bluuebunny/crossref_metadata_2025_split huggingface dataset:
2078-LB: Effects of Obesity on Bladder Cancer and the Intervention Effect of Semaglutide
Authors: LIU YANHUI , CHEN SHUCHUN , BAN JIANGLI , LI ZELIN 
Published: June 2024

Objective: Limited research has been conducted on the impact of semaglutide on bladder cancer in individuals with obesity. Hence, this study employed proteomics in conjunction with bioinformatics technology to demonstrate that semaglutide potentially operates through a mechanism that reduces the likelihood of bladder cancer among obese patients.
Methods: Thirty-six healthy male C57BL/6J mice were randomly divided into normal diet group (NCD group), high fat diet group (HFD group) and high fat diet group (Sema group). Serum indexes and SOD levels were measured, and tandem mass spectrometry combined with liquid chromatography-tandem mass spectrometry analysis was used to identify differentially expressed proteins. Bioinformatics technology was used to further analyze differentially expressed proteins, so as to explore the potential mechanism of semaglutide in reducing bladder cancer risk.
Result: In the obesity model induced by a high-fat diet, semaglutide administration resulted in decreased body weight, improved lipid profile, blood glucose levels, and enhanced antioxidant stress capacity in mice. Differential expression proteins (DEPs) were found in various cellular components such as cytoplasm, cell membrane, and nucleus. Biological processes (BPs) were enriched in fatty acid metabolism and regulation of response to external stimuli. Comparative analysis of gene expression revealed that Lama2, Lama4, Lamc1, and Thbs2 primarily participated in the extracellular matrix (ECM) pathway. Their expression was up-regulated in the high-fat group but down-regulated after treatment with semaglutide.
Conclusion: Semaglutide exhibits potential in ameliorating high-fat diet-induced obesity and delaying the onset and progression of bladder cancer. The involvement of Lama2, Lama4, Lamc1, Thbs2 in the extracellular matrix pathway may underlie semaglutide's mechanism of action against bladder cancer.

Disclosure
Y. Liu: None. S. Chen: None. J. Ban: None. Z. Li: None.
2082-LB: Heterogeneity in Adipose Progenitor (AP) Populations from Subcutaneous Abdominal and Thigh Adipose Tissues of Women
Authors: SUN YIFEI , SMITH GREGORY , ALBU JEANINE , WALSH MARTIN , FRIED SUSAN K. 
Published: June 2024

Introduction & Objective: Lower body fat distribution decreases risk for T2D, but the mechanisms involved are poorly understood. The objective of this study was to compare AP populations of paired samples of upper body abdominal (A) vs lower body thigh (T) adipose tissues that may contribute to this association.
Methods: Single nuclei RNA sequencing (snRNASeq) identified AP subclusters (Seurat); bioinformatic and within subject statistical comparisons used pseudobulk analyses and paired ttest. Cell-Cell communication analysis (CellChat) addressed depot-dependent mechanisms tissue homeostasis.
Results: Healthy, premenopausal women in this study were n=7, BMI (28.7+/- 6.3 kg/m2), age 30 +/-5.5 y, waist to hip ratio 0.79 +/- 0.02 (mean ± SD). APs (6489 (A), 7194 (T)) in 9 subclusters varied in their degree of adipogenic commitment. An early AP population expressed higher levels of CD55 in A than T, and low MGP and AREG/F3. Two other ‘early’ AP clusters expressed the highest levels of anti-adipogenic factors, AREG/F3 AP were more abundant in T (9% vs 6%, p&lt;0.007; 5.4 vs 3.7%, p=0.025). A small population (5%) of committed ‘preadipocytes’ was in both depots. Additional clusters had high expression of secreted adipokines and extracellular matrix factors and secretory pathways (Collagens, Lumicans). We found evidence for higher cell-cell communication in T (FGF-FGFR, IGF-IGFR1, PDGF-PDGFR).
Conclusion: Our results suggest that higher expression of anti-adipogenic factors in TSAT maintain a larger pool of APs that can respond to pro-adipogenic signals, as needed, to better preserve tissue and systemic metabolic homeostasis in response to a stress (e.g. obesity).

Disclosure
Y. Sun: None. G. Smith: None. J. Albu: None. M. Walsh: None. S.K. Fried: None.

Funding
National Institutes of Health (R01DK121547)
2083-LB: Effect of 8-Hour Time-Restricted Eating vs. Daily Calorie Restriction on Sleep in Adults with Type 2 Diabetes
Authors: PAVLOU VASILIKI , CIENFUEGOS SOFIA , LIN SHUHAO , CLAIRE RUNCHEY MARY , VARADY KRISTA 
Published: June 2024

Objective: This study compared the effect of 8-h time-restricted eating (TRE) versus calorie restriction (CR) and a no-intervention control (CON) group on body weight and sleep in adults with obesity and type 2 diabetes (T2D).
Methods: Adults with obesity and type 2 diabetes (n = 75) were randomized to 1 of 3 interventions for 6 months: 8-h TRE (ad libitum eating between 12:00 to 8:00 pm, water fasting between 8:00 to 12:00 pm); CR (25% energy restriction daily); or control (ad libitum food intake with no meal timing restrictions).
Results: Seventy-five participants were enrolled (mean [SD] body mass index, 39 [7]; age, 55 [12] years; 53 [71%] female; HbA1c level 8.1% [1.6%]). By month 6, body weight decreased significantly (P &lt; 0.003) in the TRE group (−3.56% [95% CI, −5.92% to −1.20%]; P = .004) but not the CR group (−1.78% [95% CI, −3.67% to 0.11%]; P = .06), relative to controls. Levels of HbA1c decreased in the TRE (−0.91% [95% CI, −1.61% to −0.20%]) and CR (−0.94% [95% CI, −1.59% to −0.30%]) groups, relative to controls, with no differences between the TRE and CR groups. The morning eveningness questionnaire (MEQ) was used to assess the participants’ chronotypes. The MEQ scores were 58 ± 7 for TRE, 55 ± 9 for CR and 54 ± 10 for the control group at baseline, which corresponds to an intermediate chronotype for all groups. Sleep quality, measured by the Pittsburgh Sleep Quality Inventory (PSQI), did not change in the TRE group (baseline: 7.6 ± 3.2; month 6: 7.4 ± 3.2), CR group (baseline: 8.2 ± 3.4; month 6: 7.0 ± 2.8), versus controls (baseline: 9.4 ± 3.8; month 6: 9.0 ± 4.4). Wake time, bedtime, sleep duration, and insomnia severity did not change (no group x time interaction) over the course of the study in any group.
Conclusions: These findings suggest that the weight loss induced by TRE and CR has no effect on sleep quality, duration, or insomnia severity in adults with obesity and type 2 diabetes.

Disclosure
V. Pavlou: None. S. Cienfuegos: None. S. Lin: None. M. Runchey: None. K. Varady: None.

Funding
Department of Kinesiology and Nutrition, University of Illinois Chicago, and National Institutes of Health (R01DK128180 and T32DK128782).
2093-LB: Aging and Beta-Cell Function
Authors: JANKAUSKAS STANISLOVAS , NIEVES GARCIA CRYSTAL , KANSAKAR URNA , GAMBARDELLA JESSICA , MONE PASQUALE , TOMER YARON , SANTULLI GAETANO , LOMBARDI ANGELA 
Published: June 2024

Introduction and Objective: Alterations of glucose homeostasis and insulin secretory capacity increase with age and represent leading causes of morbidity and mortality. In order to prevent and/or improve diabetes-associated ailments of the pancreatic beta cell during aging we propose to leverage the therapeutic properties of ketone bodies. Specifically, a functional role as key signaling molecule is increasingly acknowledged for beta-hydroxybutyrate (BHB), the most abundant ketone circulating in the human body.
Methods: The effects of BHB on metabolic fitness have been tested: 1) in vivo in 18-month-old C57BL/6J mice fed with a standard or BHB-enriched diet for 6 months; 2) ex vivo in murine islets isolated from aging mice fed with standard or BHB diet 3) ex vivo in islets isolated from brain-dead aging donors treated or not with BHB.
Results: In our preliminary studies, we found that 18-month-old C57BL/6J mice fed with a BHB-enriched diet for 6 months displayed a significantly ameliorated response to GTT compared to sex and age-matched mice fed with standard diet. Furthermore, BHB treatment increased islet yield protecting pancreatic islets from apoptosis and oxidative stress. We also observed an impaired glucose stimulated insulin secretion in islets isolated from old mice fed with standard diet and from aging donors that was significantly reduced by BHB in both systems. Moreover, BHB preserved mitochondrial membrane potential, attenuated the impaired mitochondrial respiration and mitochondrial fragmentation and rescued mitochondrial biogenesis during aging. Finally, BHB significantly increased mitophagy in aging murine and human islets after treatment with BHB, compared with control islets; confirming its pivotal role in the modulation of mitochondrial fitness.
Conclusion: In this study we produced compelling evidence that mitochondrial alterations represent a targetable molecular signature in aging beta cells and that ketone bodies are potentially useful to address age-related beta cell dysfunction.

Disclosure
S. Jankauskas: None. C. Nieves Garcia: None. U. Kansakar: None. J. Gambardella: None. P. Mone: None. Y. Tomer: None. G. Santulli: None. A. Lombardi: None.
222-OR: Overcoming Islet Scarcity through In Vitro Differentiation of Human Pluripotent Stem Cells
Authors: HOGREBE NATHANIEL , ISHAHAK MATTHEW , SANCHEZ-CASTRO ENRIQUE E. , MILLMAN JEFFREY R. 
Published: June 2024

The potential of cell therapy for Type 1 Diabetes (T1D) has been constrained by the scarcity of islets and the dependence on obtaining them from deceased donors. The in vitro differentiation of islets from human pluripotent stem cells (hPSCs) could overcome this limitation to provide a sustainable cell source, facilitating the broad availability of tissues for therapeutic purposes. Challenges face this approach, including large-scale biomanufacturing of high-quality stem cell-derived islets (SC-islets) and limited understanding of transitions of key cellular identities. Here we have developed a scaled differentiation process that produces over one billion cells by first generating β cells that co-express C-peptide and NKX6-1 along with other endocrine cell types on large-surface area culture flasks using combinations of growth factors and small molecules. These cells can be single-cell dispersed and cryopreserved using a controlled-rate freezer and subsequently thawed and aggregated into islet-like clusters. These clusters are glucose-responsive and able to reverse diabetes when transplanted into a streptozotocin-induced diabetes mouse model. Using single-nuclei multiomic sequencing, we have mapped the entire differentiation process epigenetically and transcriptionally. Using this data, we defined the cellular transition states and timings for the generation of β, α, and δ cells. In addition, we have identified the transcription factor LMX1A as a key determinant in the generation of a serotonin-producing enterochromaffin-like cell state. These results demonstrate larger-scale biomanufacturing of SC-islets and provide a novel epigenomic roadmap of their differentiation.

Disclosure
N. Hogrebe: Research Support; Sana Biotechnology. M. Ishahak: Stock/Shareholder; Vertex Pharmaceuticals Incorporated. E.E. Sanchez-Castro: None. J.R. Millman: Employee; Sana Biotechnology. Research Support; Sana Biotechnology. Stock/Shareholder; Sana Biotechnology.

Funding
National Institutes of Health (Human Islet Research Network Catalyst Award); JDRF (5-CDA-2017-391-A-N)
226-OR: Immunoprivileged Hydrogels Recover Normoglycemia for Extended Duration in Immunocompetent Diabetic Animals
Authors: STOVER HARALD 
Published: June 2024

Introduction & Objective: The application of current islet cell transplantation is limited by the need for systemic immune suppression. Physically immuno-protective hydrogels offer a route to allogenic islet transplants. To assess the functionality of islets encapsulated in our proprietary synthetic hydrogels, we assessed in hydrogel robustness and islet function both in vitro and in immunocompetent diabetic animals, without any immunosuppression.
Methods: Rat and human donor islets were encapsulated in next generation shape-agnostic hydrogels and implanted in the peritoneal space of streptozotocin (STZ)-induced diabetic immunocompetent mice and rats to assess islet functionality over time through measurement of blood glucose, C-peptide, and HbA1c. The effect of islet loading and islet density was assessed in vitro and in vivo.
Results: Hydrogels successfully excluded IgG, maintained good islet function in vitro and showed visible blood vessels early post-implant. Encapsulated rat islets demonstrated rapid and sustained blood glucose control for 140+ days in immunocompetent mice and for 110+ days in immunocompetent rats. Our hydrogels also extended human donor islet function in mice, Yorkshire pigs and Gottingen minipigs, as indicated by reduced blood glucose and increased C-peptide and HbA1c levels. We noticed a dose-dependent effect on in vivo function, despite similar in vitro GSIS indices. When explanted from mice, rats or pigs, the encapsulated islets had indicators of good function and viability; and our hydrogels had no-to-minimal tissue response, as well as good robustness and integrity.
Conclusion: Our proprietary, retrievable hydrogels showed strong immune protection for both allogenic and xenogeneic transplantation, without any immunosuppression. We are currently scaling to therapeutic doses in large animals, in pursuit of a curative therapy based on an optimal balance of Islet protection and functionality.

Disclosure
H. Stover: None.

Funding
JDRF (2-IND-2023-1449-I-X)
228-OR: Effect of Pemvidutide, a GLP-1/Glucagon Dual Receptor Agonist, on Cardioinflammatory Lipids
Authors: SUSCHAK JOHN J. , GEORGES BERTRAND , ROBERTS M S. , SCOTT HARRIS M. , BROWNE SARAH K. 
Published: June 2024

Introduction & Objective: Dysregulated lipid profiles in obesity can cause systemic inflammation and elevate cardiovascular (CV) risk. We studied the impact of pemvidutide, a dual GLP-1/glucagon receptor agonist, on lipoprotein and glycoprotein biomarkers of CV inflammation.
Methods: Subjects with overweight or obesity and without diabetes (N=34) were randomly assigned 1:1:1:1 to pemvidutide (1.2, 1.8, 2.4 mg) or placebo administered subcutaneously weekly for 12 weeks. Lipidomic and glycoprotein profiling was conducted using ultra-high performance liquid chromatography-mass spectrometry or NMR on plasma samples at Day -1, Day 43, and Day 85.
Results: Pemvidutide reduced body weight by up to 10.3% and the atherogenic lipids total cholesterol, LDL-C, and triglycerides by up to 28%, 26%, and 38%, respectively. Pemvidutide reduced pro-inflammatory lipidomic signatures such as small-dense LDL-C, short-chain, saturated diglycerides, lysophosphatidylinositols, lysophosphatidylcholines and sphingolipids. Reduction in GlycA and GlycB, biomarkers of systemic inflammation correlated with heart failure, were also observed (Table 1).
Conclusion: Pemvidutide elicited significant weight loss and decreases in pro-inflammatory lipid species associated with atherogenesis and CV risk. These results may reflect beneficial effects of glucagon on lipoprotein and glycoprotein metabolism.

Disclosure
J.J. Suschak: Employee; Altimmune Inc. B. Georges: Employee; Altimmune. M.S. Roberts: Employee; Altimmune Inc. M. Harris: Employee; Altimmune Inc. S.K. Browne: Employee; Altimmune Inc.
23-OR: Streamlining Diabetes Device Integration into the Electronic Health Record
Authors: HUNT MELANIE , DUNCAN RAYMOND , PAYNE DANIEL , WILLIAMS STEVE , ALABI BASHAR , RENELLA JENNA , SPALDING-JACKSON JOYCE R. , MATHUR RUCHI , GIANCHANDANI ROMA 
Published: June 2024

Technology has transformed diabetes management with Continuous Glucose Monitors (CGM) and Automated Insulin Delivery devices, improving A1c and reducing hypoglycemia. Multiple device usage increases download burden for clinics. To enhance this process, we integrated CGMs, pumps, smart pens and meters into the Electronic Health Record (EHR). Device data obtained via Glooko and Abbott was integrated into the EHR using HL7 v. 2.x interfaces and Single-Sign-On launches of both vendor web portals. Health care professionals (HCPs) can send orders via EHR to vendor, triggering individual enrollment and generating current data reports. Discrete data is returned as flowsheets and detailed reports load as PDF files for viewing and permanent storage. Extensive training sessions and materials were developed for HCPs and support staff. Within 6 months, over 200 patients connected devices to the EHR (Figure 1). Majority of the devices were CGMs (60%) followed by pumps. 70% of the devices were syncing remotely. AGP metrics were tracked in flowsheets. HCPs could document AGP tables and PDF reports into progress notes using dot phrases. A skilled integration team and targeted role-specific education allowed for successful integration of diabetes device data into the EHR. The efficiency for data retrieval and storage made data from people with diabetes accessible and actionable, thereby reducing retrieval and documentation burden for HCPs.

Disclosure
M. Hunt: None. R. Duncan: None. D. Payne: None. S. Williams: None. B. Alabi: None. J. Renella: None. J.R. Spalding-Jackson: None. R. Mathur: None. R. Gianchandani: None.
232-OR: Glucagon-Like Peptide-1 Receptor Agonists and Risk of Suicide/Self-Harm in U.S. Older Adults with Type 2 Diabetes—A Population-Based Cohort Study
Authors: TANG HUILIN , LU YING , DONAHOO WILLIAM T. , BIAN JIANG , GUO JINGCHUAN 
Published: June 2024

Background: A major concern has recently been raised regarding the association between glucagon-like peptide-1 receptor agonists (GLP-1RAs), especially for liraglutide and semaglutide, and an increased risk of suicide or self-harm. However, the evidence supporting this association remains extremely limited.
Methods: Using 2016-2020 national Medicare Claims data, we conducted a population-based, new-user cohort study that included individuals with type 2 diabetes (T2D) who were newly prescribed a GLP-1RA or a sodium-glucose cotransporter 2 inhibitors (SGLT2i). We employed 1:1 propensity score matching to control for potential confounding at baseline and used a Cox proportional hazards regression to estimate the hazard ratio (HR) and 95% confidence intervals (CI) of the suicide/self-harm. A secondary analysis with dipeptidyl peptidase 4 inhibitor (DPP4i) as the comparator was also performed.
Results: We identified 41,894 Medicare beneficiaries with T2D who initiated either a GLP-1RA inhibitor or an SGLT2i. The incidence rate of suicide/self-harm among GLP-1RA users and SGLT2i users were 42.79 cases and 41.84 cases per 1,000 person-years, respectively. There was no significant association between GLP-1RAs and an increased risk of suicide/self-harm compared with SGLT2i (HR, 1.02; 95%CI, 0.91-1.14). In the secondary analysis, GLP-1RAs were significantly associated with a lower risk of suicide/self-harm than DPP4i (HR, 0.77; 95%CI, 0.70-0.85).
Conclusion: Among Medicare beneficiaries with T2D, GLP-1RAs were not associated with an increased risk of suicide/self-harm. Future research is needed especially in younger populations to confirm these findings.

Disclosure
H. Tang: None. Y. Lu: None. W.T. Donahoo: None. J. Bian: None. J. Guo: None.
236-OR: Short-Term Effects of Semaglutide and Tirzepatide on Body Composition in Patients with Obesity Undergoing a Low-Calorie Diet
Authors: NAKA MASAMITSU , KAMI SAORI , HAYASHI SAHO , ISHIBASHI RYOICHI 
Published: June 2024

Objective: Severe caloric restriction, used for preoperative short-term weight loss, can lead to muscle loss, subsequently worsen glucose tolerance and cause weight regain. This observational study explored the short-term effects of semaglutide (SEMA) and tirzepatide (TZP) on weight loss and body composition in patients with obesity during a 13-day-low-calorie diet.
Methods: Japanese adults with a body mass index ≥ 25 kg/m2 who completed our hospital’s diet (800 kcal/day) and exercise therapy between 2019 and 2023 were included. Those who started oral or injectable SEMA or TZP upon admission, and those without a history of glucagon-like peptide-1 (GLP-1) receptor agonists or TZP use, were assigned to the GLP-1 (n = 28) and FREE groups (n = 19), respectively. Changes in body weight and body composition, measured by bioelectrical impedance analysis, before and after hospitalization were compared between the groups using Student t-test and analysis of covariance, respectively.
Results: Significant weight loss occurred in both groups, but no significant difference was observed between them (-4.34% with GLP-1 group vs. -4.63% with FREE group; estimated treatment difference, -0.28%; 95% confidence interval (CI), -1.06 to 0.49; p = 0.464). Fat mass decreased in the GLP-1 group (-10.10% with GLP-1 group vs. -1.93% with FREE group; estimated treatment difference, -8.17%; 95% CI, -1.42 to -14.92; p = 0.019), whereas fat-free mass decreased in the FREE group (0.98% with GLP-1 group vs. -4.58% with FREE group; estimated treatment difference, 5.56%; 95% CI, 0.03 to 0.75; p = 0.025). Analysis within the GLP-1 group suggested a greater body composition improvement with TZP than with SEMA.
Conclusion: A 13-day treatment with SEMA or TZP improves body composition in patients with obesity undergoing severe caloric restriction, with TZP demonstrating a more substantial effect.

Disclosure
M. Naka: None. S. Kami: None. S. Hayashi: None. R. Ishibashi: Research Support; Astellas Pharma Inc., Taiho Pharmaceutical Co. Ltd.