bluuebunny/crossref_metadata_2025_split huggingface dataset:
1255-P: IA-2A Autoantibody Titers Predict Subsequent Divergence between Nonprogressors (NP) and Progressors (P) to Type 1 Diabetes with Similar Degree of Initial Metabolic Abnormality
Authors: SIMS EMILY K. , CUTHBERTSON DAVID D. , JACOBSEN LAURA M. , ISMAIL HEBA M. , NATHAN BRANDON M. , REDONDO MARIA J. , SOSENKO JAY 
Published: May 2022

Even after stratification based on established risk factors, the progression to T1D is variable. Thus, we aimed to examine differences in metabolic patterns of change between NP and P to T1D, and identify non-metabolic factors contributing to the differences. Specifically, we analyzed OGTT and autoantibody (Aab) data from children &lt;18 yrs participating in Diabetes Prevention Trial-Type 1 (DPT-1) or TrialNet Pathway to Prevention (PTP) , with “baseline” DPT-1 Risk Scores (DPTRS) at initial testing in the abnormal range of 6.50 to &lt;7.50. No difference in AUC ratio (AUC C-peptide/AUC glucose) was present between P (n=85) and NP (n=161) in DPT-1 or between P (n=171) and NP (n=332) in PTP at baseline. However, during follow-up we found that by the first 6-month OGTT the AUC ratio had diverged, with lower AUC ratio in P both in DPT-1 (p=0.05) and PTP (p&lt;0.001) , adjusting for baseline age, BMI, DPTRS, and AUC ratio. Moreover, in yearly change from baseline to last OGTT (before diagnosis in P) , AUC ratio decreased in P (p&lt;0.001) and increased in NP (p&lt;0.01) in DPT-1 and PTP. In assessments of factors relating to this divergence we observed that despite their metabolic similarity, at baseline P had higher harmonized IA-2A Aab positivity (70.8 vs. 49.1%, p&lt;0.001) and titers (median 194 vs. 3, p&lt;0.001) in PTP (not harmonized in DPT-1) . Based on this, we compared P with NP for yearly changes in IA-2A from baseline to the last visit, with adjustment for baseline values. P had a greater increase in IA-2A titer over time (p=0.025) . Furthermore, T1D progression was associated with yearly increases in IA-2A titer (HR: 1.006, 95%CI: 1.003, 1.009; p&lt;0.001) .
In conclusion, when NP and P have a similar degree of metabolic abnormality, IA-2A titers are greater in P. Moreover, as AUC ratio declines in P and improves in NP, IA-2A titers increase more in P than in NP. These findings suggest that IA-2A is a sensitive indicator of active β-cell pathology.

Disclosure
E.K.Sims: Other Relationship; Medscape, Patent. D.D.Cuthbertson: None. L.M.Jacobsen: None. H.M.Ismail: n/a. B.M.Nathan: None. M.J.Redondo: Advisory Panel; Provention Bio, Inc. J.Sosenko: None.
1259-P: Using Simplification Strategies for Older Adults with Type 1 Diabetes
Authors: MUNSHI MEDHA , SLYNE CHRISTINE , HURLBERT REBECCA , TOSCHI ELENA 
Published: May 2022

Objective: Simplification of insulin regimen algorithms for older adults with type 2 diabetes have been established and recommended as the standard of care. However, simplification of insulin regimens in older adults with type 1 diabetes (T1D) has not been described.
Methods: Community-living older adults ≥65 years with T1D were randomized to assess the impact of technology use, combined with geriatric specific interventions to reduce the risk of hypoglycemia (Clinicaltrials.gov NCT03078491) . We developed simplification strategies as part of a geriatric intervention program. Glycemic parameters and quality of life measures were evaluated at baseline and 6-months after enrollment.
Results: Thirty-four out of forty-one older adults (83%) with T1D (age 71±4 years, T1D duration 41±16 years, 36% with cognitive dysfunction, 22% living alone) in the subpopulation from the intervention arm were considered appropriate for simplification. We identified four procedures for simplification.1) Liberalization of goals for A1C and/or pump and CGM targets were recommended for 16/34 (47%) participants;2) Fixed-dose boluses for routinely eaten meals, especially at breakfast and lunch, were recommended for 24/34 (71%) participants;3) Avoiding multiple correction doses was recommended for to 25/34 (74%) participants; and4) Proactive adjustment to boluses, rather than constantly reacting to hyper- and hypoglycemia was recommended to 13/34 (38%) . The change in glycemic metrics from baseline to 6-months post-enrollment showed a decreased percent of hypoglycemia (6% vs. 2%; p&lt;0.0001) and decreased glycemic variability (coefficient of variation (%)) (41% vs. 35%, p=0.0001) . A1c and time-in-range remained stable (7.5% vs. 7.6%: 56% vs. 57%, respectively) .
Conclusions: In this study, simplification procedures for insulin regimens in older adults with T1D were developed. Simplification of regimens did not contribute to worsening of glycemic parameters. Prospective studies are needed to confirm our findings.

Disclosure
M.Munshi: Consultant; Sanofi. C.Slyne: None. R.Hurlbert: None. E.Toschi: Consultant; Medtronic.

Funding
This research was supported by an NIH DP3 Grant (1DP3DK112214-01) and an NIH P30 Grant (P30DK036836) . Continuous glucose monitoring materials were partially suppliedby Dexcom.
126-LB: Type 2 Diabetes Mellitus (T2DM) Has Greater Adverse Effect on Mortality in Females than Males—Results of 10-Year Cohort Study
Authors: HEALD ADRIAN H. , STEDMAN MICHAEL , LAING IAN , ROBINSON ADAM , RAYMAN GERRY , WHYTE MARTIN B. 
Published: May 2022

Females are more prone to obesity than males. This may lead to different outcomes. We studied if sex differences were seen in mortality outcomes in a longitudinal T2D cohort study.
Data from a regional UK database (Salford) was taken between 2010-2020. Standardised Mortality Ratio (SMR) was established from actual versus expected deaths calculated from national annual statistics for mortality rate by sex and age. The SMR was then calculated for by each sex, year, age group, HbA1c level, and diabetes medication as taken by a patient in previous years.
We included 9,558 patients with 88,102 patient years and 2,909 recorded deaths against 1,851 expected, SMR men 1.46 and women 1.72 (18% higher than men) . SMR increased slightly over time (Figure 1a) . SMR in younger females (&lt;75 years) was higher than older females (Figure 1b) . SMR in females with high HbA1c (&gt;86mmol/mol) was higher (Figure 1c) than lower HbA1c. Patients currently on insulin and GLP1 had much higher SMR than oral alone (Figure 1d) .SMR analysis of the oral drug use had SGLT2i 1.28; metformin 1.50; thiazolinedione 1.61; DPP4i 1.74; sulphonylurea 1.78. Note that average age and HbA1c varied across therapies.
Diabetes has greater impact on women’s mortality than men for both age, and HbA1c. Indication bias will impact drug choice but lower SMR with SGLT2i and higher with sulphonylureas concords with trial data. Despite newer therapies, SMR for diabetes has not improved over time.

Disclosure
A. H. Heald: None. M. Stedman: None. I. Laing: None. A. Robinson: None. G. Rayman: None. M. B. Whyte: Consultant; AstraZeneca, Research Support; AstraZeneca, Sanofi.
1260-P: Gut Microbiome and Metabolic Activity in Type 1 Diabetes—An Analysis Based on the Presence of GADA
Authors: YUE TONG , ZHENG XUEYING , LIU ZIYU , DING YU , WEI JIANG W. , XU WEN , WENG JIANPING , LUO SIHUI 
Published: May 2022

Background: Type 1 diabetes (T1D) progression is affected by the level of circulating glutamic acid decarboxylase antibody (GADA) , a main manifestation of islet autoimmunity. The gut microbiome and serum metabolites may contribute to islet autoimmunity in patients with T1D.
Methods: We used radiobinding assay to measure GADA titers and identify the GADA+ ones (n=49) in 1T1D patients. The gut microbiome was assessed by 16S rRNA gene sequencing, and the serum metabolites were analysed with GC/MS.
Results: T1D patients with and without GADA exhibited compositional and functional changes in the gut microbiome. Profiles in patients with GADA were distinct, with a significant increase in the abundances of Alistipes, Ruminococcus, Prevotella, Dialister, and marked depletion of Bacteroides, Bifidobacterium, Roseburia. For the untargeted serum metabolites, compared with those of GADA-, there were 54 significantly different metabolites with tryptophan metabolism: phenylalanine, and tyrosine and tryptophan biosynthesis decreased in patients with GADA. In addition, patients with GADA had elevated concentrations of Indole-3-acetic-acid, a marker of intestinal inflammation and epithelial damage. Co-occurrence network analysis revealed that gut microbiome disturbances affected tryptophan metabolism, suggesting that disturbed gut microbiome may mediate T1D immunotypes. Tryptophan metabolism may mediate inflammation in the pathogenesis and pathophysiology of T1D.
Conclusion: These findings suggest that metabolites produced by the patients with GADA gut microbiota could cause damage to intestinal and systemic homeostasis and could be targeted for preventing the development of T1D.

Disclosure
T.Yue: None. X.Zheng: None. Z.Liu: None. Y.Ding: None. J.W.Wei: None. W.Xu: None. J.Weng: None. S.Luo: None.

Funding
the National Key r&D Program (2017YFC1309600) the Anhui Provincial Natural science foundation (006212943003)
1267-P: Fine-Mapping Type 1 Diabetes Risk at the MHC Locus
Authors: MCGRAIL CAROLYN , CHIOU JOSHUA , BENAGLIO PAOLA , GAULTON KYLE J. 
Published: May 2022

The Major Histocompatibility Complex (MHC) locus regulates the adaptive immune response and self-recognition and is the largest contributor to genetic risk of type 1 diabetes (T1D) . Protein-coding alleles in MHC class II and class I genes have long been known to contribute substantial T1D risk, yet whether additional variants affect T1D risk at this locus particularly in the non-coding genome has not been exhaustively evaluated. We therefore performed high-resolution fine-mapping of the MHC locus to identify additional coding and non-coding variants that contribute to T1D risk. We imputed genotypes for 39,270 samples from six European or American cohorts of T1D cases and controls into the T1DGC reference panel using SNP2HLA. We then performed two analyses to fine-map causal variants, first, stepwise conditional analysis using Firth bias-corrected logistic likelihood ratio test and second, iterative Bayesian stepwise selection analysis using the Sum of Single Effects (SuSiE) method. We identified 33 signals in stepwise conditional analysis with p&lt;1×10-6 and 30 signals in SuSiE, where the results were highly concordant between methods. Both methods identified the known high-risk amino acid residue 57 of HLA-DQB1 as the top signal, as well as most known and several novel protein-coding risk and protective alleles in MHC class I and II genes. In addition, we identified multiple signals where the likely causal variant was non-coding and not linked to a protein-coding variant, including those that mapped to the LST1, HLA-DRA and NOTCH4 genes. We further annotated these non-coding signals using accessible chromatin, and several likely causal variants mapped in immune cell and/or pancreatic islet accessible chromatin. In ongoing analyses, we are replicating these signals in independent cohorts and performing molecular validation studies of their regulatory effects in relevant cell types. In total, high-resolution fine-mapping of the MHC locus identified additional T1D risk including in the non-coding genome.

Disclosure
C.Mcgrail: None. J.Chiou: Employee; Pfizer Inc. P.Benaglio: None. K.J.Gaulton: Consultant; Genentech, Inc., Stock/Shareholder; Neurocrine Biosciences, Inc., Vertex Pharmaceuticals Incorporated.

Funding
National Institutes of Health (DK120429) National Institutes of Health (DK122607)
1270-P: ICA1 Is Differentially Methylated and Expressed in Familial Type 1 Diabetes
Authors: DASHTI MOHAMMED H. , NIZAM RASHEEBA , HEBBAR PRASHANTHA , JACOB SINDHU , JOHN SUMI E. , CHANNANATH ARSHAD M. , ALKANDARI HESSA , THANGAVEL ALPHONSE T. , ALMULLA FAHD 
Published: May 2022

There has recently been a growing interest in examining the role of epigenetic modifications, such as DNA methylation, in the etiology of type 1 diabetes (T1D) . This study aimed to delineate differences in methylation patterns between T1D-affected and healthy individuals by examining the genome-wide methylation of individuals from three Arab families from Kuwait with T1D-affected mono-/dizygotic twins and non-twinned siblings. Bisulfite sequencing of DNA from the peripheral blood of affected and healthy individuals from each of the three families was performed. Methylation profiles of the affected individuals were compared to those of healthy individuals. The principal component analysis on methylation profiling based on base-pair resolution clustered the T1D-affected twins together family-wide. Sites/regions that were differentially methylated between T1D and healthy samples harbored 84 genes, of which 18 were known to be differentially methylated in T1D individuals compared to healthy individuals in publicly available gene expression data resources. We further validated two of the 18 genes—namely ICA1 and DRAM1 that were hypermethylated in T1D samples compared to healthy samples—for upregulation in T1D samples from an extended study cohort of familial T1D. The ICA1 is well-known to have a role in the development of autoimmune beta-cell destruction.

Disclosure
M.H.Dashti: None. R.Nizam: None. P.Hebbar: None. S.Jacob: None. S.E.John: None. A.M.Channanath: None. H.Alkandari: None. A.T.Thangavel: None. F.Almulla: None.

Funding
Kuwait Foundation for Advancement in Sciences funding RA-2014-024
1273-P: The Interplay between Polygenic and Rare HNF1A Variant Risk in Type 2 Diabetes
Authors: STALBOW LAUREN , PREUSS MICHAEL H. , CHAMI NATHALIE , SMIT ROELOF A.J. , LOOS RUTH J. 
Published: May 2022

Rare variants in HNF1A, a pancreatic beta cell transcription factor, have been shown to be associated with T2D and monogenic diabetes. Here, we examine the effect of functionally validated rare (MAF&lt;1%) nonsynonymous variants (RNVs) in a functional domain of HNF1A on T2D risk, and whether their effect is influenced by an overall genetic susceptibility to T2D.
Using exome sequencing data of 3,443 African ancestry (AA) and 157,182 European ancestry (EA) individuals in the UK Biobank and 5,018 AA, 5,6EA and 7,1Hispanic-Latino Ancestry (HA) individuals in the BioMe Biobank, we identified 132 AA, 287 EA, and 64 HA RNV carriers (NRNVs= 30) of HNF1A variants that impair protein function ≤ 60%. T2D Polygenic Risk Scores (PRSs) were built using either trans-ethnic or EA GWAS summary statistics and standardized per ancestry. We tested the association between RNV carrier status and the PRS with T2D risk, and meta-analyzed the ancestry-specific results.
Carrying any of the HNF1A RNV mutations was associated with a 1.5 increase in the odds of T2D in the EA, albeit non-significantly (P=0.06) , but not in the AA (OR=1.1, P=0.6) or HA (OR=1 , P=1) . We then restricted analyses to RNVs within a functional domain, which results in more pronounced effects in the AA (OR=1.5, P=0.07) and EA (OR=1.9, P=0.002) but not in the HA (OR=0.8, P=0.5) . Per SD increase in the PRS, there is a significant 1.7, 1.6 and 2.1 higher odds of T2D in AA, EA and HA individuals, respectively. Even though we observed no interaction between the PRS and HNF1A RNVs (P &gt;; 0.05) , the association between RNVs and T2D was more pronounced among EA individuals with a high PRS. Functional domain carriers (NEA = 50) in the top PRS quintile had a 3.6 (P=0.0008) higher odds of T2D as compared to non-carriers in the same quintile.
Our study shows the value of large biobanks in studying rare variants, the importance of variant selection, and the need to include non-European ancestry populations. We demonstrate the utility of combining rare and common variant risks to better assess T2D risk.

Disclosure
L.Stalbow: None. M.H.Preuss: None. N.Chami: None. R.A.J.Smit: None. R.J.Loos: None.
1277-P: Spatial Whole Transcriptome Profiling of the Human Pancreas Uncovers Unique Insights into Histological Structures
Authors: YANG WEI , HOGAN MEGHAN F. , LIANG YAN , BEECHEM JOSEPH M. 
Published: May 2022

Understanding the physiology of the pancreas and pathology that occurs during diabetes requires knowing transcriptional patterns driving biological activity within the functional structures of the tissue. Previous technologies have not enabled spatially resolved high plex profiling to elucidate these biological pathways. Using the unique ability of GeoMx® Digital Spatial Profiler to resolve functional units within FFPE tissue in situ, we provide whole transcriptome expression data from islets, acini, and ducts from four pancreata of nondiabetes patients.
On average, 6000-8000 genes were detected from functional groups within each histological structure. Data were validated against the independent Human Protein Atlas, with ∼90% concordance between RNA expression and known protein localization. Deconvolution based on single-cell RNASeq enabled calculation of the proportion of distinct cell types within each structure, confirming cell composition. For example, while ductal components consist of small islands punctuating the acini, over 3000 genes were identified to be highly specific to each structure (FDR &lt; 0.05) , and enriched for pathways related to focal adhesion, ECM structure, and diabetic disease processes. Within islets, we identified &gt;300 genes with differences between α- and β-cells (FDR &lt; 0.2) . Functional characterization confirmed enrichment of insulin biosynthesis and secretion pathways, with genes such as insulin, glucagon, and IAPP expression captured accurately with a single assay. Determination of expression in four individual pancreas samples identified variation between tissues, which may be central to health and disease processes.
In conclusion, whole transcriptome data for spatial gene expression profiles of structures of the non-diseased pancreas are publicly available and can be used as standards to inform future profiling studies in normal and diseased tissue.
FOR RESEARCH USE ONLY. Not for use in diagnostic procedures.

Disclosure
W.Yang: None. M.F.Hogan: Employee; NanoString. Y.Liang: None. J.M.Beechem: None.
1278-P: The Tale of Caveolin 1 rs1997623 Variant in Obesity and Metabolic Syndrome
Authors: MADHOUN ASHRAF AL , HADDAD DANIA , KOCHUMON SHIHAB P. , NIZAM RASHEEBA , JACOB SINDHU , SINDHU SARDAR T. , AHMAD RASHEED , ALMULLA FAHD 
Published: May 2022

We Have previously established that caveolin-1 (CAV1) rs1997623 C/A variant is associated with metabolic syndrome in obese children (PMID: 30622557) and adults (ADA 82) . Here, we evaluated the functional role of the identified variant in association with obesity. Sequence analysis revealed that the variant is located at CAV1 regulatory region and creates a site for EBF Transcription Factor 1 (EBF1) . DNA fragment (240pb) flanking the variant was cloned upstream luciferase reporter gene. Wildtype, CAV1-C-Luc, and the generated mutant, CAV1-A-Luc, were individually transfected into pre-adipocytes. CAV1-A-luc significantly upregulated Luciferase activity indicating a prospective functional role of CAV1-A allele in CAV1 regulation. The reporter gene activity was differential regulated in lean versus obese pre-adipocytes. Co-transfections with EBF1 construct resulted in a significant upregulation in CAV1-A Luc activity, particularly in pre-adipocytes from obese individuals. The role of EBF1 was further evaluated in vivo using ChIP assays. PCR analysis using specific primers flanking the CAV1 variant and anti-bodies against EBF1 showed a significant elevated enrichment of chromatins from obese individuals, which was also associated with an enrichment for H3K27ac at the same locus, indicating active transcription. Moreover, CAV1 expression was differentially regulated in response to EBF1 siRNA/overexpression in pre-adipocytes harboring CAV1 A/A or A/C alleles relative to that with C/C allele. Furthermore, a significant reduction of DNA methylation at the variant locus was observed particularly in preadipocytes with A/A alleles. Finally, RNA isolated from adipose tissue of lean and obese individuals showed a significant correlation between CAV1 and cytokines transcripts in healthy obese individuals, at least in part, is due to CAV1 rs1997623 variant as verified by sequence analysis. Taken together, our study delineates the role of CAV1 rs1997623 variant in the context of obesity and MetS.

Disclosure
A.Al madhoun: None. D.Haddad: None. S.P.Kochumon: None. R.Nizam: None. S.Jacob: None. S.T.Sindhu: None. R.Ahmad: None. F.Almulla: None.

Funding
Kuwait Foundation for the Advancement of Sciences (KFAS) and Dasman Diabetes Institute, Project RA CB-2021-007
1286-P: Plasma-Induced Signatures Measured at Type 1 Diabetes (T1D) Onset Correlate with Post-onset Beta-Cell Function
Authors: BEDRAT AMINA , JIA SHUANG , ROETHLE MARK , DEW KRISTEN , CABRERA SUSANNE M. , LIN CHIEN-WEI , HESSNER MARTIN 
Published: May 2022

Significant phenotypic diversity exists among T1D patients, supporting the existence of distinct disease endotypes (e.g. duration of the post-onset partial remission period) . To broaden our understanding of T1D heterogeneity and its relationship to disease progression and therapeutic responsiveness, we studied 566 new onset T1D patients (241 females, 325 males; mean age 16.5 +/- 8.2 years) that had participated in TrialNet clinical trials: TN02/MMF DZB; TN05/anti-CD20; TN08/GAD-alum; TN09/CTLA4-Ig; TN14/Canakinumab; and TN19/ATG-GCSF. Baseline samples were analyzed with a sensitive bioassay, where subject plasma is used to induce transcription in a well-controlled peripheral blood mononuclear cell population. The response was measured with a microarray, data were normalized, and transcripts exhibiting the highest median absolute deviation within each trial were identified. Weighted gene correlation network analysis was used to cluster patterns of variation into modules of co-expressed transcripts. Co-expression networks were correlated with clinical data collected over the 24-months following clinical onset. In the placebo arms of all 6 trials, we identified modules that significantly correlated with post-onset C-peptide AUC, post-onset insulin dose, Insulin-Dose Adjusted A1c, and/or the rate of C-peptide decline. This suggests that the baseline analyses identified modules that differentiated subjects in terms of post-onset beta-cell function, supporting the existence of T1D endotypes. While TN02, TN08, and TN14 did not show overall efficacy in slowing post-onset C-peptide decline, the module correlations with phenotypes related to beta-cell function were fewer in number and of lesser statistical significance in the treatment arms of all 6 trials. This suggests that there was greater beta-cell function in the treatment arms of all trials, and that varying degrees of immunomodulation had occurred even in those trials that did not show efficacy.

Disclosure
A.Bedrat: None. S.Jia: None. M.Roethle: None. K.Dew: None. S.M.Cabrera: None. C.Lin: None. M.Hessner: None.

Funding
National Institutes of Health (R01DK121528)