bluuebunny/crossref_metadata_2025_split huggingface dataset:
113-OR: Lipocalin-2, a Mitokine That Mediates White–to–Brown Fat Cross Talk
Authors: WANG FENFEN , HUYNH PHU M. , AN YU 
Published: June 2024

Introduction & Aim: Metabolic dysfunction, exemplified by obesity, often results from dysregulated crosstalk among metabolically active tissues. Brown adipose tissue (BAT) undergoes whitening during obesity, yet understanding the underlying white adipose tissue (WAT) to BAT crosstalk and the factors driving BAT whitening remains a significant gap.
Methods: Using our reported amyloid precursor protein (APP) overexpression-induced mitochondrial distress model in adipocytes (APP AOE), we identified lipocalin-2 (LCN-2) through in vivo, ex vivo, and in silico screenings as a key mitokine mediating the WAT to BAT crosstalk. To further investigate the role of LCN-2, we utilized recombinant LCN-2 protein treatment in vitro and in vivo and generated the adipocyte-specific deletion of Lcn2 mouse model (Lcn2 AKO).
Results: Mitochondrial distressed adipocytes from APP AOE model induced BAT whitening, and white fat pad transplant studies confirmed that stressed WAT alone induces BAT whitening through a putative crosstalk. LCN-2, identified as a potential mitokine through a comprehensive screening (in vivo, ex vivo, and in silico), downregulates BAT browning markers following an LCN-2 recombinant protein treatment. Lcn2 AKO mice on a high-fat diet maintain similar body weights but exhibit elevated mRNA levels of Ucp1 and Pgc1a in BAT, preserving BAT characteristics.
Conclusion: Our project highlights a novel mechanism for white-to-brown fat crosstalk, whereby WAT under mitochondrial stress secretes a mitokine, LCN-2, which mediates the crosstalk from WAT to BAT, leading to BAT whitening. This study further implies LCN-2 as a promising target for preventing BAT whitening and treating obesity.

Disclosure
F. Wang: None. P.M. Huynh: None. Y. An: None.

Funding
This work is supported by National Institutes of Health (NIH) (K01-DK125447, R03-DK135783, and P30-DK056338 (Pilot Award)) to Y.A.A., and American Diabetes Association (ADA) Postdoctoral Fellowship Award (11-23-PDF-23 to F.W.)
1133-P: Value of Dexcom CGM for Therapy Optimization and Glycemic Outcomes in Post-Hospital Discharge Type 2 Diabetes Patients—An Exploratory Study
Authors: CRAWFORD MARGARET A. , HICKS CHRISTIAN , ZHOU TERESA , XU YING , SINGH HARSIMRAN , CHERÑAVVSKY DANIEL R. , LEVISTER CAMILLA , SHAH NIRALI , ROUVIERE MADELEINE , TAMRU ABIGAIL , KAPLAN LEAH , LAM DAVID W. , O'MALLEY GRENYE , LEVY CAROL J. 
Published: June 2024

Post-hospital discharge (PHD) can be a challenging time for health care providers (HCPs) and patients. We analyzed use of Dexcom G6 CGMs in PHD T2D patient management.
This study analyzed 30 days of PHD remote monitoring data for 28 T2D patients. Hospital discharge summaries and telehealth notes were analyzed for details around hospital stay, PHD outcomes, and patient-HCP interactions.
Study sample was categorized into 3 cohorts to reflect disease severity and risk of mortality during hospitalization- Group A (Organ Transplants), Group B (High Severity), Group C (Medium Severity) (Table). Overall, Group B was the youngest (median (IQR): 37 years (37,55)) vs. Groups A & C (54 (47,59) & 55 (50,57)), had the shortest hospital stay (3 days (2,5)) vs. Groups A & C (8 (8,10) & 11 (7,15)) and the shortest diabetes duration (7 years (1,20) vs. Groups A & C (15 (2,27) & 10 (6,17)). Group A had the most telehealth encounters (20 (9,21) vs. Groups B & C (12 (11,15) & 12 (10,13)). Telehealth encounter notes detailed HCP interactions with CGM data including response to Dexcom Follow alerts, insulin titration, and diabetes self-care coaching. Using CGM, groups A & B showed decreased mean glucose and frequency of severe hypo- and hyper-glycemic events over the study period (Table).
These early findings demonstrate the value of CGM to inform critical therapy adjustments for optimizing outcomes during PHD.

Disclosure
M.A. Crawford: Employee; Dexcom, Inc. C. Hicks: Employee; Dexcom, Inc. T. Zhou: None. Y. Xu: Employee; Dexcom, Inc. H. Singh: Employee; Dexcom, Inc. D.R. Cherñavvsky: None. C. Levister: Research Support; Dexcom, Inc., Tandem Diabetes Care, Inc. N. Shah: None. M. Rouviere: None. A. Tamru: None. L. Kaplan: None. D.W. Lam: Research Support; Renalytix. G. O'Malley: Research Support; Dexcom, Inc., Insulet Corporation, Abbott, Tandem Diabetes Care, Inc., MannKind Corporation. C.J. Levy: Research Support; Dexcom, Inc. Consultant; Dexcom, Inc. Research Support; MannKind Corporation, T1D Exchange, Tandem Diabetes Care, Inc., Abbott, Insulet Corporation.
115-OR: Adipose m6A Reader YTHDF2 Regulates White Adipose Tissue Growth and Metabolism
Authors: ZHOU RUOYU , RUI LIANGYOU , KANG QIANQIAN 
Published: June 2024

Introduction & Objective: White adipose tissue (WAT) releases free fatty acids (FFAs) via lipolysis to meet metabolic demand in a negative energy state. Excessive WAT growth imposes risk for type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD), but mechanism for aberrant WAT growth is poorly understood. We previously reported that adipose METTL14, a m6A writer installing m6A methylation on RNA, promotes obesity by suppressing lipolysis. The objective of this work is to identify m6A readers mediating METTL14’s action.
Methods: Adipocyte-specific Ythdf2 knockout mice (Ythdf2Δfat) were generated by crossing Ythdf2f/f with Adipoq-Cre mice and fed high fat diet (HFD) for 12 weeks. Lipolysis assays were performed in mice and in WAT explants. RNA immunoprecipitation was used to assess m6A levels and YTHDF2-binding to RNA.
Results: We found that Ythdf2Δfat mice, both males and females, were resistant to HFD-induced obesity. Fat content was significantly lower in Ythdf2Δfat than in Ythdf2f/f littermates. Ablation of adipose Ythdf2 mitigated insulin resistance and MASLD. β-agonist treatment increased plasma FFAs to a higher level in Ythdf2Δfat than in Ythdf2f/f mice. β-agonists also stimulated lipolysis to a higher level in Ythdf2Δfat WAT ex vivo. Adipose triglyceride lipase (ATGL) and CGI-58 (ATGL cofactor) levels were markedly higher in Ythdf2Δfat than in Ythdf2f/f WAT. YTHDF2 bound to Atgl and Cgi-58 mRNAs, and ablation of METTL14 suppressed YTHDF2 interactions with these transcripts. These results suggest that YTHDF2 binds to m6A-marked transcripts to inhibit ATGL and CGI-58 syntheses, thereby suppressing lipolysis.
Conclusion: Our results unveil YTHDF2-based epitranscriptomic reprogramming that governs lipolysis and WAT growth.

Disclosure
R. Zhou: None. L. Rui: None. Q. Kang: None.

Funding
National Institutes of Health (R01DK130111)
1152-P: Treatment Trends in Youth-Onset Type 2 Diabetes—Changing Landscape after GLP-1RA Approval
Authors: SHIN HOJIN , PAIK JULIE M. , WEXLER DEBORAH J. , PATORNO ELISABETTA 
Published: June 2024

Introduction: The approval of glucagon-like peptide-1 receptor agonists (GLP-1RA), starting with liraglutide in 2019, has expanded treatment options in youth-onset type 2 diabetes (T2D). However, the uptake of GLP-1RA in this population is unknown.
Methods: In two US commercial claims databases (Optum and MarketScan), we identified individuals aged &lt;30 years with T2D who initiated first-line glucose-lowering drugs between 2010 (aligning with the US market entry of liraglutide) and 2023. We examined first-line use by plotting annual trends overall and within age subgroups (≤18, 19-25, 26-29 years) and escalation patterns using Sankey diagrams, comparing the periods before (2010-2018) and after (2019-2023) the 2019 approval of GLP-1RA in youth.
Results: Metformin was the most commonly initiated first-line agent (overall: 71.1%), followed by insulin (overall: 9.4%, ≤18 years: 18.8%) (Figure A). The use of GLP-1RA increased considerably (from 2.9% in 2019 to 12.6% in 2023), yet it remained low overall. This trend was consistent across all age groups. With respect to escalation patterns (Figure B), sulfonylureas and insulin were most frequently prescribed after metformin failure in 2010-2018, whereas GLP-1RA were the most frequently prescribed after metformin in 2019-2023.
Conclusion: In youth-onset T2D, the use of GLP-1RA as first-line and subsequent therapies has increased but remains overall low.

Disclosure
H. Shin: None. J.M. Paik: None. D.J. Wexler: Other Relationship; Novo Nordisk. E. Patorno: Research Support; Boehringer-Ingelheim, Food and Drug Administration (FDA), National Institutes of Health, Patient-Centered Outcomes Research Institute.
116-OR: GL0034 (Utreglutide), a Novel GLP-1RA, Increases Liver FGF-21 and Demonstrates Significant Efficacy on Weight Loss, HbA1c, and Triglycerides in db/db Mice
Authors: THENNATI RAJAMANNAR , BURADE VINOD S. , NATARAJAN MUTHUKUMARAN , GARCIA-OCANA ADOLFO , RUTTER GUY A. , PRATLEY RICHARD E. , THORENS BERNARD , VILSBØLL TINA 
Published: June 2024

Introduction & Objective: Glucagon-like peptide receptor agonists (GLP-1RA) stimulate fibroblast growth factor (FGF-21) production and both have overlapping metabolic effects like glycemic control, suppression of food consumption, and body weight reduction. GL0034 has demonstrated excellent safety and tolerability in phase 1 trials. Further, a single dose of subcutaneous administration of GL0034 in individuals with obesity resulted in 3.3 kg of weight loss that was sustained till day 22
Methods: We explored a fixed dose (21nM/kg) of GL0034, semaglutide (Sema) and tirzepatide (TZP) given to db/db mice every third day for 4 weeks. Biomarkers were measured on days 14 and 28.
Results: GL0034 increased liver FGF-21 and, uncoupling protein-1 (UCP-1) in brown and white adipose tissues significantly more than Sema and similarly to TZP. The effects of GL0034 on HbA1c (↓), insulin (↑), glucagon (↓), weight loss (↑), triglycerides (↓), and cholesterol (↓) were similar to those induced by Sema and TZP. Food consumption was similar to TZP and lower than with Sema (Table).
Conclusion: In conclusion, GL0034 shows robust efficacy on multiple metabolic parameters and may serve as a promising new super GLP-1RA for individuals with obesity +/- type 2 diabetes and for the treatment of MASLD with enhanced therapeutic benefits partly due to increased liver FGF-21.

Disclosure
R. Thennati: None. V.S. Burade: None. M. Natarajan: None. A. Garcia-Ocana: Consultant; Sun Pharmaceutical Industries Ltd. G.A. Rutter: Advisory Panel; Sun Pharmaceutical Industries Ltd. R.E. Pratley: Other Relationship; Bayer AG, Dompé, Endogenex, Inc., Gasherbrum Bio, Inc., Hengrui (USA) Ltd., Intas Pharmaceuticals Ltd., Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk, Novo Nordisk, Pfizer Inc., Rivus Pharmaceuticals Inc., Sun Pharmaceutical Industries Ltd. Consultant; AbbVie Inc., AstraZeneca. Other Relationship; Bayer HealthCare Pharmaceuticals, Inc., Biomea Fusion, Carmot Therapeutics, Inc., Corcept Therapeutics, Fractyl Health, Inc., Genprex. Consultant; Getz Pharma. Other Relationship; Lilly USA LLC, Sanofi. Consultant; Scholar Rock, Inc. B. Thorens: Advisory Panel; Sun Pharmaceutical Industries Ltd. T. Vilsbøll: Consultant; AstraZeneca. Advisory Panel; Boehringer-Ingelheim. Speaker's Bureau; Mundipharma. Advisory Panel; Novo Nordisk, Lilly Diabetes, Sanofi. Speaker's Bureau; Bayer Inc., Gilead Sciences, Inc. Advisory Panel; Sun Pharmaceutical Industries Ltd. Research Support; Lilly Diabetes.
117-OR: Effects of Triple-Hormone Receptor Agonist Retatrutide on Lipid Profiling in Participants with Obesity
Authors: PIRRO VALENTINA , PEARSON MACKENZIE J. , LIN YANZHU , HARTMAN MARK L. , ROTH KENNETH D. , DUFFIN KEVIN L. , WILLENCY JILL , HAUPT AXEL , RUOTOLO GIACOMO 
Published: June 2024

In phase 2 (n=338), retatrutide (RETA), an agonist of GIP, GLP-1 and glucagon receptors, reduced body weight, fasting glucose, triglycerides (TG), LDL and VLDL cholesterol in participants with obesity. To understand changes in energy metabolism, lipidomic profiling was conducted. Adult participants with obesity (BMI ≥30 kg/m2), or overweight (BMI ≥ 27 kg/m2) with a weight related comorbidity, were randomized to RETA 1, 4, 8, 12 mg or PBO for 48 wk. Fasting plasma collected at baseline, 24 and 48 wk, was used to measure acylcarnitines and complex lipid species using targeted mass spectrometry. Data were analyzed using a mixed model for repeated measures. An increase in 3-hydroxybutyrate (3-HB) was noted after 24 wk, accompanied by an increase in 3-hydroxybutyrylcarnitine (C4OH), acetylcarnitine-to-free carnitine ratio (C2/C0), and medium-chain ACs. The decrease of TGs at 48 wk was bias towards short-chain and saturated species. RETA 12 mg decreased total dihydroceramides (DhCers) at 48 wk by −20.1%, p-value &lt;0.001. The increase in ketone body and C2/C0 observed after 24 wk is suggestive of adipose tissue lipolysis and reliance on fat oxidation. Inverse changes in TGs and DhCers were observed which associate with improved insulin sensitivity, reduced hepatic steatosis and systemic inflammation. Evaluation of potential benefits on cardiovascular events and MASLD may merit further investigation.

Disclosure
V. Pirro: Employee; Eli Lilly and Company. M.J. Pearson: Employee; Eli Lilly and Company. Y. Lin: Stock/Shareholder; Eli Lilly and Company, Pfizer Inc., AstraZeneca. M.L. Hartman: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. K.D. Roth: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. K.L. Duffin: Employee; Eli Lilly and Company. J. Willency: Employee; Eli Lilly and Company. A. Haupt: Employee; Lilly Diabetes. Stock/Shareholder; Lilly Diabetes. G. Ruotolo: None.

Funding
Eli Lilly and Company
1171-P: Cytokines Do Not Consistently Change Proinsulin (PI) Cargo in Global Human Islet-Derived Extracellular Vesicle (EV) Populations
Authors: DE OLIVEIRA ANDRE G. , XU JERRY , SIMS EMILY K. , RAO CHAITRA 
Published: June 2024

Introduction and Objective: Multiple factors may trigger or exacerbate progression of Type 1 diabetes (T1D). EVs, nanoparticles housing molecular cargo, have been implicated in many diseases, including diabetes. β-cell EVs can present antigens and carry PI as cargo. Cytokine exposure leads to β-cell ER stress, reduces PI processing enzyme expression, and increases PI secretion relative to insulin or C-peptide. Cytokine-induced stress is also associated with changes in EV cargo, as well as intracellular formation of immunogenic peptides, including modified PI. We sought to understand if β-cell EV PI cargo might be changed under cytokine exposure.
Methods: INS1 or EndoC-βH1 cells and human islets were treated with 5 ng/mL IL-1β, or IL-1β + 100 ng/mL IFNγ + 10 ng/mL TNFα, for 48 hrs. Plasma (450 µL) from five children with recent onset type 1 diabetes and age, sex, and BMI-matched nondiabetic controls was also assayed. EVs were isolated by ultracentrifugation (30000 x g, 1.5 hrs) or size exclusion chromatography. EV proteins were precipitated by the TCA-acetone method and PI was quantified by immunoblotting or ELISA for human samples.
Results: Cytokine treatment did not consistently change EV concentration or EV PI cargo in INS1, EndoC-βH1, or islet-derived EVs. Tunicamycin, but not thapsigargin treatment of cells yielded an increase in EV PI content, suggesting a potential link to protein trafficking rather than ER stress. EV PI content in human plasma was frequently undetectable, and when detectable, was not significantly different in plasma from children with T1D vs. controls.
Conclusion: Global changes in human islet EV PI cargo were not detected under conditions of cytokine stress or recent onset T1D. These findings point away from EV-derived PI as a large-scale or frequent contributor to the development of neoantigens in T1D.

Disclosure
A.G. De Oliveira: None. J. Xu: None. E.K. Sims: Consultant; Sanofi. Board Member; American Diabetes Association. Other Relationship; American Diabetes Association, Medscape. Consultant; DRI. C. Rao: None.
1177-P: Practice Patterns of Medical Management of Pediatric Obesity and Type 1 Diabetes (T1D)
Authors: DOOLAN JADE , ISGANAITIS ELVIRA M. , LAFFEL LORI M. , MAXWELL TARA K. 
Published: June 2024

Aim: Recent pediatric guidelines emphasize the need for aggressive treatment of childhood obesity, including use of recently approved pediatric weight loss medications like glucagon-like peptide receptor agonists (GLP1-RA), in order to preserve health. Given additional health risks related to T1D, we sought to assess practice patterns of obesity pharmacotherapy in a clinic sample of adolescents with T1D.
Methods: We extracted electronic health record (EHR) data from 12/1/17-12/1/23 of obese (BMI ≥95th %ile) youth with T1D aged 12 to &lt;18 years prescribed ≥1 of FDA-approved pediatric weight loss (liraglutide, semaglutide, topiramate/phentermine, and orlistat) and type 2 diabetes (metformin and dulaglutide) medications.
Results: From 6 years of clinical observations, there were 540 unique adolescents with T1D aged 12-&lt;18 years. Of these, 124 (23%) were obese. We identified 41 adolescents (63% female) with obesity prescribed ≥1 of the listed medications. Mean age at medication initiation was 14.6±2.2 years, and 46% saw a registered dietitian within a year before medication initiation. Metformin alone was prescribed for 33 youth and GLP1-RA for 8 adolescents (2 started directly on GLP1-RA; remaining 6 prescribed metformin first). All GLP1-RA were started after 2020 FDA approval for pediatric obesity treatment. No adolescents were prescribed topiramate/phentermine or orlistat. Of those with complete BMI data, those on metformin alone (29/33) had stable mean BMI percentile at up to 1 year follow-up, while those on GLP1-RA (6/8) experienced a small reduction in mean BMI percentile.
Conclusion: In this clinic sample, nearly 1 in 4 adolescents with T1D were obese. Despite recent FDA approval of new weight loss medications for children and adolescents, few were prescribed GLP1-RA. Further research is needed to understand patient/family and provider perspectives on these medications and their potential benefits for young people with T1D.

Disclosure
J. Doolan: None. E.M. Isganaitis: Research Support; Dexcom, Inc., Tandem Diabetes Care, Inc., Insulet Corporation, MannKind Corporation. L.M. Laffel: Consultant; Dexcom, Inc. Advisory Panel; Medscape, Medtronic, Vertex Pharmaceuticals Incorporated. Consultant; Novo Nordisk. Advisory Panel; Lilly Diabetes, Provention Bio, Inc., Sanofi-Aventis U.S., Janssen Pharmaceuticals, Inc., MannKind Corporation. T.K. Maxwell: None.
1189-P: Challenges Recruiting Adolescents and Young Adults (AYA) with Type 1 Diabetes and Higher A1Cs for Clinical Research
Authors: VOLKENING LISA K. , MORRISSEY BRENDEN , ALAMARIE SELMA A. , HERNDON CHRISTOPHER , SCHNEIDER-UTAKA AIKA K. , ADAM ATIF , HANES SARAH , OJUKWU SANDO , HOOD KOREY K. , LAFFEL LORI M. 
Published: June 2024

Introduction: Recruiting a representative study sample is critical but can be challenging. We assessed potential differences between AYA with T1D who consented vs declined to participate in a 2-year RCT aimed at improving glycemic outcomes and reducing diabetes distress.
Methods: AYA were recruited at 2 US sites for a study involving monthly virtual 1-1 psychoeducational sessions. Eligibility criteria included age 14-25 years, T1D ≥1 year, and A1c 7-13%.
Results: Over 15 months, we approached 482 potential participants; 217 (45%) consented, 232 (48%) declined, and 33 (7%) were ineligible. Most AYA were identified via clinic schedules (77%). Other recruitment methods were: participation in a previous study (14%), recruitment flyer (5%), provider referral (4%), and social media (1%). Reasons for decline were: too busy/not a good time (n=41, 18%), not interested (n=29, 13%), other/no reason given (n=7, 3%), and passive decline (expressed interest but no decision before enrollment closed) (n=155, 67%). There was no difference in the number of contacts made to those who consented vs declined (median=2 for both, range=1-8). Limited demographic data at 1 site for 217 potential participants (105 consented, 112 declined) showed no difference in % consented according to age (14-18 years: 46% consented; 19-25: 50% consented; p=.58) or SES using Social Deprivation Index (higher SES: 47% consented; lower SES: 51% consented; p=.49). However, there was a difference by A1c (7-8.4%: 59% consented; 8.5-13%: 39% consented; p=.002). Further, 65% of those with A1c 8.5-13% who declined were passive declines (compared to 51% of decliners with A1c 7-8.4%), suggesting that they had some interest but no follow-through. Number of contacts did not differ by age, SES, or A1c.
Conclusion: AYA with suboptimal glycemic control, often the target of research, may hesitate to participate in clinical trials. Creative outreach and extra effort (e.g., more contacts) may help to recruit them for future studies.

Disclosure
L.K. Volkening: None. B. Morrissey: None. S.A. Alamarie: None. C. Herndon: None. A.K. Schneider-Utaka: None. A. Adam: None. S. Hanes: None. S. Ojukwu: None. K.K. Hood: Consultant; Cecelia Health, Sanofi. L.M. Laffel: Consultant; Dexcom, Inc. Advisory Panel; Medscape, Medtronic, Vertex Pharmaceuticals Incorporated. Consultant; Novo Nordisk. Advisory Panel; Lilly Diabetes, Provention Bio, Inc., Sanofi-Aventis U.S., Janssen Pharmaceuticals, Inc., MannKind Corporation.

Funding
National Institutes of Health (R01DK129479)
1198-P: Sex Differences in Chinese Adult-Onset Type 1 Diabetes
Authors: CHEN SHUANG , GU YONG 
Published: June 2024

Introduction & Objective: Growing evidence on the heterogeneity of type 1 diabetes (T1D) has been accumulated, there is still insufficient evidence to explore sex differences, particularly in adults with T1D. The study was to explore the sex differences among adult patients with autoimmune diabetes, focusing on the clinical characteristics, autoantibody profile, and β-cell secretion.
Methods: Clinical characteristics, islet autoantibody profile, and β cell function were assessed by sex in 191 adults with T1D between Jan 2015 to Nov 2022. Subgroup analysis was conducted in different age groups according to the age of diagnosis.
Results: Women had a higher median age at diagnosis than men (51.0 vs. 38.0 years, P=0.008) and were more likely to be positive for multi-autoantibodies (54.2% vs. 39.8%, age-adjusted odds ratio [OR] 2.21 [95% confidence interval (CI) 1.20, 4.09], P=0.011), GADA (age-adjusted OR 5.62 [1.68, 18.86], P=0.005) and IA2A (age-adjusted OR 2.16 [1.18, 3.94], P=0.012). Moreover, women were at a higher risk of experiencing a decline in fasting C-peptide to 30% from baseline (age-adjusted OR 6.97 [1.88, 25.83], P=0.004). Subgroup analysis were shown in the following figure.
Conclusion: Analyzing the sex disparities of T1D provides new insight into the heterogeneity of this disease, and demands further investigation for understanding biological mechanisms, hence guiding personalized diagnosis and management for this disease.

Disclosure
S. Chen: None. Y. Gu: None.

Funding
the National Natural Science Foundation of China (82170837, 81770777, 82230028); Jiangsu Provincial Medical Key Discipline (Laboratory)+ZDXK202202.