bluuebunny/crossref_metadata_2025_split huggingface dataset:
2029-LB: Myokine X, a New Therapeutic Approach for Type 2 Diabetes
Authors: BERNARD DAPHNÉ , VION-CHAMBRIAL JULIE , PINGET MICHEL , SULTAN ARIANE , BOUZAKRI KARIM 
Published: June 2024

An energy imbalance, often involved in Type 2 diabetes (T2D), leads to adipose tissue dysfunction which will worsen the disease and lead to complication. Thus, the need to find new therapies targeting adipose tissue is necessary. We have already demonstrated the beneficial impact of Myokine X on pancreatic islets survival and functionality. This study aims to investigate the impact of Myokine X, which is secreted after a resistance effort, on adipose tissue of a rodent model of T2D.
Zucker Diabetic Sprague-Dawley (ZDSD) rat, naturally developing type 2 diabetes, received a daily peritoneal injection of either a saline solution (control group) or a Myokine X solution at 1 µg/mL for 20 weeks. Animals were sacrificed at the end of the 20 weeks and adipose tissue was analysed by western blotting or by qPCR for gene expression. Figures and statistical analyses were performed using GraphPad Prism software. The significance of the data was assessed using Student's t test to compare two conditions. When several factors were present, two-way ANOVAs were performed.
Myokine X treatment revealed (i) an impact on insulin pathway with an increase of 16.5% of Akt p-ser473 phosphorylation capacity, with simultaneously a significant increase of 78% for GLUT4 mRNA expression, (ii) a significant decrease of HSL phosphorylation on ser660 (-24%), (iii) an increase of adipokines mRNA expression with beneficial impact on insulin pathway.
This study shows that Myokine X treatment had a positive impact on adipose tissue in a rodent model of T2D, in terms of insulin sensitivity improvement, HSL activation decrease and improvement of adipose tissue secretion, adipokines. Thus, Myokine X could represent a therapeutic approach for T2D treatment.

Disclosure
D. Bernard: None. J. Vion-Chambrial: None. M. Pinget: Other Relationship; ASDIA, Novo Nordisk, VitalAir. A. Sultan: Speaker's Bureau; Abbott. Board Member; Lilly Diabetes, Amgen Inc., Novartis AG. Speaker's Bureau; Sanofi, Servier Laboratories, Boehringer-Ingelheim. Board Member; Pfizer Inc. Speaker's Bureau; AstraZeneca. K. Bouzakri: None.
2043-LB: hERG Potassium Channels as Novel Targets for GLP-1 and GIP Secretagogue Therapies in Diabetes and Obesity
Authors: YUAN YING-CHAO , WANG HAO , YANG JIN-KUI 
Published: June 2024

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), derived from enteroendocrine cells (EECs), play critical roles in blood glucose regulation as incretin hormones. While medications targeting GLP-1 analogues and GLP-1 receptor activators are widely used for managing type 2 diabetes (T2D) and obesity, there remains a need for agents that stimulate endogenous incretin secretion. In this study, we uncover the pivotal role of hERG potassium channels in regulating incretin secretion. Co-localization of hERG channels with EECs in the intestinal epithelium of rodents underscores their significance. Intestine-specific knockout of hERG in mice enhances glucose tolerance and augments GLP-1 and GIP secretion triggered by oral glucose intake. Moreover, primary intestinal epithelial cells deficient in hERG exhibit heightened incretin secretion upon glucose stimulation. Mechanistically (see Figure 1), (1) hERG deficiency leads to reduced Kv currents and (2) prolonged repolarization in enteroendocrine cells, (3) resulting in increased Ca2+ influx and intracellular Ca2+ accumulation, (4) ultimately leading to augmented incretin secretion. Given the therapeutic benefits associated with GLP-1 and GIP, these findings underscore the potential of hERG as an auspicious novel target for addressing obesity and diabetes therapeutically.

Disclosure
Y. Yuan: None. H. Wang: None. J. Yang: None.
2052-LB: Semaglutide Depot, a Long-Acting Injection of Semaglutide Administered Once Every Four Weeks, Demonstrates Similar Efficacy and PK Profile to Daily Semaglutide Administration
Authors: RUBNOV SHAI , ZATS GALINA , BLEICH KIMELMAN NADAV , POPPER LAURA , DANON URI , MAROM EHUD 
Published: June 2024

Introduction and Objectives: Semaglutide Depot consists of extended-release microspheres administered every 28 days, aiming to provide improved dosing regimen over the currently available once weekly dose Semaglutide Depot efficacy and PK profile were evaluated in mice and minipigs. The study aimed to assess the efficacy and the PK profile of Semaglutide Depot injected once compared to Semaglutide API daily in mice or every 72 hours in minipigs.
Methods: In the PK study, db/db mice received SC injection of 2mg/kg Semaglutide Depot on day 0 or daily injections of 0.02mg/kg Semaglutide API for 42 days. In a parallel PD study, db/db mice were injected IM with 2mg/Kg Semaglutide Depot on day 0 or daily injections of 0.02mg/kg Semaglutide API, for 28 days. The PK profile, fasting blood glucose, HbA1c levels and feed intake were measured. In the minipigs PK study, animals were injected with 0.5mg/kg Semglutide Depot IM on day 0 or with 0.008mg/Kg Semaglutide API SC once every 72 hours for 28 days.
Results: PK studies in both species demonstrate sustained release profile maintaining plasma concentrations within the therapeutic range for at least 30 days. The PK profile is correlated with PD in mice. Significant reductions in fasting glucose levels at days 14 and 28, as well as HbA1c levels at day 28 in Semaglutide Depot-treated mice were noted, compared with vehicle treated controls. Additionally, feed intake was significantly lower in Semaglutide Depot-treated mice. Notably, a single dose of Semaglutide Depot given on day 0 was comparable to 28 daily doses of Semaglutide API.
Conclusions: Semaglutide Depot given as a single dose on day 0 showed a one-month lasting PK profile and a comparable efficacy to that of Semaglutide API given daily or every 72 hours in mice and minipigs, respectively. Phase I/IIa clinical study is planned to explore Semaglutide Depot bioavailability and efficacy in diabetic patients.

Disclosure
S. Rubnov: Employee; MAPI pharma ltd. G. Zats: None. N. Bleich Kimelman: Employee; Mapi Pharma Ltd. L. Popper: Employee; Mapi Pharma. U. Danon: None. E. Marom: Stock/Shareholder; Mapi Pharma Ltd.
2060-LB: Erythropoietin Regulation of Fat Mass and Glucose Tolerance Mediated by Receptor Expression in Adipose Tissue
Authors: ROGERS HEATHER , NOGUCHI CONSTANCE T. 
Published: June 2024

The cytokine erythropoietin (EPO) is known for the regulation of red blood production, but its receptor (EpoR) is expressed beyond hematopoietic tissues. Studies in animal models have suggested that EPO regulates glucose homeostasis and fat mass accumulation. To assess EPO metabolic activity, wild-type mice (WT, C57BL/6) and mice lacking EPOR in adipose tissue, ΔEpoRAdipo (using Adipo-Cre) and ΔEpoRaP2 (using aP2-Cre), were fed a high-fat diet (HFD, 60% kCal fat) and treated with EPO (3000U/kg 3X per week) or saline for 3 weeks at ages 3, 4, and 6 months. Endogenous EPO regulated fat mass in WT mice, and ΔEpoRAdipo and ΔEpoRaP2 mice had increasing trends in fat mass accumulation, becoming significant in older mice. EPO treatment increased hematocrit and decreased fat mass accumulation and body weight in WT male mice at 6 months, showing EPO protection against diet induced obesity (DIO) in male mice while estrogen in female mice protects against DIO. ΔEpoRAdipo and ΔEpoRaP2 mice had increased GTT indicating that endogenous EPO activity in adipose tissue improves glucose tolerance. EPO treatment decreased GTT in WT mice. EPO treatment in ΔEpoRAdipo and ΔEpoRaP2 mice decreased GTT at 3 months and only in female mice at 4 months that was diminished at 6 months. This demonstrates that with age, adipose tissue response to EPO treatment improves glucose tolerance in a sex dimorphic manner, beginning in male mice at 4 months of age and then in female mice to a lesser extent by 6 months of age. Overall, these findings highlight the potential role of EPO in metabolic regulation beyond erythropoiesis and the contribution of sex and EpoR in adipose tissue in mice to regulate fat mass accumulation and glucose tolerance. Further research into the molecular mechanisms by which EPO signaling influences glucose and lipid metabolism may lead to new therapeutic strategies for the treatment of metabolic disorders such as obesity and type 2 diabetes.

Disclosure
H. Rogers: None. C.T. Noguchi: None.
2063-LB: Transgenic Erythropoietin Overexpression Inhibits Dermal Fat Formation and HIF1a in the Skin and Causes Telogen Effluvium in Mouse Pups during the First Hair Cycle
Authors: YIN WEIQIN , ROGERS HEATHER , AN XIULI , GASSMANN MAX , NOGUCHI CONSTANCE T. 
Published: June 2024

Erythropoietin (EPO) plays an important role in promoting red blood cell production. In non-erythroid tissue, the EPO:EPO receptor (EPOR) interaction might affect fat synthesis and catabolism. Mice with deletion of EPOR in non-erythroid tissue become obese while transgenic mice overexpressing human EPO (Tg6) exhibit reduced body weight and fat mass compared with wild-type controls. How EPO:EPOR affects the synthesis and breakdown of dermal fat in skin, thereby affecting hair growth, is unknown. We verified EPOR expression in the dermal fat by fluorescent staining of skin tissue of EPOR-TdTomato-cre mice. We observed that EPOR knockout in HF stem cells did not affect skin hair growth nor showed significant differences in body weight and fat mass. In contrast, HF development in Tg6 mice was disrupted during the first catagen phase, resulting in formation of epithelium-lined HF cysts, filled with disorganized cysts. Transgenic human EPO in skin tissue was significantly higher than murine EPO during the first degenerative phase of HF development in Tg6 mice. The concomitant decrease in BODIPY positive cells suggested that high expression of transgenic EPO may affect hair growth during the first catagen phase by modulating lipogenesis and lipolysis of dermal fat. We assessed expression of transcription factors associated with EPO expression, HIF1aby Q-PCR. Indeed, increased EPO was accompanied by an increase in HIF1a. We found that EPO overexpression affected lipogenesis and lipolysis of dermal fat and HIF1a expression, disrupted hair growth during the first catagen phase and led to the formation of epithelial-lined HF cysts filled with disorganized keratin that ultimately manifest as truncal alopecia. In summary, we show here for the first time that EPO-HIF1a is essential in hair growth for the normal development and homeostasis of HFs.

Disclosure
W. Yin: None. H. Rogers: None. X. An: None. M. Gassmann: None. C.T. Noguchi: None.
2064-LB: Novel Amylin and Calcitonin Receptor Coagonists Reduce Food Intake and Body Weight in Rodents
Authors: YAGIZ KADER 
Published: June 2024

Amylin analogs have been shown to significantly reduced body weight and dosage of insulin. Dual amylin and calcitonin receptor agonists (DACRAs) are the most potent amylin receptor agonists. We developed a series of novel long-acting amylin agonists to assess the potency on both calcitonin (CTR) and amylin 3 (AMY3) receptor activation on body weight and other metabolic parameters. We report herein the results from an evaluation of these compounds in rodent models.In vitro screening consisted of measurement of ligand-induced β-arrestin recruitment and assessment of cAMP production on human CTR and AMY3 receptors as an indicator of receptor activity, followed by in vivo evaluation. Acute food intake and pharmacokinetic evaluations in lean rats were determined following single subcutaneous administration of selected analogs. Diet-induced obese (DIO) mice were treated with subcutaneous injections of vehicle or one of a series of amylin agonists for 24 days. Cagrilintide was used as positive control. Cohorts were assessed for changes in BW, food intake and other markers.A series of amylin agonists reduced food intake in rats in the range of 56-93%, compared to vehicle, in the period from 0-72 hr post-dose. In comparison, cagrilintide was able to reduce food intake mostly from 0-48 hr and up to 72 hr only at 30 nmol/kg. Durable appetite suppression was further confirmed in a pharmacokinetic study. Treatment with selected novel amylin agonists resulted in reductions to BW in rats up to 10% compared to vehicle. In DIO mice, BW loss effects were comparable to those observed in cagrilintide-treated animals. Improvements in other metabolic markers were also observed.
A novel series of amylin analogs produced significant reductions in BW in rodents, with effect sizes comparable to those observed in an active control group. Dual agonism of CTR and AMY3 receptors represents a promising therapeutic approach to metabolic disorders such as obesity and diabetes. Further evaluation of these compounds is ongoing.

Disclosure
K. Yagiz: None.
2077-LB: Regional Differences in Obesity Awareness, Prevalence, and Management in India
Authors: MAKKAR BRIJ , J ARAVINDA , GUPTA AMIT , JETHWANI PRATAP , AGARWAL SANJAY , KAPOOR NITIN , DESHPANDE NEETA 
Published: June 2024

Introduction & Objective: India is a large country that can be broadly categorized into regions based on geography with diverse lifestyle and cultural habits. The current observational study explores the disparities in the prevalence of metabolic disturbances and the role of lifestyle habits across regions.
Methods: A nationwide survey conducted via social media and awareness events assessed for sociodemographic nuances and health patterns among participants based on their region.
Results: The survey included 60,325 participants distributed between east, E (N=8736), west, W (N=17387), north, N (N=12694), south, S (N=19018) and central, C (N=2282). The majority (40-42%) were between 30-60 years of age in all groups. Overall male-to-female ratio was 1.9 but was a slightly higher in the central (2.18) and Northern (2.03) regions. Higher proportion of master’s degree holders resided in the North (40.4%), Central (38%), East (38%) than other regions (31-33%). Obesity was highest among the central region (67.3%) and lowest in the west (65.2%). The survey underscored regional variations in chronic diseases: Diabetes (E-45.5%, W-51.9%), N-48.1%, S-54.3%, C-53.1%); High BP (E-43.3%, W-41.4%, N-42.3%, S-40%, C-45.9%); high cholesterol (E-27.3%, W-21.7%, N-26.1%, S-22.9%, C-28.2%). South reported the highest prevalence of diabetes (54.3%), and East, the highest prevalence of high blood pressure (45.9%). South had the highest proportion of screentime spent (18% vs 12-15% other regions) and eating out (22.7% vs 13-16% other regions). Respondents from Central (72%) followed by South (57.2%) were inclined to exercise. Higher proportion of respondents from Central (42%) were willing to receive weight loss related information compared to others (14-21%).
Conclusion: This study contributes to a holistic understanding of the complex interplay between geography, sociodemographic, and health behaviours in India.

Disclosure
B. Makkar: None. A. J: None. A. Gupta: None. P. Jethwani: None. S. Agarwal: None. N. Kapoor: None. N. Deshpande: None.
213-OR: Widespread Age-Associated Changes in the Chromatin Architecture of Skeletal Muscle Cell Types
Authors: MOO KEAGAN G. , D'OLIVEIRA ALBANUS RICARDO , VARSHNEY ARUSHI , ORCHARD PETER , MANICKAM NANDINI , LAAKSO MARKKU , TUOMILEHTO JAAKKO , LAKKA TIMO A. , MOHLKE KAREN L. , BOEHNKE MICHAEL , SCOTT LAURA , KOISTINEN HEIKKI A. , COLLINS FRANCIS S. , PARKER STEPHEN 
Published: June 2024

Introduction & Objective: Genome-wide association studies (GWAS) have found &gt;1,000 signals associated with type 2 diabetes (T2D), most of which occur in noncoding genomic regions. T2D risk increases with age, and aging is accompanied by changes in the epigenomic landscape. Together, these findings suggest that age-related epigenomic change may contribute to T2D risk. Here we profile age-associated epigenomic changes in skeletal muscle, a T2D relevant tissue.
Methods: We analyzed single nucleus ATAC-seq data from 284 Finnish skeletal muscle biopsies (donor age 20-79 years; mean = 60) to identify age-associated patterns in chromatin accessibility. We used Type 1, 2a, and 2x muscle fiber, endothelial, and fibro/adipogenic progenitor nuclei for analysis. To find age-associated open chromatin regions (OCRs) without assuming linearity, we used Auto-Regressive Integrated Moving Average (ARIMA) models. We then characterized these OCRs with k-means clustering as well as logistic and linkage disequilibrium score (ldsc) regression enrichment tests.
Results: Across cell types 6.2 - 15.5% of tested OCRs were age-associated (11,925 - 23,143 OCRs). These OCRs clustered into four patterns of age association: linear positive (Up)/negative (Down) and parabolic positive (Valley)/negative (Arch). These patterns showed distinct enrichment in both gene sets, such as the fast to slow fiber transition gene set in arch patterned Type 1 OCRs (FDR = 2x10^-6), and chromatin states, such as active enhancer chromatin in down patterned Type 2a OCRs (nominal p = 2x10^-29). Ldsc analysis found T2D GWAS signal enrichment in Type 2a up patterned OCRs (nominal p = 0.03). Additionally, 12 age-associated OCRs are chromatin accessibility quantitative trait loci that colocalize with T2D GWAS signals.
Conclusion: These results highlight age-associated epigenomic changes and enrichment for T2D GWAS signals in skeletal muscle cell types, providing a basis for research into development and aging in a T2D relevant tissue.

Disclosure
K.G. Moo: None. R. D'Oliveira Albanus: None. A. Varshney: None. P. Orchard: None. N. Manickam: Employee; 10x Genomics. M. Laakso: None. J. Tuomilehto: Stock/Shareholder; Orion Pharma, Aktivolabs, Digostics. T.A. Lakka: None. K.L. Mohlke: None. M. Boehnke: None. L. Scott: None. H.A. Koistinen: Other Relationship; AstraZeneca, Novo Nordisk. F.S. Collins: None. S. Parker: Research Support; Pfizer Inc.
221-OR: Skeletal Muscle Insulin Resistance—The Rate-Limiting Step in Humans Is at the Level of the Vasculature
Authors: VAN RAALTE DANIËL 
Published: June 2024

Type 2 diabetes (T2D) is characterized by impaired insulin-stimulated glucose disposal in skeletal muscle tissue (SKM), called insulin resistance. Insulin facilitates glucose uptake through GLUT4 recruitment following insulin receptor-mediated signal transduction pathways. Insulin also regulates glucose uptake through 1) regulation of arterial blood flow, 2) capillary recruitment and 3) rate of its own transendothelial transport. The rate-limiting step of insulin on SKM glucose uptake in humans is currently unknown.
In a cross-sectional study, 20 people with T2D [age 67±6 years, BMI 30±4 kg/m2, HbA1c 7.6±1.1%] and 20 matched controls (HC) [age 68±7, years, BMI 29±2 kg/m2, HbA1c 5.7±0.7%] underwent a frequently-sampled 75-g oral glucose tolerance test (OGTT) with paired forearm arterial and venous glucose and insulin concentrations to calculate glucose (FEgluc) and insulin (FEins) fractional extraction. Forearm blood flow was measured by Doppler ultrasound.
Area under the glucose curve was increased in T2D vs HC (p&lt;0.01). FEgluc increased from 4±3% to 16±3% in both groups from the fasted state to T=30 min, but was higher in T2D vs HC from min T=60 to T=120 of the OGTT (p&lt;0.001). Fasting FEins was 13±9% for T2D and 14±12% for HC and peaked at T=15 (27±13% for HC and 22±12% for T2D; p=0.16). FEins was similar between groups during the OGTT. FEgluc/FEins, as measure for insulin metabolic effects, was not different between groups. Brachial arterial blood flow was not changed during OGTT.
We show that FEgluc is reduced in T2D vs HC under physiological conditions. As reduced SKM glucose uptake was not driven by changes in insulin uptake into SKM interstitium, the glucose uptake defect is likely secondary to impaired vascular actions of insulin. With arterial blood flow unchanged, we propose that reduced insulin-induced capillary recruitment may be the key defect. Microvascular recruitment measured by contrast-enhanced ultrasound (CEUS) are being analyzed and are available at the ADA.

Disclosure
D. van Raalte: Consultant; Eli Lilly and Company. Research Support; Eli Lilly and Company, Boehringer-Ingelheim. Consultant; Boehringer-Ingelheim. Research Support; Merck & Co., Inc. Advisory Panel; Merck & Co., Inc. Consultant; Bayer Inc.

Funding
MSD (ROCKIES study)
252-OR: Psychosocial Predictors of Diabetes Self-Efficacy in Young Adults with Youth-Onset Type 2 Diabetes
Authors: TRIEF PAULA M. , WEN HUI , ANDERSON-THOMAS BARBARA J. , BURKE BRIAN K. , BULGER JANE D. , WEINSTOCK RUTH S. 
Published: June 2024

Objective: To identify psychosocial predictors of diabetes self-efficacy (DSE) in the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY2) cohort, now young adults with youth-onset type 2 diabetes (T2D).
Methods: In this longitudinal study (T1=baseline, T2=1 year), 348 TODAY2 participants completed measures of: diabetes self-efficacy, beliefs about medicines, depression and anxiety symptoms, diabetes distress, diabetes attitudes, self-management support, and material need insecurities. Multivariable logistic regression models evaluated independent associations of each psychosocial factor with the likelihood of being in the high/low DSE tertile groups at T2; multivariable linear regression assessed associations with T2 DSE as a continuous variable.
Results: Mean (SD) age was 26.0 (2.5) years, 67.9% were women, mean (SD) HbA1c= 9.4 (2.8), with mean (SD) of 2.5 (1.4) complications. Greater self-management support increased the odds of high (vs. low) DSE (OR, 2.23, 95% CI, 1.30-3.83, p=0.004). Greater beliefs that medicines are overused (OR, 0.58, 95% CI, 0.34-0.99, p=0.046), moderate-to-severe depression/anxiety symptoms (OR, 0.30/0.03, 95% CI, 0.09-0.97/0.003-0.34, p=0.045/0.004), food insecurity/healthcare coverage insecurity/≥1/≥2 insecurities decreased the odds of high DSE by 80%/65%/78%/74%; p=&lt;0.0001/0.025/0.001/0.001). More support, fewer depressive and anxiety symptoms, and fewer unmet needs were also predictors of absolute T2 DSE scores.
Conclusions: Cognitions (beliefs that medicines are overused), emotions (depressive/anxiety symptoms), and social factors (self-management support, unmet material needs), were significant longitudinal predictors of DSE in young adults with youth-onset T2D. These potentially modifiable factors should be considered when screening for, and designing, interventions to enhance DSE, to improve health behaviors and forestall the development of complications in this at-risk group.

Disclosure
P.M. Trief: None. H. Wen: None. B.J. Anderson-Thomas: None. B.K. Burke: None. J.D. Bulger: None. R.S. Weinstock: Research Support; Eli Lilly and Company, Tandem Diabetes Care, Inc., Diasome, Amgen Inc., MannKind Corporation, Insulet Corporation, Novo Nordisk. Other Relationship; Dexcom, Inc.

Funding
National Institutes of Health (RO1DK110456, U01-DK61212, U01-DK61230, U01-DK61239, U01-DK61242, and U01-DK61254)