bluuebunny/crossref_metadata_2025_split huggingface dataset:
181-OR: Pancreatic Gene Therapy Durably Improves Glycemia and Delays Disease Progression in a Murine Model of Type 2 Diabetes
Authors: FITZPATRICK ALICE L. , COZZI EMILY , WAINER JACOB , REESE REBECCA , KHANNA NIDHI , CAPLAN JAY , RAJAGOPALAN HARITH , WEST JASON A. 
Published: June 2023

Beta-cell (β-cell) failure is a root cause of the progression of type 2 diabetes (T2D). GLP-1 receptor agonists (GLP1RA) have proven clinical efficacy and improve β-cell function. However, systemic side effects limit patient adherence and long-term efficacy. Localized pancreatic GLP1RA production may engender durable islet cell benefit while diminishing side effects. We developed a novel adeno-associated virus (AAV) gene therapy delivery platform to enable local and durable production of therapeutic proteins by the pancreas. We assessed to what degree a β-cell restricted GLP1RA gene therapy impacts disease progression in the db/db mouse compared to semaglutide (Sema).
To establish a baseline for chronically administered systemic GLP1RA, Sema (10 nmol/kg) or vehicle were given daily to 5-week-old mice for 10 weeks (n=8/group). Sema treated mice had a 64% decrease in fasting blood glucose (FBG; p&lt;0.0001) and a 3.5-fold increase in fasting insulin (FI; p=0.01) across the time course. Glucose tolerance was significantly improved during IPGTT at weeks 3, 6, and 9 (p&lt;0.001).
To determine the impact of a single dose GLP1RA gene therapy, 1) β-cell restricted AAV-GLP1RA, 2) AAV control, or 3) vehicle were given to 5-week-old mice (n=8/group). Remarkably, AAV-GLP1RA treatment decreased FBG levels by 70% (p&lt;0.0001) and elevated FI by 1.9-fold (p&lt;0.01) compared to controls for 10 weeks. Glucose tolerance was improved during IPGTT at weeks 3, 5, 7, and 9 (p&lt;0.01). AAV-GLP1RA protein was undetectable in serum and restricted to the islet, suggesting improved glycemic control was due to intra-islet GLP1RA production and signaling.
These results demonstrate that a single dose β-cell restricted GLP1RA gene therapy can comparably improve glycemia and delay disease progression in a murine model of T2D when compared to chronic systemic GLP1RA administration. These data provide proof of concept that a gene therapy has the potential to durably treat metabolic diseases, including T2D.

Disclosure
A.L.Fitzpatrick: Employee; Fractyl Health, Inc. E.Cozzi: Employee; Fractyl Health, Inc. J.Wainer: Employee; Fractyl Health, Inc. R.Reese: Employee; Fractyl Health, Inc. N.Khanna: Employee; Fractyl Health, Inc. J.Caplan: Employee; Fractyl Health, Inc. H.Rajagopalan: Employee; Fractyl Health, Inc. J.A.West: Employee; Fractyl Health, Inc.

Funding
Fractyl Health, Inc.
182-OR: C-Peptide and Metabolic Outcomes in Immunotherapy Studies of New-Onset Type 1 Diabetes
Authors: TAYLOR PETER , COLLINS KIMBERLY S. , KARPEN STEPHEN , ATABAKHSH ELNAZ , AHMED SIMI , MARINAC MARJANA , LATRES ESTHER , LAM ANNA , SENIOR PETER A. , RIGBY MARK , GOTTLIEB PETER , DAYAN COLIN 
Published: June 2023

Background: Despite advances in insulin therapy, metabolic outcomes in T1D remain suboptimal. Immunotherapy to preserve beta cell function has enormous potential but the metabolic benefits and the size of trial needed to demonstrate them remain unclear, hindering drug development.
Methods: Our dataset comprised 1315 adults and 1396 children enrolled in 20 immunotherapy intervention trials within 100 days of diagnosis. End points assessed were AUC c-peptide, HbA1c, IDAAC, Beta-2 Score and hypoglycemia. Differences in outcomes between active and control arms in positive and negative studies were assessed using the Wilcoxon rank test.
Results: C-peptide preservation in positive studies resulted in greater improvements in HbA1c within 3 months of beginning therapy. Beyond the initial 3 month “honeymoon” period, 20% greater preservation of C-peptide in active versus placebo subjects was associated with a 0.5% lower HbA1c. Higher initial C-peptide levels and greater C-peptide preservation were associated with better glycemic outcomes.
Sample size for HbA1c, IDAAC, and Beta-2 Score required 2-3 times as many subjects per armto demonstrate a difference at 6 months as compared to C-peptide. Smaller samples sizes were required in children. Longer studies are required to demonstrate durability but not efficacy. Hypoglycaemia rates required substantially larger sample sizes and more than 1 year follow-up.
Conclusion: Immunotherapy to preserve beta cell function is effective at improving metabolic outcomes in new-onset T1D. Beyond the initial 3 month period, improvements in HbA1c are proportional to C-peptide preservation. Early intervention and sustained high C-peptide levels are required for ongoing benefits.

Disclosure
P.Taylor: None. M.Rigby: None. P.Gottlieb: Advisory Panel; ViaCyte, Inc., Board Member; ImmunoMolecular Therapeutics, Research Support; Imcyse, Hemsley Charitable Trust, Novartis, National Institute of Diabetes and Digestive and Kidney Diseases, Precigen, Inc., Dompé, Nova Pharmaceuticals, Provention Bio, Inc. C.Dayan: Advisory Panel; AstraZeneca, Consultant; Provention Bio, Sanofi, Avotres Inc., Other Relationship; Dompé, Merck & Co., Inc. K.S.Collins: None. S.Karpen: None. E.Atabakhsh: None. S.Ahmed: None. M.Marinac: None. E.Latres: None. A.Lam: None. P.A.Senior: Advisory Panel; Novo Nordisk Canada Inc., Consultant; Novo Nordisk Canada Inc., Bayer Inc., Viatris Inc., Vertex Pharmaceuticals Incorporated, ViaCyte, Inc., Insulet Corporation.

Funding
JDRF; Diabetes UK
186-OR: Genetic Variants That Lower Hemoglobin A1c Independently of Glycemia Are Associated with Higher Diabetic Retinopathy Risk in Diverse Ancestries
Authors: SCHROEDER PHILIP H. , MANDLA RAVI , FLOREZ JOSE C. , MERCADER JOSEP M. , LEONG AARON 
Published: June 2023

Introduction: People with type 2 diabetes (T2D) who carry genetic variants that lower hemoglobin A1c (A1c) independently of glycemia may have higher real, but undetected, hyperglycemia compared to those who do not despite achieving similar A1c targets, placing them at greater risk for complications.
Methods: Using data from 39,199 T2D cases of European ancestry (EA) and African ancestry (AA) in UK Biobank and All of Us, we calculated a nonglycemic A1c polygenic score (ngA1cPS) composed of 123 variants previously associated with A1c at genome-wide significance, but not with glucose. We tested the association of the ngA1cPS with DR (n = 3,859), adjusting for A1c and known DR risk factors (T2D duration, kidney disease, hypertension, lipids, smoking).
Results: Participants at the bottom ngA1cPS quintile showed 25-50% higher DR prevalence vs. the rest despite having lower measured A1c (6.6 vs 6.7%). Odds ratios were 1.28 in EA and 1.37 in AA (Fig. 1). Among carriers of the African-specific G6PD variant rs1050828 known to lower A1c, DR prevalence was 27% higher among those with ngA1cPS below the median vs. above the median.
Conclusions: The aggregate effect of variants that lower A1c independently of glycemia is associated with a higher DR risk in both EA and AA. Genetic effects need to be considered to define personalized A1c targets to improve the outcomes of patients with T2D.

Disclosure
P.H.Schroeder: None. R.Mandla: None. J.C.Florez: Consultant; AstraZeneca, Novo Nordisk, Other Relationship; AstraZeneca, Merck & Co., Inc. J.M.Mercader: None. A.Leong: Other Relationship; Merck & Co., Inc.

Funding
Doris Duke Charitable Foundation (2020096)
187-LB: Preclinical Biomarkers of Alzheimer's Disease Neuropathology in Young Adults with Youth-Onset Diabetes (YDM)—A Proof-of-Concept Study
Authors: SHAPIRO ALLISON , COUGHLAN CHRISTINA , KIM JEONGCHUL , POTTER HUNTINGTON , BJORNSTAD PETTER , PAULEY MEGHAN E. , RAJIC BENJAMIN S. , TRUONG JENNIFER , GLUECK DEBORAH H. , HARRALL KYLIE K. , BARCUS RICHARD A. , TAN JOSH , BETTCHER BRIANNE , THAKER ASHESH , WALKER KEENAN A. , LIESE ANGELA D. , DABELEA DANA , WHITLOW CHRISTOPHER T. 
Published: June 2023

Adult-onset diabetes increases one's risk for Alzheimer's disease and its related dementias (AD/ADRD). However, little is known about the risk for AD/ADRD in young adults with YDM. The current study quantified preclinical plasma and imaging biomarkers of AD/ADRD in a subset of young adults with YDM from the SEARCH for Diabetes in Youth study cohort (type 1 diabetes [T1D], n=20; type 2 diabetes [T2D], n=21; mean [SD], age=27.4 years [2.2], diabetes duration=13.6 years [2.4], 59% female). Plasma biomarkers were assayed from stored samples at two timepoints: within 1-year of YDM diagnosis (baseline) and in young adulthood via the Quanterix Simoa platform including glial fibrillary acidic protein (GFAP), neurofilament light chain protein (NfL), phosphorylated tau-181 (pTau181), amyloid beta (Aβ)40, and Aβ42. Seven participants from the SEARCH subset (T1D=6, T2D=1; age=30.7 years [2.4], 87% female) and four age-similar controls (age=26.5 years [4.4], 50% female) underwent [18F]PI-2620 tau positron emission tomography (PET) to quantify brain tau density. Tau standardized uptake value ratios (SUVRs) with partial volume correction were derived in AD/ADRD sensitive brain regions. From baseline to young adulthood, plasma pTau181 significantly increased in both YDM-T1D and YDM-T2D (mean change=9.5 pg/mL [3.8] and 12.4 pg/mL [6.3], respectively; p&lt;0.001). Average tau SUVRs in the middle temporal poles (SUVR=1.26 [0.14] vs 1.17 [0.04]) and parahippocampal gyri (SUVR=1.01 [0.33] vs 0.92 [0.05]) were greater in YDM vs. controls. However, these differences were not statistically significant. Our preliminary results suggest that YDM may increase the risk of AD/ADRD via accelerated accumulation of soluble phosphorylated tau. Additional measurement of AD/ADRD neuropathology, including amyloid PET scans, is currently underway to further understand the trajectory of preclinical AD/ADRD pathology in YDM.

Disclosure
A. Shapiro: None. K. K. Harrall: None. R. A. Barcus: None. J. Tan: None. B. Bettcher: None. A. Thaker: None. K. A. Walker: None. A. D. Liese: None. D. Dabelea: None. C. T. Whitlow: Consultant; Biogen, Genentech, Inc. C. Coughlan: None. J. Kim: None. H. Potter: None. P. Bjornstad: Advisory Panel; AstraZeneca, Novo Nordisk, Lilly, Horizon Therapeutics plc, Boehringer Ingelheim (Canada) Ltd., LG Chem, Consultant; Bayer Inc., Bristol-Myers Squibb Company. M. E. Pauley: None. B. S. Rajic: None. J. Truong: None. D. H. Glueck: None.

Funding
American College of Radiology
187-OR: Circulating MicroRNAs Predict Weight Loss in Participants from the Diabetes Prevention Program
Authors: GONG XINGYUE , LEWIS KIMBERLY A. , FLOREZ JOSE C. , AOUIZERAT BRADLEY , KANAYA ALKA M. , ZHANG LI , FLOWERS ELENA 
Published: June 2023

Introduction: Weight loss is an important strategy for prevention of type 2 diabetes (T2D). Circulating microRNAs (miRs) are emerging as promising biomarkers of risk for T2D and responses to risk reduction interventions. The purpose of this study was to determine whether baseline microRNAs predict weight loss in a subset of participants in the Diabetes Prevention Program (DPP).
Methods: This study was a secondary analysis of a subset of participants from DPP (n=150, equally stratified by trial arm (intensive lifestyle, metformin, and placebo)). MiRs (58 total) were measured in banked plasma from the baseline timepoint using a custom Fireplex assay. Lasso was used to apply shrinkage for feature selection to identify a composite score of optimal miR predictors and logistic regression was used to model &gt;7% weight loss after 2 years.
Results: Five miRs (miR-122, miR-151a, miR-192, miR-197, miR-23b) were identified as the optimal predictors of weight loss using Lasso. After adjustment for significant covariates (age, gender, race or ethnicity, and trial arm), the odds ratio of composite score for &gt;7% weight loss was 3.16 (95% confidence interval (CI) 1.62, 6.18; p&lt;0.001). There was no significant interaction between the composite score and the trial arms (p=0.239), where odds ratio of composite score in the metformin arm, the intensive lifestyle arm and placebo are 1.16, 4.67, 2.42, respectively. Five-fold cross validation showed an accuracy score of 80%. The area under the receiver operating characteristic curve for &gt;7% weight loss after 2-years was 0.85.
Conclusions: MiRs are significant predictors of weight loss for prevention of T2D. Future directions include external validation in order to determine whether this risk score may have clinical utility, and functional analysis of the potential genes and pathways targeted by the miRs that were included in the risk score.

Disclosure
X.Gong: None. K.A.Lewis: None. J.C.Florez: Consultant; AstraZeneca, Novo Nordisk, Other Relationship; AstraZeneca, Merck & Co., Inc. B.Aouizerat: None. A.M.Kanaya: None. L.Zhang: None. E.Flowers: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK124228, X01DK115999)
19-LB: Metabolomics and Continuous Glucose Monitoring Analyses during the Perioperative Period of Coronary Artery Bypass Graft Surgery
Authors: GUERRERO ARROYO LIZDA I. , ZAHEDI TAJRISHI FARBOD , SAM VARGHESE JITHIN , PEREZ-GUZMAN MIREYA , ABRAHAM AMALIA , SMITH MATTHEW R. , PASQUEL FRANCISCO J. 
Published: June 2023

Hyperglycemia is common after Coronary Artery Bypass Graft (CABG) surgery. Many patients with stress hyperglycemia experience poor outcomes after surgery. The metabolic pathways associated with glycemic control during this period remain unknown. We used prospective observational data from 17 patients without diabetes who underwent CABG surgery and wore blinded Dexcom G6 pro devices during the perioperative period to explore associations with changes in the metabolome. We estimated the percentage time spent in the target range (70-140 mg/dL) using CGM values calibrated to point-of-care measurements. We categorized patients according to time spent (≥70 or &lt;70%) in the target range. Nine participants spent &gt;70% of time in the target range, while eight participants spent &lt;70% of time in the target range. Metabolic pathways were identified from HILIC positive and Reverse Phase C18 analysis, with metabolites mapped to Kyoto Encyclopedia of Genes and Genomes (KEGG) human pathways using mummichog. Baseline characteristics were similar between groups. Acylcarnitines and microbiome-related metabolites (e.g. 2-Dehydro-3-deoxy-D-gluconate 6-phosphate) were associated with worse glycemic control in the perioperative period, Figure. Metabolomics analysis suggests microbiome interactions and lipid pathways are associated with glycemic control after CABG surgery.

Disclosure
L. I. Guerrero arroyo: None. F. Zahedi tajrishi: None. J. Varghese: None. M. Perez-guzman: None. A. Abraham: None. M. R. Smith: None. F. J. Pasquel: Consultant; Dexcom, Inc., Medscape, Research Support; Dexcom, Inc., Ideal Medical Technologies.

Funding
National Institutes of Health (K23GM128221); Dexcom, Inc.
190-LB: Differences in Postprandial and Counterregulatory Glucagon Excursions in Healthy Relatives to Type 1 Diabetes with Different Number of Islet Autoantibodies
Authors: IGBE TOBORE , MONTASER ESLAM , BRETON MARC D. , BROWN SUE A. , DEBOER MARK D. , MCCALL ANTHONY L. , KOVATCHEV BORIS , FARHY LEON 
Published: June 2023

Background and aims: Early changes in glucagon during the progression to type 1 diabetes (T1D) are not well understood. We investigate whether the glucagon responses to a mixed meal and hypoglycemia depend on the number of islet autoantibodies (Ab) in individuals at risk for T1D.
Methods: Sixty healthy relatives of T1D with mean±SD age of 23.7±10.7 years, HbA1c of 5.3±0.3%, and BMI of 23.8±5.6 kg/m2 and zero (N=21), one (N=18), and ≥2 (N=21) Ab, were enrolled in an ancillary study from the NIH-funded TrialNet Pathway to Prevention study. Participants underwent a clinical test consisting of a mixed meal tolerance test (MMTT) followed by insulin-induced hypoglycemia. Glucagon was measured from -30 to 120 min around the MMTT and 0 to 40 min during hypoglycemia to estimate the Ab group differences in the meal and counter-regulatory glucagon responses assessed via the glucagon incremental area under the curve (iAUC).
Results: There were significant differences in the net iAUC of the glucagon responses to the MMTT (p=0.024), while the group difference in the glucagon counter-regulation estimated via the total AUC approached significance (p=0.08).
Conclusion: The study suggests that the glucagon responses to a meal and possibly, hypoglycemia, may be altered during the very early stages of the progression to T1D.

Disclosure
T. Igbe: None. E. Montaser: None. M. D. Breton: Consultant; Dexcom, Inc. Research Support; Dexcom, Inc. Consultant; Tandem Diabetes Care, Inc. Research Support; Tandem Diabetes Care, Inc., Novo Nordisk. Consultant; Roche Diabetes Care, Sanofi, Arecor. S. A. Brown: Research Support; Dexcom, Inc., Insulet Corporation, Tandem Diabetes Care, Inc. M. D. DeBoer: Research Support; Dexcom, Inc., Tandem Diabetes Care, Inc. A. L. McCall: None. B. Kovatchev: Speaker's Bureau; Tandem Diabetes Care, Inc. Research Support; Dexcom, Inc., Novo Nordisk, Tandem Diabetes Care, Inc. Other Relationship; Dexcom, Inc., Johnson & Johnson Medical Devices Companies, Novo Nordisk, Sanofi. L. Farhy: Research Support; Dexcom, Inc., Novo Nordisk.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (DP3DK106907); Commonwealth Research Commercialization Fund (MF20-007-LS); The Leona M. and Harry B. Helmsley Charitable Trust (2204-05134); JDRF (2-SRA-2022-1260-S-B)
195-LB: Type 2 Diabetes Data Quality in the All of Us Dataset
Authors: SULIEMAN LINA , GIANNINI JOHN , DEDE YILDIRIM ELIF , OSTCHEGA YECHIAM , OCHSENFABER EVAN , BERMAN LEW , RAMIREZ ANDREA 
Published: June 2023

Data quality significantly impacts the reproducibility and validity of clinical research. The All of Us Research Program aims to collect biomedical data from one million or more participants, with the goal of enabling discoveries and improving targeted management of diseases like type 2 diabetes (T2D). All of Us data include whole genome sequences (WGS), electronic health records (EHRs), device measurements of physical activity, physical measures, and surveys available for analysis on the Researcher Workbench. The program's Spring 2023 curated data release makes All of Us the world's largest, most diverse genomic dataset of its kind available for broad research use, including 413,457 participants among which 60.4% are female, 44.6% are non-white.
To ensure maximum utility of this dataset for T2D researchers, we set out to quantify the data quality among participants who have T2D diagnosis codes in their EHRs. We identified the measurements and laboratory tests (hemoglobin A1C, height, weight, body mass index), medications (Insulin and non-insulin), and procedures commonly used in T2D research. We quantified data fitness using five dimensions of quality: completeness, concordance (i.e., agreement), conformance to data standards, plausibility, and temporality.
Among 287,012 participants who shared EHRs, 40,093 (14%) had T2D diagnosis codes where the mean age at first diagnosis was 56. Regarding measurements, 68% had A1C, 89% had height, and 70% had weight recorded in their EHR. For plausibility, 99.7% of weights, 99.9% of heights, and 99.3% of BMI were valid, and 97% of heights and weights have high concordance values. For medications, 99.7% of T2D participants had T2D medications, and 47.6% were prescribed after T2D diagnosis. Of these T2D participants, 69% have WGS or array data available.
Our analysis shows that the All of Us dataset offers a valuable and high-quality dataset for T2D phenotyping and diagnosis research. Our quality report and code will be available for replication and reuse by researchers with the upcoming release.

Disclosure
L. Sulieman: None. J. Giannini: None. E. Dede yildirim: None. Y. Ostchega: None. E. Ochsenfaber: None. L. Berman: None. A. Ramirez: n/a.
196-OR: The Long-Chain Fatty-Acid Receptor FFA4 Stimulates Insulin Secretion via Inhibition of Somatostatin Release from the Delta Cell
Authors: REININGER LAURA , ETHIER MÉLANIE , TREMBLAY CAROLINE , GHISLAIN JULIEN , HUISING MARK , POITOUT VINCENT , FLISHER MARCUS 
Published: June 2023

The long-chain fatty-acid receptor FFA4 exerts beneficial effects on glucose homeostasis and insulin secretion and is considered a potential therapeutic target for type 2 diabetes. FFA4 is expressed in islets, but its precise mechanism of action remains unknown. Previous studies from our group suggest that FFA4 is expressed in delta cells and regulates somatostatin secretion. The objective of this study was to test the hypothesis that FFA4 agonists indirectly stimulate insulin secretion via inhibition of somatostatin release. In 1-h static incubations of isolated, wild-type mouse islets, the FFA4 agonist CpdA dose-dependently potentiated glucose-induced insulin secretion from 2.2±0.2 to 3.4±0.2 % of insulin content at the concentration of 50 μM (n=8; p&lt;0.001), and simultaneously decreased somatostatin secretion from 28.4±2.1 to 10.5±0.9 pM (n=8; p&lt;0.0001). No effect of CpdA on insulin or somatostatin secretion was observed in islets from mice that do not express somatostatin (insulin: 3.2±0.1 vs 2.9±0.4, n=6, NS; somatostatin: 11.4±1.2 vs 11.9±1.2, n=6, NS). No sex differences were observed. Likewise, in delta-cell deficient islets isolated from diphtheria toxin-treated male mice expressing the diphtheria toxin receptor under the somatostatin promoter, no effect of CpdA was observed on insulin or somatostatin release (insulin: 4.9±0.9 vs 4.1±0.8, n=3, NS; somatostatin: 10.1±4.9 vs 9.2±5.3, n=6, NS). We conclude that FFA4 stimulation of insulin secretion is exclusively mediated by inhibition of somatostatin secretion from delta cells.

Disclosure
L.Reininger: None. M.Ethier: None. C.Tremblay: None. J.Ghislain: None. M.Huising: Consultant; AstraZeneca, Research Support; Crinetics Pharmaceuticals, Inc. V.Poitout: Consultant; AstraZeneca. M.Flisher: None.

Funding
National Institutes of Health (R01DK132597)