bluuebunny/crossref_metadata_2025_split huggingface dataset:
1268-P: Underlying T Cell Receptor Methylation Defects in Type 1 Diabetes Associated with Quantitative Defects
Authors: KUHTREIBER WILLEM , LEE AMANDA H. , ARISTARKHOVA ANNA , DIAS HANS F. , NG NATHAN , BIEN STEPHANIE A. , FAUSTMAN DENISE L. 
Published: May 2022

The T cell receptor (TCR) is a central regulator of the adaptive immune system. Efficient structural organization and signaling of TCR/CD3 underlies the development and function of T cells. T cell maturation defects are associated with autoimmunity, suggesting an underlying defect in TCR selection. To explore quantitative defects as a cause for altered TCR selection at the level of the TCR/CD3 protein complex, we compared TCR expression densities on CD4 T cells from subjects with type 1 diabetes (T1D) (n=80) and nondiabetes controls (n=37) . We also investigated a quantitative defect in genes in the TCR/CD3 genome for possible underlying overmethylation in T1D. All 13 gene regions of the TCR segments and all 4 versions of CD3 proteins were studied for methylation and protein differences in T1D vs. controls. Significant quantitative defects in TCR and CD3 proteins were observed in CD4+ T cells of patients with T1D vs. controls. As a cause for these defects, the TCR complex genes and associated CD3 genes were overmethylated, resulting in downregulated cell surface expression. Evaluation of TCRαβ expression in CD4+ T cells at the protein level confirmed methylation patterns, showing that the population of TCRαβ+ cells was significantly reduced in T1D vs. controls (p=0.005) . The MFI density of TCRαβ antibody in T1D was also significantly decreased vs. controls (p=0.01) . All CD3 genes except CD3ε had hypermethylated patterns in T1D, confirmed by RNAseq analysis. The percentage CD3+ T cells in the CD4+ T cell population was reduced in T1D vs. controls (p=0.04) , as was the MFI of CD3+ T cells (p=0.02) . Patients with T1D have quantitative defects in the TCR/CD3 protein complex, resulting in decreased expression. It is recognized that TCR triggering is affected by intermolecular distance between TCR proteins and that activation diminishes when proximity is increased between TCR surface proteins. In T1D, this might be a novel mechanism for failed T cell selection leading to autoimmunity.

Disclosure
W.Kuhtreiber: None. A.H.Lee: None. A.Aristarkhova: None. H.F.Dias: None. N.Ng: None. S.A.Bien: Employee; Adaptive Biotechnologies. D.L.Faustman: None.
1272-P: Genomic Rearrangement in Noncoding Region of Chromosome 1 Leads to Spontaneous Obesity and Type 2 Diabetes
Authors: WHITE DONNELL , WU JIAN , LAUTERBOECK LOTHAR , KANG SUNG WOOK , ELGAZZAZ MONA , ALAHARI SURESH , LAZARTIGUES ERIC D. , YANG QINGLIN 
Published: May 2022

Obesity is a major health risk for type 2 diabetes, along with many other disease conditions. We discovered spontaneous obese mice among a conditional transgenic mouse line (Floxed-stop Overexpression of IF1, or FEI) , which was originally generated and maintained for Cre-mediated conditional transgenic IF1 expression. Severe obesity became a fixed phenotype in FEI mice after inbreeding for 5-6 generations. Targeted-Locus-Amplification (TLA) analyses revealed that a rearrangement occurred in upstream sequences (48,224,9 to 48,248,586) of the transgenic integrated site, and are duplicated downstream at a non-coding region of chromosome 1. Early-onset obesity was consistent in both male and female FEI mice with progressive weight gain from 2 months and reached 50-60 grams at 6-8 months. Body composition analyses revealed that FEI mice have markedly increased fat mass and modestly increased lean mass compared to wild-type (WT) mice. Consistently, the FEI mice exhibited increased peripheral fat pads and dyslipidemia. The FEI mice exhibited increased food intake but reduced systemic metabolic rates. Moreover, we detected increased fed and fasting blood glucose, insulin, and leptin with impaired glucose and insulin tolerance in FEI mice as early as 6 weeks of age. Histology analyses with H&E staining revealed markedly enlarged adipocytes with crown-like structures on visceral white adipose tissue sections and increased fat deposition in liver sections from FEI mice. RNAseq analyses on RNA samples from subcutaneous white adipose tissues demonstrate the upregulation of adipogenesis and inflammation genes. These results indicate that the FEI mouse line is a novel obese mouse model with genomic rearrangement in a non-coding region, which may serve as cis-regulatory elements for obese genes. Further studies on these mice should yield novel and translational insight into the molecular and metabolic mechanisms underlying obesity development with complex genetic traits.

Disclosure
D.White: None. J.Wu: None. L.Lauterboeck: None. S.Kang: None. M.Elgazzaz: None. S.Alahari: None. E.D.Lazartigues: None. Q.Yang: None.
128-LB: Real-World A1C Changes and Prescribing Provider Types among T2DM Patients Initiating Treatment with Once-Weekly (OW) Semaglutide
Authors: FRAZER MONICA S. , SWIFT CAROLINE , SARGENT ANDREW , LESZKO MICHAEL , BUYSMAN ERIN , ALVAREZ SARA B. , NOONE JOSHUA , GAMBLE CORY L. 
Published: May 2022

Purpose: Characterize A1c changes and characteristics among patients with T2DM initiating OW semaglutide (sema) , by baseline A1c ≥9% and &lt;9%.
Methods: Retrospective analysis using medical and pharmacy claims data between 01/01/2017-12/31/2020 from commercial and Medicare Advantage with Part D insurance enrollees, age 18+. Patients had ≥1 claim for OW sema (first claim=index date) , ≥1 T2DM diagnosis, continuous enrollment for 12 months before and including index (baseline) and 12 months after (follow-up) and were excluded if pregnant. Results were stratified by whether patient’s last baseline A1c value was ≥ or &lt;9%.
Results: Patients initiating OW sema with ≥1 baseline A1c value (n=7,653) had a mean age of 59 years, 51.4% were female, and 62.5% had commercial coverage. Among patients with baseline and follow-up A1c value (n=6,042) , mean A1c change was -0.8 (1.6) . Among a subset of patients with ≥90 days of continuous OW sema treatment and at least 1 A1c value after 90 days of treatment (n=3,456) , the A1c ≥9% group had a mean A1c reduction -2.5%. While many study patients had index claims prescribed by primary care and internal medicine providers (46.1% overall) , a higher percentage of patients with A1c &lt;9% had OW sema prescribed by an endocrinologist (28.5% vs. 25.5%; p=0.008) .
Conclusions: Results suggest that OW sema is an effective T2DM treatment in the real-world, especially among patients with A1c ≥9% prior to treatment initiation. Additionally, patients with T2DM in this study were more often prescribed OW sema by primary care physicians than by endocrinologists.

Disclosure
M. S. Frazer: None. C. Swift: Employee; Novo Nordisk. A. Sargent: None. M. Leszko: None. E. Buysman: None. S. B. Alvarez: Employee; Novo Nordisk, UnitedHealth Group. J. Noone: Employee; Novo Nordisk. C. L. Gamble: Employee; Novo Nordisk.
1281-P: Understanding the Interaction between Type 2 Diabetes and COVID-via Extracellular Vesicle Proteomic and Phosphoproteomic Signatures
Authors: NUNEZ LOPEZ YURY O. , ILIUK ANYON , CASU ANNA , LUPU DANIEL S. , PRATLEY RICHARD E. 
Published: May 2022

Evidence supporting the involvement of EVs in the pathogenesis/severity of SARS-CoV-2 infection is starting to accumulate. However, little is known about their specific associations in the context of COVID-and type 2 diabetes interaction. Our study included 48 plasma samples (N=12/group) obtained from COVID-patients with and without diabetes and from patients with non-COVID-acute respiratory diagnosis (RSP) with and without diabetes. Participants were identified from a set of 494 patients hospitalized at AdventHealth in June-August 2020. Important efforts were made to ensure the homogeneity of the study cohort. Patients with type 1 diabetes, or pregnant, or that went directly into the ICU were excluded, and 4 balanced groups were identified after 10,000 random cohorts were generated and differences in age, gender, race, and ethnicity statistically assessed. EVs were isolated using EVTRAP (Tymora) . Mass spectrometry-based methods were used to detect the global EV proteome and phosphoproteome. Differentially expressed features, enriched pathways, and enriched tissue-specific protein sets were identified. Multidimensional scaling of all EV proteomic and phosphoproteomic data and unsupervised clustering of differentially expressed (absolute fold change ≥ 2, P &lt; 0.05, FDR &lt; 0.05) EV proteins and phosphoproteins successfully distinguished the 4 study groups with close to 100% accuracy. Importantly, we detected enriched pathway networks that suggest the potential therapeutic utility of PKC inhibitors such as bisindolylmaleimide IX, sotrastaurin, and enzastaumn, and inhibitors of ROCK1 such the isoquinoline derivative Fasudil.
In conclusion, we characterized the proteomic landscape of the interaction between type 2 diabetes and COVID-and defined disease-specific EV proteomic signatures that provide insight into the disease pathobiology and druggable targets with potential clinical utility.

Disclosure
Y.O.Nunez lopez: None. A.Iliuk: None. A.Casu: None. D.S.Lupu: None. R.E.Pratley: Other Relationship; Bayer AG, Corcept Therapeutics, Dexcom, Inc., Hanmi Pharm. Co., Ltd., Merck & Co., Inc., Metavention, Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd.
1287-P: Deep Immune Phenotyping of Type 1 Diabetes by Machine Learning
Authors: VERA-RAMOS JOSÉ ANTONIO , PRIETL BARBARA , HERBSTHOFER LAURIN , PFEIFER VERENA , LÓPEZ-GARCÍA PABLO , STRADNER MARTIN , PIEBER THOMAS 
Published: May 2022

Breakdown of self-tolerance is an important common mechanism in autoimmunity. We use machine learning (ML) to identify common patterns and dissimilarities between type 1 diabetes (T1D) , rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) based on immune phenotyping. PBMCs were isolated from patients with T1D, RA, SLE, and controls. A FACS approach was applied, and a traditional analysis was compared to a ML method implemented on R and based on self-organizing maps (Fig) . Our pipeline includes unsupervised pre-gating, normalization, FlowSOM clustering, and a statistical model (GLMM) , to check for significant differential abundances of cell populations among the autoimmune conditions. After applying our automated workflow to one T cell panel we could identify 14 new cell clusters present in all the samples. The GLMM test revealed a cluster with a significant difference (p=0.035) and a trending one (p=0.059) on the abundance across the different diseases. In particular, CD4pos T cells expressing high IL-7 receptor (CD127) levels and median amounts of CD15s but low CD25, CD161 and FoxP3 are increased in T1D whereas CD4+CD25++CD15s+FoxP3lowCD161lowCD45RA- cells are increased in SLE.
In conclusion, our ML workflow identifies a new subtype of T cells significantly increased in T1D. This unsupervised analysis approach for large datasets enables the discovery of new biomarkers complementing traditional workflows.

Disclosure
J.Vera-ramos: None. B.Prietl: None. L.Herbsthofer: None. V.Pfeifer: None. P.López-garcía: None. M.Stradner: Consultant; AbbVie Inc., AstraZeneca, Speaker's Bureau; Janssen Pharmaceuticals, Inc. T.Pieber: Advisory Panel; Arecor, Novo Nordisk A/S, Research Support; AstraZeneca, European Union, JDRF, Novo Nordisk Foundation, Sanofi, Speaker's Bureau; Novo Nordisk A/S, Roche Diagnostics.

Funding
JDRF, LRA, & NMSS Joint RFA (2-SRA-2021-1043-S-B)
1290-P: A Rare Case of HNF1A-MODY
Authors: VELAYATI SARA , SHANIK MICHAEL , ROMAO ISABELA J. 
Published: May 2022

Introduction: Maturity onset diabetes of the young (MODY) is a monogenic nonimmune type of diabetes mellitus. It is rare and sometimes misdiagnosed as type 1 or type 2 diabetes (T2DM) . The age of onset is usually below 25 years. It is more common in the European population. Hepatocyte nuclear factor 1-alpha (HNF1A) is one of the most common mutations and is associated with cardiovascular and renal complications.1 Genetic testing in patients with strong hereditary factors results in definitive diagnosis and subsequent appropriate treatment.2 The aim of this report is to emphasize the importance of distinguishing MODY by considering the family history of diabetes and relative clinical features.
Case presentation: A 58-year-old Filipino woman was diagnosed with T2DM at age 15. Her mother, 5 of 8 siblings and her daughter all had diabetes. They all died in the 2nd or 3rd decades of their life due to diabetes complications. Her grandfather was European. She has renal insufficiency, coronary heart disease and heart failure. Treatment included glimepiride 2 mg daily and sitagliptin 25 mg daily. The physical exam was unremarkable. Body mass index (BMI) was 21. GAD 65 antibody and Islet cell antibody were negative, C peptide: 3.6 ng/mL, blood sugar: 1mg/dL, HbA1c: 7.3%, creatinine: 2.15 mg/dL and GFR: 25 mL/min/1.73m2. A diagnosis of MODY was considered due to strong family history of diabetes, young age at the onset of diabetes and normal BMI. DNA sequencing demonstrated positive HNF1A mutation compatible with HNF1A-MODY. Due to post prandial hyperglycemia, glimepiride was replaced with pre-meal lispro.
Conclusion: This is a rare case of HNF1A-MODY found in a Filipino patient. MODY should be included in the differential diagnosis of diabetic patients with an extensive family history of diabetes, young age of onset of diabetes and negative pancreatic antibodies. Early diagnosis with genetic profiling can guide therapy and hopefully decrease the vascular complications of long-term poor glycemic control.

Disclosure
S.Velayati: None. M.Shanik: Consultant; Bigfoot Biomedical, Inc., Proteomics International, Research Support; Better Therapeutics, Speaker's Bureau; Abbott, Boehringer Ingelheim International GmbH, Novo Nordisk, Xeris Pharmaceuticals, Inc. I.J.Romao: None.
1295-P: Learning from Immune Privileged Tissue Stem Cells to Generate Hypoimmunogenic Islets
Authors: AGUDO JUDITH 
Published: May 2022

The ultimate goal to accomplish a definitive cure for Type 1 Diabetes (T1D) is to replace the lost beta-cell mass while ensuring its long-lasting survival. This could be done by transplantation of pancreatic islets or stem cell-derived insulin-producing cells. However, any replacement will irrevocably succumb to the same autoimmune attack that killed the original beta-cells. Moreover, a mismatch between donor cells and recipient patients adds an allo-graft rejection. Thus, it is of the utmost importance to develop strategies to protect transplanted pancreatic islets from immune attack. Unfortunately, many approaches aiming at restoring tolerance by manipulating immune cells have been tested and, although safe, have shown only limited efficacy. Inflammatory processes, infections or major lifestyle changes can easily alter the balance again towards immune activation. We recently discovered the existence of immune privileged stem cells in the skin and muscle, and found that their ability to resist direct attack by T cells was not dependent on a physical barrier. Instead, it is a cell-autonomous process that allows independent cloaking from immune cells. Here we propose to exploit the molecular circuits controlling this striking phenomenon (that already naturally occurs in our bodies) to provide similar protection to islets for transplantation. We identified a molecular pathway that reduces antigen presentation allowing protection from T cells while preserving enough MHC class I to not trigger a Natural Killer (NK) cell response. Since this mechanism of protection is cell intrinsic, changes in overall immune function should not alter the ability of engineered islets to hide from immune rejection allowing for long-lasting survival.

Disclosure
J.Agudo: None.

Funding
American Diabetes Association (1-20-ACE-08)
13-LB: A Prediction Model of Chronic Kidney Disease Progression among Individuals with Type 2 Diabetes in the United States
Authors: LIN YILU , SHAO HUI , ANDERSON AMANDA H. , FONSECA VIVIAN , BATUMAN VECIHI , SHI LIZHENG 
Published: May 2022

CKD progression among individuals with T2D is associated with poor outcomes and high costs. The risk factors for CKD progression in T2D have not been fully studied. This study aimed to predict CKD progression among individuals with T2D. Using the ACCORD clinical trial, a time-varying Cox model was developed to predict the risk of CKD progression among patients with CKD. CKD progression was defined as a 50% decline, or 25 mL/min/1.73 m2 decline in eGFR from baseline, doubling of the serum creatinine, or onset of ESKD. A list of candidate variables included demographic characteristics, physical exam, laboratory, medical history, drug use, and healthcare utilization. A stepwise algorithm was used for variable selection. Data was separated into training and validation set. Model performance was evaluated by Brier score (BS) and C statistics. Confidence intervals (CI) were calculated by bootstraping. Decomposition analysis was conducted to assess the predictor contribution. Generalizability was assessed on patient-level data of the HARMONY Outcome clinical trial. A total of 6,982 T2D patients with CKD were used for model development, with a median follow-up of 4 years and 3,346 CKD progression events. The predictors for CKD progression included female sex, age at T2D diagnosis, smoking status, BP, HR, HbA1c, ALT, eGFR, UACR, retinopathy event, hospitalization, interaction of SBP and smoking, and SBP and ALT. The model demonstrated good discrimination (C-statistics 0.745 [95% CI 0.723-0.763]) and calibration (BS 0.0923 [95% CI 0.0873-0.0965]) . The most contributing predictors for CKD progression were eGFR, HbA1c, and SBP. There were 2,954 patients with CKD extracted from HARMONY with 640 CKD progression events and median follow-up of 2 years. The model demonstrated acceptable discrimination (C-statistics: 0.742 [95% CI 0.721-0.7645]) and calibration (BS: 0.0988 [95% CI 0.0952-0.1022]) in the external data. For high-risk patients with both diabetes and CKD, the tool as a dynamic risk prediction of CKD progression may help develop novel strategies to lower the risk of CKD progression.

Disclosure
Y. Lin: None. H. Shao: Board Member; BRAVO4HEALTH, LLC. A. H. Anderson: None. V. Fonseca: Consultant; Abbott, Asahi Kasei Corporation, Bayer AG, Novo Nordisk, Sanofi, Research Support; Fractyl Health, Inc., Jaguar Gene Therapy, Stock/Shareholder; Abbott, Amgen Inc., BRAVO4Health, Mellitus Health. V. Batuman: None. L. Shi: None.
1302-P: Inhibitory Effect of Advanced Glycation End Products on Proinsulin Processing
Authors: BRINGS SEBASTIAN , MIER WALTER , BEIJER BARBRO , SZENDROEDI JULIA M. , NAWROTH PETER P. , FLEMING THOMAS H. 
Published: May 2022

Advanced glycation end-products (AGEs) form at an accelerated rate in diabetes and are associated with the development of diabetic complications. So far, the effect of AGEs on proteases was mostly investigated with substrates modified non-specifically with hexoses amongst others in combination with proteases of broad specificity. Here, we investigated the effect of AGEs on the proinsulin processing peptidases preprotein convertase 1 (PC1) and carboxypeptidase E (CPE) via two ways: - Measuring of activity towards peptide substrates. These contained chemically defined AGEs carboxymethyllysine (CML) or methylglyoxyl-hydroimidazolone-1 (MGH1) or unmodified amino acids. - Recombinant human proinsulin was incubated with methylglyoxal for 24 h and was processed by addition of PC1 and CPE in vitro. Formation of insulin was compared to unmodified proinsulin. In parallel formation of AGE-modified proinsulin was quantified.
Artificial peptide substrates were synthesized by solid phase peptide synthesis and purified by HPLC. A protected building block was used for MGH1 incorporation while CML was introduced on the resin. Protease activity towards artificial substrates was measured by fluorescence assay or LC MS/MS. Proinsulin, insulin and AGE-modified proinsulin were quantified by LC MS.
Strong activity of PC1 and CPE was seen towards arginine containing substrates. Activity was completely absent towards modified amino acids MGH1 and CML for both, PC1 and CPE. Incubation of proinsulin with MG resulted in MGH1 modified proinsulin. At low MG (µM) concentrations this was associated with a 25 % reduction of insulin formation while high MG concentrations (95 µM) led to a 75 % reduction in insulin formation.
Here we demonstrate for the first time the effect of substrate modifications with AGEs on physiologically important proteases PC1 and CPE. The latter are not only involved in the processing of proinsulin but a range of endocrinologically and neurophysiologically important peptide hormones.

Disclosure
W. Mier: None. B. Beijer: None. J.M. Szendroedi: Consultant; Boehringer Ingelheim International GmbH. T.H. Fleming: None.

Funding
DFG (SFB 1118)
131-OR: Effect of a Value-Based Medication Benefit on Acute Preventable Diabetes Complications and Related Disparities
Authors: WHARAM J. FRANK , ZHANG FANG , LAKOMA MATTHEW , GARABEDIAN LAURA F. , ARGETSINGER STEPHANIE , ROSS-DEGNAN DENNIS 
Published: May 2022

Employers are increasingly purchasing "preventive drug list" (PDL) insurance plans that make cardiometabolic medications $0. PDL designs improve adherence, but effects on health outcomes are unknown. We analyzed 2004-2017 commercial health insurance claims using a large, national data set. The intervention group included 12,853 commercially-insured diabetes patients aged 12-64 years who experienced employer-mandated PDL switches; the control group included 12,989 matched counterparts whose employers offered no PDL. We defined the index date as the day the intervention group received the PDL, and matched controls had a contemporaneous index date. Both groups had a 1-year baseline and 1-year follow-up study period. We measured monthly rates of aggregated acute preventable diabetes complication episodes (e.g, hyperglycemic coma, angina, and pneumonia) presenting to (1) the outpatient setting or (2) the emergency department, observation, or inpatient settings ("high acuity") . We constructed cumulative interrupted time series plots of these two measures and conducted segmented regression analysis and marginal effects estimation. Low-income members were a subgroup of interest. Annual outpatient and high-acuity complication episodes decreased by -13.5% (-15.2%, -11.7%) and -13.9% (-15.3%, -12.5%) , respectively, in the PDL group relative to controls. Low-income PDL members also experienced decreased outpatient (-27.2% [-32.1%, -22.4%]) and high-acuity complication episodes (-4.4% [-6.5%, -2.4%]) . This rigorous, quasi-experimental study is the first to demonstrate that a value-based medication benefit is associated with improved health outcomes and reduced disparities. Employer adoption of PDLs thus represents a relatively expedient approach to improving health and equity, and our results support a strategy of incentivizing such targeted cost sharing reductions for vulnerable diabetes populations.

Disclosure
J.Wharam: None. F.Zhang: Research Support; GlaxoSmithKline plc. M.Lakoma: None. L.F.Garabedian: None. S.Argetsinger: None. D.Ross-degnan: None.

Funding
CDC and NIDDK