bluuebunny/crossref_metadata_2025_split huggingface dataset:
1638-P: Metformin Enhances Upper Small Intestinal Lipid Sensing to Regulate Food Intake Independent of GDF15 Release
Authors: KUAH RACHEL , BRUCE KYLA , ZHANG SONG-YANG , LI ROSA J.W. , BARROS DANIEL R. , LAM TONY K. 
Published: June 2024

Metformin, a first-line therapy for obesity-associated diabetes, lowers feeding and weight by increasing plasma growth differentiation factor 15 (GDF15) levels, but whether GDF15-independent mechanisms are involved is unknown. The upper small intestine (USI) detects lipids and triggers a gut-brain axis to lower food intake in chow but not high fat (HF)-fed conditions, while metformin enhances USI glucose sensing to lower glucose levels in HF rats. Here, we assessed whether metformin enhances lipid sensing in the USI of HF rats to lower food intake. We performed refeeding studies and measured plasma GDF15 levels after infusing 10% Intralipid into the USI of male rats. Infusion of Intralipid vs. saline into the USI suppressed food intake (lipid: 31±1 vs. sal: 43±2 kcal; p&lt;0.01; n=18, 15) and increased plasma GDF15 levels (lipid: 113±9 vs. sal: 70±6 pg/ml; p&lt;0.01; n=4, 5) up to 6h after refeeding in chow rats. In HF rats, both the effects of USI Intralipid vs. saline on feeding (lipid: 42±3 vs. sal: 41±1 kcal; n=10, 11) and plasma GDF15 levels (lipid: 68±6 vs. sal: 73±5 pg/ml; n=5, 3) were consistently abolished. Interestingly, metformin (50 mg/kg) administered to the USI of HF rats 1d prior to the refeeding studies enhanced USI Intralipid vs. saline infusion to suppress food intake (met-lipid: 35±2 vs. met-sal: 45±3 kcal; p&lt;0.01; n=24,17), but notably did not increase plasma GDF15 levels (met-lipid: 69±3 vs. met-sal: 76±13 pg/ml; p&gt;0.05; n=6, 5). Thus, for the first time we found that metformin enhances lipid sensing in the USI to lower food intake independent of GDF15 release. We propose that metformin lowers feeding in GDF15-dependent and -independent pathways.

Disclosure
R. Kuah: None. K. Bruce: None. S. Zhang: None. R.J.W. Li: None. D.R. Barros: None. T.K. Lam: None.

Funding
Canadian Institutes of Health Research (PJT-183901)
1641-P: Effect of Specific Weight-Reducing Interventions on Metabolic and Immunological Outcomes in Mice
Authors: BOSCH ANGELA J.T. , KELLENBERGER WANJA T. , KELLER LENA , LOW ANDY J.Y. , CAVELTI-WEDER CLAUDIA 
Published: June 2024

Introduction & Objective: Obesity leads to glucose intolerance and immune cell alterations in different organs. Nevertheless, it remains unknown whether these metabolic and immunological changes are reversible following weight loss and if they differ with specific weight-reducing interventions. This study aimed to address whether obesity-associated metabolic and immunological changes are reversed after weight loss, comparing the effects of caloric restriction versus switch to a healthier diet.
Methods: Male C57Bl/6j mice were fed high fat diet (HFD), and randomized after 8 weeks into the following groups: continued HFD, HFD combined with caloric restriction or switched back to standard diet (HFD/SD), while an additional group was on SD throughout the experiment. Metabolic parameters were assessed at distinct timepoints and immune cells characterized by flow cytometry at the end of the experiment.
Results: The body weights of mice on SD, HFD/caloric restriction and HFD/SD were comparable from two weeks after the intervention onwards, while HFD fed mice had higher body weights. Initially, both HFD/caloric restriction and HFD/SD mice showed similar improvements in glucose tolerance and insulin secretion compared to mice on SD. However, glucose tolerance deteriorated over time in mice on HFD/caloric restriction, while their insulin levels remained low. Weight loss correlated with a decrease in inflammatory adipose tissue macrophages (ATMs), an increase in anti-inflammatory ATMs and eosinophils in AT, colon and liver. Colon B-cells decreased only in HFD/SD mice, while liver neutrophils and regulatory T-cells in AT increased.
Conclusion: Independent of the weight loss strategy, weight loss is associated with a reversal of hyperinsulinemia and AT inflammation as well as increased eosinophils in various organs. In contrast, a switch from HFD to SD specifically leads to reduced B-cells in the colon and increased neutrophils in liver and regulatory T-cells in AT.

Disclosure
A.J.T. Bosch: None. W.T. Kellenberger: None. L. Keller: None. A.J.Y. Low: None. C. Cavelti-Weder: None.

Funding
The Swiss National Science Foundation (SNSF) (32003B_204937/2)
1646-P: Apolipoprotein A4 Improves Glucose Homeostasis through Activation of BAT Thermogenesis in Obese Mice
Authors: LARUSSA ZACHARY D. , KUO HSUANCHIH , BAUMGARTE JACE , SHI HAIFEI , LO CHUNMIN C. 
Published: June 2024

Obesity is associated with impaired insulin sensitivity and the development of type 2 diabetes. Activation of brown adipose tissue (BAT) thermogenesis enhances triglyceride clearance and insulin sensitivity. Apolipoprotein A4 (ApoA4) induced by dietary lipids elevates BAT thermogenesis in lean mice. Chronic consumption of high-fat diet (HFD) attenuates APOA4 production in small intestine and BAT thermogenesis. The hypothesis of this study was that the continuous infusion of mouse ApoA4 protein would increase BAT thermogenesis and improve glucose homeostasis in HFD-induced obese mice. Male mice were maintained on an HFD (60% kcals fat) for 10 weeks, during the last 4 weeks, mice received a pump infusion of vehicle or ApoA4 at a physiological dose (1.2 mg ApoA4/kg body weight). Glucose tolerance test, BAT thermogenesis, lipid accumulation in liver, and body weight were measured in mice with ApoA4 or vehicle treatment. Serum glucose and plasma insulin in ApoA4-treated mice was lower than in saline-treated mice following a glucose challenge. BAT temperature and thermogenesis were elevated in ApoA4-treated mice compared to saline-treated mice. Further, ApoA4-treated mice had increased fatty acid oxidation, reduced lipid content, and attenuated steatosis in the liver and decreased body weight gain relative to the saline control mice.
In conclusion, maintenance of ApoA4 protein elevates BAT thermogenesis, reduces body weight gain and hepatic lipid accumulation, and improves glucose homeostasis in HFD-induced obesity.

Disclosure
Z.D. LaRussa: None. H. Kuo: None. J. Baumgarte: None. H. Shi: None. C.C. Lo: None.

Funding
National Institutes of Health (AG078768); National Institutes of Health (DK118611)
1651-P: Effect of New Antidiabetics on Steatosis in of Nerve Tissues and Nerve Conduction Velocity—Possible Role of NGF/Synaptophysin and Nrf2/HO-1 Pathways
Authors: HUSSEIN ABDELAZIZ , EID ELSAYED M. , YEHYA YOMNA M. , TAHA MEDHAT , MOSA AHMED A.H. , AMMAR OMAR A. , ABDEL-HALIM NEHAL H. 
Published: June 2024

Objectives: The current study examined the effects of new antihyperglycemic drugs (GLP1 analogue, semaglutide) and SGLT2 inhibitor; dapagliflozin) on nerve functions and morphology in obese rats as well as their underlying mechanisms.
Methods: 40 male Sprague Dawley rats, aged 6-8 weeks and classified into 5 groups; normal group, high-fat diet (HFD): HFD for 12 weeks, Metformin group: HFD for 12 weeks + metformin in last 4 weeks, DAPA group: HFD for 12 weeks +dapagliflozin in last 4 weeks, semaglutide group: HFD for 12 weeks + semaglutide in last 4 weeks. At the end of the experiment, sciatic nerve was collected for nerve conduction study, oxidative stress marker (MDA), real time PCR study (for HO-1 and Nrf2), red o oil staining, electron microscopic examination and immunohistochemistry for NGF and synaptophysin.
Results: HFD group showed significant rise in blood glucose, serum lipids, HOMA index, lipid deposition in nerve tissues and lipid peroxidation (MDA) in nerve tissues with significant attenuation in NCV, the expression of Nrf2 and HO-1 genes and significant attenuation in area stained with NGF and synaptophysin. On the other hand, pretreatment with either DAPA or semaglutide led to considerable enhancement in the deteriorated serum and nerve tissue parameters and reverse the pathological changes.
Conclusion: New antidiabetic drugs like SGLT2 inhibitors (more powerful) and GLP1 analogue might have neuroprotective beneficial effects beside controlling the glycemic state in obese rats. This effect may result from reduced oxidative stress and increased Nrf2 levels., HO-1, synaptophysin and NGF in nerve tissues of obese rats.
Keywords: nerve conduction velocity, obese, Nrf2, HO-1, NGF, synaptophysin, DAPA, semaglutide.

Disclosure
A. Hussein: None. E.M. Eid: None. Y.M. Yehya: None. M. Taha: None. A.A.H. Mosa: None. O.A. Ammar: None. N.H. Abdel-Halim: None.
1663-P: The Impact of Time-Restricted Eating on Beta-Cell Function in Overweight Adults with Type 2 Diabetes—A Randomized Crossover trial
Authors: KRAMER CAROLINE K. , RETNAKARAN RAVI , ZINMAN BERNARD 
Published: June 2024

Time-restricted eating (TRE) has been proposed as a non-pharmacological strategy with cardio-metabolic benefits in overweight individuals but little is known about its metabolic impact in type 2 diabetes (T2DM). Thus, we sought to evaluate whether TRE can improve beta-cell function and metabolic status in overweight individuals with early T2DM. In a cross-over randomized trial, 39 participants (25 women, age 56.3 yrs, BMI 32.4 kg/m2, T2DM duration 2.9 yrs, A1c 6.6%) were randomized to either 6-weeks of TRE (20h-fasting/4h-eating) or standard lifestyle, followed by 4-weeks washout before 6-weeks of the other approach to eating. The primary outcome of beta-cell function was assessed by Insulin Secretion-Sensitivity Index-2 (ISSI-2) derived from an oral glucose tolerance test. As compared to standard lifestyle, TRE induced a 14% increase in ISSI-2 (p=0.03) accompanied by 14% reduction of HOMA-IR (p=0.03) (Figure). Fasting glucose did not differ between interventions, but TRE yielded a significant reduction in A1c (-0.32%, p&lt;0.001). These metabolic improvements were likely driven by its effects in reducing body weight by 3.86% (p&lt;0.001) and waist circumference by 3.8 cm (p=0.003).
In conclusion, TRE improved beta-cell function and insulin resistance in overweight patients with early T2DM, likely through its beneficial effects on adiposity.

Disclosure
C.K. Kramer: Research Support; Boehringer-Ingelheim. R. Retnakaran: Research Support; Boehringer-Ingelheim. Consultant; Eli Lilly and Company, Novo Nordisk, Sanofi. B. Zinman: Advisory Panel; Abbott, Eli Lilly and Company, Novo Nordisk.

Funding
Canadian Institutes of Health Research (PJT166091)
1673-P: Metaboepigenetic Regulation of Gene Expression in Obesity and Insulin Resistance
Authors: DAS SWAPAN K. , COMEAU MARY , LANGEFELD CARL D. 
Published: June 2024

Altered DNA methylation (DNAm) in adipose tissue is involved in the pathogenesis of obesity and insulin resistance. The activity of enzymes involved in altering DNAm levels is dependent on several metabolite cofactors. To understand the role of metabolites as mechanistic regulators of epigenetic marks, we tested the association between selected plasma metabolites and DNAm levels in the adipose tissue of African Americans. In the AAGMEx cohort, plasma levels of metabolites were measured by untargeted LC-MS (DiscoveryHD4 panel; Metabolon, N=256), adipose tissue DNAm and transcript levels were measured by RRBS (Diagenode), and HumanHT-12V4 ExpressionBeadChips (Illumina), respectively. Among the 21 one-carbon metabolism pathway metabolites evaluated, six were associated with gluco-metabolic traits (FDR &lt;0.05, for BMI, SI, or Matsuda index) in AAGMEx. We tested the association of three of these metabolites with DNAm levels in adipose. Methylation levels of 196, 116, and 180 CpG-sites were associated (P&lt;0.0001) with S-adenosylhomocysteine (SAH), cystine, and hypotaurine, respectively. The CpG sites chr22:31002992 (P = 2.96x10-8), chr11:89135566 (P = 4.92x10-7), and chr21:38120202 (P = 5.53x10-8) were most significantly associated with plasma SAH, cystine, and hypotaurine levels, respectively. Cis-expression quantitative trait methylation (cis eQTM) analyses suggested the role of these metabolite-level-associated CpG sites in regulating the expression of adipose tissue transcripts. Plasma SAH level-associated CpG sites chr19:3403712 and chr19:3403735 were also associated with the expression of G protein subunit alpha 15 (GNA15) in adipose. The expression of GNA15 was significantly correlated with BMI (β = 1.87, P = 1.9x10-16) and SI (β = -1.61, P = 2.49 x 10-5). In summary, our study suggests that a subset of metabolites locus-specifically modulates the CpG-site methylation levels and, in turn, regulates the expression of transcripts involved in obesity and insulin resistance.

Disclosure
S.K. Das: None. M. Comeau: None. C.D. Langefeld: None.

Funding
American Diabetes Association (1-18- ICTS-113); National Institutes of Health (R01 DK118243)
1674-P: Development of a Once-a-Month Formulation of Semaglutide from an Innovative Injectable and Biodegradable Hydrogel
Authors: MARECHAL AUDREY , BESNARD ROMAIN , HAKIM SANA , NAESSENS ULYSSE , SOULA OLIVIER , GAUDIER MARTIN , DAUTY EMMANUEL , MEGRET CLAIRE 
Published: June 2024

Semaglutide is a GLP-RA currently authorized for treatment of type 2 diabetes patients with insufficient glycaemic control and long-term weight management. Current dosage forms are administered either by once-weekly subcutaneous injection or by daily oral pill. AdoGel® is a hydrogel platform consisting of cross-linked degradable polymers injectable with 25G needle that allows sustained release of soluble peptides over 1 to 3 months duration. The challenge is to tailor the hydrogel to entrap the peptides to limit initial burst and, at the same time, to allow smooth release by controlled degradation of the hydrogel without generating toxic molecules. An AdoGel-semaglutide formulation was tested in rats (N=6) following a subcutaneous injection. The pharmacokinetics analysis showed limited burst and a regular release over a one-month period. The product is well tolerated with no inflammatory reaction during the one-month period. The results showed that a regular release of semaglutide over one month is achievable and could be a real benefit for patient compliance by limiting the injection frequencies, reduction of side effects and improved efficacy.

Disclosure
A. Marechal: Employee; ADOCIA. Stock/Shareholder; ADOCIA. R. Besnard: Employee; ADOCIA. Stock/Shareholder; ADOCIA. S. Hakim: Employee; ADOCIA. Stock/Shareholder; ADOCIA. U. Naessens: Employee; ADOCIA. Stock/Shareholder; ADOCIA. O. Soula: Board Member; ADOCIA. Stock/Shareholder; ADOCIA. M. Gaudier: Employee; ADOCIA. Stock/Shareholder; ADOCIA. E. Dauty: Stock/Shareholder; ADOCIA. Employee; ADOCIA. C. Megret: Employee; ADOCIA. Stock/Shareholder; ADOCIA. Consultant; Avadel. Stock/Shareholder; Avadel, Sanofi.
1684-P: CONCRETE—Characterization of Patients Receiving Telemedicine and Branded Antiobesity Medication for Medical Weight Management—A Retrospective Analysis
Authors: SHUKLA ALPANA , LI DAVID , CASPER ANTHONY J. , ARONNE LOUIS , D'ANGELO DEBRA , SAUNDERS KATHERINE H. , IGEL LEON I. , LUCAS EUGENE , PALEPU KATHYA , ZACHERLE EMILY , TRAINA ANDREA , OLSSON KELLY 
Published: June 2024

Introduction & Objective: Use of branded anti-obesity medications (bAOMs) has increased concurrently with the rise of telemedicine, a convenient, cost-effective modality for patient care. However, limited data exist regarding characteristics of telemedicine users in medical weight management. This study examines the profile and treatment course of patients prescribed bAOMs for overweight or obesity via telemedicine at an academic weight center in New York City.
Methods: This is a retrospective observational study of patients who started telemedicine treatment between May 1, 2020, and September 30, 2022, received a bAOM prescription (Contrave®, Qsymia®, Saxenda®, or Wegovy®), and had ≥6 (±2) months’ follow-up. Data were abstracted by electronic medical record query using relevant ICD/diagnosis codes and biomarker data to curate a dataset of eligible patients for analysis.
Results: Patients who met inclusion criteria (N=1286) had a mean age of 47.2 (SD=12.8) years, initial weight of 220.9 (50.6) lb (n=934), initial BMI of 35.2 (6.5) (n=930), and an average of 2.2 weight-related comorbidities (most commonly dyslipidemia [n=705], hypertension [n=355], and prediabetes [n=595]). Most patients identified as White (63.7%); 72.2% of patients were female. Patients had a mean (SD) of 9.5 (7.2) telemedicine visits with physicians, nurse practitioners, and registered dietitians over 17.7 (7.2) months; 36.2% used both telemedicine and in-person visits, and 63.8% used only telemedicine. The most frequently prescribed bAOM was Wegovy® (70.3% of patients), followed by Saxenda® (17.6%), Contrave® (13.6%), and Qsymia® (12.4%).
Conclusion: In this study, Wegovy® was the most commonly prescribed bAOM, and telemedicine facilitated frequent appointments (every 1.9 months on average). Future research is necessary to examine the impact of this treatment model on obesity and obesity-related comorbidities.

Disclosure
A. Shukla: Research Support; Eli Lilly and Company, Novo Nordisk. Consultant; Sun Pharmaceutical Industries Ltd. D. Li: None. A.J. Casper: None. L. Aronne: Advisory Panel; Novo Nordisk. Consultant; Novo Nordisk. Advisory Panel; Lilly Diabetes, Altimmune Inc. Consultant; Lilly Diabetes. Advisory Panel; Pfizer Inc. Consultant; UnitedHealth Group. Advisory Panel; Boehringer-Ingelheim. Board Member; AstraZeneca. Advisory Panel; Amgen Inc. D. D'Angelo: None. K.H. Saunders: Other Relationship; Intellihealth. L.I. Igel: Consultant; Novo Nordisk. Employee; Intellihealth. E. Lucas: Consultant; Intellihealth. K. Palepu: None. E. Zacherle: Employee; Novo Nordisk. A. Traina: Employee; Novo Nordisk. Stock/Shareholder; Novo Nordisk. K. Olsson: Employee; Novo Nordisk.
1693-P: Irisin Levels, Glycometabolic Characteristics, and Muscle Performance in Type 2 Diabetes Patients with Sarcopenic or Nonsarcopenic Obesity
Authors: ROSSI ERICA , DI GIOIA LUDOVICO , MARRANO NICOLA , PERRINI SEBASTIO , LAVIOLA LUIGI , NATALICCHIO ANNALISA , GIORGINO FRANCESCO 
Published: June 2024

Introduction: Sarcopenic obesity (SO), characterized by concurrent excessive body fat and reduced muscle mass, amplifies the risk of metabolic abnormalities, especially insulin resistance (IR). Irisin, a myokine linked to energy homeostasis, has shown inconsistent associations with sarcopenia. This study investigated irisin levels in T2DM patients with SO or non-sarcopenic obesity (NSO).
Methods: Patients with T2DM and BMI &gt;30 kg/m² underwent glycometabolic assessment and irisin measurements. Muscle efficiency was evaluated using Handgrip Strength (HGS) and 5-times Sit To Stand Test (5-STST). Patients were categorized into SO and NSO groups per the 2022 ESPEN/EASO Consensus.
Results: Of 67 patients affected by obesity and T2DM, 50 had NSO and 17 SO. SO patients were older (70 [6] vs 66 [7] years, p=0.028), with higher BMI (36.7 [4.3] vs 34.7 [4] kg/m², p=0.036), FM (41.9 [7.7] vs 37.6 [8.7] kg, p=0.049), alcohol use (47.1% vs 22%, p=0.048), 5-STST (13.3 [4.1] vs 10.8 [3.1] s, p=0.016), and lower HGS results (24 [7.9] vs 36.4 [10.2] kg, p&lt;0.001). No difference in HOMA-IR, HbA1c or irisin levels was found between SO and NSO patients. Irisin correlated negatively with HbA1c (r=-0.288, p=0.018), HGS (r=-0.249, p=0.042), muscle mass (r=-0.26, p=0.033), and creatinine (r=-0.308, p=0.011), and positively with relative FM (r=-0.274, p=0.025). Increasing HGS results predicted lower irisin levels (beta=-316, p=0.032). Multivariate logistic regression analysis associated older age with higher SO risk (OR=1.16, p=0.02), with a trend relationship for insulinemia (OR=1.05, p=0.073) and 5-STST (OR=1.19, p=0.068) (p=0.039, area under the curve=0.804).
Conclusion: People with T2DM and SO exhibit poorer lifestyle, anthropometric profile and physical performance. Irisin levels are linked with better glycemic control, negatively correlating with muscle mass and strength, suggesting a compensatory role in this context.

Disclosure
E. Rossi: None. L. Di Gioia: Consultant; Roche Diabetes Care, Eli Lilly and Company, Novo Nordisk, Sanofi. N. Marrano: None. S. Perrini: None. L. Laviola: Speaker's Bureau; A. Menarini Diagnostics, Abbott, AlfaSigma. Advisory Panel; Boehringer-Ingelheim, Eli Lilly and Company, Medtronic, Novo Nordisk. Speaker's Bureau; AstraZeneca. Advisory Panel; Roche Diabetes Care, Sanofi. Speaker's Bureau; Terumo Corporation. A. Natalicchio: Speaker's Bureau; AstraZeneca, Novo Nordisk, Sanofi, Eli Lilly and Company. F. Giorgino: Consultant; AstraZeneca, Boehringer-Ingelheim, Eli Lilly and Company, LifeScan Diabetes Institute, Merck Sharp & Dohme Corp., Medtronic, Novo Nordisk, Roche Diabetes Care, Sanofi. Research Support; Eli Lilly and Company, Roche Diabetes Care.
1718-P: Retinol-Binding Protein 4, an Adipokine Provoking Pancreatic Beta-Cell Apoptosis in Type 2 Diabetes
Authors: QU SHEN , MAO WANGJIA , CHENG XIAOYUN 
Published: June 2024

Pancreatic b-cell apoptosis plays a decisive role in the progression of type 2 diabetes. Retinol-binding protein 4 (RBP4) is a prominent adipokine in type 2 diabetes(T2D), has been confirmed to that it may be involved in the pathogenesis of insulin resistance and T2D, but the underlying mechanisms of RBP4 inducing islet b-cell apoptosis are unknown. The stimulated by retinoic acid6 (STRA6), RBP4’s only known specific membrane receptor, is expressed in b-cells and mediates the inhibitory effect of RBP4 on insulin synthesis. Here, we found that at the cellular level apo-RBP4 can induce apoptosis in pancreatic b-cells by binding to STRA6. Compared to holo-RBP4, apo-RBP4 has a stronger induction effect, and this induction effect is dose-dependent. We also found that elevated circulating RBP4 levels were inversely correlated with pancreatic b-cell apoptosis in T2D mice across different glycemic stages. Islets isolated from RBP4 overexpressing mice showed a significant decrease of GSIS while injecting shRBP4 AAV mice showed a recovery of GSIS. Moreover, decreasing circulating RBP4 level could effectively restore b-cell dysfunction and ameliorate hyperglycemia in T2D mice. These observations revealed a role of RBP4 in promoting apoptosis of pancreatic b cells, which provides new insight into the diabetogenic effect of RBP4.

Disclosure
S. Qu: None. W. Mao: None. X. Cheng: None.