bluuebunny/crossref_metadata_2025_split huggingface dataset:
1958-LB: Overnight Glycemia’s Relevance to Insulin Resistance (IR) in Type 1 Diabetes (T1D)
Authors: CREE MELANIE G. , SIMON STACEY L. , BERNARD ANGEL , CHARTIER-LOGAN CATHERINE J. , BAUMGARTNER AMY , HINES ASHTON , BAILEY ALEXANDER , PTASZYNSKA SARA M. , BEST KYLA C. , CAREY GRAYSON , PYLE LAURA , SNELL-BERGEON JANET K. , NADEAU KRISTEN J. 
Published: June 2024

IR is a key contributor to cardiovascular disease in T1D but is difficult to measure. The relevance of mean overnight glycemia (MOG) in IR assessments by gold-standard hyperinsulinemic-euglycemic clamps (HEC) in T1D is unclear. We assessed the relationship between pre-HEC MOG and HEC-assessed IR in pubertal adolescents ages 12-19 yrs with T1D.
Each youth underwent admission with variable overnight intravenous insulin infusion titrated with a standardized protocol to a goal blood glucose (BG) of 100-120 mg/dL, followed by an AM HEC with 80mU/m2/min insulin infusion paired with a variable glucose infusion rate (GIR, 20% dextrose infusion, goal BG 95-100 mg/dL). MOG and insulin infusion rates were assessed overnight. Achieved MOG was categorized as ≤100, 101-120, and 121-140 mg/dL. IR was assessed by end-HEC steady-state GIR and free fatty acids (FFA).
80 youth (42 girls, 38 boys) with T1D enrolled (mean age 16 ± 2.1 yrs, HbA1c 8.4 ± 1.6%, T1D duration 6.9 ± 4.0 yrs, BMI 24.0 ± 4.7 kg/m2). Mean BG at end-HEC was 99.0 ± 7.4 mg/dL. Results categorized by MOG category are shown in the Table. As MOG category increased, overnight insulin infusion requirements and end-HEC FFA’s increased and GIR decreased.
In T1D, more difficult to control overnight BG in a controlled setting likely reflects greater overnight IR and HEC whole-body and adipose IR. Future directions include home overnight pump/CGM-based simpler methods for assessing IR in T1D.

Disclosure
M.G. Cree: Consultant; Pollie, Inc. Research Support; Amino Co. A. Bernard: None. A. Baumgartner: None. A. Hines: None. A. Bailey: None. G. Carey: None. L. Pyle: None. J.K. Snell-Bergeon: None. K.J. Nadeau: None.

Funding
American Diabetes Association (7-11-CD-08); JDRF (2-SRA-2022-1144-M-B)
1959-LB: An Insulin-Modified Oral Glucose Tolerance Test (OGTT) to Assess Insulin Resistance (IR) in Type 1 Diabetes (T1D)
Authors: NADEAU KRISTEN J. , SIMON STACEY L. , BERNARD ANGEL , CHARTIER-LOGAN CATHERINE J. , BAUMGARTNER AMY , HINES ASHTON , BAILEY ALEXANDER , PTASZYNSKA SARA M. , BEST KYLA C. , CAREY GRAYSON , PYLE LAURA , DINIZ BEHN CECILIA , SNELL-BERGEON JANET K. , CREE MELANIE G. 
Published: June 2024

IR is a key contributor to cardiovascular disease in T1D and increasingly so with increased rates of obesity in T1D. IR is difficult to measure in T1D due to absent insulin secretion. The hyperinsulinemic euglycemic clamp (HEC) is the gold-standard method for assessing IR in T1D, but is cumbersome, especially in youth. We thus adapted the simpler and more physiologic OGTT to T1D and assessed its performance vs. the HEC in T1D adolescents who use insulin pumps.
Each youth underwent admission with variable overnight intravenous insulin infusion, followed by an AM HEC with 80mU/m2/min insulin infusion paired with a variable glucose infusion rate (GIR, 20% dextrose infusion). IR was assessed by end-HEC steady-state GIR. On a separate day, each youth underwent an OGTT. The participant’s insulin pump basal rate was left running with autocorrection mode suspended, and a subcutaneous injection of regular insulin given using the participant’s home insulin:carbohydrate ratio and blood glucose correction factor. 30 minutes later, a 75-gram Glucola was consumed (T=0). Blood samples were taken at T=-30, -20, -5, 0, +10, +20, +30, +45, +60, +75, +90, +120, and IR calculated via the Matsuda Index, which correlates well with HEC in non-T1D populations. Spearman correlations between GIR and Matsuda Index were performed. Descriptive statistics were examined for normality, then expressed as median (25th,75th) or mean ± SD.
17 pubertal youth (10 girls, 7 boys) 14-17 yrs of age (15.8 ± 0.9 yrs) were enrolled (BMI 20.0 [19.4, 24.8 kg/m2], HbA1c [7.6 ± 1.1%]). Mean HEC GIR was 10.0 ± 4.6 mg/kg/min; Matsuda was 4.9 ± 4.0 (unitless). GIR correlated with Matsuda Index (r=0.54, p=0.025).
In T1D youth, HEC-assessed IR correlated well with insulin-augmented OGTT Matsuda Index. Future work will compare different methods of calculating IR from an OGTT to determine the optimal method and incorporate isotope tracers to allow tissue-specific IR measures. An insulin-modified OGTT is a viable option to assess IR in T1D.

Disclosure
K.J. Nadeau: None. A. Bernard: None. A. Baumgartner: None. A. Hines: None. A. Bailey: None. G. Carey: None. L. Pyle: None. C. Diniz Behn: Research Support; Lumos Tech. J.K. Snell-Bergeon: None. M.G. Cree: Consultant; Pollie, Inc. Research Support; Amino Co.

Funding
JDRF (2-SRA-2022-1144-M-B)
1986-LB: Feasibility and Acceptability of an Intervention to Improve Metabolic Liver Disease in Latino/a and Black Patients with Diabetes
Authors: ALEXOPOULOS ANASTASIA-STEFANIA , DANUS SUSANNE , PARISH ALICE , OLSEN MAREN , BATCH BRYAN , MOYLAN CYNTHIA A. , CROWLEY MATTHEW J. 
Published: June 2024

Patients with type 2 diabetes (T2D), and particularly those from historically marginalized racial/ethnic groups, are at high risk of poor outcomes from metabolic dysfunction-associated steatotic liver disease (MASLD). In this 3-month feasibility pilot, we proactively delivered evidence-based care for MASLD in Latino/a and/or Black patients with T2D and elevated liver enzymes, with a goal of reducing risk of MASLD progression. We recruited 10 patients (5 Latino/a and 5 Black) with T2D and alanine aminotransferase level (ALT) &gt;40 U/L; exclusions for non-MASLD liver disease were applied. The intervention was entirely remote and included: a) MASLD education; b) monthly diet/lifestyle counseling sessions; c) T2D medication management, with prioritization of glucagon-like peptide-1 receptor agonists and pioglitazone as appropriate; and d) clinically-indicated ordering of liver tests and referrals. Primary outcomes were feasibility and acceptability as measured by the Treatment Acceptability and Preferences (TAP) measure and participant interviews. Mean patient age was 51.1 (SD 9.6) and 5/10 participants were female. Mean BMI was 36 (SD 5.6), HbA1c was 6.9% (SD 1.2) and ALT was 58 U/L (SD 17.6). At 3 months, retention rate was 100% and all 30 study visits were completed. Mean TAP was 3.98 (SD 0.13) with a maximum score of 4, indicating high intervention acceptability. All participants felt the intervention was helpful in improving their awareness of MASLD and motivating behavioral change to reduce MASLD risk. Of the 10 participants, 5 had their T2D medications adjusted, 2 underwent liver ultrasound (both had steatosis) and 1 was referred to Hepatology. This study demonstrates feasibility and acceptability of an intervention that delivers evidence-based care for MASLD in Latino/a and Black patients with T2D.

Disclosure
A. Alexopoulos: None. S. Danus: Other Relationship; Novo Nordisk, Fractyl Health, Inc., Lilly Diabetes. A. Parish: None. M. Olsen: None. B. Batch: Advisory Panel; LLENA (AI). C.A. Moylan: Research Support; Madrigal Pharmaceuticals, Inc. Consultant; Novo Nordisk. Research Support; GlaxoSmithKline plc, Exact Sciences. Consultant; Sirtex. M.J. Crowley: None.

Funding
The Duke Clinical and Translational Science Award (CTSA) program funded by the National Center for Advancing Translational Sciences (NCATS) at the National Institutes of Health (NIH), award number KL2 TR002554.
1993-LB: Subgroups of Type 2 Diabetes (T2D) by Clinical Features and Islet Autoimmunity
Authors: PILLA SCOTT J. , KNOWLER WILLIAM C. , BALASUBRAMANYAM ASHOK , HAMPE CHRISTIANE S. , PIETROPAOLO SUSAN , LIN DARREN , ANDERSON ANDREA M. , ZHAO NI , LERNMARK ÅKE , MATHIOUDAKIS NESTORAS N. , BANCKS MICHAEL , CLARK JEANNE , MARUTHUR NISA M. 
Published: June 2024

Introduction: Adults with T2D may have phenotypic subgroups; prior clustering analyses had limited measures of beta-cell function, islet autoimmunity, or both. We aimed to characterize T2D subgroups in Look AHEAD (Action for Health in Diabetes), a randomized trial of adults with clinically-diagnosed T2D and overweight/obesity.
Methods: In 3,952 participants, we measured islet autoantibodies (GADA, ZnT8A) and performed homeostatic model assessment v2 of beta cell function (HOMA2-B) and insulin resistance (HOMA2-IR) using fasting C-peptide. We applied k-means clustering using these measures plus age at T2D diagnosis, BMI, and HbA1c.
Results: We identified four subgroups (Figure): lower adiposity with good glycemic control (LA/GC, 42% of the sample), high adiposity with good glycemic control (HA/GC, 26%), poor glycemic control (PC, 30%) and islet autoimmunity (IA, 3%). The LA/GC subgroup had high HOMA2-B (median 73%) and low HOMA2-IR (median 2.4). HA/GC had the highest HOMA2-B (median 113%) and HOMA2-IR (median 3.8). The PC subgroup had low HOMA2-B (median 46%) and youngest T2D diagnosis. Only the IA subgroup had frequent islet autoimmunity (95% GADA+, 18% ZnT8A+) and had low HOMA2-B (median 55%). Insulin use was infrequent in LA/GC (9%) and HA/GC (4%), and common in PC (32%) and IA (41%).
Conclusions: Using clinically-available measures, we identified four distinct T2D subgroups with important physiologic differences.

Disclosure
S.J. Pilla: None. W.C. Knowler: None. A. Balasubramanyam: None. C.S. Hampe: None. S. Pietropaolo: None. D. Lin: None. A.M. Anderson: None. N. Zhao: None. Å. Lernmark: Advisory Panel; DiaMyd Medical AB, Stockholm, Sweden. M. Bancks: None. J. Clark: Advisory Panel; Boehringer-Ingelheim. N.M. Maruthur: Other Relationship; Johns Hopkins Health Care Solutions.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK126825, K23DK128572)
1997-LB: Curation of an AI-Ready Dataset Using Domain-Informed Features Derived from Type 1 Diabetes TrialNet Studies
Authors: TALLON ERIN M. , SHAPIRO MELANIE R. , SHRIKRISHNA WAGHMODE AMEY , MERRITT RYAN , WASSERFALL CLIVE , BACHER RHONDA , LOCKEE BRENT , VANDERVELDEN CRAIG , PANFIL KELSEY , MOORE WAYNE V. , ATKINSON MARK A. , BRUSKO TODD M. , CLEMENTS MARK A. 
Published: June 2024

Introduction: Machine learning and artificial intelligence (ML/AI) will increasingly have pivotal roles in advancing scientific discoveries related to diabetes. The NIDDK Central Repository (NIDDK-CR) hosted a “Data Centric Challenge” (DCC) between December 2023 and February 2024 to enhance the potential for using its data resources in innovative ML/AI research that aligns with the FAIR (Findable, Accessible, Interoperable, Reusable) principles.
Objective: As DCC participants, we describe our experience transforming data from multiple Type 1 Diabetes (T1D) TrialNet (TN) studies into a single AI-ready dataset for ML/AI applications.
Methods: For its intermediate/advanced Challenge, the NIDDK-CR provided fully deidentified data from four studies: TN01 (TN participant screening and monitoring), TN16 (long-term TN participant follow-up), TN19 (immunotherapy in new-onset T1D), and TN20 (antigen-specific immunotherapy). We first generated a single “raw” dataset comprising all data from the four studies by joining on participant ID. We then transformed structured data from TN01 and TN20 to create an AI-ready dataset.
Results: Our raw dataset contained data for 237,324 TN participants (TN01 [n=237,048]; TN16 [n=561]; TN19 [n=119]; TN20 [n=115]). Since few individuals participated in ≥3 of these studies, we curated an AI-ready dataset comprised of fully harmonized, longitudinal immunologic, genetic, phenotypic, and demographic data - including numerous new, AI-ready data features (e.g., normalized fold change in autoantibody titers and CyTOF tetramers, genetic risk score, T1D stage) - from individuals who completed participation in TN01 and TN20 (n=75). All data handling processes are repeatable and thoroughly documented.
Conclusion: Data from multiple TN studies can be transformed into domain-informed, AI-ready data. Future efforts will entail analyses of newly engineered data variables to inform ML modeling efforts for predicting progression to Stage 2 and Stage 3 T1D.

Disclosure
E.M. Tallon: None. M.R. Shapiro: None. A. Waghmode: None. R. Merritt: None. C. Wasserfall: None. R. Bacher: None. B. Lockee: None. C. Vandervelden: None. K. Panfil: None. W.V. Moore: None. M.A. Atkinson: None. T.M. Brusko: None. M.A. Clements: Research Support; Abbott. Consultant; Glooko, Inc. Research Support; Dexcom, Inc.

Funding
Emilie Rosebud Diabetes Research Foundation; Orlando Brown Jr.
2005-LB: Optimization of Single Nuclei Isolation from Frozen Human Skeletal Muscle and Pancreatic Tissue Samples for Single Nuclei Multiome ATAC + Gene Expression
Authors: DOLGACHEV VLADISLAV , VARSHNEY ARUSHI , MOO KEAGAN G. , WANG XIAOOU , ORCHARD PETER , SAUNDERS DIANE C. , BRISSOVA MARCELA , PARKER STEPHEN C. 
Published: June 2024

Background: Dysfunctional pancreatic islets beta cells are a well established hallmark of type 2 diabetes. Despite intense research, we still lack understanding of the underlying gene dysregulation mechanisms, including gene regulatory pathways driving the shift between normal and diabetic cells. Single-nucleus (sn) multiome (joint RNA and ATAC profiling on the same nucleus) sequencing is a powerful technique to acquire multi-modal data from the same nucleus. sn-multiome quality depends on the quality of the input material. Increasing the quality of single nuclei isolated from previously frozen human skeletal muscle and pancreas samples can enhance sn-multiome output.
Goal of the study: Reduce noise in sn-multiome data by isolating high quality nuclei from human samples.
Methods: We compared data from nuclei isolated with citric acid and sucrose gradient protocols to nuclei sorted with the MACS Quant Tyto flow cytometer. The quality of isolated nuclei was visually determined by light microscopy, quantified by ATAC library trace, and RNA integrity number (RIN) score.
Results: We optimized isolation of nuclei from frozen human skeletal muscle samples. Quality controls checks revealed intact nuclei microscopically, all expected peaks on ATAC library traces, and 9.2 RNA RIN. Optimization of nuclei isolation from frozen pancreatic human tissues was more challenging due to the high amount of RNases, which quickly degrade RNA quality and compromise subsequent library preps, even with high-quality nuclei. We optimized nuclei isolation protocol by fine tuning experimental procedures along with adjustment of concentrations of RNase inhibitors.
Conclusions: Optimization of nuclei isolation from frozen human skeletal muscle and pancreatic tissue with MACS Quant Tyto cell sorter demonstrated high quality of sorted nuclei by visual integrity, ATAC trace and high RNA RIN and high sn-multiome data quality.

Disclosure
V. Dolgachev: None. A. Varshney: None. X. Wang: None. P. Orchard: None. D.C. Saunders: None. M. Brissova: None. S.C. Parker: Research Support; Pfizer Inc.
2010-LB: Glycemic Responses to Metformin Montherapy by SNP Clusters in Patients with Type 2 Diabetes
Authors: SHEU WAYNE H.H. , LEE CHUN-YI , LIAO CAI-SIAN , HSIAO TZU-HUNG , ROTTER JEROME I. 
Published: June 2024

Introduction and Objective: Glycemic responses to metformin based on 8 SNP clusters in diabetes individuals, published by Suzuki (Nature, 2024), are unknown. Employing dataset from part of Taiwan Precision Medicine Initiative (TPMI), we explored the glycemic responses to metformin by quintile SNP cluster scores.
Methods: Tracking EMR from a medical center in Taiwan, we analyzed changes of fasting glucose and HbA1c, based on SNP clusters, in newly diagnosed type 2 diabetes who received metformin monotherapy for 6 months. (Fig. 1). GEE was used to compare the glycemic responses in those with Q1 vs. Q5 in each or two SNP clusters.
Results: Significant reduction of fasting glucose (FG) (p=0.007) and HbA1c (p&lt;0.001) in those carrying Q1 vs. Q5 in beta cell dysfunction with negative proinsulin (BDNP). Greater lowering of FG (p=0.008) and marginally lowering of HbA1c (p=0.079) in those carrying Q1 vs. Q5 in beta cell dysfunction with positive proinsulin (BDPP). When considering both clusters together, diabetes subjects having clusters of both BDNP and BDPP showed better FG reduction in Q1 as compared to Q5 (p=0.015). Diabetes subjects carrying clusters of both metabolic syndrome and BDNP had greater HbA1c reduction in Q1 compared to Q5 (p=0.013).
Conclusion: We identified that SNP clusters with BDNP and BDPP, and metabolic syndrome, contributed to glycemic responses to metformin monotherapy in patients with type 2 diabetes.

Disclosure
C. Liao: None. T. Hsiao: None. J.I. Rotter: None.

Funding
National Health Research Institutes, Taiwan (MG-112-PP-18, MG-113-PP-18)
2013-LB: Population-Scale Skeletal Muscle Single-Nucleus Multiomic Profiling Reveals Extensive Context-Specific Genetic Regulation
Authors: VARSHNEY ARUSHI , MANICKAM NANDINI , ORCHARD PETER , TOVAR ADELAIDE , ZHANG ZHENHAO , FENG FAN , LAKKA TIMO A. , LAAKSO MARKKU , TUOMILEHTO JAAKKO , MOHLKE KAREN L. , KITZMAN JACOB , KOISTINEN HEIKKI A. , LIU JIE , BOEHNKE MICHAEL , COLLINS FRANCIS S. , SCOTT LAURA , PARKER STEPHEN C. 
Published: June 2024

Skeletal muscle, the largest human organ by weight, is relevant to several polygenic metabolic traits and diseases including type 2 diabetes (T2D). Identifying genetic mechanisms underlying these traits requires pinpointing the relevant cell types, regulatory elements, target genes, and causal variants. Here, we used genetic multiplexing to generate population-scale single nucleus (sn) chromatin accessibility (snATAC-seq) and transcriptome (snRNA-seq) maps across 287 frozen human skeletal muscle biopsies representing 456,880 nuclei. We identified 13 cell types that collectively represented 983,155 ATAC summits, cataloging caQTL peaks that atlas-level snATAC maps often miss. We integrated genetic variation to discover 6,866 expression quantitative trait loci (eQTL) and 100,928 chromatin accessibility QTL (caQTL) (5% FDR) across the five cell types. We identified 1,973 eGenes colocalized with caQTL and used mediation analyses to construct causal directional maps for chromatin accessibility and gene expression. 3,378 genome-wide association study (GWAS) signals across 43 relevant traits colocalized with sn-e/caQTL, 52% in a cell-specific manner. 77% of GWAS signals colocalized with caQTL and not eQTL, highlighting the critical importance of population-scale chromatin profiling for GWAS functional studies. A C2CD4A/B T2D GWAS signal colocalized with caQTL in muscle fibers and multiple chromatin loop models nominated VPS13C, a glucose uptake gene. Sequence of the caQTL peak overlapping caSNP rs7163757 showed allelic regulatory activity differences in a human myocyte cell line massively parallel reporter assay. These results illuminate the genetic regulatory architecture of human skeletal muscle at high-resolution epigenomic, transcriptomic, and cell state scales and serve as a template for population-scale multi-omic mapping in complex tissues and traits.

Disclosure
A. Varshney: None. N. Manickam: Employee; 10x Genomics. P. Orchard: None. A. Tovar: None. Z. Zhang: None. F. Feng: None. T.A. Lakka: None. M. Laakso: None. J. Tuomilehto: Stock/Shareholder; Orion Pharma, Aktivolabs, Digostics. K.L. Mohlke: None. J. Kitzman: Advisory Panel; Myome Inc. H.A. Koistinen: Other Relationship; AstraZeneca, Novo Nordisk. J. Liu: None. M. Boehnke: None. F.S. Collins: None. L. Scott: None. S.C. Parker: Research Support; Pfizer Inc.

Funding
R01DK072193UM1DK126185R01DK117960P30AR069620
2034-LB: Drug Screening Identifies Dicoumarol as a Novel IRE1α Inhibitor That Protects Mice from ER Stress-Induced Liver Damage
Authors: YANG JIFENG , WEN SHIYI , CHEN YANMING , SHI GUOJUN 
Published: June 2024

Excessive nutrition intake leads to endoplasmic reticulum (ER) stress and activate unfolded protein response (UPR) in the liver. Depending on the level and duration of ER stress, IRE1α, the most conserved branch of UPR, a dual-functional ER transmembrane protein promotes either adaptation or apoptosis. Transient activation of IRE1α induces trans auto-phosphorylation and binds an ATP to its kinase domain, subsequently driving homo-oligomerization and exposure of its RNase domain, which catalyzes an unconventional splicing of XBP1 mRNA and generates an adaptive transcription factor XBP1s to restore ER homeostasis. However, under excess and chronic ER stress, hyperactivation of IRE1α expands RNase substrate repertoire to many other mRNA species, known as regulated IRE1-dependent decay (RIDD), which leads to apoptosis. To modulate the activity and effects of IRE1α, we performed a virtual screening targeting the kinase domain of IRE1α which contains a natural pocket structure to identify ATP-competitive small molecules. To validate the effects of those small molecules, an IRE1α-XBP1s activity reporter cell line was employed to further discriminate the candidates that inhibit IRE1α activity using fluorescence-activated cell sorting. Based on these strategies, we identified dicoumarol as a novel IRE1α inhibitor, which inhibits ER stress agonist-induced activation of IRE1α both in vitro and in vivo. Particularly, dicoumarol ameliorates tunicamycin- and tetrachloromethane-induced acute hepatic ER stress consequently protecting the liver from damage. Thus, dicoumarol shows a powerful hepatic protective effect, however, the potency of dicoumarol in the application of chronic ER stress, such as obesity and type 2 diabetes, needs further determination.

Disclosure
J. Yang: None. Y. Chen: None.

Funding
National Natural Science Foundation of China (82070811); National Natural Science Foundation of China (81770826); Key Area Research & Development Program of Guangdong Province (2019B020227003)