bluuebunny/crossref_metadata_2025_split huggingface dataset:
6519 BCG Clinical Trial Programs in Advanced Type 1 Diabetes - 2024 Update
Authors: Kühtreiber Willem M , Thach Bethany , Hayashi Hikaru , Adams Lindsey , Hullavarad Neeshi , Mounier Daniel A , Le Khoi , Bulczynski Emily , Dorsey Jack L , Kartsounis Nicholas , Braley Joan , Zheng Hui , Faustman Denise L 
Published: October 2024

Abstract
Disclosure: W.M. Kühtreiber: None. B. Thach: None. H. Hayashi: None. L. Adams: None. N. Hullavarad: None. D.A. Mounier: None. K. Le: None. E. Bulczynski: None. J.L. Dorsey: None. N. Kartsounis: None. J. Braley: None. H. Zheng: None. D.L. Faustman: None.
The bacillus Calmette-Guerin (BCG) vaccine, originally developed a century ago to prevent tuberculosis infection, has today advanced in multiple clinical trials for the treatment of the type 1 diabetes (T1D), other forms of autoimmunity and infectious disease. At our institution, over 500 individuals with type 1 diabetes have been enrolled in ongoing BCG clinical protocols to test BCG’s ability to lower HbA1c, reduce insulin requirements and stabilize day-to-day fluctuations in blood sugars; 300 have been treated with BCG. In a completed randomized, placebo-controlled Phase I trial in adults with established T1D, long-term follow up continues to show that HbA1c values are durably lowered for 8+ years after multi-dose BCG treatment. In two open-label clinical trials in adults with juvenile-onset diabetes, a 10-15% reduction of HbA1c was observed after multi-dose BCG treatment. A randomized, double-blinded Phase II trial in adults with longstanding T1D has followed all patients in the BCG-treated (n=100) and placebo groups (n=50) for five years and is pending read-out. The primary outcome of all the trials is HbA1c lowering. Two new, randomized, double-blinded pediatric trials are testing the potential benefits of BCG vaccination with active enrollment ongoing. One is testing BCG in children ages 12 to 18 with more than 2 years since T1D diagnosis. The other is enrolling children ages 8 to 18 with less than 1 year since T1D diagnosis. BCG vaccine therapy may provide a safe and affordable medical intervention in individuals with longstanding T1D and works decades after disease onset by changing glucose metabolism within lymphocytes, independently of the pancreas.
Presentation: 6/3/2024
7970 C3 and C4 Levels Decrease Post-prandial in Adolescents with type 1 Diabetes
Authors: Damilano Cecilia Paola , Yu Chack-Yung , Zhou Danlei , Mamilly Leena , Hoffman Robert Paul 
Published: October 2024

Abstract
Disclosure: C.P. Damilano: None. C. Yu: None. D. Zhou: None. R.P. Hoffman: None.
Introduction: Cardiovascular disease will be the primary cause of future death for adolescents with type 1 diabetes (T1D) and its origins are likely to occur in this age group. Adolescents with T1D have increased systemic inflammation which is likely to play a significant role in the pathogenesis of cardiovascular disease. The complement system, in particular, components C3 and C4 are part of the innate immune system that regulates inflammation. Increased C3 and C4 levels are associated with increased cardiometabolic risk. Objective: Most studies of inflammation are done while fasting but TNFα and IL6 increase postprandially in adolescent T1D following both high and low glycemic index (GI) meals. The goal of this study was to determine whether there are similar post-prandial changes in C3 and C4 levels. Methodology: Twelve, non-obese children and adolescents, 10-18 years old, with T1D were recruited from the Diabetes Clinic of Nationwide Children's Hospital. A randomized cross-over design for their two subsequent visits was used. After an overnight fast baseline blood samples were taken to measure plasma glucose, C3, total C4 protein, and total C4. Rapid acting insulin was given to cover meal carbohydrate without glucose correction, and blood samples were repeated (30, 60, 90, and 120 minutes) to measure glucose and C3 and C4 levels. Visits 1 and 2 were identical except for GI of the given meal. Visits were rescheduled if the fasting glucose was greater than 200 mg/dl. Repeated measures ANOVA and Spearman’s correlation were used. Results: Glucose response was significantly greater following high GI meal (Δglucose: high 52±12 vs low 6±5 mg/dl, mean±SE, p&lt;0.001). For C3 levels, there was a significant post-prandial decrease (time effect p=0.049), but no meal effect or meal x time interaction. No specific time differences were found. C4 levels were also suppressed postprandially (p&lt;0.001) and there was again no meal effect or meal by time interaction. Post hoc analysis found that C4 levels were lower at 60 min than at 0 min (p=0.007), 90 min (p=0.002) or 120 min (p&lt;0.001). Conclusions: C3 and C4 levels decrease post-prandially in adolescents with T1D in contrast to increases in TNFα and IL6. Future research is clearly needed to clarify the postprandial interactions between the complement and inflammatory systems and potential pathogenic role in cardiovascular disease.
Presentation: 6/3/2024
8052 carRNA m6A methylation regulates transcription state and chromatin accessibility in human islets in normal physiology and type 2 diabetes
Authors: Shukla N , Ju C W , Li H , He C , Kulkarni R 
Published: October 2024

Abstract
Disclosure: N. Shukla: None. C. Ju: None. H. Li: None. C. He: None. R. Kulkarni: Advisory Board Member; Self; Novo Nordisk, Biomea Fusion Inc, REDD Pharma. Grant Recipient; Self; Inversago.
Chromatin-associated regulatory RNAs (carRNA), which include promoter- and enhancer-associated RNAs as well as several non-coding repeat elements have been established in the literature as important regulators of global gene transcription. However, the regulation of carRNAs themselves has been an enigma. Recent publications from the He Lab at UChicago have shown the role of RNA N6-methyladenosine (m6A) in regulating carRNA stability and function. m6A is among the most abundant mRNA modifications in mammals. Seminal work from our lab has reported that the “writers” of m6A (e.g. methyltransferase-like [METTL3] and METTL14) are significantly downregulated in islets of humans with type 2 diabetes (T2D). Consequently, the global m6A landscape in the islets segregates the T2D from the control group significantly better than the transcriptome (n=7 for Control and n=8 for T2D islets). Hypomethylation of key transcripts in the insulin/IGF-1-AKT-PDX1 pathway led to impaired insulin secretion and decreased β-cell proliferation. We now show this decreased m6A on RNA is not limited to the mRNA but also affects chromatin-associated regulatory RNAs (carRNA). Intriguingly, downregulation of METTL3 and METTL14 in human β-cell line EndoC-βH1 differentially regulates these regulatory versus protein-coding transcripts. We observe that while METTL14 KD causes global downregulation of transcripts belonging to pathways important for β-cell identity and function (including calcium signaling, PI3K-AKT/MAPK signaling pathway, pancreatic secretion etc.), it leads to an upregulation of pathways involved in RNA processing and global gene transcription (Transcription by RNA Pol II, metabolism and splicing of mRNA, chromatin organization and modification etc.) {false discovery rate (FDR) &lt; 0.05}. Considering carRNAs have been previously reported to regulate global chromatin accessibility and transcription, our observations on their ability to get differentially regulated m6A writer proteins provide novel insights into the epigenetic regulation of human islet cells. These findings provide opportunities to develop therapeutic approaches to regulate β-cell identity and/or insulin secretion in T2D.
Presentation: 6/3/2024
8715 Cholinergic Signaling in the Mouse Embryonic Pancreas Targets Early Endocrine Cells
Authors: Duarte C , Panzer J K , Borowsky N , Caicedo A 
Published: October 2024

Abstract
Disclosure: C. Duarte: None. J.K. Panzer: None. N. Borowsky: None. A. Caicedo: None.
The parasympathetic vagus nerve affects pancreas function by activating local intrapancreatic neurons that release acetylcholine (ACh). These neurons are derived from progenitors of the vagal neural crest and colonize the pancreas during embryonic development. The specific mechanisms by which ACh is released from these neurons influence embryonic development of the islet and, specifically, beta cells remain largely unknown. The purpose of this study was to identify cholinergic signaling components and assess early physiological responses to ACh during murine development of endocrine lineage cells. We extracted pancreatic rudiments from mice at embryonic stages E15 to E18 and stained them for neuronal and endocrine markers, along with components associated with cholinergic signaling. We further performed Ca2+ imaging of the pancreatic rudiments from NGN3CRE-GCaMP3 mice to record responses to ACh in cells of the endocrine lineage. At E15, we observed a significantly higher concentration of glucagon+ cells compared to insulin+ cells, consistent with the earlier differentiation of alpha cells in the developing pancreas. Neuronal body clusters were identified in close proximity to endocrine lineage cells from E15 to E18, with the neuronal network becoming more dispersed and interconnected. At E15, wide distribution of the presynaptic vesicular acetylcholine transporter (VAChT) was observed later becoming localized around insulin+ and glucagon+ cells at E18. Postsynaptic acetylcholinesterase (AChE) colocalized with glucagon+ cells from E15 to E18 and with insulin+ cells by E18. ACh elicited Ca2+ responses in individual endocrine cells as early as E15. Our results show that cholinergic nerve terminals target early endocrine cells and elicit responses to ACh, indicating that local cholinergic neurons innervate and activate endocrine progenitors in the embryonic pancreas. Our current studies are aimed at determining how cholinergic signaling contributes to beta cell differentiation and function. We expect this knowledge to guide future protocols for deriving beta cells from stem cells.
Presentation: 6/2/2024
8642 Continuous glucose monitor: reclaiming type 2 diabetes self-efficacy and mitigating disparities
Authors: Ni Kevin , Tampe Carolyn A , Sol Kayce , Cervantes Lilia , Pereira Rocio Ines 
Published: October 2024

Abstract
Disclosure: K. Ni: None. C.A. Tampe: None. K. Sol: Employee; Self; Patient accepted job with Dexcom Jan 2024. L. Cervantes: None. R.I. Pereira: None.
Context: The increase in continuous glucose monitor (CGM) use has been notable for widening disparities between the least and most socially marginalized. Given access barriers, there is limited CGM patient experience information that is inclusive of those with type 2 diabetes mellitus from socially marginalized backgrounds. Objective: To understand the CGM usage experience across a U.S. Medicaid population with type 2 diabetes at federally qualified health centers (FQHCs). Methods: This qualitative study used semi-structured phone interviews with 28 English or Spanish speaking participants prescribed CGM who were enrolled in a U.S. Medicaid program that subsidized CGM. Audio-recordings of interviews were transcribed and analyzed by inductive thematic analysis. Results: Participants had a median age 56 (interquartile range 48-60) with varying levels of formal schooling (55% with 9 years or less) and were from diverse racial or ethnic backgrounds (57% Hispanic, 18% non-Hispanic Black, 21% non-Hispanic White). Interviews were conducted in English (68%) or Spanish (32%). We identified six major themes: initial expectations and overcoming initiation barriers (subthemes: initial expectations, overcoming initiation barriers), convenience and ease promote daily use (subthemes: benefits over fingersticks), increased knowledge leads to improved self-management (subthemes: increased understanding and knowledge, glucose level self-awareness, motivating healthy behaviors), collaboration with provider and clinical team, improved self-reported outcomes (subthemes: improved glucose and non-glucose targets, positive emotional effect, essential for management), and barriers and burdens are generally tolerated (subthemes: barriers to monitoring, burden of self-monitoring). Conclusions: CGM was experienced as easy to understand and use and viewed as a tool for diabetes self-efficacy. Expanded CGM access for socially marginalized patients with type 2 diabetes can enhance diabetes self-management to help mitigate diabetes outcome disparities.
Presentation: 6/2/2024
12392 Decoding LADA: A Closer Look At A Suspected Case Influenced By Prior IVIG Therapy
Authors: Gondhi A , Antharam S , Bantu S S , Abdulhadi B 
Published: October 2024

Abstract
Disclosure: A. Gondhi: None. S. Antharam: None. S.S. Bantu: None. B. Abdulhadi: None.
Introduction: LADA(Latent Autoimmune Diabetes of Adults) is defined as a new diagnosis of diabetes after the age of 35, presenting with features of T2DM but with the presence of T1DM associated autoantibodies. Correct diagnosis of LADA is important since prognosis and therapy differs from T2DM. We report an interesting case of transient elevation of Glutamic Acid decarboxylase (GAD-65) antibodies due to IVIG therapy leading to a misdiagnosis of LADA. Case presentation:A 46-year-old women with hypothyroidism was referred for management of LADA. A few months prior to the referral, she was hospitalized for acute bacterial meningitis and developed flaccid quadriparesis concerning for Guillain Barre syndrome (GBS). She received multiple IVIG infusions, steroids with resultant hyperglycemia requiring insulin and was transferred to a rehabilitation facility. During her stay in rehab, her initial dose of glargine 20 units twice daily was titrated down rapidly once steroids are tapered. Blood work revealed HbA1C 6.1%, blood glucose 116 mg/dL, C-peptide levels 4.1 ng/ml (0.9 -7 ng/ml), and GAD-65 antibodies &gt;250 (N&lt;5 IU/ml). She was diagnosed with LADA and discharged on 2 units of glargine. Her primary care physician advised to stay on the 2 units of glargine since her GAD-65 antibodies were significantly elevated and then referred to the endocrine clinic. Repeat bloodwork in our clinic revealed HbA1c of 5.8%, GAD-65 antibodies were repeated twice and were found to be undetectable &lt;5. She was taken off insulin and has been doing well since. Discussion:IVIG is derived from plasma pooled from donors, used to treat a variety of diseases. Autoantibodies contained in IVIG may result in false positive serum tests if levels are checked soon after the infusion. This phenomenon has been documented in previous cases involving treponemal, H. pylori, hepatitis C as well as ANA antibodies. Increases in anti-GAD levels post-IVIG therapy have been previously reported. We saw a similar scenario in our patient, who was initially diagnosed with LADA and started on insulin due to an observed elevation in GAD 65 levels. However, this elevation was transient with negative repeat levels a few months later. Conclusion: Our case highlights the importance of recognizing that IVIG infusions can lead to the transfer of and to transient elevations in autoantibodies including GAD-65, which may lead to misdiagnosis and unnecessary therapies. References: 1. de Beer, F. C., Schreurs, M. W. J., & Foncke, E. M. J. (2009). False positive autoantibodies to glutamic acid decarboxylase in opsoclonus-myoclonus-ataxia syndrome after intravenous treatment with immunoglobulin. Clinical neurology and neurosurgery, 111(7), 643-644.
Presentation: 6/3/2024
8569 Defining Cell-Intrinsic Defects In Hepatic Insulin Resistance In Type 2 Diabetes Using A Human iPS Cell-Derived Disease-In-A-Dish Model
Authors: Gattu A , Tanzer M , Yaron T , Cantley L , Kahn C R 
Published: October 2024

Abstract
Disclosure: A. Gattu: None. M. Tanzer: None. T. Yaron: None. L. Cantley: None. C.R. Kahn: None.
Hepatic insulin resistance is central to type 2 diabetes (T2D). Understanding the cellular drivers underlying insulin resistance in the liver is challenging since, in vivo, this can be due to cell-intrinsic defects in insulin signaling, as well as the effects of multiple circulating factors that can modify insulin signaling. Here, we have utilized inducible pluripotent stem cells (iPS) from 8 control and 8 T2D patients differentiated in vitro into hepatocytes (iHeps) to dissect the cell-intrinsic defects in hepatic insulin resistance. We find that following stimulation with insulin, T2D iHeps displayed “pathway-selective insulin resistance,” in which insulin failed to suppress gene expression of critical gluconeogenic enzymes (PCK1, G6PC) but continued to stimulate expression of the lipogenic enzymes (FASN, ACACA). This was associated with a 1.5-fold higher level of insulin stimulation of C[1]4 acetate into lipids, i.e., de novo lipogenesis. Immunoblotting analysis showed T2D iHeps exhibited a 50% reduction in phosphorylation of the insulin receptor IRY[1][1]35 and ∼ 30% reductions in AKTT308, GSK3αS2[1]/GSK3βS9, and FOXO1T24/FOXO3aT32 in T2D following insulin stimulation for 10 minutes. To define the full spectrum of alterations in signaling in iHeps, we used unbiased LC-MS/MS-based phosphoproteomics. This revealed alterations in 987 insulin-regulated phosphosphorylations that had increased phosphorylation after insulin treatment and alterations in 723 sites for which insulin decreased phosphorylation (with a |fold-change| &gt;1.5 and adj. p &lt; 0.05). These alterations were of two types: 43% of the altered insulin-regulated phosphosites showed reduced or “impaired” insulin regulation, but 57% of the phosphosites displayed new or significantly increased insulin-regulated phosphorylations in T2D, i.e., “emergent” signaling. The impaired signaling in T2D included losses in the insulin receptor signaling cascade, Rho-GTPase pathway, Notch-HLH, and anti-viral mechanisms of IFN-stimulated genes. In contrast, emergent signaling included other components of the Rho-GTPase pathway, metabolism of RNA, membrane trafficking, and chromatin-modifying enzymes. Using an AI-based kinase-substrate association analysis, we found that the deficiencies in signaling represented reduced actions of kinases AKT2, AKT3, PKCθ, CHK2, PHKG2, and/or STK32C kinases, while the emergent changes represented increases in ROCK1, ROCK2, MST4 and/or BCKDK kinase activity. In summary, phosphoproteomic analyses of iHeps revealed a comprehensive insulin signaling network disrupted in insulin resistance in the liver in T2D, which underlies the etiology of insulin resistance. These alterations can be ascribed to changes in the activity of two classes of upstream kinases, representing potential new targets for treating T2D.
Presentation: 6/1/2024
12474 Demographic Characteristics Of Patients With Prediabetes Who Reverted To Normoglycemia Or Progressed To Diabetes At 1 Year Follow Up
Authors: Niedzialkowska Ewelina Marta , Sayed Farah El , Townsend Mary , Bhatia Unnati , Roy Sujoy , Homayouni Ramin , Halalau Alexandra 
Published: October 2024

Abstract
Disclosure: E.M. Niedzialkowska: None. F. El Sayed: None. M. Townsend: None. U. Bhatia: None. S. Roy: None. R. Homayouni: None. A. Halalau: None.
Background: Pre-diabetes (PD), characterized by hyperglycemia influenced by lifestyle factors, genetics, age, and ethnicity, is considered a risk factor for development of diabetes. However, only a small proportion of PD individuals progress to type-2 diabetes (T2D) each year. More refined diabetes risk prediction tools are needed to direct proactive health management strategies for at-risk populations. Question and Significance: Our study explored the associations between age, race, gender and BMI in PD individuals who either progressed to T2D or reverted to normoglycemia (NG) over a one-year follow-up period. Methods and Design: This is a retrospective observational study of 38,228 patients with PD, based on having two consecutive years of hemoglobin A1c (HbA1c) between 5.7% and 6.5%. We compared the demographic characteristics of individuals who progressed to T2D or regressed to NG within one year using bivariate (Kruskal-Wallis or Chi-squared) or multivariate logistic regression analysis. Results: The study cohort included 57.36% females, 66.13% Whites, 19.41% Blacks and 4.36% Asians with a median age of 69. Bivariate analysis revealed significant age differences between PD patients who reverted to NG with median age of 67 in those who reverted vs 70 in those who did not revert (p&lt; 0.0001). In addition, the proportion of males who progressed to T2D was significantly higher and the proportion of Blacks who reverted to NG was significantly lower.Using multivariate regression (adjusting for age, gender, race and BMI), we found that each year in age significantly lowered the odds of reversion from PD to NG (OR 0.98, p&lt;0.0001) but was not associated with progression to T2D. PD males had significantly higher odds of progression to T2D (OR 1.28, p&lt;0.0001). Both Asians (OR 0.62, p&lt;0.0007) and Blacks (OR 0.68, p&lt;0.0004) had significantly lower odds of reversion to NG from PD compared to Whites. Surprisingly, BMI was not associated with neither reversion to NG nor progression to T2D, after adjusting for age, gender, and race. Discussion: Our findings underscore significant racial disparities and gender differences in regression to normoglycemia and progression to diabetes. This emphasizes the need for personalized interventions and targeted strategies for prediabetic populations to mitigate progression to T2D and to achieve normoglycemia.
Presentation: 6/1/2024