bluuebunny/crossref_metadata_2025_split huggingface dataset:
2014-LB: Association between Variants in Genes Involved in the Metabolism of Uric Acid and the Risk of Type 2 Diabetes
Authors: TSEKMEKIDOU XANTHIPPI , KOUFAKIS THEOCHARIS , PAPAVASILEIOU MARIA , TSETSOS FOTIOS , GEORGITSI MARIANTHI , GRAMMATIKI MARIA , ROUMELIOTIS ATHANASIOS , PAPANAS NIKOLAOS , PAPAZOGLOU DIMITRIOS , PASCHOU PERISTERA , KOTSA KALLIOPI 
Published: June 2024

Introduction & Objective: Epidemiological and experimental evidence suggests that hyperuricemia is involved in the pathophysiology of type 2 diabetes (T2D), inducing insulin resistance or beta cell failure. Therefore, our objective was to investigate a possible association between variants in genes related to uric acid metabolism and T2D in a case-control study design.
Methods: Our sample consisted of 624 T2D patients from Greece and 356 normoglycemic, ancestry-matched controls. In the control group, individuals over 65 years of age were included to minimize the probability that T2D will present at a later stage in their life. The samples were genotyped on Illumina Human PsychArray 24 v1.1. We focused our investigation on 30 genes involved in the metabolism of uric acid. We conducted allelic and genotypic tests using PLINK v1.9. The significance of the association was determined using permutation for each type of test. Furthermore, we performed haplotypic tests using BEAGLE v3.2.3. SNPs with association P-values &lt;0.05 were selected for permutation analysis.
Results: In the allelic tests our top hit was a rare variant, rs35008345 residing on the SLC22A1 gene, which was detected only in the control group, suggesting a potential protective role against the development of T2D (p&lt;0.001). Genotypic tests revealed significant associations in the REN and ABCG4 genes, with ABCG4 harboring four markers (rs4301800: OR 1.269; 95% CI 1.053-1.530, p=0.012, rs643423: OR 1.210; 95% CI 1.001-1.463, p=0.048, rs4245191: OR 1.213; 95% CI 1.004-1.467, p=0.045, rs7234: OR 0.801; 95% CI 0.666-0.963, p=0.018) and REN harboring one marker (rs6693954: OR 0.748; 95% CI 0.613-0.914, p&lt;0.01).
Conclusion: Our results suggest a potential role for variants in uric acid genes in the pathogenesis of T2D. Further studies are needed to validate these findings and clarify whether the detected associations are causal.

Disclosure
X. Tsekmekidou: None. T. Koufakis: Speaker's Bureau; Novo Nordisk, Lilly Diabetes, AstraZeneca, Boehringer-Ingelheim. M. Papavasileiou: None. F. Tsetsos: None. M. Grammatiki: None. A. Roumeliotis: None. N. Papanas: None. D. Papazoglou: None. P. Paschou: None. K. Kotsa: None.

Funding
This research was supported by the European Social Fund and Greek funds through the Operational Programme 'Education and Lifelong Learning' of the National Strategic Reference Framework-Research Funding Programme: THALES. Investing in knowledge society through the European Social Fund (MIS 380273).
2015-LB: Actionable Pharmacogenomic Variants in the Kuwaiti Population
Authors: JOHN SUMI E. , CHANNANATH ARSHAD M. , MALIK ZUBBAIR , NIZAM RASHEEBA , AL-MULLA FAHD , THANGAVEL ALPHONSE T. 
Published: June 2024

Pharmacogenomics plays a pivotal role in advancing precision medicine by addressing critical public health concerns like Adverse Drug Reactions (ADRs) and dosage regulations. The emergence of Next Generation Sequencing (NGS) techniques, coupled with the rapid expansion of pharmacogenomic data, offers a unique opportunity to accelerate progress in this field. This study aims to investigate the frequency and classification of actionable pharmacogenomic findings in the Kuwaiti population. Exome sequence data from 474 individuals of Kuwaiti descent were analyzed to evaluate the quantity and clinical relevance of incidental pharmacogenomic variants. Using a panel of 293 pharmacogenomic genes, the dataset was filtered, and resulting variants were categorized based on variant type, population frequency, functional impact, pathogenicity, and annotations from PharmGKB and ClinVar databases. In Clinvar, 33 missense variants related to drug response were identified. Additionally, 591 rare pharmacogenomic variants were detected in this population, predicted to be pathogenic using pathogenicity prediction tools. We observed 15 known pharmacogenomic variants classified as actionable (PharmGKB 1A or 1B level of evidence), impacting approximately 16 drugs. In conclusion, this study provides a comprehensive examination of known pharmacogenomic variants in the Kuwaiti population, highlighting their potential impact on drug response. We observed a higher frequency of genetic variants affecting drug response to medications like Ivacaftor, Tramadol, Efavirenz, and Capecitabine compared to global populations. Notably, a prominent actionable variant identified in this population is a VKORC1 variant associated with warfarin dosage. These findings underscore the significance of pharmacogenomic considerations in optimizing drug therapy for Kuwaiti individuals.

Disclosure
S.E. John: None. A.M. Channanath: None. Z. Malik: None. R. Nizam: None. F. Al-Mulla: None. A.T. Thangavel: None.
2016-LB: Uptake Kinetics and Presentation of Donor Alloantigen by Lymph Node Stromal Cells for Attenuating the Alloimmune Response in Pancreatic Islet Transplantation
Authors: LI CHRIS , MULLIGAN CALLIE , TELES LEONOR N. , GONZALEZ GRISELL , UMLAND OLIVER , TOMEI ALICE A. 
Published: June 2024

Objective & Background: Pancreatic islet transplantation requires lifelong immunosuppression, reducing its applicability. We aim to eliminate the need for immunosuppression by co-transplanting fibroblastic reticular cells (FRCs), a lymph node stromal cell subtype. FRCs are unconventional antigen-presenting cells that contribute to restraining autoreactive T cells and could be used in transplantation to prevent alloreactive T cell activation. We hypothesize that autologous FRCs co-transplanted with allogeneic donor islets can uptake alloantigen and reprogram the recipient’s alloimmune response toward inactivation/anergy.
Methods: In all experiments, recipient-matched C57BL/6 FRCs were pre-conditioned with or without 10ng/mL interferon-γ (IFNγ) for 72h. FRCs were incubated with CellTrace-labeled NIT1 (fully mismatched to B6) cell lysate or 50µM OVA257-264 (SIINFEKL) peptide overnight. No, low (7.5:1 NIT1:FRC cells), or high (75:1) doses of NIT1 cell lysate were administered. For kinetics, cells were cultured in regular media after overnight treatment. Flow cytometry was used to detect labeled lysate uptake and anti-SIINFEKL-H2Kb for antigen presentation. Data was analyzed by two-way ANOVA. Three biologically distinct cell lines were tested.
Results: With NIT1 lysate, FRC viability was not affected. Uptake of fluorescent lysate was dose-dependent, and 96.3±2.6% of FRCs took up NIT1 lysate at high dose. Confocal microscopy demonstrated donor antigen localization within lysosomes. Donor antigen was cleared from FRCs by 72h. IFNγ potentiates SIINFEKL presentation and 99.9±0.1% of IFNγ-treated FRCs presented SIINFEKL.
Conclusion: In vitro, FRCs can acquire exogenous antigen and present in MHC I. These results predict that FRCs can uptake allogeneic donor cell antigen and can present to alloreactive recipient T cells in in vitro co-culture studies and in vivo co-transplantation.

Disclosure
C. Li: None. C. Mulligan: None. G. Gonzalez: None. O. Umland: None. A.A. Tomei: Other Relationship; Isla Technologies, Sernova, Corp.

Funding
National Institutes of Health (F30 DK136276-01); National Institutes of Health (R01 DK109929-01); Juvenile Diabetes Research Foundation (3-SRA-2024-1477-S-B).
2021-LB: FABULINUS—A Randomized, Controlled Trial with FrexalimAB, to Assess Endogenous Insulin Secretion in New-Onset Stage 3 Type 1 Diabetes Adults and Adolescents
Authors: HALLER MICHAEL J. , ROTTHAEUSER BAERBEL , CHERKAS ANDRIY , COUDERT MATHIEU , LABARD PASCALE , BACCARA-DINET MARIE , BOKA GABOR , RESCHKE FELIX 
Published: June 2024

Introduction: Type 1 diabetes (T1D) is caused by autoimmune destruction of pancreatic β-cells. The CD40/CD40L immune checkpoint leads to activation of both innate and adaptive immune cells. Frexalimab is the first second-generation antibody against CD40L to be studied in T1D.
Objective: To demonstrate the efficacy and safety of different doses of frexalimab on endogenous insulin secretion in participants with newly diagnosed T1D.
Methods: FABULINUS (NCT06111586) is a 52-week randomized (2:1), double-blind, placebo-controlled phase 2b study with a 52-week blinded extension conducted in the US and Europe. It consists of 2 parts: Part A evaluates the safety of the highest dose of frexalimab in adults (18 - 35 years). In Part B, which is based on 3-month safety data from Part A, adolescents, and young adults (12 - 21 years) are treated with 3 sequentially escalated doses of frexalimab or placebo. Study entry criteria include diagnosis of Stage 3 T1D according to American Diabetes Association standards, initiation of insulin therapy &lt;u&gt;&lt;&lt;/u&gt; 90 days prior to screening and random C-peptide levels ≥0.2 nmol/L. Change from baseline to Week 52 in the mean 2h stimulated AUC C-peptide concentration is used as a primary efficacy endpoint. Secondary endpoints include time in range (TIR, 70-180 mg/dL blood glucose), insulin dose, glycated hemoglobin A1c (HbA1c), remission, and safety.
Results: The study design of FABULINUS ensures the stepwise assessment of anti-CD40L antibodies in adults and then adolescents with type 1 diabetes.
Conclusion: FABULINUS is an innovative combined proof-of-concept and dose-finding study tailored to specific clinical development requirements for ß-cell preservation in T1D.

Disclosure
M.J. Haller: Consultant; Sanofi. Advisory Panel; SAB Biotherapeutics, Inc. Consultant; MannKind Corporation. B. Rotthaeuser: None. A. Cherkas: Employee; Sanofi-Aventis Deutschland GmbH. Stock/Shareholder; Sanofi. M. Coudert: None. P. Labard: None. M. Baccara-Dinet: Employee; Sanofi. G. Boka: None. F. Reschke: None.

Funding
Sanofi
2022-LB: Diabetes Primes Neutrophils for Neutrophil Extracellular Trap by Metabolic Reprogramming
Authors: JEON JAE-HAN , KIM MI-KYUNG , LEE IN-KYU 
Published: June 2024

Neutrophils are primed for neutrophil extracellular trap (NET) formation during diabetes and excessive NET formation from primed neutrophils compromises wound healing in patients with diabetes. Here, we demonstrate that trained immunity mediates diabetes-induced NET priming in neutrophils. Under diabetic conditions, neutrophils exhibit robust metabolic reprogramming comprising enhanced glycolysis via the pentose phosphate pathway and fatty acid oxidation, which result in the accumulation of acetyl-coenzyme A (CoA). ATP-citrate lyase (ACLY)-mediated accumulation of acetyl-CoA and histone acetyltransferases (HATs) further induce the acetylation of lysine residues on histone 3 (AcH3K9, AcH3K14, and AcH3K27) and histone 4 (AcH4K8). The pharmacological inhibition of ACLY and HATs completely inhibited high glucose-induced NET priming. The trained immunity of neutrophils was further confirmed in neutrophils isolated from patients with diabetes. Our findings suggest that trained immunity mediates functional changes in neutrophils in diabetic environments, and targeting neutrophil-trained immunity may be a potential therapeutic target for controlling inflammatory complications of diabetes.

Disclosure
J. Jeon: None. M. Kim: None. I. Lee: None.
2024-LB: Reversal of Diabetes by Human Stem Cell–Derived Islets Implanted with an Immunomodulatory Microgel in a Retrievable Site
Authors: RECH TONDIN ARTHUR , YOLCU ESMA S. , HERRING SARAH K. , HESTER DENNIS M. , GADEA YELENA , VEGA GREYCY , SZUST JOEL , REVEL ARIEL , SHIRWAN HAVAL , GARCIA ANDRÉS , JAPOUR ANTHONY , REVEL MICHEL , MOLAKANDOV KFIR , RICORDI CAMILLO , LANZONI GIACOMO 
Published: June 2024

Introduction & Objective: Islet transplantation for T1D is limited by donor availability and need for immunosuppression. Stem cell-derived islets could represent a solution as an unlimited source, but chronic immunosuppression remains a critical barrier. Immunomodulatory SA-FasL engineered microgel (iTOL-100, iTolerance Inc) represents a viable option to eliminate chronic immunosuppression. This study aimed to investigate the effect of human stem cell-derived islets (IsletRx, Kadimastem Ltd) co-transplanted with SA-FasL microgel in streptozotocin-diabetic immunodeficient NSG mice, to assess potential clinical translation.
Methods: IsletRx cell clusters were shipped via intercontinental flight. IsletRx was implanted in the epidydimal fat pad at doses from 3 to 9 kIEQ per mouse, alone or with iTOL-100. Over three months of follow-up, animal body weight and glycemia were monitored to assess transplantation effects. Human C-peptide levels were periodically measured and Intraperitoneal Glucose Tolerance Tests (IPGTT) performed.
Results: The study demonstrated that IsletRx engrafted, resulting in substantial human C-peptide release and normalization of blood glucose levels. At the highest IsletRx dose (9 kIEQ, approximately 5 million cells), glycemic control improved over 3 months, reaching euglycemia. Importantly, iTOL-100 did not adversely affect stem cell-derived IsletRx function. Histological analyses of the grafts revealed well-preserved stem cell-derived islets.
Conclusion: The results indicate the potential of IsletRx as a stem cell-derived islet candidate for the treatment of subjects with T1D. Notably, IsletRx can be shipped intercontinentally, and thus could be delivered worldwide as a functionally competent clinical product. Additionally, our findings indicate that the combination of stem cell-derived IsletRx with the immunomodulatory iTOL-100 microgel does not compromise beta cell function and reversal of diabetes.

Disclosure
A. Rech Tondin: None. E.S. Yolcu: None. D.M. Hester: None. Y. Gadea: None. G. Vega: None. J. Szust: None. A. revel: None. H. Shirwan: None. A. Garcia: Board Member; iTolerance. Stock/Shareholder; iTolerance, CorAmi. A. Japour: None. M. Revel: Employee; Kadimastem Ltd, Nes Ziona, Israel. C. Ricordi: Advisory Panel; Vertex Pharmaceuticals Incorporated. Consultant; iTolerance, Inc. G. Lanzoni: Stock/Shareholder; Novo Nordisk, Eli Lilly and Company, Pfizer Inc., Medtronic, UnitedHealth Group, Provention Bio, Inc.

Funding
iTolerance, Inc. (ITOL-SOW-00018263)
2025-LB: Anti-apoptotic BCL2 Delivery to Protect Stem Cell–Derived Beta Cells from Transplantation-Induced Cell Death
Authors: BAKER ALEXANDER , CASTRO GUTIERREZ ROBERTO , KRATZ AUSTIN T. , RUSS HOLGER A. 
Published: June 2024

Cadaveric islet transplantation in most type 1 diabetic (T1D) patients restores euglycemia. However, cadaveric islets are limited, transplantation often requires multiple organ donors, and significant apoptotic cell death shortly after transplantation prevents widespread implementation of this curative approach. Recent improvements in the differentiation of stem cell-derived beta cells (sBC) provide an abundant source of functional beta cells, with the first clinical trials evaluating the efficacy and safety of sBCs. Similar to cadaveric islets, sBCs experience severe apoptotic cell death following transplantation with the majority of graft mass lost within the first day following transplantation. We hypothesize that temporarily arresting the intrinsic apoptotic pathway by expression of BCL2 in transplanted sBCs can prevent significant cell death and improve graft survival. Using genome engineering strategies, we inserted a doxycycline inducible BCL2 expression cassette into a human induced pluripotent stem cell line. Under nutrient deprivation conditions, cells with induced BCL2 expression displayed a 60% increase in viable cells after treatment, this increase in viability was also observed in complementary in vitro models of apoptosis and radical oxygen species. These results give evidence to the role of BCL2 in saving cells under intrinsic apoptosis stress conditions. Future experiments will evaluate if BCL2 can similarly rescue sBCs cell death after transplant in vivo. Rescuing transplanted sBCs from apoptotic cell death will increase the efficacy of islet transplantation therapy for T1D patients by reducing the total beta cell mass needed to achieve insulin independence.

Disclosure
A. Baker: None. R. Castro Gutierrez: None. A.T. Kratz: None. H.A. Russ: Advisory Panel; Sigilon Therapeutics, Inc. Consultant; Minutia. Advisory Panel; Prellis Biologics. Consultant; Eli Lilly and Company.
203-OR: Metabolic and Clinical Outcomes with One Abnormal Value on Carpenter Coustan Criteria
Authors: SCIFRES CHRISTINA M. , DAVIS ESA , COSTACOU TINA , ORRIS STEVEN R. , LALAMA CHRISTINA M. , ABEBE KALEAB , CATALANO PATRICK 
Published: June 2024

Objective: To examine the metabolic profile and neonatal outcomes of 1 abnormal (1ABNL) value on a 100g OGTT using Carpenter Coustan (CC) compared to no GDM (NGDM) and treated GDM (GDM) by the IADPSG or CC Criteria.
Methods: This is a secondary analysis of an RCT of GDM diagnosis using the IADPSG or CC criteria. Those with 1ABNL on CC GDM were not treated and compared to NGDM and GDM. Propensity score models with inverse probability of treatment weighing (IPTW) were used to balance groups.
Results: Of 827 participants 82 (10%) had 1 ABNL, 80 (10%) had GDM (22% CC, 78% IADPSG), and 665 (80%) NGDM. After IPTW, glucose and insulin were significantly higher whereas insulin sensitivity and beta cell response were lower in 1ABNL vs. NGDM. Insulin sensitivity/resistance and glucose/insulin AUC were similar between 1ABNL vs. GDM (Table) After IPTW, LGA (OR 1.4, 95% CI 1.0-2.0) and maternal composite (OR 2.0, 95% CI 1.6-2.6) were higher while neonatal composite (OR 0.5, 95% CI 0.4-0.7) and SGA (OR 0.1, 95% CI 0.1-0.2) were lower when comparing untreated 1 ABNL vs. NGDM. Compared to GDM, 1ABNL was associated with higher LGA (OR 3.4, 95% CI 1.4-8.4) and lower risk for SGA (OR 0.2, 95% CI 0.1-0.8), and neonatal composite (OR 0.3, 95% CI 0.2-0.6).
Conclusions: Women with 1ABNL on a 100g OGTT have a similar metabolic profile compared to GDM but metabolic dysfunction compared to NGDM resulting in increased fetal growth compared to both NGDM and treated GDM.

Disclosure
C.M. Scifres: None. E. Davis: None. T. Costacou: None. S.R. Orris: None. C.M. Lalama: None. K. Abebe: None. P. Catalano: None.

Funding
National Institutes of Health (1R01HD079647)
2030-LB: Matairesinol and Its Metabolite Enterolactone Promote Glucose Uptake in 3T3-L1 Adipocytes via a Glut4/Akt-Dependent Mechanism
Authors: MILLER ROCHELLE , FROMMACK ABIGAIL , WOODFIN SETH F. , CHAPPLE BROOKE , BONES MEGAN , JAMPOLE SHELBY , MOORE WILLIAM 
Published: June 2024

Type-2 diabetes (T2D) is marked by dysregulated glucose homeostasis resulting in chronic fasting hyperglycemia and insulin resistance. Previous studies indicate that habitual coffee consumption is negatively correlated with the development of T2D. Matairesinol (MA) is a low molecular weight polyphenol that is found in coffee. MA and its gut microbial metabolite, enterolactone (ENL), have previously been shown to elicit anti-diabetic properties in studies analyzing skeletal muscle. However, their effects have not been demonstrated in adipocytes. In this study, 3T3-L1 adipocytes were treated with either MA or ENL in a dose-dependent manner and subsequently assayed for glucose uptake efficacy. We found that 1 and 10 µM ENL as well as 10, 15, 50, and 100 µM MA significantly increased glucose uptake in 3T3-L1 adipocytes compared to the vehicle. We also demonstrated that both MA- and ENL-stimulated glucose uptake were blunted by selective chemical inhibitors of Glut4, but not Glut1, thus indicating a potential Glut4-dependent mechanism. In addition, we show that ENL (50 µM) significantly increases Akt phosphorylation compared to the vehicle and to an extent that is statistically indistinguishable from the effects of insulin. Our data indicate that these compounds work through an Akt/Glut4-dependent mechanism thus warranting continued investigation into the molecular mechanisms by which they promote glucose uptake.

Disclosure
R. Miller: None. A. Frommack: None. S.F. Woodfin: None. B. Chapple: None. M. Bones: None. S. Jampole: None. W. Moore: None.
2033-LB: Dulaglutide Improves Metabolic Dysfunction–Associated Steatohepatitis (MASH), but Not Atherosclerosis, Independent of Weight Loss in Middle-Age LDLR-/- Mice
Authors: SHANTARAM DHARTI , RIMA XILAL Y. , BRADLEY DAVID , LIU JOEY Z. , WRIGHT VALERIE P. , AMARI ANASTASIIA , ROTTINGHAUS JOSEPH , FERNANDES JADEN M. , HSUEH WILLA 
Published: June 2024

Clinical trials have demonstrated that glucagon-like peptide-1 receptor agonist (GLP-1 RA) reduces atherosclerosis risk in individuals with obesity independent of their diabetes status and is currently under investigation as a treatment for metabolic dysfunction-associated steatohepatitis (MASH). Several studies have associated weight loss with improvements in metabolic comorbidities, such as metabolic dysfunction-associated fatty liver disease (MAFLD) and type 2 diabetes (T2D). To determine the contribution of weight loss to the effect of dulaglutide; a GLP-1 RA, on atherosclerosis and MASH, we pair-fed western high-fat diet (WHFD) to middle-aged low-density lipoprotein receptor knockout (LDLR-/-) mice which develop accelerated atherosclerosis and MASH, compared to fatty streaks and simple steatosis in younger LDLR-/- mice. We administered dulaglutide and a placebo twice a week for the last 6 weeks of 12 weeks of WHFD. As a result, both dulaglutide and placebo-treated mice gained weight equally which was maintained throughout the study. Atherosclerosis extent measured with en-face analysis was similar between dulaglutide vs. placebo (18± 5% vs.14± 4% aorta covered by plaque), but dulaglutide-treated mice showed reduced liver fat by 50% (p&lt;0.01), MASH pathology grade by 30% (p&lt;0.05), and liver function testing by 50% (p&lt;0.05). Furthermore, dulaglutide improved glucose tolerance but did not impact insulin sensitivity between the two groups. In addition, dulaglutide treatment substantially reduced the expression of de novo lipogenesis and inflammation genes in the liver. Together, these results reveal that weight loss contributes to the anti-atherosclerosis effects of GLP-1 RAs, but reduced liver fat accumulation and MASH are independent of weight loss.

Disclosure
D. Shantaram: None. X.Y. Rima: None. D. Bradley: None. J.Z. Liu: None. V.P. Wright: None. A. Amari: None. J. Rottinghaus: None. W. Hsueh: None.