Metabolic Derangements Research Articles

Utilizing a Machine Learning Approach to Define Racial Difference in Multi-Systemic Impact of Monoclonal Protein in Patient with Multiple Myeloma

Multiple myeloma (MM) is the second common hematologic malignancy characterized by the clonal proliferation of plasma cells. While the clinical outcomes of MM have been improved significantly, there remains an intriguing observation regarding the potential influence of race on disease biology and treatment response. In MM, the malignant plasma cell clone not only disrupts the local bone marrow microenvironment but also exerts a systemic impact on various physiological processes result in significant derangements in immune function, hematopoiesis, renal function, bone metabolism, and electrolyte homeostasis. Understanding the extent of this systemic impact and its potential variation between racial groups is crucial for optimizing patient care and treatment strategies. Here, we hypothesized that the systemic impact of the plasma cell clone does not differ significantly between African American and Caucasian patients. We employed a machine learning approach to capture the full spectrum of systemic effects comprehensively. Our novel model was trained to predict the magnitude of the plasma cell clone, as represented by serum monoclonal protein levels. By systematically comparing model performance with and without the inclusion of race as a variable, we sought to evaluate the potential influence of race on the systemic impact of the plasma cell clone. Method: A total of 171 patients with plasma cell dyscrasias including 1,472 observations were analyzed. where the upper limit of the observed M-spike was 3.5 gr/dL. Forty three clinical and lab variables as predictors of M-spike were fed into the machine learning model. Two lagged variables as the last two preceding M-spike values by the same subject were included. The random forest model was used, where regression forests are an ensemble of different regression trees and are used for nonlinear multiple regression. The goal of using a large number of trees was to train enough that each feature had a chance to appear in several models. The data was randomly split into a training set (80%) and a test set (20%), and a regression tree was built with the training set and then validated using the test set. Bootstrapping was used to generate a collection of data sets (n=500). Importance was measured by leaving a covariate out of models and comparing performance with its inclusion. Result: The training set used to develop the ML algorithm comprised 749 patient-based observations, which represented ~50% of the patient-based observations. The number of observations at each M-Spike value and the distribution of M-Spike values measured by SPEP are shown (Fig. 1). The residual distribution of the RF model indicated that nearly all M-spike values determined using the 43 variables distributed equally on either side of zero. The addition of race as variables did not significantly change the residual plots. The weighted value of each of the 43 independent variables was determined by individually removing a variable from the ML algorithm and measuring its effect on the mean squared error (MSE). As shown, removal of the first lagged M-spike, serum total protein, second-lagged M-spike, serum IgG, serum IgM, and serum IgA, had the greatest effects on the ML algorithm. The effect of race was then added to the ML algorithm. However, patient race had a low weighted value compared to the other variables included in the ML algorithm (Fig-2). M-spike values determined using the ML algorithm correlated highly with M-spike values determined using the laboratory measured SPEP values as indicated by the proximity of the Pearson and Spearman correlation coefficients to +1 . Using the 43 independent variables, the Pearson coefficient was 0.96 and the Spearman coefficient was 0.91, when M-spike values determined using the ML algorithm were compared to laboratory determined M-spike values. When race was added as a variable in the ML algorithm, the Pearson coefficient was 0.95 and the Spearman coefficient was 0.94 which is not significantly different. Conclusion: Here, we present the results of our machine learning analysis, which further supports our hypothesis and sheds light on the potential racial difference in the overall systemic impact of MM. Understanding the factors underlying racial disparities in MM will pave the way for more personalized and equitable treatment strategies, ultimately improving patient outcomes and overall disease management.

Parkin depletion prevents the age-related alterations in the FGF21 system and the decline in white adipose tissue thermogenic function in mice.

Parkin is an ubiquitin-E3 ligase that is involved in cellular mitophagy and was recently shown to contribute to controlling adipose tissue thermogenic plasticity. We found that Parkin expression is induced in brown (BAT) and white (WAT) adipose tissues of aged mice. We determined the potential role of Parkin in the aging-associated decline in the thermogenic capacity of adipose tissues by analyzing subcutaneous WAT, interscapular BAT, and systemic metabolic and physiological parameters in young (5month-old) and aged (16month-old) mice with targeted invalidation of the Parkin (Park2) gene, and their wild-type littermates. Our data indicate that suppression of Parkin prevented adipose accretion, increased energy expenditure and improved the systemic metabolic derangements, such as insulin resistance, seen in aged mice. This was associated with maintenance of browning and reduction of the age-associated induction of inflammation in subcutaneous WAT. BAT in aged mice was much less affected by Parkin gene invalidation. Such protection was associated with a dramatic prevention of the age-associated induction of fibroblast growth factor-21 (FGF21) levels in aged Parkin-invalidated mice. This was associated with a parallel reduction in FGF21 gene expression in adipose tissues and liver in aged Parkin-invalidated mice. Additionally, Parkin invalidation prevented the protein down-regulation of β-Klotho (a key co-receptor mediating FGF21 responsiveness in tissues) in aged adipose tissues. We conclude that Parkin down-regulation leads to improved systemic metabolism in aged mice, in association with maintenance of adipose tissue browning and FGF21 system functionality.

Diabetes Mellitus, Energy Metabolism, and COVID-19.

Obesity, diabetes mellitus (mostly type 2), and COVID-19 show mutual interactions because they are not only risk factors for both acute and chronic COVID-19 manifestations, but also because COVID-19 alters energy metabolism. Such metabolic alterations can lead to dysglycemia and long-lasting effects. Thus, the COVID-19 pandemic has the potential for a further rise of the diabetes pandemic. This review outlines how preexisting metabolic alterations spanning from excess visceral adipose tissue to hyperglycemia and overt diabetes may exacerbate COVID-19 severity. We also summarize the different effects of SARS-CoV-2 infection on the key organs and tissues orchestrating energy metabolism, including adipose tissue, liver, skeletal muscle, and pancreas. Last, we provide an integrative view of the metabolic derangements that occur during COVID-19. Altogether, this review allows for better understanding of the metabolic derangements occurring when a fire starts from a small flame, and thereby help reducing the impact of the COVID-19 pandemic.

Association of serum immunoglobulin M and immunoglobulin G antibody levels with different indicators of metabolic syndrome

Background: Metabolic syndrome (MS) is an assemblage of biochemical derangements of glucose metabolism, dyslipidemia, hypertension, and central obesity allied with implacable low-grade inflammation. Aims and Objectives: The current cross-sectional study was conducted to evaluate the levels of serum Immunoglobulin IgM, and IgG concentrations in subjects with and without MS. Materials and Methods: The study population included 50 adults with MS as cases confirmed by estimation of serum triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), Fasting Plasma Glucose, waist circumference, and blood pressure. Serum IgM and IgG levels were evaluated in cases and controls (from a healthy population), followed by statistical analysis, with the significance level set at P<0.05. Results: The comparison of the serum IgM levels between the case and control groups revealed that the level was significantly higher in the former (P<0.001) compared to the latter, but no statistically significant difference existed in the IgG values. Correlation analysis showed significant positive correlation of IgM with TG (ρ=+0.870, P<0.001), waist circumference (ρ=+0.683, P=0.009) and negative correlation with HDL-C (ρ=−0.751, P<0.001). A significant positive correlation of IgG with waist circumference (ρ=+0.889, P<0.001) was derived. Regression analysis affirmed that statistically, TG (R2=0.768), waist circumference (R2=0.751), and HDL-C (R2=0.705) significantly explained the variance in IgM, whereas IgG was related to only waist circumference. Conclusion: The present study provides a novel perspective that IgM may be involved in the pathogenesis of MS in a population from eastern India, and the outcome suggests the association between IgM and MS may be through lipid metabolism disorders and obesity.

Body mass index is a good predictor of metabolic abnormalities in polycystic ovary syndrome.

To assess which parameters among hyperandrogenism (total testosterone-tT-or free androgen index-FAI), sex hormone binding globulin (SHBG) or body mass index (BMI) could better predict a worse metabolic profile in women with polycystic ovary syndrome (PCOS). Five hundred and eighty-six women with PCOS and clinical or biochemical hyperandrogenism were included. Receiver Operating Characteristics (ROC) curves with tT, FAI, SHBG and BMI were performed for metabolic parameters and a cut-off with sensitivity and specificity was obtained for each parameter. The women were then divided into three groups and compared according to their BMI. Based on the ROC curves, tT proved not to be a good predictor of metabolic alterations. FAI and SHBG resulted to be good predictors of some markers of metabolic damage. The area under the curves (AUC) of SHBG were greater than those of FAI. SHBG levels affects the values of homeostasis model assessment of insulin resistance (HOMA-IR), fasting insulin, high density lipoproteins (HDL), low density lipoproteins (LDL), and total cholesterol also when corrected for BMI. However, the highest AUCs of the ROC curves were observed when BMI was used, which was significantly related to all the metabolic parameters analyzed. Dividing women according to their BMI, BMI between 25.00 and 30.00 kg/m2 had a worse metabolic profile but still in a normal range, while BMI≥30 kg/m2 women had a significant metabolic derangement. BMI is a good predictor factor of metabolic changes in PCOS women at any age, and obesity is associated to the appearance of metabolic complications. Overweight and obese PCOS women should be addressed to perform a complete metabolic assessment.

Periprostatic adipose tissue thromboinflammation triggers prostatic neoplasia in early metabolic impairment: Interruption by rivaroxaban

AimsProstate cancer is among the highest incidence malignancies in men with a prevalence rate increasing in parallel to the rising global trends in metabolic disorders. Whereas a sizeable body of evidence links metabolic impairment to negative prognosis of prostate cancer, the molecular mechanism underlying this connection has not been thoroughly examined. Our previous work showed that localized adipose tissue inflammation occurring in select adipose depots in early metabolic derangement instigated significant molecular, structural, and functional alterations in neighboring tissues underlying the complications observed at this stage. In this context, the periprostatic adipose tissue (PPAT) constitutes an understudied microenvironment with potential influence on the prostatic milieu. Main methods and resultsWe show that PPAT inflammation occurs in early prediabetes with signs of increased thrombogenic activity including enhanced expression and function of Factor X. This was mirrored by early neoplastic alterations in the prostate with fibrosis, increased epithelial thickness with marked luminal cellular proliferation and enhanced formation of intraepithelial neoplasia. Significantly, interruption of the procoagulant state in PPAT by a 10-day anticoagulant rivaroxaban treatment not only mitigated PPAT inflammation, but also reduced signs of prostatic neoplastic changes. Moreover, rivaroxaban decreased the murine PLum-AD epithelial prostatic cell viability, proliferation, migration, and colony forming capacity, while increasing oxidative stress. A protease-activated receptor-2 agonist reversed some of these effects. SignificanceWe provide some evidence of a molecular framework for the crosstalk between PPAT and prostatic tissue leading to early neoplastic changes in metabolic impairment mediated by upregulation of PPAT thromboinflammation.

Serum Selenium-Binding Protein 1 (SELENBP1) in Burn Injury: A Potential Biomarker of Disease Severity and Clinical Course.

Oxidative stress, systemic inflammation, and metabolic derangements are hallmarks of burn pathophysiology. Severely burned patients are highly susceptible to infectious complications. Selenium-binding protein 1 (SELENBP1) modulates intracellular redox homeostasis, and elevated serum concentrations have been associated with adverse clinical outcomes in trauma patients. We hypothesized that serum SELENBP1 at hospital admission and during hospitalization may constitute a meaningful biomarker of disease severity and the clinical course in burn injury, with pulmonary infection as primary endpoint. To this end, we conducted a prospective cohort study that included 90 adult patients admitted to the Burn Center of the University Hospital Zurich, Switzerland. Patients were treated according to the local standard of care, with high-dose selenium supplementation during the first week. Serum SELENBP1 was determined at nine time-points up to six months postburn and the data were correlated to clinical parameters. SELENBP1 was initially elevated and rapidly declined within the first day. Baseline SELENBP1 levels correlated positively with the Abbreviated Burn Severity Index (ABSI) (R = 0.408; p < 0.0001). In multiple logistic regression, a higher ABSI was significantly associated with increased pulmonary infection risk (OR, 14.4; 95% CI, 3.2-88.8; p = 0.001). Similarly, baseline SELENBP1 levels constituted a novel but less accurate predictor of pulmonary infection risk (OR, 2.5; 95% CI, 0.7-8.9; p = 0.164). Further studies are needed to explore the additional value of serum SELENBP1 when stratifying patients with respect to the clinical course following major burns and, potentially, for monitoring therapeutic measures aimed at reducing tissue damage and oxidative stress.

Characterising diabetes in Kazakhstan: a cluster analysis

Abstract Background Diabetes is a global pandemic, affecting 537 million adults worldwide in 2021. Diabetes is much more complex than the classification into type 1 diabetes and type 2 diabetes suggests. We aimed to identify homogeneous groups of patients with diabetes based on routinely collected measurements using unsupervised, data-driven cluster analysis. Methods We analyzed the data from Electronic Medical Records of 558 patients with newly diagnosed diabetes from 4 outpatient clinics in Astana. We performed a k-means cluster analysis of 9 routinely measured variables using the KMeans function (iterations=3 million) from the Scikit-Learn Python library. Results Cluster 1, consisting of 176 (31,5%) patients, was defined by late-onset diabetes, relatively low blood pressure (BP) and body mass index (BMI), moderate metabolic derangements, and comparably low glomerular filtration rate (GFR). The 83 (14,9%) patients in cluster 2 were characterized by a late manifestation of diabetes, high BP and BMI, relatively poor glycemic control, moderate dyslipidemia, and comparably low GFR. Cluster 3, including 98 (17,6%) patients, was represented by a low age at onset, comparably low BP and BMI, moderately poor glycemic and lipid controls, and high GFR. The 110 (19,7%) patients in cluster 4 had late-onset diabetes, high BP and BMI, subcompensated diabetes, poor lipid control, and relatively low GFR. Cluster 5, which involved 91 (16,3%) patients, was characterized by comparably low BP and BMI, poor glycemic control, modest dyslipidemia, and high GFR. Conclusions We intend to continue the project for further conducting a prospective study with dynamic monitoring of study participants, tracking specific patterns in the development of diabetic complications in each cluster. The results of this work will contribute to the development of a model for identifying patients with an initially predictable course of diabetes and a high risk of its complications at the time of diagnosis. Key messages • We identified five clusters of patients with diabetes with clinically significant characteristics in each cluster. • Identification of subgroups of patients with an initially predictable course can be useful for recognizing those at highest risk of complications and applying personalized treatment strategies.

Efficacy of therapeutic plasma exchange in pediatric cases of acute liver failure as an extracorporeal liver support system

BackgroundAcute liver failure in the pediatric population is often accompanied by deranged metabolism, severe encephalopathy and coagulopathy. A liver transplant is the most viable option for the management of such patients. Therapeutic plasma exchange (TPE) is helpful in improving the liver biochemistry profile, thereby, increasing their likelihood of undergoing a liver transplant MethodThe study was conducted over a period of 3 years (January 2018 to December 2021). Indications mainly consisted of ALF with hepatic encephalopathy, worsening liver parameters in spite of medical management, and candidacy for undergoing a liver transplant. Plasma exchange was performed daily or alternatively until the patient recovered, succumbed, or was stable enough to undergo a transplant. Biochemical parameters serum bilirubin, ALT, AST serum ammonia serum urea, serum creatinine were recorded before and after TPE sessions. ResultsThe study group comprised 14 patients of which a total of 28 TPE was performed. There were a total of 5 cases of cryptogenic ALF, 4 of Wilson disease, 2 cases each of infection-related ALF and autoimmune hepatitis, and a single case of drug-induced hepatitis. A total of 5 out of 14 patients underwent a liver transplant and amongst the 9 who did not undergo a transplant, 4 patients expired due to septic shock syndrome; the remaining 5 were discharged in a stable condition following TPE sessions. The disease-free survival was 78.9% and the transplant-free survival was 35.71%. ConclusionTPE plays a crucial role in improving the biochemistry profile of the liver in children with liver failure.

Capnography-An Essential Monitor, Everywhere: A Narrative Review.

Capnography is now recognized as an indispensable patient safety monitor. Evidence suggests that its use improves outcomes in operating rooms, intensive care units, and emergency departments, as well as in sedation suites, in postanesthesia recovery units, and on general postsurgical wards. Capnography can accurately and rapidly detect respiratory, circulatory, and metabolic derangements. In addition to being useful for diagnosing and managing esophageal intubation, capnography provides crucial information when used for monitoring airway patency and hypoventilation in patients without instrumented airways. Despite its ubiquitous use in high-income-country operating rooms, deaths from esophageal intubations continue to occur in these contexts due to incorrect use or interpretation of capnography. National and international society guidelines on airway management mandate capnography's use during intubations across all hospital areas, and recommend it when ventilation may be impaired, such as during procedural sedation. Nevertheless, capnography's use across high-income-country intensive care units, emergency departments, and postanesthesia recovery units remains inconsistent. While capnography is universally used in high-income-country operating rooms, it remains largely unavailable to anesthesia providers in low- and middle-income countries. This lack of access to capnography likely contributes to more frequent and serious airway events and higher rates of perioperative mortality in low- and middle-income countries. New capnography equipment, which overcomes cost and context barriers, has recently been developed. Increasing access to capnography in low- and middle-income countries must occur to improve patient outcomes and expand universal health care. It is time to extend capnography's safety benefits to all patients, everywhere.

Endoplasmic Reticulum Stress Promotes the Expression of TNF-α in THP-1 Cells by Mechanisms Involving ROS/CHOP/HIF-1α and MAPK/NF-κB Pathways.

Obesity and metabolic syndrome involve chronic low-grade inflammation called metabolic inflammation as well as metabolic derangements from increased endotoxin and free fatty acids. It is debated whether the endoplasmic reticulum (ER) stress in monocytic cells can contribute to amplify metabolic inflammation; if so, by which mechanism(s). To test this, metabolic stress was induced in THP-1 cells and primary human monocytes by treatments with lipopolysaccharide (LPS), palmitic acid (PA), or oleic acid (OA), in the presence or absence of the ER stressor thapsigargin (TG). Gene expression of tumor necrosis factor (TNF)-α and markers of ER/oxidative stress were determined by qRT-PCR, TNF-α protein by ELISA, reactive oxygen species (ROS) by DCFH-DA assay, hypoxia-inducible factor 1-alpha (HIF-1α), p38, extracellular signal-regulated kinase (ERK)-1,2, and nuclear factor kappa B (NF-κB) phosphorylation by immunoblotting, and insulin sensitivity by glucose-uptake assay. Regarding clinical analyses, adipose TNF-α was assessed using qRT-PCR/IHC and plasma TNF-α, high-sensitivity C-reactive protein (hs-CRP), malondialdehyde (MDA), and oxidized low-density lipoprotein (OX-LDL) via ELISA. We found that the cooperative interaction between metabolic and ER stresses promoted TNF-α, ROS, CCAAT-enhancer-binding protein homologous protein (CHOP), activating transcription factor 6 (ATF6), superoxide dismutase 2 (SOD2), and nuclear factor erythroid 2-related factor 2 (NRF2) expression (p ≤ 0.0183),. However, glucose uptake was not impaired. TNF-α amplification was dependent on HIF-1α stabilization and p38 MAPK/p65 NF-κB phosphorylation, while the MAPK/NF-κB pathway inhibitors and antioxidants/ROS scavengers such as curcumin, allopurinol, and apocynin attenuated the TNF-α production (p ≤ 0.05). Individuals with obesity displayed increased adipose TNF-α gene/protein expression as well as elevated plasma levels of TNF-α, CRP, MDA, and OX-LDL (p ≤ 0.05). Our findings support a metabolic-ER stress cooperativity model, favoring inflammation by triggering TNF-α production via the ROS/CHOP/HIF-1α and MAPK/NF-κB dependent mechanisms. This study also highlights the therapeutic potential of antioxidants in inflammatory conditions involving metabolic/ER stresses.

Effects of myostatin gene knockout on white fat browning and related gene expression in type 2 diabetic mice.

Myostatin (Mstn) plays an important role in adipocyte growth, differentiation and metabolism, leading to the development of obesity. We aimed to explore the effect of Mstn on white fat browning in a mouse model of type 2 diabetes mellitus (T2DM). Twelve wild-type (WT), 12 heterozygous (Mstn(+/-)) and 12 homozygous (Mstn(-/-)) male mice were randomly divided into 6 groups: WT, Mstn(+/-), Mstn(-/-), WT+DM, Mstn(+/-)+DM, and Mstn(-/-)+DM. The first 3 groups were fed normal chow, while the last 3 were fed high-fat diet and administered streptozotocin to generate T2DM. Subsequently, body mass, length, and white and brown fat masses were measured, after which Lee's index, white-brown ratio and fat index were calculated. The serum free fatty acid (FFA) levels were detected using enzyme-linked immunosorbent assay (ELISA). Hematoxylin and eosin (H&E) staining was used to analyze white and brown fat cell morphology. The relative expression levels of peroxisome proliferator-activated receptor-gamma (PPARγ), peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α), uncoupling protein 1 (UCP1), and cluster of differentiation 137 (CD137) protein were determined with western blotting. The Mstn(-/-) group displayed higher levels of PPARγ, PGC-1α and CD137 proteins in white and brown fat compared to the WT and Mstn(+/-) groups, while the expression level of UCP1 protein in the Mstn(-/-) group was higher than in the WT group. The expression levels of PPARγ, PGC-1α, UCP1, and CD137 proteins in the WT+DM group were lower than in the WT group. Moreover, PPARγ, PGC-1α, UCP1, and CD137 proteins were more highly expressed in the Mstn(-/-)+DM group compared to the WT+DM and Mstn(+/-)+DM groups. The Mstn gene inhibition antagonizes obesity phenotypes, such as white fat accumulation and lipid metabolism derangement caused by T2DM, thus promoting white fat browning.

Sleep in pediatric neuromuscular disorders

Sleep disordered breathing (SDB) is prevalent among children with neuromuscular disorders (NMD). The combination of respiratory muscle weakness, altered drive, and chest wall distortion due to scoliosis make sleep a stressful state in this population. Symptomatology can range from absent to snoring, nocturnal awakenings, morning headaches, and excessive daytime sleepiness. Sequelae of untreated SDB includes cardiovascular effects, metabolic derangements, and neurocognitive concerns which can be compounded by those innate to the NMD. The clinician should have a low threshold for obtaining polysomnography and recognize the nuances of individual disorders due to disproportionately impacted muscle groups such as hypoventilation in ambulating patients from diaphragm weakness. Non-invasive or invasive ventilation are the mainstay of treatment. In this review we explore the diagnosis and treatment of SDB in children with various NMD.

Management of Vatarakta with Yashtyahwa Niruha Basti: A Case Study

Convenience and busy schedules have become typically major issues in today’s society, with unhealthy food habits and sedentary lifestyle, leading to increase in various types of health issues day by day. Vatarakta is a disease explained in Ayurveda, in which derangement of metabolism occurs due to indulgence in unwholesome dietary habits and sedentary lifestyle. It occurs when both Vata and Rakta are vitiated by distinct etiological factors.[1] Initially vitiated Vata obstructs the path of vitiated Rakta and then gets obstructed by Rakta itself. It can be correlated with Gout due to similarity in the clinical presentation. Various Ayurvedic drugs and Panchakarma procedures have been proved useful for this disease. Here is a case of Vatarakta, which was treated for 16 days with Yashtyahwa Niruha Basti.[2] Observations and results were drawn on the basis of assessment criteria. Marked improvement in signs and symptoms in Patient’s condition were seen.

The Reciprocal Interplay between Infections and Inherited Metabolic Disorders.

Infections represent the main cause of acute metabolic derangements and/or the worsening of the clinical course of many inherited metabolic disorders (IMDs). The basic molecular mechanisms behind the role of infections in these conditions have not been completely clarified. This review points out the different mechanisms behind the relationship between IMDs and infections, providing an overview of this still-under-investigated area. Classically, infections have been considered as the consequence of a compromised immune system due to a biochemical defect of energy production. An adjunctive pathogenetic mechanism is related to a genetically altered protein-attached glycans composition, due to congenital glycosilation defects. In addition, a dietary regimen with a reduced intake of both micro- and macronutrients can potentially compromise the ability of the immune system to deal with an infection. There is recent pre-clinical evidence showing that during infections there may be a disruption of substrates of various metabolic pathways, leading to further cellular metabolic alteration. Therefore, infective agents may affect cellular metabolic pathways, by mediation or not of an altered immune system. The data reviewed here strongly suggest that the role of infections in many types of IMDs deserves greater attention for a better management of these disorders and a more focused therapeutic approach.

FRI014 Exploring The Epigenetic Fingerprint Of Sedentary Behavior

Abstract Disclosure: A. Brener: None. D. Lorber: None. A. Reuveny: None. Y. Lebenthal: None. T. Volk: None. Eating habits and physical activity play a central role among the environmental factors that modulate biological aging. Sedentary lifestyle, characterized by increased waking time spent in minimal energy expenditure activity, is closely associated with increased cardiometabolic risk, a principal hallmark of aging. The biological mechanisms linking a sedentary lifestyle with metabolic derangements are incompletely understood. Exercise was reported as a stimulator of epigenetic modifications of the DNA in human muscle cell nuclei (myonuclei). Exploring the specific impact of sedentary behavior on epigenetics, especially among younger individuals, requires the exclusion of the effects of inflammatory and nutritional contributors to medical conditions. We developed an experimental animal model that imitates sedentary behavior in which a chromatin epigenetic landscape could be explored. We used third-instar Drosophila larvae carrying a temperature-sensitive mutation in the shibire gene coding for GTPase involved in neuronal synaptic vesicle transport. Shibire homozygous mutant larvae are paralyzed at restrictive temperature (&amp;gt;∼29°C) due to inhibition of neuromuscular junction vesicular transport, while muscle contraction is abolished without affecting other systems. Shibire and control (y,w) larvae were kept at 18°C or 30°C without food for six hours. They were then dissected, fixed and double-labeled with antibodies specific for epigenetic marks of active (H3K9ac) and repressive (H3K27me3) histone modifications. An anti-lamin fluorescent antibody served for nuclear membrane demarcation. Immunofluorescence images of epigenetic marks were acquired on a confocal microscope Zeiss LSM 800, after which a quantitative analysis of epigenetics marks was performed. At the restrictive temperature (30°C), the crawling motion of shibire mutant larvae ceased in contrast to control (shibire at 18°C). The crawling motion of the y,w larvae was similar at 18°C and 30°C. The mean repressive mark H3K27me3 decreased (p&amp;lt;0.001), while the mean active H3KPac increased (p&amp;lt;0.001) in the myonuclei of sedentary shibire larvae (30°C). The mean myonuclear active/repressed ratio of epigenetic marks (H3K9ac/H3K27me) was similar in both active shibire (18°C) and y,w at 18°C, while it increased significantly in sedentary shibire (30°C) (p&amp;lt;0.001). In contrast, this ratio decreased in the control larvae (y,w at 30°C) (p&amp;lt;0.001). The findings of this model, which was aimed at reflecting sedentary behavior in youth, revealed that muscle inactivity changed the epigenetic fingerprint in myonuclei, with a balance shift towards decreased chromatin methylation relative to acetylation. Our finding suggests a decline in the epigenetic control of gene transcription, reminiscent of decreased epigenetic repression described with aging. Presentation: Friday, June 16, 2023

SAT162 Management Of Hypoglycemia In Von Gierke's Disease

Abstract Disclosure: A. Makda: None. A. Sood: None. O. Syed: None. K. Nihan: None. Introduction: Glycogen Storage Disease Type-1 (GSD-1)is due to deficiency in Glucose-6-Phosphatase (G6P) results in excessive accumulation of glycogen and fat in the liver, kidney. GSD-1 have a wide spectrum of symptoms including hepatomegaly, hypoglycemia, lactic acidemia, hyperlipidemia, hyperuricemia, and growth retardation. Manifestations of the disease vary in age of onset, rate of disease progression, and severity. Case:18-year-old male with GSD-1a, Von Gierke's disease, hyperuricemia and hypertension presented to the hospital with nausea and vomiting. Patient followed an hourly cornstarch regimen during the day and overnight through infusion via PEG tube. The complaints started at work where he was unable to tolerate oral cornstarch. ABG showed metabolic acidosis, labs showed Leukocytosis, hyperkalemia, acute kidney injury, elevated liver enzymes, hypertriglyceridemia, lactic acidosis. CT abdomen showed hepatomegaly and fatty infiltration with PEG tube intact. He was admitted to the ICU and started on D5NS for hypoglycemia and lactic acidosis. Per request by the patient's pediatrician, he was transitioned to IV D10- 0.45NS at 110mL/Hr to maintain blood glucose above 75 mg/L. Frequent accuchecks were done till he could tolerate his dietary regimen with cornstarch. Lactic Acid downtrended to 2.9 and accuchecks ranged between 100-110. Cr improved to 1.3, and his home medications (Allopurinol and Lisinopril) were resumed. He was discharged in stable condition with plans for further genetic therapy work up. Discussion: Mainstay therapy for Von Gierke's Disease is prevention of metabolic derangements for which dietary and lifestyle changes are recommended. A low fructose and sucrose diet is recommended with limiting the intake of galactose and lactose to one serving per day. Hypoglycemia treatment in such patients is two fold; utilizing both quick and stable release sources. Cornstarch has been once such therapy since the 1980, its slow digestion provides a steady release of glucose over a longer period of time as compared with other sources of carbohydrates. Dosing guidelines vary from age to age and person to person but it is highly recommended to check BG levels frequently to maintain a BG &amp;gt; 70 mg/dL. Associated high levels of triglycerides and cholesterol can be treated with statins, fibrates, etc. Conclusion: The management of hypoglycemia in GSD 1 disease presents various obstacles which could prove to be fatal. Due to the deficiency of G6P, treatment with a specialized hypoglycemic regimen is warranted. A D10 ½ NS infusion can be used to maintain blood sugar levels as well as correct metabolic or lactate imbalances. Infusion should be gradually weaned off after the patient can tolerate oral feeds as this can help prevent the risk of hypoglycemia and other derangements. Further research is needed in regards to these patients for more sustainable regimens. Presentation: Saturday, June 17, 2023

THU389 Euglycemic Diabetic Ketoacidosis With Prolonged Ketosis Due To SGLT-2 Inhibitor

Abstract Disclosure: N. Viera Feliciano: None. J. Johannan: None. E. Nosova: None. C.J. Levy: Advisory Board Member; Self; Eli Lilly &amp; Company, Dexcom. Research Investigator; Self; NIH, Helmsley Foundation, Abbott, Dexcom, Insulet, Tandem. Background: Euglycemic Diabetic ketoacidosis is a known complication of Sodium-glucose cotransporter 2 inhibitor use. Prolonged ketosis is infrequently reported on this patient population. Clinical Case: A 67-year-old male with T2DM (HbA1c 8.3%) taking dapagliflozin, metformin and semaglutide presented with emesis, polydipsia and reduced oral intake for 2 weeks. Initial tests were consistent with euglycemic diabetic ketoacidosis (eDKA): glucose 193 (70-110 mg/dL), acidosis (pH on VBG 7.27), bicarbonate 10 mmol/L (22-26 mmol/L), anion gap of 25, beta-hydroxybutyrate &amp;gt;4.5, positive urine ketones and glycosuria. Insulin drip was initiated along with fluid resuscitation and intravenous dextrose, followed by transition to a basal/bolus regimen after anion gap closure. Despite overall clinical improvement, the patient’s labs demonstrated persistent metabolic derangements: glycosuria and ketosis that lasted 7 days after his last dose of dapagliflozin. Implementation of an insulin regimen in this insulin-naïve patient and a carbohydrate-rich diet resulted in subsequent resolution of the derangements. The patient was discharged on metformin and insulin. eDKA is defined by a blood glucose level below 200 mg/dL, metabolic acidosis and ketosis. The cause of eDKA in this case is attributed to SGLT-2 inhibitor (SGLT2i) use, which lead to a carbohydrate deficit and depletion of glycogen stores, increased glucagon/insulin ratio resulting in ketogenesis and decreased hepatic gluconeogenesis. SGLT-2i act on proximal tubules reducing reabsorption of glucose, thereby increasing urinary glucose excretion. Dapagliflozin has an approximate half-life of 12 hours; therefore, clinical recovery from SGLT2i-associated eDKA would be expected to take up to 2-3 days after cessation of the medication. Case reports have shown persistent glucosuria and ketonemia up to 10 days after discontinuation of the drug, but the data is sparse. Our patient’s laboratory tests remained consistent with eDKA for up to 7 days, suggesting a longer lasting effect of dapagliflozin. This was managed with more aggressive insulin doses and a higher carbohydrate intake which played a critical role in correction of the insulin deficit and repletion of glycogen stores for metabolic recovery. With the growing popularity of this medication class, additional controlled studies are needed for a better understanding of the pharmacodynamics as well as how to target management strategies when eDKA occurs. In this report, we highlight the prolonged clinical effects of SGLT-2i after discontinuation and resolution of symptoms with an aggressive insulin regimen and higher carbohydrate intake. Conclusion: Use of SGLT-2i therapy for diabetes has increased the incidence of eDKA. Providers should be aware of the possibility of prolonged eDKA and manage metabolic imbalances to achieve clinical recovery in an appropriate time frame. Presentation: Thursday, June 15, 2023

SAT316 Severe Cushing’s Syndrome Due To Ectopic ACTH In Newly Diagnosed Small Cell Lung Cancer: The Pivotal Role Of Etomidate In Acute Treatment

Abstract Disclosure: H. Belal: None. G.Y. Gandhi: None. Introduction: Ectopic ACTH syndrome can present as an endocrine emergency. Etomidate, the only parenteral steroidogenesis inhibitor, can rapidly treat critically ill patients with Cushing’s syndrome (CS) and concurrent significant metabolic derangements, severe hypertension, or psychosis. Case Description: A 66-year-old female presented with abdominal pain, vomiting, proximal muscle weakness, and confusion for 6 months. Physical exam revealed hypertension, bilateral supraclavicular fat pads, and abdominal distention, while laboratory evaluation uncovered severe hypokalemia &amp;lt;1.5 mmol/L, metabolic alkalosis, and elevated proBNP. A hilar soft tissue mass with mediastinal lymphadenopathy and bilaterally enlarged adrenal glands were seen on CT imaging. Serum cortisol was high at 114 mcg/dL. ACTH was inappropriately elevated at 111 pg/mL. MRI revealed a normal pituitary gland. She developed hypertensive emergency and status epilepticus, requiring intubation. Due to her life-threatening presentation, a guideline-based hypercortisolism workup was forgone for emergent treatment with continuous etomidate infusion. Serum cortisol normalized after 4 days of etomidate therapy. Due to concerns of reduced seizure threshold with etomidate therapy, it was weaned off after 14 days and replaced by ketoconazole. She subsequently developed recurrent hypercortisolism (serum cortisol 92 mcg/dL). After 14 days of etomidate, 9 days of ketoconazole, and 3 days of chemotherapy for biopsy-proven small-cell lung carcinoma, serum cortisol reached a trough of 22 mcg/dL. At this point, hydrocortisone therapy was initiated (block-and-replace). Recurrent clinical hypercortisolism then developed, and hydrocortisone was discontinued. Hypercortisolism comorbidities were treated appropriately: trimethoprim-sulfamethoxazole for pneumocystis pneumonia prophylaxis, anticoagulation for DVT prophylaxis, antibiotics for acute diverticulitis, and insulin for hyperglycemia. Despite treatment, her condition worsened; she was transitioned to comfort care one month after admission and died 4 days later. Discussion: Etomidate inhibits steroidogenesis through 11 beta-hydroxylate blockade and works rapidly (within 12-24 hours) to decrease cortisol levels versus ketoconazole (several days) and has a reduced risk of hepatic injury. Side effects of etomidate include respiratory depression, myoclonus, and reduced seizure threshold. Several experts have suggested a block-and-replace strategy in severe CS treatment. While effective, this strategy poses risks of etomidate toxicity and makes serum cortisol interpretation unreliable. Etomidate analogs are on the horizon that retain the potent adrenostatic action of etomidate without its sedative-hypnotic activity, offering an alternative treatment option for treating patients with severe CS in non-ICU hospital settings. Presentation: Saturday, June 17, 2023

Anisodamine hydrobromide in the treatment of critically ill patients with septic shock: a multicenter randomized controlled trial

Background Septic shock is the development of sepsis to refractory circulatory collapse and metabolic derangements, characterized by persistent hypotension and increased lactate levels. Anisodamine hydrobromide (Ani HBr) is a Chinese medicine used to improve blood flow in circulatory disorders. The purpose of this study was to determine the therapeutic efficacy of Ani HBr in the treatment of patients with septic shock. Methods This was a prospective, multicenter, randomized controlled trial focusing on patients with septic shock in 16 hospitals in China. Patients were randomly assigned in a 1:1 ratio to either the treatment group or the control group. The primary endpoint was 28-day mortality. The secondary outcomes included 7-day mortality, hospital mortality, hospital length of stay, vasopressor-free days within 7 days, etc. These indicators were measured and collected at 0, 6h, 24h, 48h, 72h and 7d after the diagnosis. Results Between September 2017 and March 2021, 404 subjects were enrolled. 203 subjects received Ani HBr and 201 subjects were assigned to the control group. The treated group showed lower 28-day mortality than the control group. Stratified analysis further showed significant differences in 28-day mortality between the two groups for patients with a high level of illness severity. We also observed significant differences in 7-day mortality, hospital mortality and some other clinical indicators between the two groups. Conclusion Ani HBr might be an important adjuvant to conventional treatment to reduce 28-day mortality in patients with septic shock. A large-scale prospective randomized multicenter trial is warranted to confirm our results.