bluuebunny/crossref_metadata_2025 huggingface dataset:
1613-P: Sphingolipid Imbalance and Insulin Resistance in MAFLD-Related Sarcopenia
Authors: YAN QIANHUA , SU LIANYONG , LING TAI YUN , ZHAO DERRICK , WANG XUAN , C GURLEY EMILY , B HYLEMON PHILLIP , ZHOU XIQIAO , ZHOU HUIPING
Published: June 2024

Introduction & Objective: Metabolic fatty liver disease (MAFLD) is closely related to dysregulation of systemic metabolism and insulin resistance (IR). Sarcopenia is often observed in individuals with MAFLD. Sphingolipids, known for their pivotal role in muscle cell regeneration and repair, have been suggested as key regulators in this context. This study aims to elucidate the potential connection between sphingolipid dysregulation in muscle and MAFLD.

Methods: Ten-week-old male mice with a C57BL/6J and 129S1/SvlmJ mixed background were subjected to either a WDSW (Western diet, Harlan, TD88137, and a high fructose-glucose solution, 23.1g/L D-fructose plus 18.9g/L D-glucose) or standard chow diet for 24 weeks, with free access to food and water. IPGTT and ITT tested were conducted at the end of the study. The sphingolipid profiles in the gastrocnemius muscle were determined using LC-MS/MS. The expression levels of sphingosine-1 phosphate receptors (S1PRs) were measured by qRT-PCR. The GEO data set (GSE73036) was downloaded and analyzed.

Result: Mice on the WDSW (MASH mice) exhibited significantly higher blood glucose levels and increased IR after 24 weeks of WDSW feeding. LC-MS/MS analysis indicated elevated levels of C18-Sphingomyelin (SM), C26-SM and C18:1 Dihydroceramide in the muscle of the WDSW group, while S1P levels were markedly reduced. The expression levels of S1PR1-3, the major types of S1PR in muscle, were also significantly decreased in MASH mice. Analysis of GSE73036 highlighted a strong correlation between IR and upregulation of S1P lyase (Spgl), an enzyme crucial for S1P degradation.

Conclusion: The findings of this study indicate a clear association between disrupted sphingolipid metabolism and IR in MASH mouse model. The observed increase in ceramide levels coupled with a decrease of S1P may contribute to sarcopenia associated with MAFLD.

Disclosure

Q. Yan: None. L. Su: None. Y. Tai: None. D. Zhao: None. X. Wang: None. E. Gurley: None. P. Hylemon: None. X. Zhou: None. H. Zhou: None.

Funding

National Natural Science Foundation Of China (No.82004286)
1615-P: Adrenal Gland Volume and Development of Type 2 Diabetes Using Deep Learning Techniques
Authors: JEONG KU EU , HO YOON SOON , SHIN PARK SEUNG , HEE KIM JUNG , YOON JIWON
Published: June 2024

Objectives: Current insights into the dynamic between adrenal gland volume (AGV) and changes in blood glucose levels are insufficiently explored. This research aims to establish an association between AGV, evaluated through a deep learning-based method, and the risk of developing type 2 diabetes (T2D).

Research Design and Methods: Our study included an analysis of 9,708 adults who underwent abdominopelvic CT scans during health examinations between 2011 and 2012. Eligibility for the study was contingent on the absence of adrenal nodules in participants. We obtained AGV measurements from CT scans using a three-dimensional nnU-Net deep learning framework. The research approach to understanding the AGV-T2D relationship was designed to be both cross-sectional and longitudinal.

Results: The AI model demonstrated notable precision in segmenting the adrenal gland, with a correlation coefficient of 0.71 (standard deviation [SD], 0.11) and an average volume discrepancy of 0.6 mL (SD 0.9) in an external dataset. At the outset, individuals with T2D showed higher AGV compared to those without T2D (7.3 vs. 6.7 cm³ in males and 6.3 vs. 5.5 cm³ in females, all P <0.05). Furthermore, AGV was positively correlated with various metabolic factors, including waist size, area of abdominal visceral fat, triglyceride-glucose index, and levels of glycated hemoglobin. We determined optimal AGV cutoffs for T2D prediction to be 7.2 cm³ for males and 5.5 cm³ for females. Following a median 7-year observation period, 938 subjects were diagnosed with T2D. A significant observation was that individuals with higher AGV faced a greater cumulative risk of developing T2D, this finding remained significant after controlling for other known risk factors (hazard ratio [95% confidence interval], 1.268 [1.105-1.455]).

Conclusions: In summary, AGV evaluated using deep learning techniques demonstrated a significant association with current diabetes status and can be considered a reliable predictor for T2D.

Disclosure

E. Ku: None. S. Yoon: Stock/Shareholder; MEDICAL IP. S. Park: None. J. Kim: None. J. Yoon: None.

Funding

This study was supported by the National Research Foundation of the Ministry of Science and ICT of Korea (Project No. NRF-2020R1C1C1010723) and a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute funded by the Ministry of Health and Welfare of the Republic of Korea (Project No. HI21C0032 and HI22C0049).
1622-P: Congruence of Laboratory vs. Histopathologic Findings of Acute Pancreatitis within nPOD Organ Donors
Authors: PENA LOPEZ JULIANA , CAMPBELL-THOMPSON MARTHA , BRUGGEMAN BRITTANY S.
Published: June 2024

Acute pancreatitis may both result in development of diabetes and is more common in patients with diabetes. Due to its broad presentation, diagnosis typically includes elevated amylase or lipase values three times normal. We aimed to evaluate the performance of amylase and lipase as predictors of acute pancreatitis by histopathology in deceased organ donors within The Network for Pancreatic Organ Donors with Diabetes (nPOD) tissue biobank.Demographic and clinical characteristics were collected from deidentified terminal hospital records. Acute pancreatitis by laboratory criteria was defined as an amylase >420 U/L or lipase >240 U/L. Pancreatic histopathologic analysis was performed to evaluate for acute pancreatitis (acinar cell loss, polymorphonuclear cell infiltrate, fat necrosis, and hemorrhage) in organ donors with and without diabetes.Acute pancreatitis by histopathology was associated with higher mean amylase (477 vs 194; p=0.007) and lipase (823 vs 134 U/L; p=0.003) and acute pancreatitis by laboratory criteria (p=0.0005). However, 38% of individuals with acute pancreatitis by histopathology did not meet laboratory criteria (sensitivity 61.8%; specificity 83%). The positive and negative predictive value of these cutoffs were 70% and 77.2% respectively. Within individuals with type 1 diabetes (T1D), a diagnosis of diabetic ketoacidosis (DKA) was associated with elevated amylase and lipase (mean of 74.5 U/L and 83 U/L without and 461 U/L and 725 U/L with DKA, p<0.03) and acute pancreatitis by laboratory criteria (p=0.006) but not by histopathology (p=0.23). However, the sensitivity and positive predictive value of acute pancreatitis laboratory criteria in donors with DKA improved (73.3% and 85%).Acute pancreatitis diagnosed by laboratory criteria alone is specific at 83% but with a lower sensitivity of 61.8%. These criteria can still be used in T1D individuals with DKA with a higher sensitivity and positive predictive value.

Disclosure

J. Pena Lopez: None. M. Campbell-Thompson: None. B.S. Bruggeman: Research Support; Tandem Diabetes Care, Inc.
1623-P: Artificial Intelligence with QuPATH in Pancreatic Cell Classification
Authors: GUYOT MICHAEL , WILLIAMS MACKENZIE D. , BUMGARNER BENJAMIN M. , MCGRAIL KIERAN M. , CAMPBELL-THOMPSON MARTHA , HALLER MICHAEL J. , BRUGGEMAN BRITTANY S.
Published: June 2024

We developed Artificial Intelligence classification algorithms in QuPATH containing both supervised and unsupervised components to quantify and classify the pancreas cell types into their respective subtypes based on immunofluorescence (IF) data. The staining panel was performed in formalin-fixed paraffin embedded (FFPE) pancreatic tissue sections from a pancreas organ donor with no diabetes provided by nPOD. From the IF images, a training region was selected. This region was then segmented using a watershed algorithm and then an expert classified each cell in the region. In total, there were 6,899 cells, with an emphasis on the acinar and ductal cell types. This training data was used to train a Random Trees (RT), K Nearest Neighbor (KNN) and Artificial Neural Network (ANN) algorithm. Another region was selected for a validation data set, and once again, each cell was manually classified by an expert in the field. The accuracy of each algorithm was then assessed on the validation set. The accuracy of each algorithm is as follows: RT (89.53%), KNN (85.55%) and ANN (82.97%). In the future, we will include multiple no diabetes pancreases as well as pancreases from the different stages of T1D progression to ensure diversity of the training and validation data. With a more diverse training data set, we predict that ANN’s will become more accurate, and could potentially prove to be more useful than the RT algorithm. With a more diverse validation data set, we can look at the possibility of overfitting artificially inflating the accuracy of our algorithms.From this, we plan to extract relevant feature information such as cell size, number and density among others. After we have the architecture solidified, we hope to use it to analyze differences in control and diseased pancreases, specifically with regards to Type 1 Diabetes (T1D). We hope this will uncover previously overlooked information that may prove critical to the understanding of the mechanism of disease progression of T1D.

Disclosure

M. Guyot: None. M.D. Williams: None. B.M. Bumgarner: None. K.M. McGrail: None. M. Campbell-Thompson: None. M.J. Haller: Consultant; Sanofi. Advisory Panel; SAB Biotherapeutics, Inc. Consultant; MannKind Corporation. B.S. Bruggeman: Research Support; Tandem Diabetes Care, Inc.
1626-P: Liver-Specific Silencing of INHBE with ARO-INHBE, an siRNA Therapeutic, for Metabolic Diseases
Authors: NGAI MICHELLE , LIU FENG , LI XIAOKAI , CHRISTY COLE , HAMILTON HOLLY , PEI TAO , HAMILTON JAMES , DING ZHI-MING
Published: June 2024

Introduction and Objective: Incretin-based therapies are evidently powerful and effective for obesity and cardiometabolic outcomes. However, the accompanying loss of significant lean body mass (LBM) and gastrointestinal adverse effects are of concern, and have inspired identification of novel modes of action for fat loss while preserving LBM. Loss-of-function INHBE variants are associated with a lower abdominal to gluteofemoral fat ratio, and protection against type 2 diabetes. Silencing INHBE expression represents a novel therapeutic approach for obesity and metabolic diseases. Here we describe a liver targeted siRNA therapeutic designed to silence INHBE expression.

Methods: siRNA conjugates targeting hepatic INHBE were designed. The pharmacodynamic properties of ARO-INHBE were evaluated in cynomolgus monkeys, and the pharmacological impact was assessed in DIO and db/db mice using a mouse surrogate of ARO-INHBE. Body weight, body composition, glucose homeostasis, and lipid metabolism were assessed during the studies.

Results: In cynomolgus monkeys, ARO-INHBE achieved deep knockdown of INHBE transcripts for a duration of at least 85 days with subcutaneous injections at 3 mpk on D1 and D29. In DIO and db/db mice, weekly dosing of the ARO-INHBE surrogate significantly suppressed body weight gain and decreased fat mass, but maintained lean mass and glucose homeostasis. Treatment with the surrogate of ARO-INHBE also improved the sensitivity of the DIO mice to catecholamine, indicated by the increased circulating ketone levels.

Conclusion: ARO-INHBE effectively silences hepatic INHBE mRNA. In the DIO mouse model, liver-specific silencing of INHBE mRNA caused the suppression of fat mass gain, but preservation of LBM. A clinical lead siRNA targeting INHBE has been selected.

Disclosure

M. Ngai: None. F. Liu: None. X. Li: Employee; Arrowhead Pharmaceuticals, Inc. C. Christy: None. H. Hamilton: None. T. Pei: Employee; Arrowhead Pharmaceuticals, Inc. Stock/Shareholder; Ionis Pharmaceuticals. J. Hamilton: None. Z. Ding: None.
1632-P: Wild-Derived Chromosome 1 Substitution Strains—Unveiling Novel Insights into NASH Research
Authors: YANG XUSHAN , ZHENG JIE , HOU YUMENG , WU XINYI , LI ZHIYING , QI HAO
Published: June 2024

Metabolic diseases, encompassing obesity, NASH, and diabetes, result from a complex interplay of factors, including genetics, lifestyle, and environment. However, conventional mouse models induced by diet or with single genetic alterations often fall short in accurately representing human metabolic diseases. In contrast to laboratory mice, wild mice exhibit a greater diversity of genetic polymorphisms, adapting to their natural environments. To enhance model fidelity, we created 11 wild-derived Chr1 substitution strains by replacing C57BL/6 mice's Chr1 with that from wild mice across 11 Chinese regions. Through phenotype screening, we identified 4 strains displaying spontaneously obesity and hepatic steatosis under chow diet. Notably, one strain named B6-Chr1KM mice displayed obvious obesity-related NASH phenotype (the total score of NAS was over 5).Transcriptomics analysis of the B6-Chr1KM liver tissue revealed unique gene expression patterns. KEGG analysis highlighted NASH-related pathways, including "Arachidonic acid metabolism." 398 genes specific to B6-Chr1KM were identified, with PPI analysis pinpointing top 10 hub genes as potential NASH research targets. In summary, our wild-derived Chr1 substitution strains provide valuable tools for metabolic disease study. B6-Chr1KM mice, in particular, offer a novel perspective for NASH research.

Disclosure

X. Yang: None. J. Zheng: None. Y. Hou: None. X. Wu: None. Z. Li: None. H. Qi: None.
1636-P: Targeting a Long Noncoding RNA lncMGC Ameliorates Obesity-Associated Adipose Tissue Dysfunction in Mice
Authors: ABDOLLAHI MARYAM , KATO MITSUO , LANTING LINDA L. , MALEK VAJIR , ZHANG LINGXIAO , NATARAJAN RAMA
Published: June 2024

The long noncoding RNA (lncRNA) lncMGC, plays a pathological role in the diabetic kidney. However, its role in obesity, insulin resistance (IR), and type 2 diabetes is not known. Here we examined whether targeting lncMGC with a locked nucleic acid-modified LNA-GapmeR antisense oligonucleotide ameliorates weight gain, adipose dysfunction, and IR in high-fat diet (HFD) fed mice. Mechanistically, we also examined whether lncMGC promotes adipose tissue dysfunction via up/down-regulation of targets/genes involved in perigonadal white adipose tissue (gWAT) and brown adipose tissue (BAT) function and mitochondrial health. We tested lncMGC-GapmeR in HFD-fed wild-type (WT) and partially humanized lncMGC (hlncMGC) mice to assess the translational potential of targeting human lncMGC for obesity/IR. Male and female C57BL/6 WT and female hlncMGC mice were fed chow diet (Con) or HFD and injected with GapmeR-negative control (HFD-NC), or GapmeR targeting lncMGC (HFD-Gap) at 5 mg/kg/week/8 weeks. Body composition was assessed with Echo-MRI, and plasma insulin levels by ELISA. Using qPCR, we measured angiogenesis and adipogenesis markers in gWAT and mitochondrial function-related genes in BAT. Sections from gWAT and BAT were stained for histopathology. We found WT HFD-Gap and hlncMGC HFD-Gap mice exhibited significantly lower body weight, total body fat, and insulin levels compared to HFD-NC. HFD-induced adipocyte hypertrophy, gWAT inflammation markers (Tnfα, F4/80), impaired angiogenesis (Cd31, Vegfb), and adipogenesis (Pparg, cebpb) related-genes were attenuated in HFD-Gap mice versus HFD-NC. Furthermore, lncMGC GapmeR significantly reversed HFD-induced BAT whitening and impaired mitochondrial markers (Fis1, Ppargc1α, Tfam, Dio2) versus HFD-NC. These results show GapmeR targeting lncMGC alleviates HFD-induced obesity and adipose dysfunction via changes in key gWAT and BAT markers, highlighting its therapeutic potential for obesity and its complications.

Disclosure

M. Abdollahi: None. M. Kato: None. L.L. Lanting: None. V. Malek: None. L. Zhang: None. R. Natarajan: None.
1657-P: Neonatal Adiposity Distribution in Birth Weight Categories at Term
Authors: AZIMIRAD AFSHIN , LEKSHMI DEVIKA , SPADOLA ALEXANDRA C. , CATALANO PATRICK
Published: June 2024

Introduction & Objective: Neonatal body composition may predict metabolic health over the lifespan better than birth weight (BW) alone. While lean body mass (LBM) correlates highly with BW, variation in neonatal adiposity is greater. To determine whether the conventional assignment of small, appropriate, and large for gestational age (SGA/AGA/LGA) at birth adequately characterizes neonatal adiposity.

Methods: Data were from a secondary analysis of a study of maternal metabolic differences in a cohort of term deliveries at a single academic center. Neonatal measurements and body composition analyses were performed within 72 hours using air-displacement plethysmograph (PEA POD). Anomalous newborns were excluded. Primary outcomes included body fat percentage (BF), fat mass (FM) and LBM. BW percentiles were determined using Fenton growth calculator and newborns were categorized into SGA (<10%), AGA (10-90%) and LGA (>90%).

Results: A total of 332 neonates were analyzed. The maternal cohort was 48% NHW, 39% NHB, 12% H, and 1% AAPI. Maternal characteristics were similar across BW categories except for smoking status. There were significant overlaps in measurements of adiposity between SGA and AGA, and between LGA and AGA.

Conclusion: In this diverse cohort BW category did not reliably distinguish underlying differences in neonatal adiposity. Body composition offers a novel tool to identify newborns at risk for adverse health outcomes.

Disclosure

A. Azimirad: None. D. Lekshmi: None. A.C. Spadola: None. P. Catalano: None.
1675-P: Patient Experiences with Tirzepatide in SURMOUNT-4
Authors: JOURAVSKAYA IRINA , KANU CHISOM , LING POON JIAT , MOJDAMI DONNA , COLLINS ELIZABETH , BURNS DANIELLE S. , KITCHEN HELEN , CARMICHAEL CHLOE
Published: June 2024

Introduction & Objective: Exit interviews were conducted with participants of the SURMOUNT-4 clinical trial to understand their experiences of weight loss and maintenance of weight loss with tirzepatide.

Methods: SURMOUNT-4 was a phase 3 clinical trial of tirzepatide in adults living with obesity or overweight with at least one weight-related comorbidity. Participants received 36 weeks of maximum tolerated dose of tirzepatide in an open-label, lead-in treatment period, following which they were randomized to continue on tirzepatide or switch to placebo for a double-blind maintenance treatment period of 52 weeks. After completion of a 4-week safety follow-up period, cross-sectional qualitative exit interviews were conducted with 86 US-based participants.

Results: On average, exit interview participants lost 25kg during the open-label period. Most (n=84) described at least one physiological improvement during this period, such as increased energy (n=53). Participants (n=73) also reported positive impacts on their physical functioning including improved walking ability (n=36) and increased activity levels (n=30). Other improvements during this period pertained to emotional well-being (n=78), social life and relationships (n=64), activities of daily living (n=40), ability to work (n=15), and participation in hobbies (n=7). Participants were generally positive about the efficacy of tirzepatide (n=59) and how it reduced their appetite (n=35) and/or cravings (n=19). The most common aspect of treatment disliked by participants was gastrointestinal side effects (n=34). During the maintenance period, all participants on tirzepatide reported one or more additional improvements, or sustenance of the improvements achieved pre-randomization. In contrast, nearly all participants on placebo reported some loss of improvements experienced pre-randomization.

Conclusion: Participants were largely positive about tirzepatide’s effect on weight loss and the subsequent positive impacts on their broader well-being.

Disclosure

I. Jouravskaya: Employee; Eli Lilly and Company. C. Kanu: None. J. Poon: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. D. Mojdami: Employee; Eli Lilly and Company. E. Collins: Employee; Clarivate. Stock/Shareholder; Clarivate. Other Relationship; Clarivate. D.S. Burns: Employee; Clarivate. Stock/Shareholder; Clarivate. Other Relationship; Clarivate. H. Kitchen: Employee; Clarivate. Stock/Shareholder; Clarivate. Other Relationship; Clarivate. C. Carmichael: Employee; Clarivate. Stock/Shareholder; Clarivate. Other Relationship; Clarivate.
1676-P: Tirzepatide Improved Mental and Psychosocial Function in Adults with Obesity or Overweight in the SURMOUNT-3 Trial
Authors: HUNTER GIBBLE THERESA , CAO DACHUANG , FORRESTER TAMMY D. , FRASEUR BRUMM JULIA , CHAO ARIANA
Published: June 2024

Introduction & Objective: Tirzepatide, a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, is approved in the US for treatment of type 2 diabetes and obesity. Tirzepatide showed substantial additional weight reduction vs placebo (PBO) after intensive lifestyle intervention in the phase 3 SURMOUNT-3 (NCT04657016) trial. Here we report the effect of tirzepatide vs PBO on general (Short Form-36 Health Survey Version 2 acute form; SF-36v2) and weight-related (Impact of Weight on Quality of Life-Lite Clinical Trials Version; IWQOL-Lite-CT) mental health outcomes.

Methods: This double-blind, PBO-controlled trial randomized (1:1) adults (N=579) with body mass index ≥30 or ≥27 kg/m2 and ≥1 obesity-related complication (excluding diabetes), who had ≥5% weight reduction after a 12-week (W) intensive lifestyle intervention to receive tirzepatide maximum tolerated dose (MTD; 10 or 15 mg) or PBO once weekly up to W72. Exploratory endpoints assessed were changes from randomization to W72 in SF-36v2 (norm-based) Mental Component Summary (MCS) and its domain scores and IWQOL-Lite-CT Psychosocial composite score using analysis of covariance with the last observation before discontinuation carried forward. Higher scores indicate better health.

Results: At W72, improvement in SF-36v2 MCS score was comparable between tirzepatide MTD and PBO (Least squares mean [LSM] difference [diff] vs PBO: 0.9; p=0.182). Tirzepatide MTD significantly improved SF-36v2 Vitality (LSM diff vs PBO: 2.4), Social Functioning (1.6), Role-Emotional (1.9), and Mental Health (1.5) domain scores (all p<0.05); and IWQOL-Lite-CT Psychosocial composite score (16.0; p<0.001).

Conclusion: In the SURMOUNT-3 trial, adults with obesity or overweight treated with tirzepatide experienced significant improvement in multiple domains of general mental health and weight-related psychosocial function vs PBO after intensive lifestyle intervention.

Disclosure

T. Gibble: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. D. Cao: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. T.D. Forrester: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. J. Brumm: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. A. Chao: Consultant; Eli Lilly and Company. Other Relationship; Eli Lilly and Company. Consultant; Boehringer-Ingelheim. Other Relationship; Weight Watchers International.

Funding

This study was funded by Eli Lilly and Company.
1677-P: AdOral—A Versatile Platform for Improved Oral Peptide Absorption
Authors: NAESSENS ULYSSE , GUTJAHR ALICE , BLACHE GRÉGORY , HAKIM SANA , MARECHAL AUDREY , NOEL ROMAIN , GAUDIER MARTIN , SOULA OLIVIER
Published: June 2024

Oral delivery of therapeutic peptides reduces patient burden and increases adherence. Nevertheless, existing technologies have limited performance and versatility. AdOral® is an oral delivery platform based on non-specific MoA (Mechanism of Action) via intestine paracellular passage leading to improved absorption.The MoA of AdOral® and its permeation effect on several peptides were evaluated in vitro, using gold-standard Caco-2 monolayers. Then, AdOral® platform was evaluated in vivo, in rat and dog. In vitro, apparent permeability coefficient of insulin lispro and semaglutide were improved by 16 and 25 vs. control, mostly due to the concentration-dependent and reversible tight junctions opening, leading to paracellular passage of peptides. AdOral® has a distinct MoA and higher permeation enhancing properties compared to SNAC (effective concentration of 10 mM vs. 100 mM for SNAC). In rats, AdOral® had a good safety profile after daily oral administration for 2 weeks.In dogs, AdOral® capsules allowed oral absorption of semaglutide and insulin lispro, demonstrating the versatility of the platform. AdOral® semaglutide showed 2.5-fold improvement in median semaglutide AUC0-5h and bioavailability vs. Rybelsus®. Thus, AdOral® is a versatile and performant platform that could lead to cost-effective oral formulations for a wide range of therapeutic peptides.

Disclosure

U. Naessens: Employee; ADOCIA. Stock/Shareholder; ADOCIA. A. Gutjahr: Employee; ADOCIA. Stock/Shareholder; ADOCIA. G. Blache: Other Relationship; ADOCIA. S. Hakim: Employee; ADOCIA. Stock/Shareholder; ADOCIA. A. Marechal: Employee; ADOCIA. Stock/Shareholder; ADOCIA. R. Noel: Employee; ADOCIA. Stock/Shareholder; ADOCIA. M. Gaudier: Employee; ADOCIA. Stock/Shareholder; ADOCIA. O. Soula: Board Member; ADOCIA. Stock/Shareholder; ADOCIA.
1682-P: Weight Endpoints in Randomized Controlled Trials (Rcts) of Adults Eligible for Antiobesity Medications (AOM)—A Systematic Literature Review (SLR)
Authors: BJORNSON ALISON , GARDNER MEGAN M. , DONATO BONNIE M.K. , SZABO SHELAGH M. , KORPACH SARAH G.C. , KUTI EFFIE
Published: June 2024

Introduction & Objective: Obesity affects 40% of American adults; 75% of whom have multiple obesity related comorbidities (ORC). Here we synthesize data on body weight (BW) and waist circumference (WC) from trials of adults eligible for AOM (BMI ≥30kg/m2 or ≥27kg/m2 with ≥1 ORC).

Methods: An PRISMA-guided SLR was performed to identify published manuscripts (2018-23) and conference abstracts (2021-23) of RCTs in adults eligible for AOM. Mean (95% confidence interval [CI ]) treatment differences were reported for continuous variables and odds ratios (OR; 95%CI) for categorical variables. Change in % BW and WC (cm) was summarized at ≤12 weeks, ≤26 weeks, and ≥27 weeks. ORs for achieving ≥15% BW loss were also summarized.

Results: From 1935 records, 39 eligible studies reported on BW and 20 on WC. Relative to placebo, % BW loss ranged from -1.1 (-1.2, 1.0; dapagliflozin [DAPA] 10 mg) to -4.4 (-4.5, -4.3; exenatide 10 μg) ≤12 weeks; -1.5 (-1.6, -1.4) (DAPA 10 mg) to -8.9 (-10.0, -7.8; semaglutide [SGL] 2.4 mg) ≤weeks; and -0.5 (-0.6, -0.4; DAPA 10 mg) by 156 weeks to -17.8 (-19.3, -16.3; tirzepatide [TZ] 15 mg) by 72 weeks. Compared to placebo, OR (95% CI) for achieving ≥15% BW loss ranged from 2.2 (0.9, 5.5; liraglutide [LIR] 3.0 mg) to 24.7 (17.9, 34.1; TZ 15 mg). Relative to placebo, change in WC ranged from -0.2 (-1.1, 0.7; DAPA 10 mg) to -3.1 (-4.2, -2.0; SGL 2.4 mg) ≤12 weeks, -1.7 (-2.7, -0.7; DAPA 10 mg) to -4.4 (-5.4, -3.4; SGL 2.4 mg) ≤26 weeks, and -2.7 (-3.5, -1.9); LIR 3.0 mg) by 56 weeks to -14.5 (-15.9, -13.0; TZ 15 mg) by 72 weeks. Two studies compared interventions head-to-head.

Conclusions: Emerging pharmacotherapies are showing longer term and greater weight loss. While data on WC was less frequently reported, it can provide important insights on the risk of developing ORC. Between-study heterogeneity in design and populations was high; and future studies to explore the importance of these factors will help better inform quantitative evidence syntheses.

Disclosure

A. Bjornson: None. M.M. Gardner: None. B.M.K. Donato: Employee; Boehringer-Ingelheim. S.M. Szabo: None. S.G.C. Korpach: None. E. Kuti: Employee; Boehringer-Ingelheim.

Funding

Boehringer Ingelheim Pharmaceuticals, Inc.
1691-P: Clinical Outcomes in Patients with Obesity or Overweight Treated with Semaglutide 2.4 mg—A Real-World Retrospective Cohort Study in the United States (SCOPE 2)
Authors: MICHALAK WOJCIECH , FABRICATORE ANTHONY , O HARTAIGH BRIAIN , RUSEVA ALEKSANDRINA , ZHAO ZHENXIANG , UMASHANKER DEVIKA
Published: June 2024

Introduction & Objective: This study assessed changes in clinical outcomes among patients with obesity or overweight treated with semaglutide 2.4mg versus no anti-obesity medications (AOM) in the US.

Methods: This retrospective database cohort study used the electronic health records linked to administrative claims from Komodo Health and included patients (≥18 years) with obesity, or overweight with ≥1 obesity-related comorbidity, who started therapy with semaglutide 2.4mg after June 15, 2021 and remained adherent for 12 months or those not treated with any AOM in the same period. Propensity score matching (1:4) was used to address treatment selection bias. Changes in weight from baseline to the end of 12 months follow-up, and proportions of patients achieving ≥5%, ≥10%, and ≥15% weight reduction were compared between the matched cohorts using generalized linear models.

Results: Matched cohorts (143 semaglutide 2.4mg patients and 571 no AOM patients) were balanced in baseline characteristics with mean (SD) BMI 39.8 (7.35) kg/m2, mean (SD) age 46 (10.9) years, and 77% were female. At 1-year post-index, semaglutide 2.4mg patients had a significantly greater reduction in weight (−15.0% vs. −1.3%, P<0.001) and a greater proportion of patients achieved a weight reduction ≥5% (83.9% vs 20.1%), ≥10% (74.8% vs. 7.4%), and ≥15% (49.7% vs. 3.7%) (P<0.001 for all three comparisons).

Conclusion: In this real-world study, patients with obesity or overweight treated with semaglutide 2.4mg demonstrated a greater, sustained, and clinically relevant reduction in body weight versus those not treated with an AOM. These changes are consistent with those observed in clinical trials.

Disclosure

W. Michalak: Employee; Novo Nordisk. Stock/Shareholder; Novo Nordisk, Eli Lilly and Company. A. Fabricatore: Employee; Novo Nordisk. Stock/Shareholder; Novo Nordisk. B. O Hartaigh: Employee; Novo Nordisk A/S. A. Ruseva: Employee; Novo Nordisk. Stock/Shareholder; Novo Nordisk. Z. Zhao: None. D. Umashanker: Consultant; Novo Nordisk.

Funding

Novo Nordisk Inc.
1697-P: Further Real-World Outcomes Using Medication and Intensive Lifestyle Intervention to Treat Obesity and Improve Diabetes at Scale
Authors: BOYD KIM , MEDEIROS KAELEN L. , KENYON ISABELLE , RYAN DONNA H.
Published: June 2024

Introduction: More than 2/3 adults in the US have overweight or obesity. Increasing obesity rates profoundly impact diabetes and cardiometabolic disease. We established a digital metabolic health company to provide medically-supervised obesity treatment at scale.

Methods: The program used the combination of GLP-1 medication, medical supervision, and a proprietary lifestyle intervention. Patients who reached at least 12 months (mo) in the core program and a smaller subset who reached 24 mo were analyzed for weight change, metabolic labs (baseline and 12mo) and patient-completed questionnaires (baseline, 6, and 12mo) using data where available in this real-world setting.

Results: The cohort who reached at least 12mo included 6,167 patients. For members with HbA1c at both baseline and 12mo (n=2,568), there were 3.4% and 23.7% who met baseline A1c criteria for diabetes and prediabetes. Average weight loss at 12 and 24 months was 16.39% (n=5,341) and 16.02% (n=169). Average weight loss for patients with diabetes or prediabetes at 12, 15 and 18 mo was 15.6% (n=1,375), 16.6% (n=782), and 16.7% (n=385). Patients with diabetes and prediabetes saw average improvements for HbA1c of -1.5 and -0.47 percentage points, respectively. 78.2% of patients with HbA1c levels >5.7% at baseline were <5.7% at 12 months. Across the cohort, fasting plasma insulin levels decreased in 71.3% (n=1,978). Positive changes were also seen for other metabolic markers and patient-reported outcomes.

Conclusion: Patients in a digital metabolic health program achieved robust and sustained weight loss through 24 months. For those with diabetes or prediabetes, 84.2% achieved categorical improvement to diabetes status. Significant weight loss, reduction in HbA1c and insulin, improvements to other metabolic markers, and positive changes to health behaviors were also seen. These results offer promise in addressing the obesity epidemic and reversing its adverse impact on diabetes.

Disclosure

K. Boyd: Consultant; Calibrate. Employee; Caire, WndrHLTH. K.L. Medeiros: None. I. Kenyon: Employee; Calibrate Health Inc. D.H. Ryan: Advisory Panel; Altimmune Inc., Amgen Inc., Biohaven, Calibrate, Carmot Therapeutics, Inc., CinRx. Other Relationship; Epitomee. Advisory Panel; Gila Therapeutics. Other Relationship; Eli Lilly and Company, Novo Nordisk, Scientific Intake. Advisory Panel; Structure Therapeutics, Inc., Wondr Health. Other Relationship; Xeno. Advisory Panel; Zealand Pharma A/S.
1699-P: The Conversion and Potential Mechanism of Conditionally Immortalized Human Classical Brown Preadipocytes from Proliferative to Adipogenic States
Authors: YOU LIANGHUI , HUA SIYU , YU TINGTING , JI CHENBO
Published: June 2024

Introduction & Objective: Considering to the anti-obesity and diabetic effect of brown adipose tissue (BAT), different immortalized brown preadipocytes cell lines have been established. Notably, murine preadipocyte cell lines expressed Simian virus 40 large tumor antigen (SV40LT) possess adipogenic capacity, whereas human preadipocyte cell lines with the same method failed. This study aimed to establish conditionally immortalized human classical brown preadipocytes (hcBPAs) and elucidate the mechanism underlying SV40LT-mediated regulation of adipogenesis.

Methods: hcBPAs was achieved by controlling SV40LT with doxycycline-inducible Tet-on system. Proliferation ability, adipogenic capacity, and brown adipocytes identity were compared between hcBPAs and primary brown preadipocytes. hcBPAs were transplanted into HFD-induced nude mice. Metabolic index and adipogenic capacity were evaluated after 8 weeks. ATAC-seq and RNA-seq were adopted between doxycycline-removal and -inducible hcBPAs to elucidate changes in chromatin accessibility and adipogenic genes.

Results: A hcBPAs was obtained with similar adipogenic capacity, thermogenic function, and molecular characteristics compared with primary preadipocytes. hcBPAs transplantation models have shown improvements in glucose metabolism and reconstituted functional brown adipose tissue. Differentiated doxycycline-removal hcBPAs showed increased ATAC sensitivity and mRNA expressions in adipogenic related genes and transcription factor (Fosl2 and CTCF) occupancy. RNA-seq and qPCR revealed equal expression levels of these regulatory factors in both groups, raising the possibility that downregulated of SV40TL expression promotes the binding of these factors to chromatin.

Conclusion: The model of hcBPAs was constructed and provided a reliable tool for prevention and treatment of obesity.

Keywords: hcBPAs, SV40TL, ATAC sensitivity, Fosl2, CTCF

Disclosure

L. You: None. S. Hua: None. T. Yu: None. C. Ji: None.

Funding

National Natural Science Foundation of China (82170880)
1700-P: Weight Reduction Is Associated with Improved Quality of Life in Participants with Obesity or Overweight and Type 2 Diabetes—Results from Phase 3 SURMOUNT-2 Trial
Authors: HUNTER GIBBLE THERESA , CAO DACHUANG , ZHANG MICHELLE X. , AGARWAL XAVIER NEENA , LING POON JIAT
Published: June 2024

Introduction & Objective: Tirzepatide is a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist approved in the US for treatment of type 2 diabetes and obesity. In the phase 3, randomized, double-blind, placebo (PBO)-controlled SURMOUNT-2 (NCT04657003) trial, tirzepatide-treated adults showed substantial weight reduction vs PBO. This post-hoc analysis assessed the association between achieving weight reduction targets and improvements in health-related quality of life (HRQoL).

Methods: HRQoL was assessed at baseline and week (W) 72 or early treatment discontinuation using 36-Item Short Form Health Survey, Version2 (SF-36v2), Impact of Weight on Quality of Life-Lite-Clinical Trials (IWQOL-Lite-CT), and EQ-5D-5L with higher scores representing better HRQoL. Mean changes from baseline to W72 were summarized by weight reduction targets (≥5%, ≥10%, ≥15%, ≥20%) in pooled tirzepatide-treated adults with last observed post-baseline value carried forward.

Results: At W72, adults with weight reduction showed improvements from baseline in all domains of SF-36v2 including Physical Functioning (norm-based) (≥5%, 3.78; ≥10%, 3.95; ≥15%, 4.74; ≥20%, 4.63) and Mental Health (norm-based) (≥5%, 1.65; ≥10%, 1.75; ≥15%, 2.34; ≥20%, 2.63). Adults who achieved most higher weight targets showed greater improvements from baseline in IWQOL-Lite-CT total score (≥5%, 14.68; ≥10%, 15.45; ≥15%, 18.53; ≥20%, 20.10), and Physical and Psychosocial composite scores. Greater improvement from baseline in EQ-5D VAS scores was observed in adults meeting greater weight reduction targets (≥5%, 9.75; ≥10%, 10.60; ≥15%, 12.33; ≥20%, 12.67).

Conclusion: Weight reduction in tirzepatide-treated adults was associated with improvement in all HRQoL domains, including physical function and mental health. Adults who lost the most weight generally showed the greatest HRQoL improvements.

Disclosure

T. Hunter Gibble: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. D. Cao: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. M.X. Zhang: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. N. Xavier: Employee; Eli Lilly and Company. J. Poon: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company.

Funding

Eli Lilly and Company
1702-P: High Circulating MIF Levels Indicate the Association with Atypical Antipsychotic-Induced Metabolic Adverse Effects
Authors: CHEN XI , GAO PINGYI , QI YADAN , CUI DONGHONG , QI DAKE
Published: June 2024

Atypical antipsychotics (AAPs) are first-line medications for schizophrenia (SZ). However, their use is frequently associated with the development of metabolic adverse effects, and the mechanisms behind these negative effects remain inadequately elucidated. Macrophage migration inhibitory factor (MIF) is a procytokine and involved in the development of metabolic dysfunction. To investigate the role of MIF in regulating antipsychotic-induced metabolic abnormalities, we recruited 142 healthy individuals and 388 SZ patients who had been receiving either typical antipsychotic (TAP) or AAP treatments. Subsequently, we conducted assessments of metabolic indices and measured plasma MIF levels, followed by a comprehensive statistical analysis to investigate the connection between MIF levels and metabolic dysfunction. A significant increase in plasma MIF levels was observed in groups receiving monotherapies with five major AAPs in comparison to healthy controls (all p < 0.0001). There was no such increase shown in the group receiving TAP treatment (p > 0.05). Elevated plasma MIF levels displayed a notable correlation with insulin resistance (β = 0.024, p = 0.020), as well as with the levels of triglycerides (β = 0.019, p = 0.001) and total cholesterol (β = 0.012, p = 0.038) in the groups receiving AAPs. However, while the TAP group also displayed some degree of metabolic dysfunction compared to healthy controls, no significant association was evident with plasma MIF levels (all p > 0.05).

In conclusion, Plasma MIF levels exhibit a distinctive correlation with metabolic abnormalities triggered by AAPs. Thus, MIF could be further developed as a unique marker to monitor AAP-induced metabolic adverse effects in clinical settings.

Disclosure

X. Chen: None. P. Gao: None. Y. Qi: None. D. Cui: None. D. Qi: None.

Funding

This study was supported by National Sciences and Engineering Research Council of Canada (NSERC: RGPIN-2017-04542) and Canadian Institutes of Health Research (CIHR Project Grant: PJT-156116) for Dr. Qi.
1714-P: SerpinB13 Regulates Proliferation and Cell Survival in Beta Cells
Authors: KRYVALAP YURY , CZYZYK JAN
Published: June 2024

Our studies with a monoclonal antibody (mAb) to serpinB13, a protease inhibitor of cathepsin L, and serpinB13-deficient mice, demonstrated that during development, this serpin molecule downregulates the number of Ngn3-positive pancreatic endocrine progenitor cells and their conversion to insulin-producing cells. Establishing the precise role of serpinB13 in the pancreas after birth is important, as its inhibition with a mAb may provide a novel approach to augment beta cell neogenesis, proliferation, and survival in diabetes. To address this, we injected 10 micrograms of low-endotoxin, recombinant serpinB13 (or chicken ovalbumin as a control [OVA]) once a week for 4 weeks into healthy 3-week old immunodeficient Balb/c SCID mice. In addition, during the same period, these mice received 5-EdU in two i.p. injections per week (8 injections in total). At 8 weeks of age the animals were sacrificed for microscopic examination of the percentage of EdU+/insulin+ cells. In an alternative approach, to measure the impact of serpinB13 on cell survival in vitro, immortalized MIN6 beta cells were cultured with a 4 micromolar solution of staurosporine in the presence or absence of serpinB13 at 1 microgram/mL for four hours. Early and late apoptosis was examined with antibodies to Annexin V and caspase 3 antibody, respectively. We found that female mice injected with serpinB13 had significantly reduced proliferation of beta cells with a similar trend for alpha cells. This difference was observed in females rather than males and was particularly prominent for pancreatic islets less than 180 microns in diameter. Moreover, our in vitro studies revealed a significant augmentation of apoptosis and death events following exposure of MIN6 cells to serpinB13. Together our data suggest that serpinB13 has detrimental effects on beta-cell biology, both during embryogenesis and after birth, and further suggests that impeding serpinB13 function is potentially desirable to achieve improved clinical outcomes in the treatment of diabetes.

Disclosure

Y. Kryvalap: None. J. Czyzyk: None.
1715-P: The c-Jun Transcription Factor Regulates Beta-Cell Survival following Prolactin Treatment
Authors: RUIZ OTERO NELMARI , CHUNG JIN-YONG , BANERJEE RONADIP R.
Published: June 2024

Pregnancy and postpartum states drive dynamic expansion and regression of maternal beta-cells in response to changing metabolic demands. We previously identified a critical role for prolactin receptor (PRLR) signaling in orchestrating the gestational expansion of beta-cells. Using single-cell RNA sequencing of mouse islets, we recently identified increased expression of immediate early genes (IEGs) in late gestation and early postpartum beta-cells. Furthermore, expression of a subset of IEGs, including c-Jun, appeared to be mutually exclusive with beta-cells undergoing apoptosis in the postpartum as assessed by TUNEL staining. The c-Jun transcription factor is a well-characterized IEG implicated in regulating proliferation, apoptosis, and survival in various tissues. Therefore, we hypothesized that c-Jun plays a critical role in beta-cell survival within the postpartum islet via PRLR signaling. Using immunostaining we found that c-Jun is normally expressed in islets from late pregnancy and early postpartum but is not present in mice lacking PRLR within beta-cells. This indicated PRLR signaling is required for induction of c-Jun. Prolactin treatment induces c-Jun expression within beta-cells in cultured murine islets as well as islets from a human female donor. Induction of c-Jun by prolactin is mediated by MAPK/ERK but not Stat5 or PI3K signaling as determined by selective inhibition of these pathways. Prolactin has been shown to promote survival of beta-cells. Inhibition of Jun phosphorylation blocks prolactin-mediated protection from dexamethasone-induced apoptosis of beta-cells. Together, these studies suggest c-Jun acts downstream of PRLR / MAPK signaling contributing to the pro-survival effects of prolactin signaling.

Disclosure

N. Ruiz Otero: None. J. Chung: None. R.R. Banerjee: None.

Funding

National Institutes of Health (RO1 (DK120761))
1717-P: Protein Kinase C δ Activation by Nitric Oxide Mediates Pancreatic ß-Cell Apoptosis
Authors: COLLINS JILLIAN , FARNSWORTH NIKKI L.
Published: June 2024

In type 1 diabetes (T1D), autoreactive immune cells secrete cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interferon-γ (IFN-γ), that initiate β-cell apoptosis in pancreatic islets and contribute to disease progression. Protein kinase C delta (PKCδ) activation plays a pivotal role in mediating cytokine-induced β-cell apoptosis via nuclear translocation and activation of pro-apoptotic signaling. In other cell types, nitric oxide (NO) produced in response to cytokines can also activate PKCδ via nitrosylation of tyrosine; however, the exact modification sites and effects on apoptotic signaling have not been investigated in β-cells. We hypothesize cytokine-induced production of NO activates PKCδ leading to nuclear translocation and upregulation of apoptotic signaling.

Islets from WT mice, mice with a β-cell specific knockout of PKCδ (PKCδβ-KO), or human islets were cultured for 24hr with a NO donor (SNAP, 1mM), cytokines (10ng/ml TNFα, 5ng/ml IL-1β, 100ng/ml IFN-γ), cytokines with an inducible nitric oxide synthase inhibitor (iNOSinh, 5mM), or an adenovirus to produce GFP-tagged PKCδ. Translocation was determined by GFP colocalization with a nuclear stain. Apoptosis was determined by fluorescent live/dead staining. PKCδ activity was determined with a FRET-based sensor in MIN6 cells. Nitrosylation of PKCδ was determined via a biotin switch assay and western blot.

Increases in PKCδ activity were observed in NO treated islets (p=0.05). Inhibiting PKCδ activation protected against β-cell apoptosis in cytokine and NO treated islets (p=0.004). Overall, our results support a role for cytokine induced NO in activating PKCδ and mediating downstream apoptotic β-cell death. Uncovering mechanisms to inhibit PKCδ activation that are associated with T1D can improve targeted protection of β-cells and reduce off target affects. Identifying novel mechanisms of cytokine-mediated apoptosis will provide insight into novel targets to prevent or delay β-cell death in T1D.

Disclosure

J. Collins: None. N.L. Farnsworth: None.

Funding

American Diabetes Association (7-21-JDF-020); Juvenile Diabetes Research Foundation (1-FAC-2020-891-A-N)