14 (29%) patients presented with symptomatic lesions, primarily manifesting as bone pain at the lesion site (n=6), or pathologic fracture at the lesion site (n=9). Bone biopsy (n=7) revealed thin trabeculae and extensive vascular proliferation at the lesion site. Bone marrow biopsies (n=2) and imaging (n=20) revealed normal hematopoietic marrow with a marked reduction in marrow fat. 12 patients underwent serial bone imaging revealing diffuse osteosclerosis and the absence of lytic lesions in early childhood. During adolescence, lytic lesions appeared and progressed throughout the proximal and distal ends of the long bones in the appendicular skeleton sparing the axial skeleton. Markers of bone turnover were within normal limits except for sclerostin, which was elevated in a cohort of 11 patients. High BMD (n= 65), advanced skeletal maturation (n= 49), diffuse osteosclerosis (n=30), scoliosis (n=8), pseudo-osteopoikilosis (n=6), coxa valga (n=5), enlarged epiphyses (n=7), and coarse trabeculae (n=8) were also reported. While leptin replacement therapy improved metabolic parameters in many patients, it did not reverse the high bone mineral density or significantly alter markers of bone turnover. Individuals with CGL exhibit a spectrum of skeletal abnormalities including lytic-appearing lesions, osteosclerosis, high bone mineral density, advanced skeletal maturation, and pseudo-osteopoikilosis. Further long-term follow-up is needed to comprehensively assess the progression of these lesions over the life course and to elucidate the mechanisms contributing to their development. Presentation: 6/2/2024

8000 Intestinimonas Butyriciproducens As A New Preventive Therapy For Type 2 Diabetes: a Proof Of Concept Randomized Controlled Trial

Abstract Disclosure: V. Antoniotti: None. M. Caputo: None. E. Mollero: None. A. Antonioli: None. S. Tini: None. M. Manfredi: None. S. Gul: None. N. Bui: None. J. Seegers: None. W. De Vos: None. G. Aimaretti: None. F. Prodam: None. Background. The incidence of type 2 Diabetes Mellitus (T2D) is increasing worldwide. Prevention is possible by changing lifestyle but it’s not effective alone in real life, due to poor compliance over time. New strategies are necessary, mostly for high-risk individuals. Therapeutic microbiology is a further proposed target, and butyrate-producing bacteria can improve metabolic parameters in obese patients. Our study aims to evaluate the effect of Intestinimonas butyriciproducens as a preventive therapy for T2D in prediabetes thanks to its effects in decreasing Advanced Glycation End Products (AGEs), converting sugars and proteins in butyrate, and increasing insulin sensitivity.Methods. The trial is a double-blind, randomized, placebo-controlled (phase 1) and open-label pilot study with two different doses (phase 2) of 26 weeks. I. butyriciproducens (105 CFU/day) or placebo were given for 12 weeks, then subjects in placebo will start the treatment (105 CFU/day), and the other group will increase the dose (108 CFU/day) for 14 weeks. Overweight or obese patients with impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) were included. Patients were assessed for clinical, biochemical, and microbiota parameters at the time of recruitment (V1), after phase 1 (V7) and phase 2 (V10), during which the eating and lifestyle habits were also evaluated. No dietary advice was given. Results. Nineteen have completed the study. Treated patients during the first phase had a significant improvement in glucose-insulin metabolism demonstrated through the HOMA Disposition Index (p= 0.0075). Lipid profile also ameliorates in patients treated at a low dose and then at a high dose, particularly decreasing triglycerides (phase 1: p= 0.0212; phase 2: p= 0.0261). The weight and BMI of patients were stable throughout the period of study. Data from Flash glucose Monitoring (FGM) show a more stable glucose, mainly at the end of the study. Serum AGE concentrations showed a trend towards a decrease in treated patients, whereas IL-10 slowly increased without changes in IL-6 and IL-17.Lastly, 10 out of 19 patients after 26 weeks of treatment had a remission in IFG or IGT (52.6%). Conclusions. Intestinimonas butyriciproducens seems to improve insulin sensitivity and triglycerides in treated patients. Intestinimonas butyriciproducens could be a new strategy in the work-up of T2D prevention. Presentation: 6/1/2024

Visceral adiposity in postmenopausal women is associated with a pro-inflammatory gut microbiome and immunogenic metabolic endotoxemia

BackgroundObesity, and in particular abdominal obesity, is associated with an increased risk of developing a variety of chronic diseases. Obesity, aging, and menopause are each associated with differential shifts in the gut microbiome. Obesity causes chronic low-grade inflammation due to increased lipopolysaccharide (LPS) levels which is termed “metabolic endotoxemia.” We examined the association of visceral adiposity tissue (VAT) area, circulating endotoxemia markers, and the gut bacterial microbiome in a cohort of aged postmenopausal women.MethodsFifty postmenopausal women (mean age 78.8 ± 5.3 years) who had existing adipose measurements via dual x-ray absorptiometry (DXA) were selected from the extremes of VAT: n = 25 with low VAT area (45.6 ± 12.5 cm2) and n = 25 with high VAT area (177.5 ± 31.3 cm2). Dietary intake used to estimate the Healthy Eating Index (HEI) score was assessed with a food frequency questionnaire. Plasma LPS, LPS-binding protein (LBP), anti-LPS antibodies, anti-flagellin antibodies, and anti-lipoteichoic acid (LTA) antibodies were measured by ELISA. Metagenomic sequencing was performed on fecal DNA. Female C57BL/6 mice consuming a high-fat or low-fat diet were treated with 0.4 mg/kg diet-derived fecal isolated LPS modeling metabolic endotoxemia, and metabolic outcomes were measured after 6 weeks.ResultsWomen in the high VAT group showed increased Proteobacteria abundance and a lower Firmicutes/Bacteroidetes ratio. Plasma LBP concentration was positively associated with VAT area. Plasma anti-LPS, anti-LTA, and anti-flagellin IgA antibodies were significantly correlated with adiposity measurements. Women with high VAT showed significantly elevated LPS-expressing bacteria compared to low VAT women. Gut bacterial species that showed significant associations with both adiposity and inflammation (anti-LPS IgA and LBP) were Proteobacteria (Escherichia coli, Shigella spp., and Klebsiella spp.) and Veillonella atypica. Healthy eating index (HEI) scores negatively correlated with % body fat and anti-LPS IgA antibodies levels. Preclinical murine model showed that high-fat diet-fed mice administered a low-fat diet fecal-derived LPS displayed reduced body weight, decreased % body fat, and improved glucose tolerance test parameters when compared with saline-injected or high-fat diet fecal-derived LPS-treated groups consuming a high-fat diet.ConclusionsIncreased VAT in postmenopausal women is associated with elevated gut Proteobacteria abundance and immunogenic metabolic endotoxemia markers. Low-fat diet-derived fecal-isolated LPS improved metabolic parameters in high-fat diet-fed mice giving mechanistic insights into potential pro-health signaling mediated by under-acylated LPS isoforms.7yVbQmTTfsF9b4Af3tznWNVideo

The association of plasma asprosin with anthropometric and metabolic parameters in Korean children and adolescents.

This study aimed to determine the correlation of plasma asprosin with anthropometric and metabolic parameters in Korean children and adolescents. This single-center study included 109 Korean children and adolescents: 62 (56.9%) obese participants with a body mass index (BMI) ≥95th percentile and 47 (43.1%) healthy controls with BMI between the 15th and 85th percentile. Metabolic parameters were measured, including fasting blood glucose, fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), triglyceride and glucose (TyG) index, and lipid profiles. Plasma asprosin levels were higher in the obese group than in the control group (mean 87.0 vs. 69.3 ng/mL; p = 0.001) and in the IR group than in the non-IR group (mean 98.6 vs. 70.2 ng/mL; p < 0.001). Plasma asprosin levels were not associated with sex or pubertal stage. Plasma asprosin levels were positively correlated with BMI SDS (r = 0.34; p = 0.002), glycated hemoglobin (HbA1c) (r = 0.25; p = 0.02), glucose (r = 0.33; p = 0.002), insulin (r = 0.44; p < 0.001), HOMA-IR (r = 0.47; p < 0.001), triglyceride (TG) (r = 0.33; p = 0.003), high-density lipoprotein (HDL) cholesterol (r = -0.29; p = 0.008), and TyG index (r = 0.38; p < 0.001). Multiple linear regression analysis indicated that plasma asprosin levels were independently associated with HOMA-IR (p < 0.001) and TG/HDL cholesterol ratio (p < 0.001). This study demonstrated an association between plasma asprosin levels and obesity and insulin resistance in Korean children and adolescents.

The joint effect of cumulative metabolic parameters on the risk of type 2 diabetes: a population-based cohort study

Background and aimsThis study aimed to examine the cumulative effects of body mass index (BMI), body roundness index (BRI), pulse pressure (PP), triglycerides (TG), high-density lipoprotein cholesterol (HDL) and fasting plasma glucose (FPG) on Type 2 diabetes (T2D) morbidity.MethodsA total of 78,456 participants aged older than 45 years were extracted from basic public health services in China. During the 2-year follow-up, 6,942 individuals had developed T2D. The binary logistic regression models and multinomial logistic regression models were conducted to investigate the effects of cumulative metabolic parameters on incident T2D, prediabetes regression and progression.ResultsWe found statistically deleterious impacts of exposure to high cumulative BMI, BRI, PP, TG and low cumulative HDL on T2D morbidity and prediabetes progression. Compared to the group with low cumulative of all five parameters, the adjusted ORs for new-onset T2D for participants presenting with 1–2, 3, and 4–5 elevated metabolic parameters were 1.41(1.31,1.52), 1.93(1.74,2.13) and 2.21(1.94,2.51), respectively. There was additive interaction between FPG level and cumulative metabolic parameters with T2D. Compared with participants with the lowest quartile of FPG and low cumulative of all 5 parameters, those with the highest quartile of FPG and high cumulative of 4–5 parameters had a 14.63 [95% CI (12.27, 17.42)] higher risk of incident T2D.ConclusionsParticipants with more numbers of high-cumulative metabolic parameters were associated with a higher risk of incident T2D and prediabetes progression. A high level of normal FPG could enhance these risks.

The relationship between iron metabolism markers and parameters of carbohydrate and lipid metabolism in patients with overweight and obesity

Background: Hyperferritinemia associated with obesity and insulin resistance is a link between the components of the metabolic syndrome and a possible triggering factor in the pathogenesis of carbohydrate metabolism disorders and dyslipidemia.Aim: To establish possible relationships between ferrokinetic parameters, parameters of lipid and carbohydrate metabolism in overweight and obese patients, and to analyze the possibility of using iron metabolism parameters (ferritin and serum iron) as predictors of carbohydrate metabolism disorders in this cohort of patients.Material and Methods. The study included 52 overweight or obese patients. In the course of the study, patients were stratified into groups depending on the presence of carbohydrate metabolism disorders (CMD), and depending on the state of iron metabolism. Among all patients included in the study, an assessment of anthropometric data, a study of glycated hemoglobin, a standard glucose tolerance test with 75 g of glucose, a study of hematological parameters, as well as biochemical parameters of iron metabolism – the concentration of serum iron, transferrin and ferritin, was carried out.Results. Patients with CMD – impaired glucose tolerance or impaired fasting glycaemia – had significantly higher serum ferritin levels than obese patients without CMD (p = 0.019). In persons with a high level of ferritin, CMD developed significantly more often than in patients with a ferritin content in the range below the 75th percentile (χ2 = 5.278, p = 0.022). According to the ROC analysis, ferritin showed a rather high sensitivity – 75%, and specificity – 84.4% at a diagnostic threshold of 126.65 ng/ml (area under the curve = 0.738; p = 0.016) in the diagnosis of prediabetes (IGT/IFG) in overweight and obese individuals.Conclusion. High concentrations of iron and ferritin are positively associated with CMD, with ferritin being a promising predictor of prediabetes and type 2 diabetes mellitus.

A-079 Investigation of gut microbial flavonoid catabolites in metabolic diseases

Abstract Background Flavonoids, a secondary metabolite found in plant-based diets, have gained attention in the last decade for their antioxidative properties in high-fat diet induced obesity animal models and human studies. Previous work showed that certain gut microbiota members can metabolize flavonoids into monophenolic acids (MPAs), and some of these MPAs have similar effects to insulin when administered orally. Our objective is to explore the microbiome connection between flavonoid-rich diets and improved metabolic parameters in obesity. We hypothesize that flavonoid-supplemented diets are most effective in the presence of gut microbiota capable of MPA formation and that these bacterial metabolites are the main bioactive compounds responsible for the improved metabolic parameters Methods To investigate our hypothesis, we fed male and female C57BL/6 mice a high-fat control diet (HFD) or the same diet supplemented with 1% MPA or 1% berry extract for 12 weeks. Each group was further divided into subgroups that received regular drinking water (RW) or antibiotic water (ABW) to suppress gut microbial communities. A range of metabolic parameters, such as body weight, lean and fat mass, glucose and insulin tolerance, histological assessment of liver cells, quantification of liver injury biomarkers, transcriptional changes in metabolically active tissues, and glucose and lipid metabolism pathways, were monitored. Additionally, 16s sequencing was performed on the cecal microbial composition of each group. Results Mice on HFD control with RW or ABW showed prominent hepatic steatosis and an increase in liver lipids accumulation demonstrated by a significant decrease in the activation of lipid metabolism pathways. Similarly, mice on HFD with 1% MPA and RW or ABW exhibited a significant reduction in hepatic steatosis and an increase in the activation of the lipid metabolism pathways, regardless of gut microbiota presence. In line with our hypothesis, mice on HFD with 1% berry extract and RW showed a similar reduction in hepatic steatosis to both 1% MPA groups. However, mice on HFD with 1% berry extract and ABW displayed noticeable hepatic steatosis, indicating the loss of the positive effect provided by berry extract metabolites once gut microbiota was depleted by antibiotics. Insulin tolerance test revealed a gut microbial effect as well in the HFD with 1% berry extract, illustrated by a significant reduction in glucose levels after insulin injection and an increase in insulin sensitivity. In contrast, the HFD control mice experienced an increase in glucose levels after insulin injection and insulin resistance. Although there were notable decreases in fasting blood glucose, there were no significant effects on fat and lean mass, insulin, glucagon, or liver injury marker levels. Finally, the mice on HFD with 1% berry extract had significantly more diverse cecal microbial communities than those fed HFD or HFD with 1% MPA. Conclusions Feeding mice a flavonoid-rich diet in the presence of intact gut microbiome can improve metabolic parameters associated with metabolic diseases, potentially preventing, or reversing these diseases. Our findings suggest promising avenues for treatment, such as dietary flavonoid supplementation with concurrent gut microbial probiotic therapy.

Enhanced metabolic health and immune response with bictegravir/emtricitabine/TAF: Insights from a 96‑week retrospective study.

Bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF), as a fixed dosed combination, is effective in people living with human immunodeficiency virus (PLWH) previously treated with other therapeutic regimens. The aim of the present retrospective observational real-life study was to analyze virological suppression and immunological, metabolic and safety profile of B/F/TAF. Data were collected from 127 PLHW who switched from any regimen to B/F/TAF. Viral load and virological suppression (viral load <50 copies/ml) were assessed by using real-time PCR methodologies; CD4 and CD8 T cell count as well as CD4/CD8 ratio were determined by cytofluorimetric analyses; other metabolic parameters such as total cholesterol, triglycerides, High- and Low-Density Lipoproteins were assessed by using immunoenzymatic assay. All of the aforementioned parameters were assessed at different timepoints (Baseline, 48 and 96 weeks) for the patients switching to B/F/TAF. Of 127 PLHW [96 (75.6%) male and 31 (24.4%) female, with a mean age of 46.8±10.7 years], 107 PLHW were included in the analysis. The percentage of virologically suppressed PLWH increased from 66.4 to 74.8% at 96 weeks. A statistically significant increase in absolute CD4 (P<0.0001) and CD8 T cell count (P=0.002) was observed. Of importance, there was a significant increase in CD4/CD8 ratio from 0.95 (0.52-1.31) to 1.16 (0.75-1.39) (P=0.003) after 96 weeks. There was a significant decrease in the median values of triglycerides (P<0.0001) and total cholesterol (P<0.0001). Serum creatinine showed a significant increase (P=0.0001). In real life, switching to B/F/T was safe and highly effective both virologically and immunologically. Decrease in cholesterol and triglyceride levels suggested a favorable metabolic profile, which may decrease inflammation, leading to a healthier state and less organ damage.

Prediction of preoperative lymph-vascular space invasion and survival outcomes of cervical squamous cell carcinoma by utilizing 18F-FDG PET/CT imaging at early stage.

To establish nomograms for predicting preoperative lymph-vascular space invasion (LVSI) and survival outcomes of cervical squamous cell carcinoma (CSCC) based on PET/CT radiomics. One hundred and twenty-three patients with CSCC and LVSI status were enrolled retrospectively. Independent predictors of LVSI were identified through clinicopathological factors and PET/CT metabolic parameters. We extracted 1316 features from PET and CT volume of interest, respectively. Additionally, four models (PET-RS: radiomic signature of PET only; CT-RS: radiomic signature of CT only; PET/CT-RS + clinical data; PET/CT-RS: radiomic signature of PET and CT) were established to predict LVSI status. Calculation of radiomics scores of PET/CT was executed for assessment of the survival outcomes, followed by development of nomograms with radiomics (NR) or without radiomics (NWR). One hundred and twenty-three patients with pathologically confirmed CSCC had been categorized into two sets (training and testing sets). It was found that only maximum standardized uptake value (SUVmax) and squamous cell carcinoma antigen were independent predictors of LVSI. Meanwhile, the PET/CT-RS + clinical data outperformed the other three models in the training set [area under the curve (AUC): 0.91 vs. 0.861 vs. 0.81 vs. 0.814] and the testing set (AUC: 0.885 vs. 0.857 vs. 0.783 vs. 0.798). Additionally, SUVmax and LVSI had been demonstrated to be independent prognostic indicators for progression-free survival and overall survival. Decision curve analysis and calibration curve indicated that NRs were superior to NWRs. The survival outcomes were assessed. PET/CT-based radiomic signature nomogram enables a new method for preoperative prediction of LVSI and survival prognosis for patients with CSCC.

Irregular breakfast eating in type 2 diabetes mellitus is associated with greater social jetlag and poorer metabolic health.

Circadian disruption, arising from conflict between internal circadian time and behavioural sleep-wake and fasting-feeding rhythms, may contribute to the prevalence of type 2 diabetes mellitus and disease severity. Previous studies have demonstrated a link between irregular breakfast eating and poorer metabolic health. We aimed to further explore the relationships between breakfast habits, circadian misalignment (social jetlag), and metabolic parameters in a cohort of adult participants with type 2 diabetes mellitus. A total of 330 adult participants with type 2 diabetes mellitus attending for routine clinical review completed structured questionnaires to assess habitual sleep timing, chronotype, and social jetlag. Statistical analysis was via inferential groupwise approaches and path analysis to establish interdependencies of effects of social jetlag, chronotype, and breakfast eating regularity on HbA1c. 22.7% of the participants reported eating breakfast five times or fewer a week, and were categorised as irregular breakfast eaters. Compared with those who ate breakfast six or seven times a week, irregular breakfast eaters had significantly higher HbA1c and diastolic blood pressure, were younger and had greater social jetlag. In the path analysis, irregular breakfast eating exerted a direct effect on HbA1c, whilst social jetlag exerted only an indirect effect on HbA1c through breakfast eating regularity. Chronotype did not exert any effect on HbA1c, but did exert an indirect effect on breakfast eating regularity via social jetlag. Our results showed that adult participants with type 2 diabetes mellitus, who ate breakfast irregularly had poorer metabolic health and greater social jetlag. The relationship between social jetlag and glycaemic control appears to be mediated through breakfast eating habits.

Feeding twin-bearing Merino ewes above the metabolisable energy requirements for maintenance during late gestation increases the duration of parturition of the first-born lamb

Context In Australia, approximately 53% of lamb deaths are caused by dystocia. One of the main welfare concerns in the sheep industry is under- and overfeeding ewes, which may be contributing to cases of dystocia. Aims This pilot study aimed to investigate how increasing energy intake affects the duration of parturition and predictors of lamb survival. Methods On Day 100 of gestation (dG), 20 twin-bearing and 10 singleton Merino ewes were selected and allocated to three treatment groups; (1) singleton ewes fed at 1.0× maintenance levels (n = 10); (2) twin-bearing ewes fed at 1.0× maintenance levels (n = 10) or (3) twin-bearing ewes fed at 1.25× maintenance (n = 10). Ewes were housed indoors in individual pens. Urine and blood were sampled from ewes on dG 130, 140, then daily from dG 145 through to parturition, and blood was sampled at the onset of parturition and 30 min post-partum. Urine was analysed for pH and blood was analysed for metabolic parameters, mineral concentration and acid–base balance. Predictors of lamb survival from birth to 24 h consisted of weight, rectal temperature, blood glucose and lactate, and body morphology. Key results Serum calcium in late gestation and blood base excess pre-parturition were higher in Singletons 1M compared with Twins 1M (P &lt; 0.05). The Twins 1.25M group took longer to give birth to the first-born lamb (104.4 ± 21.1 min) compared with the Twins 1M group (44.1 ± 6.6 min; P = 0.015). There were no differences in the predictors of lamb survival measures between the twin-bearing groups (P &gt; 0.05). Conclusions Ewes from the Twins 1.25M group took significantly longer to give birth to the first-born lamb. There were no other significant findings between the twin-bearing groups, including lamb liveweight, however, lambs born to ewes from the Twins 1.25 group were numerically heavier, which may explain the increase in parturition length. Implications Feeding ewes above maintenance did not provide any production benefits to metabolic health or any other physiological parameters. Producers should avoid overfeeding ewes during late gestation.

B-140 Use of the metabolic health index for correlation with comorbidity reduction for patients undergoing bariatric surgery

Abstract Background Bariatric surgery is a commonly performed procedure aimed at addressing obesity and its associated health issues. However, while weight loss is often a primary focus, the broader improvements in metabolic health, including reductions in conditions such as type 2 diabetes mellitus (T2DM) and dyslipidemia, are not consistently quantified. The recent development of the Metabolic Health Index (MHI) by van Loon et al. provides a potential laboratory index that encompasses various metabolic parameters to predict improvements in comorbidities post-surgery. Our study aimed to assess the utility of MHI in correlating with changes in metabolic health status among patients undergoing bariatric surgery at a U.S. medical center. Methods In our current study, we conducted a retrospective analysis of 300 patients who had undergone bariatric surgery between 2012 and 2019 at the University of Minnesota. We selected patients who had both baseline and one-year post-surgery laboratory values available, including age, hemoglobin A1C (HbA1c), triglycerides, potassium, and creatinine for estimated glomerular filtration rate (eGFR), which were necessary for calculating MHI using the equation of van Loon et al. Thirty patients met the inclusion criteria and their eGFRs were calculated using the 2021 CKD-EPI equation. Using the published formulae, we calculated the MHI for each patient before and after surgery. Patients were stratified based on improvements in diabetic (T2DM) and dyslipidemic status, with lower stratification numbers indicating better outcomes. We then conducted correlation analyses to examine the relationship between changes in MHI, individual components of MHI, BMI, and the reduction in the two comorbidities. We also examined if any of the initial values of MHI, its components and BMI correlated with the magnitude of reduction in the two comorbidities. Results In the patient cohort examined, initially 46.7% of the population were non-diabetic and this changed to 53.3% one year after surgery. The number of patients with diabetes decreased from 33.3% to 13.3%, indicating a benefit of bariatric surgery in alleviating type 2 diabetes mellitus (T2DM). Dyslipidemia decreased from 36.7% to 13.3% post-surgery. Most of the patients had reductions in both the BMI and MHI scales and a linear relationship between the two values was observed. A Spearman correlation analysis revealed that the values of HbA1c (rho= 0.56, p = 0.0014)) and MHI (rho = 0.5, p = 0.005) had a correlation with the reduction in T2DM and the reduction in triglycerides (rho= 0.73, p= 0.0) correlated with reduction in dyslipidemia. On the other hand, the reduction in BMI did not correlate with the improvement in the comorbidities examined. It was determined that the initial values of MHI, its components, and BMI had no correlation to the degree of reduction in comorbidities. Conclusions Our findings suggest that MHI and HbA1C may serve as valuable indicators of metabolic health improvements following bariatric surgery, while BMI changes alone may not fully capture these improvements. Laboratory-based measurements such as MHI offer a promising approach for assessing and monitoring metabolic health outcomes in bariatric surgery patients, providing insights beyond traditional weight-based metrics.

B-301 Deciphering Neuropathy features in the Context of Nitrous Oxide abuse: An Integrated Analysis of Electrophysiology and Metabolism

Abstract Background Nitrous oxide (N2O), used medically for its analgesic and anxiolytic properties, has emerged as a common recreational substance, leading to a rise in chronic toxicity cases. N2O abuse induces peripheral neurological damage with a spectrum of clinical presentations, ranging from mild sensory disturbances to severe motor deficits. Neurological complications from N2O include axonal and demyelinating neuropathies, leading to diagnostic and prognostic challenges. The pathophysiology of N2O toxicity is linked to functional inactivation of vitamin B12, resulting in biochemical and electrophysiological alterations. This study aims to enhance understanding of N2O pathophysiology by examining metabolic changes in consumers with axonal and demyelinating patterns. Methods This study included 35 patients with recent N2O abuse (last declarative consumption within the past week) who were treated at Lille University Hospital between March 2020 and April 2023 and underwent electromyography. The collected clinical features encompassed sensory symptoms, motor weakness, gait abnormalities and deep tendon reflexes. Patients were classified based on clinical phenotypes, distinguishing between length-dependent and non-length dependent, sensory or sensory-motor involvement and their peripheral neuropathy disability (PND) score (ranging from I to IV). Neurophysiological data analysis followed the criteria of Hadden et al. to identify patients with demyelinating criteria, while those lacking demyelinating criteria were categorized as “axonal” in the neuropathy group. Simultaneously, biochemical evaluations of serum vitamin B12 and B9 by CLIA methods (Roche), along with plasma homocysteine by LC/MS/MS and CLIA methods (Snibe), methylmalonic acid (MMA), and methionine by LC/MS/MS, were systematically performed for all patients. Results 40% of the selected patients exhibited demyelination criteria. The demyelinated group showed a significantly higher disability PND score compared to the axonal group (3.0 and 2.2, respectively; p-value = 0.028). Elevated levels of homocysteine and methylmalonic acid were found in all patients. Interestingly, plasma concentrations of homocysteine were significantly higher in the group of patient with axonal outcomes compared to the demyelinating group (90 µM and 114 µM; p-value = 0.04), suggesting an involvement of homocysteine in the type of lesion related to N2O abuse. Conclusions This study highlights the diverse electrophysiological manifestations of N2O-induced neuropathy and highlight the potential role of metabolic parameters as biomarkers to understand the pathophysiology. Indeed, lower hyperhomocysteinemia levels were observed in demyelinating patterns, highlighting a potentially biochemical difference between the groups: plasma homocysteine could also be used as a marker of neurological severity. The homocysteine assay used in these conditions must enable the patient to be managed rapidly: it would therefore be preferable to use rapid methods such as immunoanalysis. On the other hand, plasma methylmalonic acid did not differ between groups, which also suggests that other mechanisms have yet to be identified in the pathophysiology of N2O abuse.

The relationship between sarcopenia and metabolic parameters of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and the prognostic value of sarcopenia in early-stage non-small cell lung cancer.

Patients with lung cancer face a heightened risk of developing sarcopenia. Despite this known risk, the impact of sarcopenia on the long-term prognosis of lung cancer patients, specifically concerning progression-free survival (PFS) and overall survival (OS), remains unclear. The primary objective of our study was to examine the correlation between metabolic parameters derived from 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and sarcopenia, as well as the prognostic value of sarcopenia in patients with surgically resected early-stage non-small cell lung cancer (NSCLC). In this retrospective cross-sectional study, we analyzed 187 NSCLC patients who underwent 18F-FDG PET/CT at the First Affiliated Hospital of Soochow University between March 2019 and October 2023. Patients were divided into two groups based on the presence (n=46) or absence (n=141) of sarcopenia. The correlation between sarcopenia, metabolic parameters, and patient characteristics was evaluated using chi-square and Mann-Whitney U tests. Survival analyses, including PFS and OS, were conducted using Kaplan-Meier analysis and Cox proportional hazards regression. Based on sarcopenia, metabolic parameters and patient characteristics, patients were classified into high-risk (n=28), intermediate-risk (n=121), and low-risk (n=38) groups. Our analysis identified gender, body mass index (BMI), psoas Hounsfield unit (HU), and maximum standardized uptake value of the psoas major muscle (SUVmax-Muscle) as independent predictors of sarcopenia (P<0.05 for all). A nomogram model, utilizing these parameters, was constructed to predict sarcopenia. Survival analysis further demonstrated that total lesion glycolysis [hazard ratio (HR) =2.499; 95% confidence interval (CI): 2.014-3.267; P=0.016], sarcopenia (HR =3.323; 95% CI: 1.748-6.316; P<0.001), and programmed death ligand-1 (PD-L1) expression (HR =0.093; 95% CI: 0.012-0.698; P=0.021) emerged as independent predictors of OS in early-stage NSCLC. Notably, patients categorized as high-risk, characterized by elevated total lesion glycolysis, presence of sarcopenia, and PD-L1 positivity, exhibited a significantly poorer prognosis compared to the intermediate-risk (P<0.05) and low-risk groups (P<0.05). Our findings indicated an inverse relationship between SUVmax-Muscle or psoas HU with the incidence of sarcopenia in NSCLC patients. Additionally, total lesion glycolysis, sarcopenia, and PD-L1 expression were identified as independent prognostic factors for OS in early-stage NSCLC. The risk stratification model, incorporating total lesion glycolysis, sarcopenia, and PD-L1 expression, assumed a pivotal role in guiding personalized therapy decisions and post-treatment monitoring.

Changes in Transient Elastography with Glucagon-Like Peptide-1 Receptor Agonist Use in Metabolic Dysfunction-Associated Steatotic Liver Disease: A Real-World Retrospective Analysis.

Introduction: Current guidelines recommend the use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD), especially in patients with comorbid diabetes and obesity. This study investigated the effects of GLP-1RAs on hepatic steatosis and fibrosis in patients with MASLD, as measured by changes in vibration-controlled transient elastography (VCTE) and other clinical parameters in a real-world clinical setting. Methods: We conducted a single-center, retrospective analysis of 96 patients with MASLD from a multidisciplinary care clinic who completed VCTE at baseline and follow-up within 6-24 months to compare changes in controlled attenuation parameter (CAP) and liver stiffness measurement (LSM), as well as other metabolic markers, between GLP-1RA users and nonusers using two-sample t-tests and Wilcoxon rank-sum tests. We also assessed whether improvements in hepatic steatosis, defined as a change in CAP >38 dB/m as previously described in the literature, were associated with improvement in fibrosis. Results: GLP-1RA use resulted in significant improvements in weight (-8.1 kg vs. -3.5 kg, P = 0.009), body mass index (BMI) (-2.9 kg/m2 vs. -1.3 kg/m2, P = 0.012), alanine aminotransferase (-15.0 IU/L vs. -4.0 IU/L, P = 0.017), aspartate aminotransferase (-5.0 IU/L vs. -1.0 IU/L, P = 0.021), glycated hemoglobin (HbA1c) (-0.7% vs. 0.1%, P = 0.019), and CAP (-59.9 dB/m vs. -29.1 dB/m, P = 0.016). Responders also had significant improvements in weight (-9.2 kg vs. -1.9 kg, P < 0.001), BMI (-3.3 kg/m2 vs. -0.7 kg/m2, P < 0.001), diastolic blood pressure (-6.1 mmHg vs. -0.7 mmHg, P = 0.028), HbA1c (-0.8% vs. 0.3%, P < 0.001), and LSM (-1.5 kPa vs. 0.1 kPa, P < 0.001). Conclusions: Patients with MASLD treated with GLP-1RAs showed significant improvements in hepatic steatosis and multiple other metabolic parameters, with weight loss as the proposed mechanism for this liver improvement. In addition, change in CAP >38 dB/m was associated with improvements in LSM and other metabolic parameters, suggesting the clinical utility of VCTE in the surveillance of MASLD.

S1494 Efficacy and Safety of GLP-1 Agonists on Metabolic Parameters in Non-Diabetic Patients With Inflammatory Bowel Disease

S1494 Efficacy and Safety of GLP-1 Agonists on Metabolic Parameters in Non-Diabetic Patients With Inflammatory Bowel Disease

Unveiling Resmetirom: A systematic review and meta-analysis on its impact on liver function and safety in non-alcoholic steatohepatitis treatment.

The role of Resmetirom in non-alcoholic steatohepatitis (NASH) represents a promising therapeutic approach in addressing the growing global burden of liver disease. With NASH emerging as a leading cause of liver-related morbidity and mortality worldwide, there is an urgent need for effective treatments. Resmetirom, a selective thyroid hormone receptor-β agonist, offers potential benefits in improving liver histology and metabolic parameters in patients with NASH. This review examines the current evidence surrounding Resmetirom's role in NASH management. A systematic review and meta-analysis was done by searching in Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, MEDLINE (including MEDLINE InProcess) (OvidSP), Web of Science, Embase (OvidSP), and Scopus databases. ROB2 Cochrane tool was used for assessing risk of bias in randomized controlled trials (RCTs). In the analysis, we used RevMan Cochrane software. The study showed that patients who were treated with Resmetirom had significantly lower low-density lipoprotein-cholesterol (LDL-C) levels (mean difference [MD] -10.45; 95% confidence interval [CI] -15.86 to -5.83; P < 0.001) and alanine aminotransferase (ALT) levels (MD -7.18; 95% CI -12.67 to -1.68; P = 0.01) as compared with those in the placebo group. The risk of adverse events including diarrhea [risk ratio (RR)1.81; 95% CI 1.40 to 2.35; P < 0.001] and nausea (RR 1.72; 95% CI 1.31 to 2.27; P < 0.001) was significantly increased for the Resmetirom group as compared with the placebo group. Resmetirom presents a promising therapeutic option for NASH, offering potential benefits in reducing liver fat content and improving histological outcomes. The encouraging results from clinical trials suggest that Resmetirom may address an unmet need in NASH management, providing hope for patients with this progressive liver disease. Further research and long-term studies are warranted to validate its efficacy and safety profile in larger patient populations.