bluuebunny/crossref_metadata_2025_split huggingface dataset:
2002-LB: New Model for Type 1 Diabetes Differential Screening
Authors: MENDIZABAL LEIRE , SASO-JIMÉNEZ LAURA , APAOLAZA NAIARA , MARTÍNEZ ROSA , ZULUETA MIRELLA , URRUTIA INÉS M. , SIMON LAUREANO , CASTANO LUIS 
Published: June 2024

Introduction & Objective: Determining whether a patient has type 1 (T1D), type 2 (T2D) or monogenic diabetes is an important diagnostic and therapeutic concern. Recent successes in T1D disease-modifying therapies to impact the course of early-stage T1D have ignited the consideration of the need for and feasibility of population screening to identify those at increased risk of T1D. Our objective was to develop a non-invasive method for early differential screening of individuals with increased susceptibility to T1D based on a Polygenic Risk Score (PRS).
Methods: We analyzed a retrospective cohort of 1,911 individuals (475 controls, 486 T1D, 464 T2D, 486 MODY) from Hospital Cruces (Bilbao, Spain). Training (70%) and validation (30%) sets were established. A total of 306 SNPs were selected after exhaustive exploration of databases published to date of SNPs associated with T1D and T2D. Chi square test and Pearson correlation analysis preceded development of a multinomial logistic regression model and a combination of binomial models. Models’ performance was assessed by receiver operating characteristic (ROC) curve in training and validation data sets.
Results: We developed a Multinomial PRS Model that differentially discerns T1D susceptibility from susceptibility to other diabetes types and controls with an AUC of 0.87, 81% sensitivity and 83% specificity.
Conclusions: This new tool for T1D differential screening shows the possibility to discriminate susceptibility to T1D versus no susceptibility and susceptibility to other diabetes types. It may aid in management of clinical and population strategies to best assist those at increased T1D susceptibility.

Disclosure
L. Saso-Jiménez: None. N. Apaolaza: None. R. Martínez: None. M. Zulueta: None. L. Simon: None.

Funding
This study was supported by grants from the Department of Health of the Basque Government (GV2019111064) and the University of the Basque Country UPV/EHU (IT1739-22). Laura Saso is the recipient of a predoctoral grant from the Education Department of Basque Government (PRE_2023_2_0084).
2037-LB: Fumarate Hydrataseorchestrates Hepatic Steatosis via ULK1-Mediated Lipophagy
Authors: JIANG HAOWEN 
Published: June 2024

Hepatic lipid homeostasis is coordinated by various metabolic pathways, such as lipogenesis, lipid uptake, storage, and oxidation. However, the underlying mechanism that orchestrates metabolic crosstalk remains unclarified. Herein, we demonstrated that fumarate hydratase (FH) functioned as an indispensable adaptor governing mitochondria metabolism and lipid droplets (LDs) degradation. Hepatic FH overexpression prevented hepatic steatosis in normal mice and ob/ob mice without interfering mitochondrial lipid oxidation and lipogenesis. Strikingly, we found that FH selectively activated lipophagy-mediated LDs lipidolysis. Mechanistically, FH interacted with ULK1 and stabilized ULK1 through preventing its ubiquitination and degradation, resulting in lipophagy activation and the elimination of hepatic lipid accumulation. Meanwhile, hepatic ULK1 deficiency abrogated the protective effects in FH-overexpressing mice. Also, we clarified that the interaction between FH and ULK1 occurred in cytoplasm, but not in mitochondria. Cytoplasmic FH was sensitive to lipids and downregulated without affecting mitochondrial FH in vivo. Moreover, the FH-ULK1 axis was identified closely associated with hepatic steatosis in human patients. Taken together, our research demonstrates a “two-side” insight of FH on hepatic lipid metabolism and provides a promising strategy for fatty liver treatment.

Disclosure
H. Jiang: None.

Funding
This work was supported by grants from the National Natural Science Foundation of China grants (82273983, 82130099, and 92253306), National Key R&D Program of China (2022YFA1303800), Science and Technology Commission of Shanghai Municipality (23ZR1474700).
205-OR: Association of Geographic Factors with Use of Metabolic Disease Specialty Care among Adults with Type 2 Diabetes and ASCVD
Authors: BAUER JESSICA , ROTHENBERGER SCOTT D. , JOHNSON AMBER E. , ROSLAND ANN-MARIE , KINNEE ELLEN , ZUPA MARGARET 
Published: June 2024

Metabolic disease specialty care (endocrinology or cardiology) for T2D and ASCVD may improve quality of care and clinical outcomes. However, little is known about the associations of patient demographics and geographic, transportation, and technological barriers with use of specialty care.
In this retrospective cohort study, we linked geospatial and patient-level data for adults with T2D and ASCVD who had ongoing primary care in a large health system from 1/2018 to 6/2022. Patients were mapped to their residential ZIP Code centroids. Multivariate logistic regression assessed associations between baseline community predictors (public transit access, walkability, cellular data access) which were converted to within-cohort percentile rank, and patient predictors (distance from specialty clinic, demographics) with any specialty care visit.
Our cohort included 9,546 adults: 89% white, 83% urban residents. Greater neighborhood walkability was associated with increased specialty care use (AOR = 1.08, 95% CI (1.05-1.11) per 10th percentile increase, p&lt;0.001), while higher public transit stop density was associated with decreased use (AOR = 0.84 (0.72 - 0.98) 4th vs 1st quartile, p&lt;0.001). Increased access to cellular data was associated with increased use (AOR=1.06 (1.03-1.09) per 10th percentile, p&lt;0.001). Distance to nearest clinic of either specialty was not significantly associated with overall care use (endocrinology AOR=0.986 (0.97 - 1.01) per 10 miles; cardiology AOR=1.01 (0.99-1.03)). Age (AOR 0.87 (0.84-0.91) per 10 years, p&lt;0.001), race (AOR 0.78 (0.66-0.91) for Black vs white, p&lt;0.001), and local area deprivation (AOR 0.94 (0.90-0.97) per 10th percentile, p&lt;0.001) were associated with less specialty care use.
Community and patient factors are independently associated with use of specialty care for adults with T2D and ASCVD. Differential utilization of specialty care may contribute to disparities in health outcomes for under-resourced populations.

Disclosure
J. Bauer: None. S.D. Rothenberger: None. A.E. Johnson: Speaker's Bureau; Sanofi. Consultant; Edwards Lifesciences. Other Relationship; Women As One. A. Rosland: None. E. Kinnee: None. M. Zupa: None.

Funding
University of Pittsburgh CTSI Exploring Existing Data Resources Pilot Award; National Center for Advancing Translational Sciences KL2-TR001856
2054-LB: Mitigating Adipose Tissue Dysfunction and Insulin Resistance in Obesity via SVEP1 Peptide-Mediated Suppression of Adipose Tissue Macrophage-Induced Inflammation
Authors: KISLEV NADAV , KAVIN NACHUM , IZGILOV ROZA , BENAYAHU DAFNA 
Published: June 2024

Introduction: Adipose tissue dysfunction in obesity poses a critical threat, causing metabolic impairment and systemic inflammation. This study explores the therapeutic potential of a peptide from SVEP1, targeting its integrin α9β1 receptor, to alleviate obesity-induced adipose dysfunction and insulin resistance by reducing pro-inflammatory macrophage activity.
Methods: We comprehensively examined the peptide's effect on adipose tissue dysfunction using in silico predictive binding, LPS-activated mono and co-culture cell systems, and diet-induced obese mice.
Results: Analysis of integrin α9β1 revealed specific expression in myeloid cells, particularly dysfunctional adipose tissue macrophages. In silico predictions confirmed the peptide's integrin affinity and ability to block ligand interactions. Peptide-treated LPS-activated BMDM exhibited reduced adhesion and mobility on decellularized matrices from adipocytes. The peptide suppressed pro-inflammatory activation, by inhibiting the MAPK and NF-κB pathways, altered transcriptomics, and reduced cytokine production in ex vivo isolated adipose tissue macrophages. Epididymal adipose tissue peptide administration in diet-induced obese mice reduced body and tissue weight, improved glucose sensitivity, hepatic function, and lessened adipose inflammation through modulated macrophage phenotype. Bulk and single-cell transcriptomics indicated decreased pro-inflammatory responses, improving adipocyte status, insulin sensitivity, and thermogenic capacity due to the anti-inflammatory state of tissue macrophages and upregulated mitochondrial activity.
Conclusions: The SVEP1-derived peptide emerges as a regulator of macrophages in obesity, effectively mitigating inflammation and restoring glucose homeostasis. This study offers insights into potential therapeutic avenues for addressing adipose tissue dysfunction.

Disclosure
N. Kislev: None. N. Kavin: None. R. Izgilov: None. D. Benayahu: None.
2072-LB: Effect of 5:2 Fasting Diet on Liver Fat Content in Patients with Type 2 Diabetic with Nonalcoholic Fatty Liver Disease
Authors: YAN XIN XIAO 
Published: June 2024

Background: The prevalence of nonalcoholic fatty liver disease (NAFLD) is rapidly growing in China, especially in patients with type 2 diabetes mellitus (T2DM). Weight loss strategies have been shown to treat NAFLD effectively. We conducted a 24-week, prospective, randomized study in T2DM patients with NAFLD to evaluate the effects of 5:2 fasting diet on liver fat content.
Methods: In total, sixty-one T2DM patients with NAFLD were enrolled and randomly divided into a intervention group (5:2 diet group, n=31) and 1.8mg/day liraglutide intervention group (Lira group, n=30). Data of the body weight, waist circumference, plasma lipids and glucose profile, fasting plasma insulin, and liver function parameters were collected. Controlled attenuation parameter (CAP) was measured to assess the liver fat content. Superoxide dismutase (SOD) and malondialdehyde (MDA) were measured to evaluate oxidative stress status.
Results: At 24 weeks after intervention, compared to those at baseline, CAP was significantly decreased in both 5:2 diet group and Lira group, which was 7.4% and 5.5%, respectively. Body weight, plasma lipids and glucose profile, and liver function parameters improved significantly, while homeostasis model assessment-β (HOMA-β) was significantly increased in both groups (all P&lt;0.05). Stepwise linear regression showed that increased HOMA-β and SOD, as well as reduced body mass index (BMI), were the independent predictors of CAP decrease in Lira group (P=0.000, 0.000, 0.015). In contrast, reduced BMI and MDA were the independent influencing factors of CAP decrease in 5:2 diet group (P=0.011, 0.043). The common side effects in 5:2 diet group were hunger (60%), weakness (10%) and constipation (0.3%).
Conclusions: A 5:2 fasting diet achieved comparable effects with liraglutide on liver fat content in patients with T2DM with NAFLD by reducing BMI and the oxidative stress. Both treatment strategies were safe and effective for glucose control.

Disclosure
X. Yan Xin: None.
2076-LB: Physician Views on Management of Patients with Both Obesity and Type 2 Diabetes (PwOT2D) in the U.S. and Germany
Authors: TAN MICHELLE S.F. , LOGENDRA RAMYA , CORTESE ROBERTO , SCHMUECKING RHODA 
Published: June 2024

Obesity is a key risk factor for developing type 2 diabetes (T2D) and treating obesity is central to its management. In our study, we aimed to understand how anti-obesity medications (AOMs) impact US and German healthcare professionals’ (HCPs) views on managing patients with both obesity and Type 2 Diabetes (PwOT2D).
Data are from an online medical chart review study conducted among 141 primary care physicians (PCPs) and 128 endocrinologists treating PwOT2D in the US and Germany from Oct-Dec 2023. Physicians were screened for caseload.
A significantly higher percentage (p&lt;0.01) of sampled US endocrinologists (66%, n=79) and PCPs (58%, n=71) reported higher agreement to ‘I proactively prescribe weight-loss strategies to prevent weight-related comorbidities’ compared to the German endocrinologists (29%, n=49) and PCPs (30%, n=70) [‘higher agreement’ based on top 2 box (6-7) of 7-point scale, where 7=completely agree]. A significantly higher percentage (p&lt;0.01) of the US endocrinologists (62%) and PCPs (51%) also agreed (same scale) that ‘AOMs are top-of-mind when managing PwO with weight-related complications’ compared to the German endocrinologists (20%) and PCPs (24%). This aligns with our findings on HCP management of PwO, whereby 81% of sampled German HCPs would recommend lifestyle changes (versus 51% of US HCPs) and only 37% would prescribe AOMs (versus 56% of US HCPs). When specifically asked about treatment strategies for PwOT2D, 45% of the German endocrinologists would prioritize treating T2D over obesity; this is notably higher than the US sample (15%), where instead 80% of this cohort would choose to treat both conditions together.
In this study, there are significant differences in the cited approach to managing obesity and related comorbidities such as T2D between sampled German and US HCPs. US HCPs are more likely to prescribe AOMs for weight loss, but also consider their impact on other weight related comorbidities when doing so compared to German HCPs.

Disclosure
R. Logendra: None. R. Cortese: None. R. Schmuecking: None.
2084-LB: Real-World Effectiveness of Tirzepatide among People with Obesity or Overweight without Type 2 Diabetes (T2D)
Authors: HANKOSKY EMILY R. , DESAI KARISHMA , CHINTHAMMIT CHANADDA , GRABNER MICHAEL , STOCKBOWER GRACE , HE XUANYAO , MOJDAMI DONNA , WENZIGER CACHET , HUNTER GIBBLE THERESA 
Published: June 2024

Introduction & Objective: Tirzepatide is a once weekly GIP and GLP-1 receptor agonist approved in the US for treatment of T2D (May 2022) and obesity (Nov 2023). We assessed real-world patient characteristics and effectiveness in people with obesity or overweight without T2D.
Methods: This retrospective study was conducted using the Healthcare Integrated Research Database (HIRD®). Date of first tirzepatide claim (index date; NDCs for Mounjaro®) was between May 13, 2022 - June 30, 2023. Because tirzepatide was only approved for the treatment of T2D during the index period, any use of tirzepatide by individuals without T2D during this time was off-label and solely at the discretion of their prescribing physician. Demographic and clinical characteristics were assessed among adults (≥18 years) without T2D diagnostic codes or treatment, but eligible for anti-obesity medication (AOM; BMI ≥30 kg/m2; or BMI ≥27 kg/m2 with ≥1 obesity-related comorbidity; ORC). Weight changes were assessed among individuals with ≥6 months tirzepatide persistence (&lt;60-day gap) and weight data at baseline and 6-months post-index.
Results: Among the 699 AOM-eligible adults without TD2 diagnostic codes who filled a prescription for tirzepatide, most were female (77.1%), White (81.1%), mean age 47.2 years, mean BMI 38.3 kg/m2, mean weight 109.3 kg (241.0 lbs), and of those with a 6th prescription fill (n=405), 44.4% was for ≥10 mg. At least one ORC was reported in 86.4% of patients. Hypertension (44.5%), dyslipidemia (43.6%), and anxiety (35.8%) were the most common ORCs. Of the 68.8% (n=481) who were persistent for ≥6 months, weight data were available at baseline and 6-months post-index for n=199; 88.4% had ≥5%, 68.8% had ≥10%, and 36.7% had ≥15% weight reduction at 6-months post-index. The average weight reduction was 12.7% (14.1 kg [31.1 lbs]).
Conclusion: At 6-months, most users of tirzepatide without T2D diagnostic codes were persistent and lost ≥10% body weight with an average body weight loss of 12.7%.

Disclosure
E.R. Hankosky: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. K. Desai: Employee; Carelon Research. Stock/Shareholder; Anthem, Inc. C. Chinthammit: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. M. Grabner: Employee; Carelon Research. Stock/Shareholder; Anthem, Inc. G. Stockbower: None. X. He: Employee; Eli Lilly and Company. D. Mojdami: Employee; Eli Lilly and Company. C. wenziger: None. T. Gibble: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company.
2089-LB: An Adult Clock Component Links Circadian Rhythms to Pancreatic ß-Cell Maturation
Authors: ALVAREZ JUAN R. 
Published: June 2024

Pancreatic β cell clocks attune insulin secretion to daily energy cycles, and desynchrony from genetic or behavioral disruptions triggers metabolic dysfunction, fueling type 2 diabetes risk. How ubiquitous circadian clocks orchestrate β cell-specific outputs, however, is not well understood. In particular, major questions remain as to how core vs. ancillary clock components synchronize β cell genes to coordinate overall metabolism.
To dissect the control of metabolism by state specific clock components, we studied DEC1, as it partakes in the transcriptional regulatory circuit defining mature β-cell identity. We show that DEC1 is specifically induced in adult β cells, and coordinates their glucose responsiveness by synchronizing energy metabolism and secretory gene oscillations. Dec1-ablated mice develop lifelong hypo-insulinemic diabetes, despite normal islet formation and intact circadian Clock and Bmal1 activators. Dec1-/- mice show normal food intake and patterns of activity and energy expenditure, with delayed phase onset but sustained period length. Yet, Dec1-/- mice show low energy expenditure during the active phase, consistent with a hypometabolic state. DEC1, but not CLOCK/BMAL1, binds maturity-linked genes that mediate respiratory metabolism and insulin exocytosis, and Dec1 loss disrupts their transcription synchrony. Accordingly, β-cell Dec1 ablation causes hypo-insulinemia due to poor insulin responses to glucose, as with immature fetal/neonatal islets. Thus, DEC1 links circadian clockwork to the β-cell maturation process, aligning metabolism to diurnal energy cycles.
These findings show that synchrony of energy metabolism pathways by adult-specific clockwork is critical for physiological coordination of metabolism. As clocks are activated in metabolic tissues during onset of feeding-fasting rhythms, an intriguing possibility is that they unlock phenotypic maturity by optimizing specialized cellular tasks to daily cycles in energy availability.

Disclosure
J.R. Alvarez: None.
2091-LB: Viral Infection Drives Aberrant Pancreatic Beta-Cell Bioenergetics and Autophagy via a Candidate Type 1 Diabetes Gene PGM1
Authors: MILLER YI , QIU YUNPING , SUN YAN , JANKAUSKAS STANISLOVAS S. , KULKARNI RUCHA J. , SIDOLI SIMONE , KURLAND IRWIN J. , TOMER YARON 
Published: June 2024

Introduction & Objective: Viral infection is one of the major environmental factors in Type 1 Diabetes (T1D). PGM1 is a T1D GWAS gene encoding phosphoglucomutase 1, which bidirectionally converts G6P to G1P. PGM1 resides at the junction between many arms of metabolic pathways. Our previous study suggests that PGM1 is potentially causal to T1D via epigenetic changes driven by genetic / environmental factors. We hypothesised that PGM1 is a crucial regulator of beta cell metabolism in response to viral infection.
Methods: Purified human islets, EndoC-BH1, and INS-1 cells were used. Poly (I:C), a double stranded viral RNA analogue was delivered into the cells via transfection or electroporation. PGM1 was knocked down by shRNA lentivirus. RNA and protein were analyzed using qPCR, western blot, and proteomics. For stable isotope labeling, EndoC-BH1 cells were cultured with 50% U-13C6 glucose. Metabolites and stable isotopes were analysed using LC-/GC-MS. Autophagy and mitophagy were assessed using western blot and live cell imaging. Unpaired t - test was used for statistical analyses.
Results: PGM1 expression was significantly lowered after the intracellular delivery of 10 μg/ml Poly(I:C) to human islets and EndoC-BH1 cells. Proteomics identified translational arrest in PGM1 shRNA treated human islets. ATF3 mRNA increased by approximately two-fold, suggesting integrated stress response. In EndoC-BH1 cells, PGM1 suppression increased flux to glycolysis, TCA cycle, pentose phosphate pathway, and hexosamine biosynthetic pathway. We found activation of autophagy but impaired autophagic and mitophagic flux in PGM1 deficient beta cells. Insulin secretion was unchanged, proinsulin content was lowered.
Conclusion: PGM1 is a novel driver of beta cell metabolic and energy stress following viral infection. The aberrant autophagic flux additionally suggests lysosomal defects. Activation of PGM1 potentially improves beta cell resistance to viral infection.

Disclosure
Y. Miller: None. Y. Qiu: None. Y. Sun: None. S.S. Jankauskas: None. R.J. Kulkarni: None. I.J. Kurland: None. Y. Tomer: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (1K01DK131329-01); Integrated Islet Distribution Program (BS526P)
21-OR: Use of Electronic Best Practice Advisories (BPA) to Increase Referral to Diabetes Self-Management Education and Support (DSMES) Services
Authors: YOUNG LAURA A. , HALLADAY JACQUIE , CHEN PING , MOTTUS KATHLEEN M. , GOEKE-AUSTIN KAREN K. , RICHMAN ERICA L. , REES JENNIFER , DONAHUE KATRINA 
Published: June 2024

Introduction & Objective: DSMES is underutilized by people with Type 2 diabetes (T2D), in part due to low rates of referral by health care providers. We sought to determine if rates of referral to DSMES increase through the use of a BPA deployed during clinic visits to health care providers via the electronic health record.
Methods: In this randomized controlled trial in central North Carolina, we created a BPA within the Epic electronic health record that fired when a patient with T2D who qualified for DSMES attended a routine visit with their primary care provider. The BPA was deployed in four primary care practices within a large, university-based health care system. Two additional practices served as controls and did not receive the intervention. We conducted multilevel binary logistic regressions with patient data nested within the provider, using the indicator of the intervention (vs. control clinics) as the predictor to estimate the odds ratio of provider referring an eligible patient to DSMES services after a patient encounter. Clinic-level (percentages of patients with Medicare and Medicaid use) and patient-level (age, sex, and race) variables were controlled in the adjusted model.
Results: Between April and October 2023, 1,326 BPAs fired in the intervention clinics resulting in an 11% referral rate to DSMES. Control clinics had 938 patient visits that qualified for DSMES referral with a 4% referral rate of eligible patients to DSMES. The 7% increase in referral rate between the intervention and control practices is statistically significant (p&lt;0.001). In the adjusted multivariate model, controlling for the covariates, patients who are in the intervention clinics with BPA firing have significantly higher odds of being referred for DSMES services than those who are in the control clinics without BPA firing (OR = 4.19 [95% CI 2.63-6.67], p &lt; 0.001).
Conclusions: Electronic BPAs do significantly increase patient referrals to DSMES services.

Disclosure
L.A. Young: Research Support; Novo Nordisk, Eli Lilly and Company, vTv Therapeutics, Beta Bionics, Inc., Corcept Therapeutics, Rhythm Pharmaceuticals, Inc., Bayer Inc., Jaeb Center for Health Research. J. Halladay: None. P. Chen: None. K.M. Mottus: None. K.K. Goeke-Austin: None. E.L. Richman: None. J. Rees: None. K. Donahue: None.