bluuebunny/crossref_metadata_2025_split huggingface dataset:
2090-LB: Characters of Intra-islet Ductal Cells Related to Alpha-Cell Regeneration in Zinc-Binding Site–Mutated CRY1-Expressing Diabetic Mice
Authors: OKANO SATOSHI , YASUI AKIRA , KANNO SHINICHIRO , SASAKI YU , SATOH KENNICHI , IGARASHI MASAHIKO , NAKAJIMA OSAMU 
Published: June 2024

Introduction & Objective: We previously suggested that the regions of intra-islet ductal cells (IIDCs) play roles as the source for endocrine cells, particularly for α-cells, in C414A-CRY1 transgenic mice (TG) (ADA 2023), the characters of IIDCs relevant to the α-cell neogenesis are yet unknown. To clarify the points, we conducted experiments in terms of reactivity to DBA-lectin as well as of the expression of TFF2.
Methods: The cells constituting developed IIDC (of duct periphery longer than 500 µm) in TG were classified as strongly or weakly positive both for anti-TFF2 antibodies and for DBA-lectin. The positional correlation among glucagon-producing cells present in IIDC compartments and the classified IIDC were examined.
Results: Immature IIDCs embedded inside islets were homogeneous for DBA-lectin-reactivity as reported previously: DBA-lectin-weakly positive (ADA 2019). By contrast, it was newly uncovered that developed IIDCs showed variations in phenotypes for the reactivities to DBA-lectin. Heterogeneity in TFF2 expression was also observed in developed IIDCs. Glucagon-producing cells were more frequently located near DBA-lectin-weakly positive IIDCs (~54% higher than near DBA-lectin-strongly positive ones; P&lt;0.01, t-test). While glucagon-producing cells were more frequently located near TFF2-strongly expressing IIDCs (~42% higher than near TFF2-weakly expressing ones; P&lt;0.001, t-test). Furthermore, DBA-lectin-strongly positive IIDCs tended to be TFF2-weakly expressing ones.
Conclusion: Our results suggest that TFF2 in IIDCs promotes α-cell neogenesis and/or plays some important roles in the maintenance of newborn α-cells. DBA-lectin-strongly positive characteristics of IIDCs possibly suppress TFF2 expression, thereby acting inhibitory manner for α-cell neogenesis in such IIDCs.

Disclosure
S. Okano: None. S. Kanno: None. Y. Sasaki: None. M. Igarashi: None. O. Nakajima: None.

Funding
Grants-in-Aid for Scientific Research (19K07498); Tohoku University Institute of Development, Aging and Cancer.
2104-LB: Alpha- and Beta-Cell Intercellular Communication via Extracellular Vesicles
Authors: KALIVARATHAN JAGAN , BALAJI SARAVANAN PRATHAB , MOHAMMED SHUJAUDDIN , LEVY MARLON F. , KANAK MAZHAR A. 
Published: June 2024

Introduction & Objective: Type-1 diabetes (T1D) is characterized by autoimmune destruction of β-cells which is further associated with α-cells dysfunction leading to hypoglycemic unawareness. Both α and β cell types regulate each other in a paracrine manner. Exosomes are extracellular vesicles naturally secreted by most cell types and are involved in cell-to-cell communication. β-cells and α-cells also release exosomes, but the pathophysiological function needs investigation. Thus, the main objective is to study the intercellular communication between α and β-cell via exosomes.
Methods: Mouse α-TC-1 and βTC-6 cell lines were stimulated in low (2.5mM), basal (5.5mM) and high glucose (25mM) exosome depleted media for 24hrs. Exosomes are isolated using differential centrifugation and their presence were confirmed by using TEM, and western blot for exosomal markers. Quantification and characterization were done using micro-BCA, ELISA, and nanosight analysis. Exosomes were further used to cross-stimulate α and β cells under low and high glucose at various time points (6h, 12h, 24h, 48h). Insulin and Glucagon levels in media was measured by ELISA and regulation of transcription factors were measured by qPCR.
Results: TEM analysis revealed that α and β cells released cup-shaped, rounded vesicles of exosomes (30-300nm). Western blot analysis for exosomal markers (CD9) was confirmed. Glucagon expression in α-cells was significantly increased when stimulated with β-cell exosomes under low glucose condition (6h:P=0.0134; 24h:P=0.0455; 48h:P= 0.0532). The expression of glucagon in α-cell was not affected by β-cell exosomes under high glucose. MafB expression in α-cells correlated with glucagon expression. Interestingly, expression of insulin in β-cells was not significantly affected by α-cell exosomes.
Conclusion: Exosomes from β-cells seem to play a role in regulation of glucagon. Further investigation relating to production and release of insulin and glucagon in response to exosomes is warranted.

Disclosure
J. Kalivarathan: None. P. Saravanan: None. S. Mohammed: None. M.F. Levy: None. M.A. Kanak: None.
212-OR: Differential Cell-Type-Specific Gene Expression and Chromatin Accessibility by Type 2 Diabetes Status and Physical Activity Levels in Human Skeletal Muscle
Authors: CIOTLOS DAN , HANKS SARAH , VARSHNEY ARUSHI , ERDOS MICHAEL , MANICKAM NANDINI , STRINGHAM HEATHER M. , HILL-BURNS ERIN , ORCHARD PETER , NARISU NARISU , BONNYCASTLE LORI L. , SWEENEY MICHAEL D. , LAAKSO MARKKU , TUOMILEHTO JAAKKO , LAKKA TIMO A. , MOHLKE KAREN L. , BOEHNKE MICHAEL , KOISTINEN HEIKKI A. , COLLINS FRANCIS S. , PARKER STEPHEN , SCOTT LAURA 
Published: June 2024

Introduction: Skeletal muscle plays a role in regulation of glucose metabolism, and physical activity is a preventive factor for type 2 diabetes (T2D). To understand the relationships of T2D status and vigorous physical activity with gene expression and chromatin regulation in skeletal muscle cell types, we analyzed skeletal muscle single nucleus RNA-sequencing and ATAC-sequencing data from 279 Finnish adults from the FUSION Tissue Biopsy Study.
Methods: Participants had varying glucose tolerance, ranging from normal glucose tolerance (NGT) to newly-diagnosed T2D, based on an oral glucose tolerance test. We estimated the level of 12-month vigorous physical activity (VPA) based on a questionnaire. Nucleus-level data were clustered using LIGER. We used negative binomial models to test for associations between glucose tolerance or VPA and cell-type composition, gene expression, or chromatin accessibility (genes: 23,841; peaks: 924,519).
Results: Participants were 60.2 (SD 7.4) years-of-age, and 41.5% were female, where 102 participants had NGT and 72 had T2D. Of 12 cell types, individuals with lower VPA had a higher proportion of type 2x muscle fibers (Log2 fold change=0.96, p=3.9e-2) with no significant difference by T2D status. Across muscle fiber types, associated genes generally had the same direction of gene expression when having higher VPA or NGT (as compared to T2D). We observed a similar pattern for chromatin accessibility. For example, in type 1 muscle fiber, NGT (as compared to T2D) or higher VPA were each associated with higher expression of cellular respiration genes (VPA: OR=1.77, p=1.4e-9, T2D vs. NGT: OR=0.80, p=8.9e-5) and lower expression of protein K48-linked polyubiquitination genes (VPA: OR=0.64, p=5.2e-3, T2D vs. NGT: OR=2.03, p=6.2e-5).
Conclusion: These findings suggest that both normal glucose tolerance and higher vigorous physical activity have similar regulatory effects on gene expression.

Disclosure
D. Ciotlos: None. S. Hanks: None. A. Varshney: None. M. Erdos: None. N. Manickam: Employee; 10x Genomics. H.M. Stringham: None. E. Hill-Burns: Other Relationship; GE HealthCare. P. Orchard: None. N. Narisu: None. L.L. Bonnycastle: None. M.D. Sweeney: None. M. Laakso: None. J. Tuomilehto: Stock/Shareholder; Orion Pharma, Aktivolabs, Digostics. T.A. Lakka: None. K.L. Mohlke: None. M. Boehnke: None. H.A. Koistinen: Other Relationship; AstraZeneca, Novo Nordisk. F.S. Collins: None. S. Parker: Research Support; Pfizer Inc. L. Scott: None.
219-OR: Loss of Insulin Signaling in Microglia Impairs Cellular Uptake of Aß and Neuroinflammatory Response Exacerbating Alzheimer-Like Neuropathology
Authors: CHEN WENQIANG , MUÑOZ VITOR R. , RONALD KAHN C. 
Published: June 2024

Insulin receptors are present on cells throughout the body. Dysregulation of insulin signaling in the brain has been implicated in mood, cognitive disorders, and pathogenesis of Alzheimer’s disease (AD). However, the brain is composed of multiple cells types, and little is known as to how brain insulin resistance in particular in different brain cell types contributes to the comorbidity of type 2 diabetes (T2D) and AD. In this regard, microglia are particularly interesting, since microglia are involved in the uptake and clearance of amyloid-β (Aβ) and formation of neuroinflammation. To investigate the role of insulin signaling in microglial function and development of AD, we have created an inducible microglia-specific insulin receptor knockout (MG-IRKO) and found that loss of microglial insulin signaling in these mice results in alterations in mood, social behavior and impairment in systemic metabolism. At a molecular level, utilizing RiboTag to isolate and profile microglial-specific ribosome-bounded mRNA, we found that loss of insulin receptor resulted in alterations in pathways associated with innate immunity and cellular metabolism in microglia. In vitro, loss of insulin signaling in microglial resulted in metabolic reprograming with a switch to more glycolytic metabolism, and this was associated with impaired ability of microglia in Aβ uptake. When the MG-IRKO mice were crossed with an AD mouse model (5xFAD mice) to create MGIRKO/5xFAD mice, the resultant mice exhibit increased levels of Aβ plaque formation and elevated neuroinflammation marked by increased IFN-γ. Thus, insulin signaling in microglia plays a key role in microglial cellular metabolism, neuroinflammation and the ability of the cells to uptake Aβ, such that loss of insulin signaling in microglia accelerates AD pathogenesis. Together, these data indicate the potential importance of targeting insulin signaling in microglia in treatment of AD.

Disclosure
W. Chen: None. V.R. Muñoz: None. C. Kahn: Consultant; Cellarity. Other Relationship; 1825 Therapeutics. Advisory Panel; TIXiMED, Senseion, ERX.

Funding
National Institutes of Health (R01 DK031036)
22-OR: Burden of Diabetes Survey—Perspectives from People Living with Diabetes in the United States
Authors: YEHL KIRSTEN , FIELDS SHERECCE A. , LEE FELIX , SHOGER ERIK , SMALLMAN RACHEL , ELLBOGEN KATE A. , KERR DAVID 
Published: June 2024

Objective: People with diabetes (PWD) have limited access to healthcare professionals. To provide PWD with the support they need, there must be a comprehensive understanding of the daily burdens associated with self-management.
Methods: An on-line questionnaire using the dQ&A US Patient Panel was created to understand the daily burden associated with self-management. Respondents from this survey (n=3,241) included adults with type 1 diabetes (T1DM), adults with type 2 diabetes (T2DM) on intensive insulin therapy, adults with T2DM on non-intensive insulin therapy, and adults with T2DM not on insulin. The sample included demographic and health characteristics.
Results: 1,204 respondents had an annual income of less than $50,000. PWD in this income category are more likely to have housing and food insecurity and problems with paying their bills. Both PWD with an annual income of less than $50,000 and PWD with T1DM are more likely to report experiencing severe psychological and practical diabetes management burdens. PWD with T1DM are more likely to think about the impact of their diabetes on future events and experience sleep disruptions on a weekly basis.
Conclusion: Concerns about long-term health and food choices are the leading causes of distress for all groups. Respondents have more difficulty ‘affording’ rather than ‘accessing’ items/facilities. There are many burdens related to diabetes, many caused by SDOH.

Disclosure
K. Yehl: None. S.A. Fields: None. F. Lee: Employee; Sanofi. Stock/Shareholder; Sanofi. E. Shoger: Other Relationship; Dexcom, Inc., Abbott, Tandem Diabetes Care, Inc., Beta Bionics, Inc., MannKind Corporation, Insulet Corporation, Medtronic, Association of Diabetes Care & Education Specialists. R. Smallman: None. K.A. Ellbogen: None. D. Kerr: Advisory Panel; Abbott Diagnostics. Consultant; Sanofi, Better Therapeutics, Inc. Stock/Shareholder; Glooko, Inc.

Funding
Sanofi US (77230685)
22-PUB: Machine Learning–Based Optimization of Patient Eligibility for Oral Insulin Treatment—A Post Hoc Analysis of Phase III Trial Results
Authors: KIDRON MIRIAM , BERKMAN ELAD , MACHLUF OSHRI , PRYLUK RAVIV , HOMER KENNETH E. , NEUTEL JOEL M. 
Published: June 2024

Background & Objectives: The growing shift toward implementation of precision medicine to improve the prospects of achieving treatment targets requires comprehensive profiling of an array of patient-specific data. Research efforts in this arena include review of anthropometric, epidemiological and clinical features to optimize eligibility criteria for specific treatments. In a recent Phase III, randomized, placebo-controlled, multi-center study in which T2DM patients were treated with oral insulin QD or BID for 26 weeks, the primary endpoint defined as a decrement of 0.6% HbA1c by treatment end was not met. The current post hoc analysis aimed to identify subpopulations with substantial clinical responses to active treatment.
Methods: Data were fitted with a nonparametric causal machine learning model to estimate the impact of various baseline covariates on the expected treatment effect. A recursive partitioning search was then conducted to identify clinically meaningful patient subgroups with high predicted susceptibility to treatment. Results were validated on external datasets, and by running a permutation test and sensitivity analyses to the exact criteria and sample.
Results: Patients with baseline BMI &lt;30.5 kg/m2 and age &gt;58 years achieved a conditional average 0.6% reduction in HbA1c by Week 26. Stricter criteria of BMI &lt; 27.0 kg/m2 and age &gt;58 years were associated with a mean 0.96% reduction in HbA1c. Gender-specific training of the models suggested different impacts of age and BMI across sex. Male subjects with BMI&lt;30 kg/m2 and female subjects &gt; 60 years exhibited improved clinical outcomes.
Conclusions: Variability in response to oral insulin can be minimized by segmenting the patient population based on BMI, age and sex. These findings will inform eligibility criteria for a newly planned Phase III study.

Disclosure
M. Kidron: Employee; Oramed Pharmaceuticals. E. Berkman: Consultant; Oramed Pharmaceuticals. O. Machluf: Consultant; Oramed Pharmaceuticals. R. Pryluk: Consultant; Oramed Pharmaceuticals. K.E. Homer: None. J.M. Neutel: None.
234-OR: Performance of a Machine-Learning Gene Risk Score Biomarker to Predict Weight-Loss Response to Tirzepatide and Semaglutide
Authors: TAMA ELIF , FANSA SIMA , ANAZCO DIEGO , RIVERA RENE , GHUSN WISSAM , CIFUENTES LIZETH , ACOSTA ANDRES , HURTADO MARIA D. 
Published: June 2024

Introduction: Abnormal post-prandial satiety obesity phenotype (APS+) is characterized by rapid gastric emptying. The GLP-1 analog liraglutide delays gastric emptying and in adults with APS+, its use is associated with greater weight loss compared to individuals without APS (APS-). A machine-learning gene risk score (ML-GRS) biomarker has been shown to predict APS and the response to liraglutide with accuracy. Our aim is to determine the applicability of this ML-GRS to predict weight loss response to semaglutide and tirzepatide.
Methods: From a Mayo Clinic multi-center biobank and outcomes registry of adults with obesity undergoing weight loss interventions, we selected those taking semaglutide or tirzepatide. Using saliva or blood samples, we generated an ML-GRS to determine APS phenotype (“APS+” or “APS-”). Endpoints: total body weight loss (TBWL) % at 3, 6, and 12 months by APS status, percentage of adults achieving ≥5, 10, 15, and 20% TBWL at 12 months by APS status; and the probability of the ML-GRS to predict ≥5% of TBWL after 12 months of semaglutide and/or tirzepatide.
Results: We included 137 adults: 91 APS+ and 46 APS-. There were no significant differences in age, race, weight, BMI, medication used and dosage achieved, or co-morbidities among the two groups. Compared to APS-, APS+ had superior TBWL% at 12 months (-13 ± 10% vs -19 ± 10%, n=57, p=0.01) but not at 3 or 6 months. The percentage of adults achieving ≥5, 10, and 20% TBWL at 12 months was significantly greater in APS+. When analyzed by medication, differences in TBWL% and categorical TBWL outcomes among the two groups were replicated with semaglutide but not with tirzepatide. The AUC of the ML-GRS to predict ≥5% of TBWL after 12 months of semaglutide was 0.7 (95% CI [0.5-0.9], p=0.06).
Conclusion: An APS+ ML-GRS is associated with greater weight loss response to semaglutide but not tirzepatide at 12 months. Larger and more diverse studies are needed to better assess the accuracy of this biomarker.

Disclosure
E. Tama: None. S. Fansa: None. D. Anazco: None. R. Rivera: None. W. Ghusn: None. L. Cifuentes: None. A. Acosta: Consultant; Amgen Inc., Regeneron Pharmaceuticals Inc., Nestlé Health Science, Structure Therapeutics, Inc., Boehringer-Ingelheim. Research Support; Vivus. Consultant; Currax. Other Relationship; Gila Therapeutics, Phenomix Sciences. Speaker's Bureau; Eli Lilly and Company. M.D. Hurtado: None.
242-OR: The Impact of Glucose Threshold on the Number and Duration of Glucose Episodes
Authors: THOMAS JONAH J.C. , KOUTROUKAS VAIOS , DIVILLY PATRICK , MARTINE-EDITH GILBERTE , ZAREMBA NATALIE , AMIEL STEPHANIE A. , CHOUDHARY PRATIK , CONSORTIUM HYPO-METRICS 
Published: June 2024

Introduction and Objectives: The number of sensor-detected hypoglycemia (SDH) episodes depends on the hypoglycemia threshold used. We investigated the relationship between glucose threshold and the number and duration of events in the Hypo-METRICS dataset.
Methods: Individuals with insulin-treated diabetes wore a blinded continuous glucose monitor for 10 weeks. SDH was defined as 15 min below each threshold between 5 mmol/L (90 mg/dL) and 2.2 mmol/L (40 mg/dL) at 0.1 mmol/L increments. The number and average duration of episodes was calculated at each glucose threshold.
Results: Data from 599 (T1D=276 and T2D=323) people were analyzed; median age 56 years, HbA1c 7.4%. Event rate was higher for events between 3-5 mmol/L than &lt; 3mmol/L (10.5 vs 1.1 episodes/week, p &lt; 0.01) and average duration longer (63.1 vs 35.5 minutes/episode, p &lt; 0.01). This is shown in Figure 1a and b. Each 0.1 mmol/L increment in hypoglycemia threshold resulted in 0.5 more episodes/week between 3-5 mmol/L vs 0.05 additional episodes/week at a threshold &lt; 3 mmol/l (p &lt; 0.01). Each 0.1 mmol/l increment in hypoglycemia threshold increased average duration by 3.1 minutes/episode between 3-5 mmol/l vs 0.4 minutes/episodes for those &lt; 3 mmol/l (p &lt; 0.01).
Conclusion: These results may be useful in understanding the alarm burden at different thresholds allowing personalization in proportion to individual risks.

Disclosure
J.J.C. Thomas: None. V. Koutroukas: Other Relationship; KelCon GmbH. P. Divilly: None. G. Martine-Edith: Other Relationship; Novo Nordisk A/S. N. Zaremba: None. S.A. Amiel: Advisory Panel; Vertex Pharmaceuticals Incorporated. Other Relationship; Sanofi. P. Choudhary: Advisory Panel; Abbott, Biolinq. Speaker's Bureau; Dexcom, Inc., Eli Lilly and Company, Novo Nordisk, Sanofi. Advisory Panel; Ypsomed AG, Vertex Pharmaceuticals Incorporated.

Funding
Hypo-RESOLVE (the consortium to which the Hypo-METRICS study belongs) has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 777460. Abbott Diabetes Care providedthe continuous glucose monitors used in the study
244-OR: Association of Type 1 Diabetes Duration or Duration of Advanced Technology Utilization with Severe Hypoglycemic Event Frequency
Authors: BOATENG-KUFFOUR ADRIANA , CALLAHAN PATRICK , CHANDARANA KEVAL , BARRY DIANNE , CHEN LIANG , KELLY CAITLIN S. , NGUYEN HUYEN , CHAPMAN KATHERINE S.M. , CORNELIUS EMILEE M. , WOLF WENDY , POLONSKY WILLIAM H. 
Published: June 2024

Introduction & Objective: Adults with type 1 diabetes (T1D) may experience severe hypoglycemic events (SHE) and impaired awareness of hypoglycemia (IAH) despite use of advanced technologies. It is unclear how a longer duration of T1D or continuous glucose monitor (CGM) use is associated with SHE.
Methods: Adult CGM users in the T1D Exchange Registry completed an online survey including SHE frequency, IAH, duration of CGM use, and years since T1D diagnosis. SHE cohorts were created based on SHE frequency in the past 12 months and presence/absence of IAH (defined in the Table). Descriptive results (mean [M], standard deviation) were reported. Bivariate correlations were used to test associations between duration of T1D or duration of CGM use with SHE frequency using Pearson’s correlation.
Results: Among 1,847 CGM users, the mean age was 45.9 years. Mean T1D duration was 29.0 years. Most participants (55.0%) used CGM for ≥5 years (Table). There were no significant associations between SHE frequency and T1D duration (r=0.03; p=0.25) or duration of CGM use (r=-0.03; p=0.15). The problematic SHE cohort reported slightly longer T1D duration (M=31.9 years) than other cohorts (M=26.8-28.6 years).
Conclusion: Severe hypoglycemia remains an important clinical risk for adults with T1D regardless of time spent living with T1D or duration of advanced monitoring technology use.

Disclosure
A. Boateng-Kuffour: Employee; Vertex Pharmaceuticals Incorporated. P. Callahan: Employee; Vertex Pharmaceuticals Incorporated. K. Chandarana: Employee; Vertex Pharmaceuticals Incorporated. Stock/Shareholder; Vertex Pharmaceuticals Incorporated, Novo Nordisk, Eli Lilly and Company. D. Barry: Employee; Vertex Pharmaceuticals Incorporated. L. Chen: None. C.S. Kelly: None. H. Nguyen: None. K.S.M. Chapman: None. E.M. Cornelius: None. W. Wolf: None. W.H. Polonsky: Research Support; Abbott Diagnostics, Dexcom, Inc. Consultant; Eli Lilly and Company, Sanofi. Advisory Panel; embecta. Consultant; Vertex Pharmaceuticals Incorporated. Advisory Panel; 9am Health.

Funding
Vertex Pharmaceuticals Incorporated