bluuebunny/crossref_metadata_2025_split huggingface dataset:
197-LB: Capillary Islet Autoantibody Testing at the Preschool Vaccination Is a Feasible and Acceptable Method to Screen Children for Type 1 Diabetes
Authors: SCUDDER CLAIRE , BOWEN-MORRIS JANE , EVANS PHILIP H. , JONES SARAH C. , THOMAS NICHOLAS P.B. , FOX ROBIN , TODD JOHN , GREENFIELD SHEILA , DAYAN COLIN , TOWNSON JULIA , BESSER RACHEL 
Published: June 2023

Background: Islet autoantibody screening for type 1 diabetes (T1D) reduces life-threatening diabetic ketoacidosis, hospitalization and identifies individuals eligible for future preventative treatments. 3.5-4 years has been indicated as an optimal time to screen younger children for T1D at a single-time point. We therefore assessed the feasibility and acceptability of screening at this age, to align with the pre-school vaccination visit, in a first of its kind, proof-of-concept study in the UK.
Methods: Children attending routine pre-school vaccinations (n= 63; median age 3.5y (IQR 3.4-3.6, range 3.1-5.1y), 26 (41.3%) male) provided capillary blood samples which were posted for IAA, GADA, IA-2A and ZnT8A analysis. Serum volumes &gt;60µL were tested using Radiobinding assay (RBA), and &lt;60µL by Luciferase Immunoprecipitation Systems (LIPS) assay. Acceptability was assessed using open question postcards, and semi structured interviews.
Results: There was 97% (61/63 samples) success in sample analysis, with median serum collected 100µL (IQR 80-155) and 83% (52/63)&gt;60µL. One participant screened and confirmed positive by RBA for IAA.
Participants (n=15 interviews, n=31 postcards) were uniformly positive about screening aligning to the vaccination programme, citing that they may have been less likely to take part had screening been a separate visit. Themes identified included being prepared in the event of a T1D diagnosis, feeling reassured by a negative test result, and the long-term benefit of screening outweighing short-term upset. Parents reported that the volume of blood was higher, and collection time longer than expected.
Conclusions: Capillary islet autoantibody testing is a feasible and acceptable method to screen children for T1D. Aligning sample collection to the pre-school vaccination was not a deterrent to vaccination. The approach of combining screening with a routine health visit may enable uptake and could be cost saving.

Disclosure
C. Scudder: None. J. Townson: None. R. Besser: Consultant; Provention Bio, Inc. J. Bowen-morris: None. P. H. Evans: None. S. C. Jones: None. N. P. B. Thomas: None. R. Fox: None. J. Todd: Advisory Panel; GlaxoSmithKline plc., Precion, Qlife, Vesalius Therapeutics. S. Greenfield: None. C. Dayan: Advisory Panel; AstraZeneca, Consultant; Provention Bio, Sanofi, Avotres Inc., Other Relationship; Dompé, Merck & Co., Inc.

Funding
National Institute for Health Research (203948)
199-LB: Mitochondrial Diabetes (MD) in the University of Chicago Monogenic Diabetes Registry
Authors: BOWDEN TIANA L. , KANDASAMY BALAMURUGAN , LETOURNEAU-FREIBERG LISA R. , RODRIGUEZ KAREN , MCCULLOUGH MICHAEL , GREELEY SIRI ATMA W. , PHILIPSON LOUIS H. 
Published: June 2023

Mitochondrial diabetes (MD) results from pathogenic variants in mitochondrial (MT) genes. MT disease is associated with neuromuscular disease. MD may occur either alone or with other conditions. The most common MD genetic variant is MT-TL1 m.3243 A&gt;G, associated with Maternally Inherited Diabetes and Deafness and Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes. The incidence, variability and optimum treatment are uncertain. We describe clinical characteristics of participants in the Univ. of Chicago Monogenic Diabetes Registry with MD variants. Participants enrolled in the Univ. of Chicago Monogenic Diabetes Registry (IRB 6858,15617B). Clinical and genetic information was collected. As of February 2023, 18 participants from 13 families had a known MT variant. Clinical characteristics are in Table 1. Clinicians should consider MD when the patient is negative for T1D antibodies, is non-obese, has high frequency bilateral hearing loss, and has a strong maternal family history of diabetes. However, the features are variable and can include multiple organs and tissues. Genetic testing panels should include MT variants because MD can be misdiagnosed and the prevalence is uncertain. Clinical phenotypes are heterogenous among family members. Cascade testing and screening for related conditions is encouraged. Our data shows that MD is misdiagnosed as T1 or T2DM (16/16).

Disclosure
T. L. Bowden: Stock/Shareholder; Procter & Gamble, OPKO Biologics, Ltd. B. Kandasamy: None. L. R. Letourneau-freiberg: None. K. Rodriguez: None. M. Mccullough: None. S. W. Greeley: None. L. H. Philipson: Advisory Panel; Nevro Corp., Research Support; Novo Nordisk, Dompé, Provention Bio, Inc., Imcyse, Novo Nordisk Foundation.

Funding
National Institutes of Health (R01DK104942, P30DK020595, K23DK094866, UL1TR000430)
199-OR: Optogenetic Control of Pancreatic Delta Cells Reveals Their Central Role in Hormone Release from Pancreatic Islets
Authors: DOU HAIQIANG , MIRANDA CAROLINE A. , TOLÖ JOHAN , ZHANG QUAN , RORSMAN PATRIK 
Published: June 2023

Diabetes mellitus is a metabolic disorder resulting from insufficient insulin release and associated with dysregulation of glucagon secretion. Somatostatin secreted from pancreatic δ-cells is a strong paracrine factor for both insulin and glucagon secretion in islets. Here, we developed an optogenetic approach, through specific expressing light-sensitive channels/pumps in δ-cells, to investigate the paracrine control of hormone release from islets. We generated mouse models that express either a light-sensitive cation channel, channelrhodopsin-2 (ChR2), or a chloride pump, halorhodopsin (HR), specifically in the pancreatic δ-cells (SST-ChR2 and SST-HR mouse). Their specific expression was confirmed by immunostaining. Optoactivation of ChR2 at 1mM glucose rapidly depolarized δ-cells by 37mV (n=5) and stimulated electrical activity and somatostatin release. At high glucose or tolbutamide, light activation of HR repolarized δ-cells by 15 mV (n=3), suppressing action potentials. Optoactivation of SST-ChR2 δ-cells suppressed, after a variable delay depending on the distance from δ-cells, action potential firing in neighbouring α-cells, inhibited exocytosis by 30% (n=5) and glucagon secretion by 55% at 1mM glucose (n=7). In a subset (35%) α-cells with no spontaneous action potentials, opto-inhibition of SST-HR δ-cells caused a 9mV depolarization (n=7) and induced action potential firing, which may account for the stimulation of glucagon secretion. Neither optoactivation, nor opto-inhibition of δ-cells affected insulin secretion at hypo- and hyperglycaemia. However, at normoglycaemia (6 mM glucose), optoactivation of δ-cells depolarized neighbouring β-cells (via gap-junctions) and evoked action potential firing, leading to a paradoxical 160% stimulation of insulin secretion (n=9). We conclude that δ-cells play a central role in the regulation of both insulin and glucagon release but that the effects are more complex than appreciated to date.

Disclosure
H.Dou: None. C.A.Miranda: None. J.Tolö: None. Q.Zhang: None. P.Rorsman: None.

Funding
Swedish Research Council
200-LB: Benefit of Dual Therapy with GLP-1 RA and SGLT2i on Cardiovascular Outcomes in Type 2 Diabetes
Authors: ZAREINI BOCHRA , GERDS THOMAS A. , SØRENSEN KATHRINE K. , CLEMMENSEN KIM K.B. , KVIST KAJSA , DAVID JENS-PETER , TORP-PEDERSEN CHRISTIAN 
Published: June 2023

Background: Evidence on the cardiovascular benefit of dual glucagon like peptide-1 receptor agonist (GLP-1 RA) and sodium-glucose co-transporter-2 inhibitor (SGLT2i) therapy is lacking.
Aim: To compare the benefit of dual GLP-1 RA and SGLT2i therapy to other dual type 2 diabetes therapies with respect to heart failure and major cardiovascular adverse events (MACE).
Methods: From 2010-2021 patients from the Danish nationwide registries were followed from start of dual second-line type 2 diabetes treatment. Primary outcome was heart failure, and secondary outcomes were MACE and all-cause death. The estimated risk following 1 of 4 dual therapy combinations was determined using a longitudinal causal inference framework assuming all patients followed one dual therapy for 5 years.
Results: A total of 87,201 persons were included (GLP-1 RA and SGLT2i: 14,831, GLP-1 RA and DPP4/SU/TZD: 20,417, SGLT2i and DPP4/SU/TZD: 22,803, dual DPP4/SU/TZD: 29,150). The 5-year risk ratio (95% CI) of dual GLP-1 RA and SGLT2i therapy compared to reference (dual DPP4/SU/TZD) for heart failure was: 0.93 (0.87;1.00), for MACE: 0.91 (0.87;0.95) and for all cause death: 0.78 (0.74;0.82), see Figure.
Conclusion: Dual therapy with GLP-1 RA and SGLT2i showed a benefit on heart failure compared to other dual therapies. Dual therapy with GLP-1 RA and SGLT2i showed a benefit on MACE and all-cause death compared to the reference treatment.

Disclosure
B. Zareini: None. T. A. Gerds: None. K. K. Sørensen: None. K. K. B. Clemmensen: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. K. Kvist: Employee; Novo Nordisk A/S. J. David: Employee; Novo Nordisk A/S, Sanofi. C. Torp-pedersen: Research Support; Novo Nordisk, Bayer Inc.
201-OR: Characterization of Type 1 Diabetes (T1D) Endotypes
Authors: BEDRAT AMINA , PANT TARUN , JIA SHUANG , ROETHLE MARK , TRUCHAN NATHAN A. , CABRERA SUSANNE M. , CHEN YI-GUANG , LIN CHIEN-WEI , HESSNER MARTIN 
Published: June 2023

To better understand how T1D heterogeneity relates to disease progression and therapeutic responsiveness, we studied 566 recent onset subjects (mean age at onset: 16.5 +/- 8.2) that had participated in the following TrialNet trials: MMF-DZB, anti-CD20; GAD-alum; CTLA4-Ig; Canakinumab; and ATG-GCSF. Our analysis began with a bioassay where plasma collected pre-intervention and within 100 days of diagnosis was used to induce transcription in a well-controlled peripheral blood mononuclear cell population. Microarray analysis identified 2,854 transcripts exhibiting high variation in at least 5 out of 6 trials. Hierarchical clustering and principal component analysis of these transcripts concordantly divided the participants into 2 major groups: Group 1 and Group 2. Analysis of post-baseline samples found group assignments conserved over time. Proportional analyses of the 406 subjects aged &lt;18 years found Groups 1 and 2 distinct: subjects aged &gt;14years segregated within Group 2 (39.9% vs 29.3%, p=0.03); subjects possessing neutral/low-risk HLA haplotypes segregated within Group 1 (20.5% vs 11.8%, p=0.04); placebo arm participants with the most rapid C-peptide rate of decline (&lt;-0.15) segregated within Group 1 (20.3% vs 7.1%, p=0.04); and the subjects most responsive to anti-CD20 (p=0.01) and ATG-GCSF (p=0.07) segregated within Group 1. A local validation cohort (n=66, mean age at onset: 11.1 +/- 4.0) was analyzed by plasma induced transcription. A Random Forest model, which utilized the TrialNet data as a training set, was used to assign the local subjects to Group 1 or 2 (ROC: AUC=0.95; p=7.7E-9). Consistent with pathway analysis of the TrialNet transcriptomic data, ELISA analysis identified elevated plasma IFNγ, TNFα, IL-1β, IL-6, IL-12p70 levels (p&lt;0.05) in Group 1. Flow cytometry measured higher percentages CD4+ CD45RO+ memory T cells (among total CD4 T cells, p=0.01) in Group 1. These analyses support the existence of two major T1D endotypes that exhibit differing immune phenotypes and therapeutic responsiveness.

Disclosure
A.Bedrat: None. T.Pant: None. S.Jia: None. M.Roethle: None. N.A.Truchan: None. S.M.Cabrera: Research Support; Abbott Diabetes. Y.Chen: None. C.Lin: None. M.Hessner: None.

Funding
National Institutes of Health (R01DK121528)
202-LB: Association between Diabetes and the Vaginal Microbiota
Authors: ROBBINS SARAH J. , BROTMAN REBECCA M. , MILLER RYAN S. , BEITELSHEES AMBER L. , SHARDELL MICHELLE , RAVEL JACQUES , TAYLOR SIMEON I. 
Published: June 2023

Type 2 diabetes is a known risk factor for urinary tract infection and vulvovaginal candidiasis, and this risk is modulated in part by vaginal microbiota. We sought to assess the associations between diabetes and the vaginal microbiota, specifically whether diabetes may reduce vaginal Lactobacillus spp., which produce lactic acid and protect the urogenital tract. This study included 811 participants (2,301 person-visits) aged 35-60 recruited to a 2-year observational cohort with mid-vaginal sampling every 6 months. Diabetes was defined as self-reported diabetes medications, history, or serum glycated albumin (GA) levels &gt;16.5% (HbA1c not available). Vaginal microbiota was characterized by 16S rRNA gene sequencing and clustered into community state types (CSTs) by VALENCIA, a nearest centroid algorithm based on a reference dataset. Mixed-effects multinomial logistic regression with bootstrapping was used to assess the association between case status and CSTs. Among diabetes cases (n=45, 130 person-visits), 45% had L. crispatus, L. jensenii, L. gasseri-dominated (CST I/II/V), 12% had L. iners-dominated (CST III) and 43% had low-Lactobacillus (CST IV) microbiota. Diabetes cases had reduced odds of L. iners-dominated CST III (aOR: 0.54, 95% CI: 0.31-0.81) than controls (12% vs 24%) and no association with low-Lactobacillus CST IV (aOR=01.05, 95% CI: 0.76-1.44) compared to Lactobacillus-dominated CST I/II/V in a model adjusted for menopause status and race. Estimates were similar when only GA was used for a diabetes case definition on a subset (1,001 person-visits). The results suggest diabetes is associated with reduced L. iners dominance. Diabetes cases had even frequencies of low-Lactobacillus or the optimal Lactobacillus-dominated CSTs. L. iners is metabolically distinct from other lactobacilli, producing only L-lactic acid (not the more protective D-lactic acid), and is associated with increased reproductive tract infection risk. This data informs how diabetes may affect the vaginal microenvironment.

Disclosure
S. J. Robbins: None. R. M. Brotman: None. R. S. Miller: None. A. L. Beitelshees: None. M. Shardell: None. J. Ravel: None. S. I. Taylor: Consultant; Ionis Pharmaceuticals.

Funding
National Institute of Allergy and Infectious Diseases (F31-AI164859)
204-LB: Application of a Data Quality Framework to Diabetic Retinopathy in the All of Us Dataset
Authors: GIANNINI JOHN , OSTCHEGA YECHIAM , VOLYNSKI MICHAEL , SULIEMAN LINA , DEDE YILDIRIM ELIF , OCHSENFABER EVAN , BERMAN LEW , RAMIREZ ANDREA 
Published: June 2023

Diabetic retinopathy (DR) is the leading cause of preventable vision impairment and blindness among adults with diabetes. The All of Us Research Program aims to collect biomedical data (electronic health records (EHR), surveys, biospecimens, physiological measures, and digital health technology such as wearable devices) from one million or more participants, with the goal of improving targeted management of diseases like diabetes and DR. Because issues such as data entry and record harmonization may affect the usability of these types of data, this study examines the quality and validity of All of Us data to inform fitness for research use. This study's primary objective was to examine the quality of the EHR data as it relates to the diagnosis, treatment, and procedures related to DR. Adults were selected for inclusion if their EHR data contained one of five ICD10CM codes that are associated with DR from type 2 diabetes. Demographics, measurements, eye care procedures, and medications are analyzed using a framework of five data quality dimensions (DQDs): completeness, concordance, conformance, plausibility, and temporality. After the Spring 2023 update, the database contains over 413,000 consented participants sharing EHRs, with nearly 49,000 participants with a type 2 diagnosis (excluding type 1) and 3,600 participants with a related DR diagnosis (prevalence of 0.87%). The DR cohort was 50% female, compared to all participants at 60%. In participant EHRs, over 99% contained physical measurements (height, weight, blood pressure), 79% contained codes for blood glucose lowering drugs (excluding insulin), and 47% contained a relevant eye care procedure. 73% of participant EHRs contained a plausible diagnosis series (type 2 diabetes before DR), with a median elapsed time of 2.1 years. This exploration of EHR data using DQDs affirms the validity and trustworthiness of All of Us program data, which forms a valuable dataset for future DR research.

Disclosure
J. Giannini: None. Y. Ostchega: None. M. Volynski: None. L. Sulieman: None. E. Dede Yildirim: None. E. Ochsenfaber: None. L. Berman: None.

Funding
National Institutes of Health
206-OR: A Human Gut Commensal, Parabacteroides distasonis, Stimulates an Inflammatory Response Specific to the Pancreas but Not to the Intestines, and Induces Type 1 Diabetes
Authors: GIRDHAR KHYATI , RAISINGANI AMOL , ALTINDIS EMRAH 
Published: June 2023

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the destruction of pancreatic β-cells, resulting in insulin deficiency and hyperglycemia. Previous studies have shown that the gut microbiome is associated with the development and incidence of diabetes, however, the main trigger of T1D is unknown. Insulin protein epitopes are the primary targets of the T-cells, stimulating an autoimmune response against β-cells. We previously identified and characterized a bacterial peptide mimic of insulin B-chain 9-23 epitope (insB:9-23) in P. distasonis, a human gut commensal. This bacterial mimic, hprt4-18, is identified in the N-terminal of the hypoxanthine-guanine phosphoribosyltransferase protein. It activates both human T-cell clones and nonobese diabetic (NOD) mice T-cell hybridomas specific to insB:9-23. Reanalysis of DIABIMMUNE data confirms that exposure to hprt-4:18 in the first three years of life increases the risk of seropositivity. The colonization of female NOD mice's gut microbiome with P. distasonis accelerated the infiltration of T-cells into the islets and increased the incidence of T1D. In addition, P. distasonis colonization increased splenic CD4+ and CD8+ T-cells and decreased FoxP3+ Treg cells. Because the first interaction between the host immune system and gut microbes occurs in the intestines, we determined the direct effects of P. distasonis colonization on intestinal intraepithelial lymphocyte (IELs) composition. Notably, P. distasonis colonization decreased CD4+, CD4+ CD62L+ (Naïve), CD8+CD44+ (Effector), CD4+CD44+CD62L+ (Central) T-cell and B-cell populations. Taken together, these results support our molecular mimicry mechanism hypothesis as P. distasonis decrease inflammation in the intestines, however, induce an autoimmune response specific to pancreatic β-cells resulting in accelerated diabetes incidence in female NOD mice.

Disclosure
K.Girdhar: None. A.Raisingani: None. E.Altindis: None.

Funding
JDRF T1D (5112731); Mathers Foundation
21-OR: Insulin and Glucagon Regulate a Novel Bidirectional Long Noncoding RNA/Protein-Coding Gene Pair That Control Cell Sensitivity to Metabolic Stress
Authors: LIU XIANGYU , RONALD KAHN C. 
Published: June 2023

An imbalance of glucagon and insulin actions in type 2 diabetes (T2D) results in the dysregulation of glucose and lipid metabolism and metabolic stress throughout the body. Integrating gene expression data in multiple models of T2D and metabolic syndromes, we have identified a novel gene pair, that share the same bidirectional promoter, are coordinately upregulated by glucagon and downregulated by insulin in the liver in a variety of physiological and pathophysiological states. This gene pair consists of the long non-coding (lnc) RNA Gm15663 and the protein coding gene Tmtc2, an important regulator of endoplasmic reticulum (ER) Ca2+ flux. Gm15663/Tmtc2 are also upregulated when glucagon predominates insulin, such as during fasting, after high-fat or western diet and in ob/ob mice. Conversely, Gm15663/Tmtc2 are downregulated during feeding, when insulin predominates glucagon. This transcriptional regulation is mediated in part by the transcription factor Foxo1. Foxo1 binds with two promoter-distal enhancers, creating a spatial chromatin looping interaction with Gm15663/Tmtc2 promoter, which is involved in transcriptional regulation of this gene pair. Knockdown of Tmtc2 in hepatocytes results in a higher cytosolic Ca2+ level and lower ER Ca2+ level. This renders the cell more sensitive to both metabolic and ER stress, and impairs cell respiration, which is in part mediated by the increased cytosolic Ca2+ level and the activation of CaM kinase II (CamKII). In a unique mechanism, Gm15663 and Tmtc2 also cis-regulate the transcription of each other to maintain the homeostasis of their own expression levels. Thus, Gm15663/Tmtc2 gene pair are dynamically regulated by glucagon and insulin and serve as novel regulators of cell sensitivity to metabolic stress. This gene pair is also linked to a common subtype of T2D in GWAS studies, making them potential targets to treat or modify the development of T2D in these individuals.

Disclosure
X.Liu: None. C.Kahn: None.
211-LB: Risk of Type 2 Diabetes in Young Adults with Psychiatric Disorders
Authors: LEE MIN-KYUNG , OH HYUNJYUNG , HONG OAK-KEE , HAN KYUNGDO 
Published: June 2023

Objective: The study of the association between type 2 diabetes (T2D) and psychiatric disorders can provide significant implications for the early detection and timely intervention of T2D. As T2D is increasingly prevalent in young adults, we explores whether young adults with psychiatric disorders have higher risk of developing T2D than those without the disorders.
Research Design and Methods: We used the data collected by the South Korean National Health Insurance Service between 2009 and 2012. The nationwide population-based cohort study uses the sample data from 97% of South Korean population. Among 6,891,399 participants aged 20-39 year, we excluded 287,406 subjects with missing data and 146,002 subjects who had history of T2D were excluded. The five psychiatric disorders were evaluated, namely, schizophrenia, bipolar disorder, depressive disorder, anxiety disorder, and sleep disorder. The primary outcome was newly diagnosed T2D during the follow-up period of 7.59 years.
Results: The cumulative incidences of T2D were significantly different between individuals with and without psychiatric disorders (log-rank test, P &lt; .01). Incidence rates of T2D for individuals with and without a psychiatric disorder were 2.889 and 2.564 per 1,000 person-years. Individuals with a psychiatric disorder showed a higher risk of T2D than those without it (adjusted hazard ratio [aHR], 1.195: 95% CI, 1.174-1.217). The aHRs for T2D in individuals with schizophrenia, bipolar disorder, depressive disorder, anxiety disorder, and sleep disorder were 2.04 (95% CI, 1.826-2.28), 1.991 (95% CI, 1.726-2.115), 1.241 (95% CI, 1.202-1.282), 1.133 (95% CI, 1.108-1.159), and 1.308 (95% CI, 1.267-1.35), respectively.
Conclusions: In this large-scale prospective cohort study of young adults, all five psychiatric disorders were significantly associated with an increased risk of developing T2D. We observed that young adults with schizophrenia and bipolar disorder have a higher risk of T2D.

Disclosure
M. Lee: None. H. Oh: None. O. Hong: None. K. Han: None.

Funding
National Research Foundation of Korea (2022R1F1A061069)