bluuebunny/crossref_metadata_2025_split huggingface dataset:
1492-P: Quiescent Adipose-Derived Mesenchymal Stromal Cells (ADSCs) Rejuvenate Themselves and Provide Factors That Remotely Restore Cellular Functions of Aged ADSCs
Authors: FUNAKI MAKOTO , HATA AKIKO 
Published: June 2024

Although a number of studies have shown therapeutic effects of mesenchymal stem cells (MSCs) on type 1 diabetes or diabetic complications, clinical applications of MSCs for these diseases are still limited. One of the reasons is aging of MSCs due to older donor age and ex vivo culture of MSCs before usage, which results in attenuation of their anti-inflammatory/immunomodulatory functions, as well as their proliferation/differentiation potencies. We previously reported that adipose tissue-derived stromal cells (ADSCs), one type of MSCs used in multiple clinical trials, exhibit anti-inflammatory/immunomodulatory functions when they become quiescent in gels with a stiffness mimicking that of adipose tissue. We also showed that transplants containing quiescent ADSCs enhanced diabetic wound healing more than did those containing non-quiescent ADSCs. Here, we investigated the effect of inducing quiescence in aged ADSCs on themselves and their neighboring ADCSs. ADSCs at high passage exhibited a flattened shape and impaired DNA damage repair response, accompanied by attenuated proliferation and increased secretion of monocyte chemoattractant protein-1 (MCP-1). However, introducing quiescence into these aged ADSCs by embedding them in soft gels eliminated these phenotypes associated with aging. Furthermore, administration of conditioned medium derived from ADSCs rendered quiescent at high passage significantly improved age-associated impaired proliferation and biased differentiation (impaired osteogenic differentiation) of ADSCs at high passage. These results suggest that quiescence rejuvenates ADSCs, which in turn provide factors that contribute to rejuvenation of other ADSCs. Thus, introducing quiescence in ADSCs may contribute to overcoming challenges in ADSC-based cell therapies due to their aging.

Disclosure
M. Funaki: Board Member; Mechanogenic, Inc. Stock/Shareholder; Mechanogenic, Inc. A. Hata: None.
150-OR: Gut Microbial Metabolism of Bile Acids, Mediterranean Diet and Cardiometabolic Risk in the DIRECT-PLUS Trial
Authors: GAO PEIPEI , MEI ZHENDONG , WANG FENGLEI , DONG DANYUE , STAMPFER MEIR , SHAI IRIS , WANG DONG 
Published: June 2024

Objective: To examine the associations of fecal bile acid (BAs), interacting with the Mediterranean diet (MedDiet), with body adiposity and lipid biomarkers and explore the gut microbiome’s role in BA metabolism.
Method: In the 18-month DIRECT-PLUS Trial, 284 participants (mean 51 y, 88% men) were randomized to one of the three isocaloric interventions: healthy dietary guidelines, MedDiet, and MedDiet+polyphenols and measured for baseline fecal BA levels by LC-MS. Their gut microbiomes were profiled by shotgun metagenomics.
Results: Among 39 detected BAs, 4 were associated with body mass index (BMI) and 11 were associated with serum lipids (Fig. 1A). For example, per 1-SD increment in isoursodeoxycholic acid-sulfate level was associated with a 3.0 kg/m2 increase in BMI (95% confidence interval [CI]: 1.8-4.2) and 12.5 mg/dL increase in triglycerides (95% CI: 5.4-19.7). The MedDiet’s effects for reducing BMI varied by BA levels (Fig. 1B). For example, this effect was more pronounced in those with lower 12-dehydrocholic acid levels (qinter=0.004). We identified several Ruminococcus spp. as major BA metabolizers and their role in modifying fecal BAs’ association with body adiposity and lipid levels (Fig. 1C-D).
Conclusion: The gut microbial metabolism of BAs is associated with host adiposity and lipid profiles and potentially modifies the beneficial effects of MedDiet on cardiometabolic health.

Disclosure
P. Gao: None. Z. Mei: None. F. Wang: None. D. Dong: None. M. Stampfer: Advisory Panel; Elysium Health. I. Shai: None. D. Wang: None.

Funding
National Institutes of Health (R00DK119412, R01NR01999, and R01AG077489)
1502-P: Metabolic Dysfunction Associated Steatohepatitis–Derived HCC Model Mouse for Cancer Immunology
Authors: HASHIGUCHI TAISHI 
Published: June 2024

Introduction: Metabolic dysfunction-associated steatohepatitis (MASH) is a is linked to type II-diabetes and marked by steatosis, steatohepatitis, fibrosis and eventually HCC. The number of patients with MASH-derived HCC is increasing worldwide. Currently, the first line of cancer treatment drugs are immune checkpoint inhibitors (ICIs). Although ICls have been approved by the FDA for various cancers, it has been reported that the response rate for HCC is low, and the development of new therapeutic drugs including ICIs for HCC is expected. Therefore, a mouse model for evaluating MASH-derived liver cancer is needed for drug discovery against HCC. In this study, in order to examine whether the STAM mouse, a MASH-HCC model mouse, can be used for the evaluation of ICIs, we conducted an analysis of immunohistochemistry and RNA-seq related to the immuno-oncology (IO) of HCC derived from STAM mice.
Methods: MASH was induced in male mice by a single subcutaneous injection of 200 µg streptozotocin solution 2 days after birth and feeding with high fat diet after 4 weeks of age. The mice were sacrificed and livers collected at 6, 8, 10, 12, 16, 20 and 24 weeks of age. For RNA-seq analysis, total RNA from the left lateral lobe was isolated using RNeasy mini kit. Liver specimens were stored at -80°C embedded in Optimal Cutting Temperature compound for immunohistochemistry (IHC). IHC for CD3, CD4, CD8, FOXP3, a-SMA and FAP was performed.
Results: Expression analysis of IO-related genes was performed. Increased expression was observed in CCl5, CD4, CD8a, CD274, CXCR4, CXCR10 and PDCD1. Additionally, mutations were observed in some genes. As a result of IHC, CD3, CD4, CD8, a-SMA and FAP-positive signals were detected in the peri-tumor region. Furthermore, CD8-positive signals were also detected in the intra-tumor region.
Conclusion: STAM mouse model, is the model that allows the evaluation of drugs that genetic mutations, immune cells, and tumor microenvironment in addition to molecular targeted drugs.

Disclosure
T. Hashiguchi: None.
158-OR: Relationship between Obesity, Sarcopenia, and Insulin Resistance in Older Adults
Authors: RIZVI ALI A. , AMIN VRAJ , AMOY FRASER MARSHA , PERIASAMY MUTHU 
Published: June 2024

The prevalence of overweight/obesity is increasing in older adults worldwide. Ageing is generally associated with decline in muscle mass and strength (sarcopenia) and worsening insulin resistance (IR). We examined whether the coexistence of overweight/obesity and sarcopenia, termed sarcopenic obesity (SO), was associated with elevated IR, thus predisposing to increased cardiometabolic risk. After informed consent, we obtained the following anthropometric and laboratory data in 77 adults (43 females, 34 males, age range 65-80 years, mean age 71 years): body mass index (BMI, as a determinant of overweight/obesity); waist circumference (WC, abdominal obesity); thigh circumference and grip strength (measures of muscle mass and sarcopenia) ; fasting glucose and plasma insulin levels (for calculation of Homeostatic Model Assessment of Insulin Resistance, or HOMA-IR); and A1c.­­ 32 of the participants (42%) were normal weight, and 45 (58%) were overweight/obese. 15 individuals (19%) were classified as sarcopenic, and the prevalence was similar in normal weight vs. overweight/obese groups (19% vs. 20%). Selected mean parameters were: BMI 28.05, WC 113.8 cm, and HOMA-IR index 1.73 (normal &lt;1). Analysis of the data showed a statistically significant positive association of HOMA-IR with BMI and WC (p&lt;0.05), but not with sarcopenia. The WC correlated with glucose and insulin levels in both sexes (p&lt;0.05), and with A1c in females only. Findings from our study thus far do not support a higher prevalence of sarcopenia in overweight/obese individuals than in those of normal weight. In both sexes, IR was significantly associated with overweight/obesity and central fat deposition, but not with sarcopenia. Interventions primarily targeting weight loss, with or without enhanced muscle conditioning, would be expected to be most effective in ameliorating IR and reducing cardiovascular and metabolic risk in older adults.

Disclosure
A.A. Rizvi: None. V. Amin: None. M. Fraser: None. M. Periasamy: None.

Funding
University of Central Florida College of Medicine Internal Grant Program 2022
1594-P: Deciphering Postprandial Hypoglycemia—Dominant Influence of Insulin Sensitivity in Patients without Diabetes
Authors: HUMMEL JULIA , UFER GISA , SABIA ROZA , MÄRKER MILENA , HAUG CORNELIA , WAGNER ROBERT , PETER ANDREAS , WAGNER MARTIN , HENI MARTIN 
Published: June 2024

Introduction & Objective: Postprandial hypoglycemia describes a condition with abnormally low glucose within a few hours after carbohydrate-rich meals. Underlying mechanisms are still unclear, with hypotheses including an unusually rapid increase in blood glucose, excessive insulin release, or prolonged presence of elevated insulin. We now analyzed these possibilities in a large sample of oral glucose tolerance tests (oGTT).
Methods: Patients without diabetes underwent prolonged (180 min) 75 g oGTT as part of clinical work up. Blood samples were taken before, 15 min after glucose ingestion and every 30 min thereafter.
Results: Of the analyzed 1511 patients (median age: 43 years (IQR: 33), 966 women), 387 had plasma glucose below 70 mg/dl at 180 min post oral glucose load. Blood glucose even below 54 mg/dl occurred in 107 patients (HYPO group). The groups with and without postprandial hypoglycemia were comparable in sex while the HYPO group was older (p=0.02). The HYPO group had a slightly lower HbA1c (5.4 vs 5.5%; p=0.047 adjusted for age) and fasting glucose (p&lt;0.001). Peak glycemia was reached in both groups at 30 min and the increment in plasma glucose was comparable between groups. Insulin secretion, as assessed from insulin- or C-peptide-based indices, was lower in the HYPO group in unadjusted models. Even after adjustment for insulin sensitivity and age, second phase insulin secretion was still lower in the HYPO group. Insulin sensitivity, as assessed at fasting and during the oGTT was higher in the HYPO group which remained significant after adjustment for age.
Conclusion: Postprandial hypoglycemia affects a significant number of patients in a university hospital's endocrinology setting. Rise in blood glucose and excessive insulin secretion seem not to substantially contribute, but those with postprandial hypoglycemia exhibited notably higher insulin sensitivity. This likely contributes to better everyday glucose control, as reflected by lower HbA1c.

Disclosure
J. Hummel: None. G. Ufer: Other Relationship; Amgen Inc., Boehringer-Ingelheim, Novo Nordisk, Vitaflo. R. Sabia: Other Relationship; Amgen Inc., Novo Nordisk, Novartis AG, Vitaflo, MetaX, Biomarin, Alexion Pharmaceuticals, Inc. M. Märker: None. C. Haug: None. R. Wagner: Speaker's Bureau; Sanofi. Advisory Panel; Lilly Diabetes. Speaker's Bureau; Boehringer-Ingelheim, Novo Nordisk. A. Peter: None. M. Wagner: None. M. Heni: Research Support; Boehringer-Ingelheim. Advisory Panel; Amryt Pharma Plc. Speaker's Bureau; Amryt Pharma Plc. Advisory Panel; Boehringer-Ingelheim, Boehringer-Ingelheim. Speaker's Bureau; Lilly Diabetes, Novartis AG, Novo Nordisk, Sanofi.
16-OR: Preadministration of SGLT2 Inhibitor Reduces Frequency of Anti-VEGF Agent Administration in Patients with Mild Diabetic Macular Edema—A Multicenter Randomized Controlled Open-Label Trial
Authors: ISHIBASHI RYOICHI , KOSHIZAKA MASAYA , TAKATSUNA YOKO , TATSUMI TOMOAKI , YAMAMOTO SHUICHI , YOKOTE KOUTARO 
Published: June 2024

Introduction & Objective: There are various unmet needs for anti-vascular endothelial growth factor (VEGF) therapy for diabetic macular edema (DME). We previously reported that using sodium-glucose cotransporter 2 inhibitor (SGLT2i) reduced the frequency of anti-VEGF agent administration through observational studies. However, no interventional studies have been conducted.
Methods: Sixty patients with DME were enrolled and divided into an SGLT2i group (SG) treated with luseogliflozin and a control group treated with glimepiride. Ranibizumab (R) was first administered to the eyes with more severe DME (target eyes); hypoglycemic drugs were started simultaneously. R was administered for 48 weeks to the target eyes according to regulations, and companion eyes in cases of bilateral DME received regular medical treatment. The doses of R were evaluated using analysis of covariance.
Results: A total of 54 patients were analyzed. We found no intergroup differences in ophthalmological parameters and the number of R injections of the target eyes (Table). Significant decreases in central thickness of retina and number of R injections were observed for the companion eyes in the SG group.
Conclusion: The pre-administration of SGLT2i reduced the frequency of anti-VEGF agent administration for mild DME.

Disclosure
R. Ishibashi: Research Support; Astellas Pharma Inc., Taiho Pharmaceutical Co. Ltd. M. Koshizaka: None. Y. Takatsuna: None. T. Tatsumi: Research Support; Taisho Pharmaceutical Holdings Co., Ltd. Advisory Panel; Astellas Pharma Inc. S. Yamamoto: None. K. Yokote: Research Support; Taisho Pharmaceutical Holdings Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Boehringer-Ingelheim, Sumitomo Dainippon Pharma Co., Ltd., Kowa Company, Ltd. Speaker's Bureau; Kowa Company, Ltd., Sumitomo Dainippon Pharma Co., Ltd., Novo Nordisk, Novartis Pharmaceuticals Corporation, Daiichi Sankyo.
1601-P: Regulation of Circadian Rhythmicity of Human Adipose Tissue in Obesity
Authors: LYTLE KELLI , PETRUS PAUL , SAVVA CHRISTINA , JENSEN MICHAEL D. 
Published: June 2024

Adipose tissue (AT) is highly responsive to nutrient delivery associated with conventional feed/fast cycles over 24 hr and also has a molecular circadian clock that regulates transcriptional rhythms. The joint contribution of these dual inputs to human AT function has not been studied, nor how this interplay changes in obesity. Ten lean (BMI 20-25 kg/m2) and 7 people with upper body obesity (UBO) (BMI 30-35 kg/m2) were within group randomized to either continuous feeding (“CONT”) or intermittent feeding (“INT”) of Ensure via nasogastric tube (NG). CONT was fed at rates to meet 24 hr caloric needs and INT fed 3 evenly spaced feedings (1/3 of daily caloric needs per meal) during daylight hours and fasted overnight. Each person received 4 abdominal AT biopsies across 24 hr. We performed RNA-Seq analysis on AT samples; dryR was used to assess circadian rhythmicity of genes differential between groups and GO and ClusterProfiler for pathway analysis. Most rhythmic genes were driven by feed/fast cycles, 538 transcripts were significantly rhythmic in INT groups and lost rhythmicity in CONT groups (adj. P &lt;0.02)(BICW &gt; 0.1). These genes were enriched for lipid metabolism pathways including biosynthesis and oxidation. Many genes (237) were significantly rhythmic in lean and not UBO individuals regardless of feeding regime (adj. P&lt;0.05)(BICW &gt; 0.1), these were enriched for pathways related to immune response. 399 genes were significantly rhythmic (adj. P&lt;0.02)(BICW &gt; 0.13) in lean CONT and INT and UBO INT, but lost rhythmicity only in UBO CONT. These were enriched for metabolic pathways related to glucose and carbohydrate homeostasis and molecular circadian system. Overall, the fast/feed cycle over 24 hr drives a significant portion of AT gene rhythmicity. Our data suggests lean individuals maintain AT clock system integrity independent of feeding time while patients with UBO require feed-fast cycles to sustain AT clock circadian rhythmicity, suggesting feeding time might be particularly relevant for patients with obesity.

Disclosure
K. Lytle: None. P. Petrus: None. C. Savva: None. M.D. Jensen: Advisory Panel; Biohaven.
1619-P: Insulin Resistance Stimulates Intraislet GLP-1 Secretion from a-Cells in Diet-Induced Obese Mice
Authors: DI GIUSEPPE GIANFRANCO , JEPSEN SARA L. , VERGARA UCIN JON , HARTMANN BOLETTE , GIACCARI ANDREA , HOLST JENS J. , MEZZA TERESA 
Published: June 2024

It has been recently hypothesized that alpha α-cells are a potential source of intraislet GLP-1, eventually exerting paracrine effects on islet function. However, it is still unknown whether intraislet GLP-1 production and secretion is modulated by insulin resistance and glucose dysmetabolism. In this study, we aim to explore the impact of insulin resistance on intraislet proglucagon-derived peptides in a population of Diet-Induced Obese (DIO) mice.
We performed a 75 min pancreatic perfusion on n=8 DIO vs. n=8 C57BL/6 control mice at low (3.5 mM) and medium (7 mM) glucose concentrations + 3.5 mM Vamine and 10 mM arginine stimulation; at the end, we infused insulin receptor antagonist S961 (n=4) or GLP-1 receptor antagonist Exendin 9 (n=4) to investigate possible involvement of insulin and GLP-1 receptor signaling. Total GLP-1 levels were measured using RIA; Insulin and Glucagon levels were measured through commercial ELISA kit (Mercodia). Compared to controls, DIO mice showed a significant secretion of total GLP-1 over time during perfusions (p&lt;0.0001), with no differences between 3.5 and 7 mM glucose and with a preserved response to arginine. Further, S961 did not affect total GLP-1 secretion, whereas Exendin 9 led to increased intra-islet total GLP-1 secretion, as in a positive feedback-control mechanism. As expected, DIO mice showed increased insulin secretion at 7 mM glucose and during arginine stimulation, while no differences were observed in the glucagon secretion. S961 and Exendin 9 did not affect insulin nor glucagon secretion in the 2 groups. Our data demonstrate that intraislet GLP-1 secretion is significantly increased in a rodent model of obesity and insulin resistance. In particular, this secretion pattern seems to be regulated by the activity of GLP-1 receptor itself. Further studies will be necessary to clarify the pathophysiologic action of intrapancreatic GLP-1 on insular environment.

Disclosure
G. Di Giuseppe: None. S.L. Jepsen: None. J. Vergara Ucin: None. B. Hartmann: Board Member; Bainan Biotech. A. Giaccari: None. J.J. Holst: Advisory Panel; Novo Nordisk A/S, Merck Sharp & Dohme Corp., Kallyope. Board Member; Antag Therapeutics. T. Mezza: None.

Funding
This study was supported by grants from the Universita Cattolica del Sacro Cuore (Fondi Ateneo Linea D.3.2, Fondi Ateneo Linea D.1, anno 2019, and Fondi Ateneo Linea D.1, anno 2020); the Italian Ministry of Education, University, and Research (MIUR; GR-2018-12365577 and RF-2019û12369293); the European Foundation for the Study of Diabetes award supported by Astra Zeneca and MIUR and MUIR (PRIN 2020SH2ZZA)
1654-P: Low Dietary Vitamin D Leads to Glucose Abnormalities in an Obese Animal Model
Authors: GINNARD OLIVIA Z.B. , SISLEY STEPHANIE 
Published: June 2024

Introduction: Both obesity and type 2 diabetes (T2D) are linked to vitamin D deficiency. However, we have limited understanding of the role of vitamin D in feeding and glucose homeostasis among its vast target tissues. Furthermore, using the storage form of vitamin D may not be an accurate indicator of vitamin D status in individuals with obesity. Thus, measuring expression levels of vitamin D receptor (VDR)-target genes may be a more promising marker for vitamin D status. The aim of this study was to elucidate the impact of vitamin D on feeding and glucose homeostasis in the context of VDR-target gene expression across multiple tissues.
Methods: We fed C57/BJ mice high-fat diets (58% fat) with low (100 IU/kg), regular (1000 IU/kg), or high (5000 IU/kg) vitamin D content. After 18 weeks, we performed an intraperitoneal glucose (1.0 g/kg D20W) tolerance test (GTT). After 26 weeks, we obtained blood samples for liver function testing. qPCR was performed for Insr, and Glut-4 in subcutaneous adipose tissue (SAT) and liver tissue.
Results: Mice fed a low-D diet had higher blood glucoses than the regular and high-D groups during GTT (p&lt;0.05). Body weights were the same in all groups (p &gt;0.05). Mice fed a low-D diet had worsened liver function compared to the regular and high-D groups (p&lt;0.05). Mice fed the low-D diet had significantly higher expression levels of Glut-4 in both tissues. We found that in both tissues, there was a significant correlation between Insr and Glut4 expression (p&lt;0.05).
Conclusion: These preliminary findings suggest that a low vitamin D diet exacerbates obesity-related complications, such as dysglycemia and liver dysfunction. In addition, VDR-target gene expression correlates with glucose metabolism-related gene expression, proposing a relationship between vitamin D and glycemic pathways in obesity. Further work should investigate the role of vitamin D in hepatic glucose metabolism pathways. This study may provide the first step in utilizing vitamin D more effectively in individuals with T2D.

Disclosure
O.Z.B. Ginnard: None. S. Sisley: Speaker's Bureau; Rhythm Pharmaceuticals, Inc.
1669-P: The Joint Effect of Low Skeletal Muscle Mass and Abdominal Obesity on the Incidence of Cardiovascular Events—A 7.6-Year Follow-up
Authors: HU TINGTING , XU YITING , SHEN YUN , WANG YUFEI , MA XIAOJING , BAO YUQIAN 
Published: June 2024

Introduction & Objective: Skeletal muscle loss often accompanies with abdominal obesity in the aging process. This study was aimed to assess the joint effect of low skeletal muscle mass and abdominal obesity on incident cardiovascular events.
Methods: A total of 1330 community residents (582 men and 748 postmenopausal women) aged 50−80 years were recruited in 2013−2014. During 2021−2022, a follow-up was conducted to record their cardiovascular events via phone calls. All events were further validated by medical records. Skeletal muscle mass was estimated by bioelectrical impedance analysis and converted to skeletal muscle index (SMI) adjusted for body weight. Pre-sarcopenia was defined as SMI less than 1SD of the sex-specific mean for a young reference group. Magnetic resonance imaging was used to assess visceral fat area (VFA). VFA ≥ 80 cm2 was defined as abdominal obesity. Participants were classified into 4 groups as, normal, pre-sarcopenia alone, abdominal alone, pre-sarcopenic obesity.
Results: The prevalence of pre-sarcopenia and abdominal obesity were 15.9% and 56.5%, respectively. During a mean of 7.6-year follow-up, 139 participants (10.5%) developed cardiovascular events. SMI was negatively associated with the risk of cardiovascular events (adjusted HR 0.92, 95%CI 0.87-0.97), while VFA was positively associated with the risk of cardiovascular events (adjusted HR 1.04, 95%CI 1.00-1.09). Pre-sarcopenic obesity conferred the highest risk of incident cardiovascular events (adjusted HR 2.17, 95%CI 1.31-3.59) compared with normal body composition, pre-sarcopenia alone, or abdominal obesity.
Conclusion: Low skeletal muscle mass and abdominal obesity could additively increase the risk of cardiovascular events.

Disclosure
T. Hu: None. Y. Xu: None. Y. Shen: None. Y. Wang: None. X. Ma: None. Y. Bao: None.