bluuebunny/crossref_metadata_2025_split huggingface dataset:
1504-P: AdoShell, a Nonfibrotic Encapsulation System for Human Islets Transplantation, Shows Promising Results for Clinical Application as a Cure for People with Type 1 Diabetes
Authors: GAUME XAVIER , BESNARD ROMAIN , BRUN JULIE , LECLERC NATHALIE , GAUTIER CAMILLE , JOUANNOT OUARDANE , LAURENT NICOLAS , GAFFURI ANNE-LISE , ELOY ROSY , BOUZAKRI KARIM , SOULA OLIVIER 
Published: June 2024

AdoShell® is an easily implantable and fully retrievable scaffold for islet transplantation aiming to cure diabetes by cell therapy without requiring immunosuppression. It is based on a permselective hydrogel film allowing insulin diffusion while preventing immune cell invasion. Allogenic transplant of rat islets in immunocompetent diabetic rats has already demonstrated encapsulated islets survival, insulin secretion, and glycemic regulation.
Compatibility with human islets, good local tolerance, and scalability to deliver a therapeutic dose were studied to meet requirements for a first in human.
In vitro, AdoShell® Human Islets has shown gluco-responsive insulin secretion up to 7 months.
AdoShell® tolerance was evaluated in the intraperitoneal site of immunocompetent rodent species, with or without human islets: AdoShell was well tolerated and did not trigger inflammatory reaction or fibrosis.
AdoShell® Human Islets in vivo functionality was evaluated in immunodeficient mice. Human C-peptide secretion increased during the first two weeks to reach an average of 446 ± 130 pM/day and was maintained until explantation on day 62 (n=4 mice). These results were confirmed in a second study. In vitro analysis of the explants by static GSIS (n=6 explants) showed 21% ± 15 of preimplantation insulin secretion levels, while the mean secretion index was maintained. Therefore, AdoShell favors human islets in vivo functionality.
A human sized AdoShell® with the potential to deliver a therapeutic islet dose was successfully manufactured and implanted by laparoscopy in domestic pig.
AdoShell® Islets is suitable for human islets delivery showing good local tolerance without fibrosis and sustained islet functionality.

Disclosure
X. Gaume: Employee; ADOCIA. Stock/Shareholder; ADOCIA. R. Besnard: Employee; ADOCIA. Stock/Shareholder; ADOCIA. J. Brun: Employee; ADOCIA. N. Leclerc: Employee; ADOCIA. Stock/Shareholder; ADOCIA. C. Gautier: Employee; ADOCIA. Stock/Shareholder; ADOCIA. O. Jouannot: Employee; ADOCIA. Stock/Shareholder; ADOCIA. N. Laurent: Employee; ADOCIA. Stock/Shareholder; ADOCIA. A. Gaffuri: Employee; ADOCIA. Stock/Shareholder; ADOCIA. R. Eloy: Employee; ADOCIA. K. Bouzakri: None. O. Soula: Board Member; ADOCIA. Stock/Shareholder; ADOCIA.
1529-P: Medial Preoptic Area FoxO1 Controls Thermogenesis in a Sexually Dimorphic Manner
Authors: LUO PEI , YANG XIAOHUA , TORRES IRIZARRY VALERIA C. , YE HUI , XU QI , CARRILLO-SÁENZ LESLIE , MUNOZ MARCOS D. , SCHAUL SARAH , PATEL NIRALI , ANTONY NIMISHA , DIXIT DEVIN , UNTERMAN TERRY , XU PINGWEN 
Published: June 2024

The medial preoptic area (MPOA) is a thermointegrative center that mediates metabolic adaptation to temperature change, contributing to body weight homeostasis. The Forkhead transcription factor O1 (FoxO1) plays a crucial role in mediating the effects of leptin and insulin on metabolic homeostasis in the hypothalamus. However, the metabolic function of FoxO1 in the MPOA has not been explored. In our study, we observed that the mRNA and protein expression of FoxO1 in the MPOA decreased in female mice after a 2-week high-fat diet (HFD) challenge, but not in male mice. Specific deletion of FoxO1 in MPOA neurons (FoxO1MPOA-KO) did not affect body weight in animals fed a chow diet at room temperature. However, it prevented HFD-induced obesity (DIO) in female mice, but not in male mice. This female-specific protection was associated with increased lean mass, decreased fat mass, enhanced thermogenic activity in adipose tissues, increased energy expenditure, and unchanged food intake compared to control mice with DIO. Female FoxO1MPOA-KO mice also showed increased temperature-dependent changes in energy expenditure, specifically when exposed to cold (6 °C), but not when exposed to thermoneutrality (30 °C) or at a room temperature (22 °C). Furthermore, the protection against DIO in females induced by FoxO1MPOA-KO was diminished by ovariectomy (OVX), and supplementation with 17β-estradiol after OVX failed to restore this protection, suggesting an estrogen-independent mechanism. Finally, mice with constitutively activated FoxO1 in MPOA neurons (FoxO1MPOA-CA) showed significantly increased DIO and poor glucose tolerance in both sexes, further supporting the essential metabolic role of FoxO1MPOA. These findings indicate that FoxO1MPOA plays a crucial role in directing and coordinating the metabolic adaptation to nutritional or environmental temperature challenges in female mice.

Disclosure
P. Luo: None. X. Yang: None. V.C. Torres Irizarry: None. H. Ye: None. Q. Xu: None. L. Carrillo-Sáenz: None. M.D. Munoz: None. S. Schaul: None. N. Patel: None. N. Antony: None. D. Dixit: None. T. Unterman: None. P. Xu: None.
1542-P: Association between Fasting Plasma Glucose Levels and the Development of Alzheimer’s Disease—A Longitudinal Cohort Study
Authors: SHARMA HEM S. , KUMAR SANJAY , CHOUDHARY BINOD K. , KHAN KAMRAN 
Published: June 2024

Introduction: Alzheimer's disease (AD) is progressively linked to metabolic factors, with fasting plasma glucose (FPG) levels emerging as a potential predictor. This longitudinal study examines how baseline FPG relates to AD development, shedding light on metabolic pathways in AD pathogenesis.
Methodology: In this 2-year longitudinal study with 600 participants, subjects were divided into low, normal, and high fasting plasma glucose (FPG) groups to explore the risk of developing Alzheimer's disease (AD). They underwent annual cognitive tests and FPG monitoring. The study employed Cox models and Kaplan-Meier curves for risk and survival analysis respectively, considering factors like age and sex.
Results: Over the 2-year period, 120 participants (20%) developed AD. The incidence rate of AD was significantly higher in the high FPG group (28%) compared to the normal (14%) and low (9%) groups (p&lt;0.001). Cox regression revealed that high baseline FPG levels were associated with a two-fold increased risk of developing AD (HR=2.01, 95% CI=1.35-2.99, p&lt;0.001) after adjusting for confounders. Kaplan-Meier survival analysis showed a significantly lower AD-free survival in the high FPG group (p&lt;0.001).
Conclusion: This study reveals that higher FPG levels significantly increase the risk of Alzheimer's disease over 2 years. FPG could be a crucial predictor for early detection and intervention in AD. Further research is essential to understand the mechanisms and assess glucose management's role in AD prevention.

Disclosure
H.S. Sharma: None. S. Kumar: None. B.K. Choudhary: None. K. Khan: None.
1558-P: Postprandial CPR Index Is Valuable in Assessing Beta-Cell Function in Japanese Patients with Type 2 Diabetes
Authors: ABE TAKAHIRO , MATSUHASHI YUKI , FUJITA TOMOYUKI , CHIKAZAWA SHINJI , FUJITA YUKIHIRO 
Published: June 2024

Residual β-cell function is a key factor in achieving optimal glycemic control in patients with diabetes, Glucagon stimulation test (GST) is secure and reliable to evaluate β-cell function, but is difficult to be examined in usual clinical settings. While F-CPR-index (Fasting C-peptide (CPR) [ng/ml] / glucose[mg/dl] x100) is widely used as a surrogate marker of insulin secretion. We hypothesized postprandial CPR to glucose ratio (P-CPR-index) can be another efficient marker for evaluating β-cell function in patients with type 2 diabetes (T2DM).Five hundred of Japanese T2DM patients with inadequate glycemic control (HbA1c&gt;7.0) were eligible in this study. HbA1c, fasting CPR and glucose, postprandial (120 min after breakfast) CPR and glucose were measured, and then F-CPR-index and P-CPR-index were calculated. GST was performed as follows: 1mg of glucagon was injected intravenously, CPR was determined before and 6 min after injection, GSTΔCPR (CPR [6 min] - CPR [0 min]) was calculated. Factors correlated with GSTΔCPR were analyzed using simple and multiple stepwise regression analysis. P value&lt;0.05 was defined as statistical difference.Average F-CPR-index, P-CPR-index and GSTΔCPR were 1.60&lt;u&gt;+&lt;/u&gt;0.95, 2.67&lt;u&gt;+&lt;/u&gt;1.92 and 1.93&lt;u&gt;+&lt;/u&gt;1.21, respectively. Simple regression analysis showed that GSTΔCPR was significantly correlated with urinary CPR, F-CPR-index and P-CPR-index as well as age, height, body weight (BW), BMI, waist circumference, duration of diabetes, retinopathy, insulin therapy. Multiple stepwise regression analysis revealed that independent factors contributing to GSTΔCPR were P-CPR-index (β= 0.432), BW (β= 0.336), duration of diabetes (β= -0.107), presence of retinopathy (β= -0.121), use of DPP-4i (β= -0.099), metformin (β= -0.109), SGLT2i (β= -0.108, p= 0.002) but not F-CPR-index.Our date suggested that P-CPR-index was valuable and simple method in assessing residual beta-cell function in daily clinical practice.

Disclosure
T. Abe: None. Y. Matsuhashi: None. T. Fujita: None. S. Chikazawa: None. Y. Fujita: None.
159-OR: Sequential Measurements of Insulin Resistance in the Assessment of Individuals Participating In Diabetes Prevention Programs
Authors: MCPHAUL MICHAEL J. 
Published: June 2024

A number of studies have found that programs such as the Diabetes Prevention Program (DPP) delay or prevent the progression from prediabetes to type 2 diabetes mellitus. However, a substantial proportion of the participants in these programs eventually develop type 2 diabetes. To explore possible reasons for this persistent progression, we previously developed an Insulin Resistance Risk Score (IRRS) to assess insulin resistance (IR) using insulin and C-peptide levels measured by mass spectrometry. This method correlates well with formal assessment of whole-body insulin resistance (IR) as measured by the steady-state plasma glucose (SSPG) during the insulin suppression test. We used this relationship to create a risk score called the Insulin Resistance Risk Score (IRRS) that assesses the risk of top tertile insulin resistance as measured by SSPG and used it to examine the association of changes in IR during the course of DPPs. We found that although the IRRS declines in some individuals (4/15) with high baseline IRRS in parallel with observed weight loss and normalization of glycemic indices, this did not occur in most participants (11/15) with a high baseline IRRS. Furthermore, a substantial number of individuals who did achieve DPP targets for weight loss and normalization of fasting glucose and HbA1c, had a high IRRS at baseline and throughout the DPP. This suggests that persistence of insulin resistance at the conclusion of a DPP may contribute to the future development of diabetes and that the assessment the IRRS of participants at the conclusion of a DPP might assist in the identification of those at risk of progression to type 2 diabetes and who may benefit from additional weight loss.

Disclosure
M.J. McPhaul: Consultant; Quest Diagnostics.
1610-P: Cardiomyocyte N-acetyltransferase 10 Overexpression Protects against Diabetic Cardiomyopathy
Authors: KANG JIAYI , WANG CHUNYAN , SUGAI-MUNSON AYA , LI GUOPING , RHEE JAMES , PAN ZHIQIANG , LI HAOBO 
Published: June 2024

Introduction & Objective: Diabetic cardiomyopathy is a major complication and a leading cause of death in patients with diabetes. Treatment specific to improve outcomes of diabetic cardiomyopathy is lacking. Iron overload-induced cell death, known as ferroptosis, contributes to the development of diabetic cardiomyopathy. N-acetyltransferase (NAT10), the only known writer of N4-acetylcytidine, has been implicated in myocardial ischemia reperfusion and heart failure. However, the role of NAT10 in diabetic cardiomyopathy and its regulatory effect on ferroptosis in diabetic cardiomyopathy, are unclear.
Methods: Six-week-old wild-type mice were subjected to either chow diet or high-fat (HFD) diet feeding and injection of streptozotocin (STZ) to induce diabetic cardiomyopathy. Some of the mice were injected with AAV9 encoding cardiac troponin-T (cTnT)-driven NAT10 to overexpress NAT10 in cardiomyocytes (CMs).
Results: Mice treated with HFD+STZ exhibited decreased E/A (Chow: 1.547±0.17 vs HFD+STZ: 1.166±0.07, p&lt;0.05, n=8) and reduced global longitudinal strain as well as decreased fractional shortening (FS, Chow: 45.72%±3.18 vs HFD+STZ: 38.32%±2.04, p=0.04, n=8) and a ~50% downregulation of cardiac NAT10 protein expression (p&lt;0.05). These changes were associated with a 3-fold increase in iron accumulation in the heart (p&lt;0.01). In HFD+STZ mice, CM-specific NAT10 overexpression increased E/A (Control: 1.11±0.13 vs Overexpression: 1.47±0.11, p&lt;0.01, n=8) and FS (Control: 37.06 %±4.22: vs Overexpression: 43.58%±4.57) as well as reduced iron accumulation in the heart. In CMs exposed to high glucose and palmitate, lentiviral overexpression of NAT10 reduced while its gene knockdown increased cell death and markers of ferroptosis as well as oxidative stress (all p&lt;0.05).
Conclusion: NAT10 protects the heart against diabetic cardiomyopathy through reducing ferroptosis. NAT10 is a promising therapeutic target in preventing diabetic cardiomyopathy.

Disclosure
J. Kang: None. C. Wang: None. A. Sugai-Munson: None. G. Li: None. J. Rhee: Consultant; Takeda Pharmaceutical Company Limited. Z. Pan: None. H. Li: None.

Funding
National Institutes of Health (R21AG077040); American Heart Association (20CDA35310184)
1630-P: Therapeutic Potential of Olfactory Receptor OR51T1 in Obesity
Authors: BLEYMEHL KATHERIN 
Published: June 2024

Olfactory receptors (ORs) are classic GPCRs primarily expressed in the olfactory epithelium, where they transmit real-time sensory signals to the brain. However, they are also expressed in multiple non-olfactory tissues like brain, gut, muscle etc., which often has been described as ectopic expression. Elucidation of the physiological roles of these ectopic receptors is revealing therapeutic potential in several conditions including obesity. Indeed, the results from our collaboration with Circuit Therapeutics suggest an important role of the ectopic expressed OR51T1 mouse homologue Olfr544 in body weight regulation. This orphan OR is located in the glutamatergic Area postrema (AP) brainstem circuitry. The AP specific overexpression of Olfr574 in lean mice leads to resistance against weight gain over 7 weeks caused by high fat diet. Surprisingly these mice showed no effect on food intake and high fat preference. To test the involvement of Olfr674 further, we used complementary manipulations (shRNA) to generate AP specific Olfr574-KO mice. These mice exhibit increased body weight in the absence of any change in food intake and high fat diet. Together, these observations demonstrate Olfr574 is involved in regulation of body weight effects and further suggest the human homologue OR51T1 as a possible target for treating obesity in humans. Next steps will include the de-orphanization of the human OR51T1 and murine Olfr574 as well as ligand structure improvement and selectivity-screening of ligands against an OR-library in order to further validate the role of OR51T1 in obesity.

Disclosure
K. Bleymehl: None.
1633-P: CRISPLD2 Is Secreted by Adipocytes and Can Reduce Adipocyte Size
Authors: GRIESEL BETH A. , OLSON ANN L. , SPARLING DAVID 
Published: June 2024

Obesity is a primary risk factor for type 2 diabetes, with excess adiposity leading to worsening insulin resistance and an increase in adipose tissue inflammation. Conversely, during weight loss there is improved insulin sensitivity with decreased adiposity, including a decrease in adipocyte size, clearance of lipid, and changes to the inflammatory signaling milieu. Adipocyte-secreted factors during weight loss could be a novel target to aid in improved outcomes in diabetes and obesity. We previously identified a novel adipocyte-secreted protein, CRISPLD2, that is uniquely up-regulated in expression and secretion during weight loss. CRISPLD2 secretion is up-regulated by lipolytic signals, down-regulated by insulin, and correlates strongly with insulin sensitivity in humans. We have now found that secreted CRISPLD2 is able to specifically alter gene expression, including an increase ccl2 transcription in 3T3-L1 adipocytes by almost 2-fold (p&lt;0.005). However, the signaling pathways, receptor, and function of CRISPLD2 within adipocytes and adipose tissue have yet to be determined. To determine if excess exogenous CRISPLD2 can alter adipose function, we developed a transgenic mouse with doxycycline-inducible adipose-specific overexpression of CRISPLD2. Induced CRISPLD2 overexpression over 4 weeks leads to a significant decrease in adipocyte size in visceral adipose tissue in lean animals, despite no change in overall adipose depot size. Finally, utilizing IP-MS, we found that CRISPLD2 binds several adipocyte cell surface proteins, intriguingly including nucleolin, which has been previously shown to function as a receptor in inflammatory pathways. Taken together, these data suggest that CRISPLD2 may function as a novel adipokine, playing a role in lipid turnover and adipocyte size in weight loss.

Disclosure
B.A. Griesel: Stock/Shareholder; Pfizer Inc., Moderna, Inc., Weight Watchers International. Other Relationship; Weight Watchers International. A.L. Olson: None. D. Sparling: None.

Funding
Oklahoma Center for the Advancement of Science and Technology (PR-HR21-005)
1647-P: Nonhuman Primate Obesity Model for the Translation of Target-Based Precision Medicine
Authors: JI SHAOHUI , ZHU ZHENGHUA , WANG GUANZHONG , GABRIEL JOSEPH A. , PEREZ ROSARIO M. , YANG LICHUAN 
Published: June 2024

The prevalence of obesity has increased worldwide in the past few decades. Because of the similarity of their absorption, distribution, metabolism, and excretion profile compared to that of humans, non-human primates (NHP) models are highly valuable in predicting the clinical response to new drugs for obesity associated disease, particularly for biological products such as siRNA, oligo and antibodies. Reported here are our profiling of the characteristic features from &gt; 2000 obese male cynomolgus monkeys (Macaca fascicularis), either spontaneous or induced with a KBI proprietary high fat diet (HFD). Multiple methods were used for the profiling, such as body weight, food intake, crown-rump length (for BMI calculation) measurement, MRI or DXA scanning for body fat, tissue biopsy, and clinical chemistry measurement. Based on the results from &gt;200 monkeys, we have defined the reference range of BMI in healthy monkeys (20.05 to 36.73 kg/m2). Therefore, monkeys with BMI &gt;40 kg/m2 were used for the obesity-related metabolic studies. Monkeys with BMI &gt;40 kg/m2 were observed with significantly higher liver fat fraction (9.5 ± 4.8% vs 4.3 ± 0.5%, p &lt;0.01) and % fat (42.36 ± 8.24% vs 18.47 ± 4.43%, p&lt;0.0001) compared to monkeys with BMI &lt;40 kg/m2. Compared with obese monkeys on low fat diet, the obese monkeys on HFD displayed more severe dyslipidemia and a greater incidence of diabetes and liver fibrosis. Furthermore, monkeys showed similar response as observed in humans after the administration of reference or test compounds, such as liraglutide, semaglutide, inclisiran, pioglitazone, empagliflozin etc. Significant reduction in food intake (-38.5 ± 14.4%) and body weight (-10.9 ± 4.7%) was observed after administration of Liraglutide for 6 weeks. Administration of a novel FGF21 analog for 11 weeks resulted a reduction in liver fat fraction (-40.3±18.8%). These findings indicate that our non-human primate obesity model is uniquely valuable for the translation of target-based precision medicine for humans.

Disclosure
S. Ji: None. Z. zhu: None. G. Wang: None. J.A. Gabriel: None. R.M. Perez: None. L. Yang: None.
1652-P: The Effectiveness of Semaglutide on Glucose Tolerance and Body Composition in Obese Diabetic Rhesus Monkeys
Authors: YANG ZUNYUAN , GONG LI , LIANG YINAN , YAO ZUNWEI , ZENG LICAI , WU MINGLING , YANG ZHENYAN , ZENG WEN 
Published: June 2024

Introduction & Objective: This study aimed to investigate the changes of obesity severity, glucose metabolism, and body composition in obese and diabetic rhesus monkeys treated with semaglutide.
Methods: We enrolled 12 rhesus monkeys aged between 12-20 years with fasting plasma glucose (FPG) &gt; 5.5 mmol/L, body weight (BW) ranging from 12-20 kg, and fat mass proportion between 20-55%, and randomly assigned them to 4 weeks of treatment with once-weekly subcutaneous semaglutide or placebo, followed by an 8-week washout period. The BW, waist circumference (WC), and metabolic parameters were examined. Body composition was measured using DEXA and MRI monthly. Proportions of total fat body mass (TFM) and total lean body mass (TLM) were shown relative to total body mass.
Results: At week 4, in semaglutide group, the changes in BW and WC from baseline were -14.82±2.73% and -12.4±9.3% (vs. placebo, P&lt;0.001). This resulted in reductions from baseline in TFM (-24.08±14.21%, vs. 2.35±9.12% placebo; P=0.0025). TLM decreased from baseline (-7.32±3.37% vs. -0.12±5.99% placebo; P=0.0197); however, there was an increase from baseline in the muscle-to-weight ratio (13.15±7.03% vs. -1.24±5.35 placebo; P=0.0018) and the muscle-to-fat ratio (32.07±15.95% vs. -4.35±14.91% placebo; P=0.0014). Significant declines in FPG (-21.86±7.56% vs. 1.83±4.16% placebo, P=0.0000) and HOMA-IR (-62.46±18.11% vs. -10.58±39.49% placebo; P=0.0026) were noted compared to baseline.
Conclusion: These results suggest that semaglutide effectively improves glucose tolerance, reduces BW while increases proportion of TLM in obese T2DM rhesus monkeys. This nonhuman primate model showed similar response to GLP-1 receptor agonist in humans.

Disclosure
Z. Yang: None. L. Gong: None. Y. Liang: None. Z. Yao: None. L. Zeng: None. M. Wu: None. Z. Yang: None. W. Zeng: None.
1664-P: An Observation of an Increase in the Metabolic Syndrome Parameters after Stopping GLP-1RA Medications in STEP-4 and SURMOUNT-4 Trials
Authors: ALSAEED ABDULGHANI H. 
Published: June 2024

Introduction and Objective: GLP-1 RA (Receptor Agonist) medications are commonly used by overweight and obese individuals for weight reduction, however, there is still a question about the metabolic consequences of stopping these agents.
Methodology: Exploring the metabolic parameters in those who switched to placebo in two large clinical trials (STEP-4 and SURMOUNT-4).
Results: In SURMOUNT-4 trial, after one year of stopping Tarazepide; there was an increase of metabolic syndrome parameters in the switched placebo group as follows; an increase in waist circumference by a mean of 8.3cm(7.4to9.2), raised in HbA1c by 0.25%(0.22to0.28), an increase of fasting blood sugar by 7.7mg/dl(6.6to8.8), systolic BP by 8.4mmHg(7.2to9.7), and an increase of triglyceride by 15.6%(10.9to 20).In the STEP-4 trial, stopping semaglutide for 48 months, there were similar adverse effects on metabolic syndrome parameters in the switched placebo group. The waist circumference increased by 3.0cm(2.1to4.0), fasting blood sugar increased by 7.1mg(6.0 to 8.2), HbA1c by 0.1%(0.1to0.1), systolic BP by 4.9mmHg(3.3to6.5), and Triglyceride by 9%(4to14). The level of HDL cholesterol was increased in both groups (+18 for the semaglutide group, and +19 for the switched placebo group) which might indicate that both groups were highly motivated to do physical activities as part of the clinical trial.
Conclusion: Most of the metabolic syndrome parameters were found to be adversely increased after stopping GLP-1RA medications in individuals without diabetes mellitus. Such observation warrants further studies to check the safety of stopping such medications once used for individuals who are not affected by T2DM.

Disclosure
A.H. Alsaeed: Advisory Panel; Abbott. Speaker's Bureau; Sanofi. Advisory Panel; Novo Nordisk. Speaker's Bureau; Eli Lilly and Company, Boehringer-Ingelheim.