bluuebunny/crossref_metadata_2025_split huggingface dataset:
6413 Anti-PD1 induces T1D in an HLA-DQ8, HLA-A2.1 mouse model
Authors: Houeiss P , luce S , Boitard C 
Published: October 2024

Abstract
Disclosure: P. Houeiss: None. S. luce: None. C. Boitard: None.
Anti-PD1 is an immune checkpoint inhibitor that has revolutionized cancer treatment. It blocks the interaction between PD1, a receptor on the surface of activated or exhausted T cells, and its ligands PDL1 and PDL2, to inhibit the immune response. However, anti-PD1 induces T1D in 0.4-2% of patients raising questions about the risk factors and the mechanisms behind T1D development. Since the pancreas of these patients is inaccessible, we focus on autoimmune diabetes induction in a transgenic mouse model modified to express the T1D susceptibility genes HLA-DQ8, HLA-A2.1 and the human preproinsulin and on identifying new targets to prevent or treat this disease. Thus, 8 to 12 weeks old mice were treated initially with 500 micrograms of anti-PD1 followed by 250 micrograms every other day for 10 days. Control mice received 6 injections of PBS. Mice were followed up for evidence of hyperglycemia for 60 days. Cells and tissues from the pancreas, and the spleens were isolated 15-, 30- or 60-days post-treatment initiation and analyzed by flow cytometry and immunohistochemistry. Although diabetes incidence in treated mice was 14% (n=14), insulitis incidence progressively increased over time reaching 86% on D60 (p=0.005). On Day 15, in the spleen, a significant 10% increase of CD4+Foxp3+CD25- T cells at the expense of the CD4+Foxp3- T cells were seen in the treatment group as compared to the control (37.1±4.25 vs 26±3.5, p&lt;0.01, n=5 per group). In the treatment group, PD1 expression significantly increased on CD4+Foxp3+ T cells whereas PDL1 expression increased on CD4+Foxp3- and CD8+ T cells (p&lt;0.01). On D30, in the pancreas, infiltrates show positive staining for F4/80+, CD4+ and CD8+ T cells with scarce foxp3+ T cells. While the absolute percentage of CD4+Foxp3+ T cells increased in the insulitis and diabetes group, their percentage among CD3+ T cells decreased in the insulitis (10.2%) and diabetes group (3.9%) as compared to the control group (13.5%). Infiltrates were concentrated around the islets and the efferent and afferent vessels, and extended to the exocrine pancreas, leading to secondary acinar destruction. In the pancreatic infiltrates from anti-PD1 treated mice, we noted a significant increase in CD4+ T cells recognizing Ins13-21 monomers as compared to the negative control. PD1 blockade induced an insulitis characterized by a Treg to effector T cells imbalance. Thus, it acted on the early phase of T1D. In conclusion, this model describes a new T1D endotype that shares similarities with ICI induced diabetes in patients.
Presentation: 6/2/2024
6531 Assessing the Risk of Recurrence in Acute Pancreatitis Among Patients with Type 2 Diabetes Initiating GLP-1 Receptor Agonists Therapy
Authors: Nassar Mahmoud , Abosheaishaa Hazem , Dandona Paresh , Ghanim Husam , Chaudhuri Ajay 
Published: October 2024

Abstract
Disclosure: M. Nassar: None. H. Abosheaishaa: None. P. Dandona: None. H. Ghanim: None. A. Chaudhuri: None.
Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are recognized therapeutic agents for patients with type 2 diabetes mellitus and obesity. However, due to concerns about pancreatitis, clinicians do not recommend these agents for patients with a history of pancreatitis. Existing research presents conflicting evidence about this association. Our primary aim was to evaluate the risk of recurrence of acute pancreatitis (AP) associated with initiating GLP-1 RAs in patients with a history of AP. Methods: Our retrospective cohort study deployed the TriNetX platform, leveraging a large dataset from 106 healthcare organizations and approximately 127 million patients across 15 countries. We obtained data specific to our research on September 21, 2023. Using the ICD-10-CM code, we identified groups of adults with AP. We investigated the effect of GLP-1 RA vs. SGLT2i, DPP4i, and no medication (GLP-1 RA, SGLT2i, and DPP4i) on the recurrence of AP within 5 years of starting treatment. We ensured comparability between cohorts by employing propensity score matching, which focused on critical variables such as age, gender, body mass index (BMI), cholelithiasis, tobacco use, serum triglyceride, and HbA1c levels. Results: We matched the GLP-1 and SGLT2i cohorts, which initially had 4,680 and 7,212 patients, respectively, down to 3,926 in each group. Similarly, the GLP-1 vs. DPP4i comparison matched both cohorts to 3,324 patients from initial counts of 4,680 and 5,723 patients. In the matched cohorts, the GLP-1 group showed a lower AP recurrence risk (15.2%) than the SGLT2i group (24%). This difference was significant (-8.9%, 95% CI: -0.106, -0.071), with a notable risk ratio of 0.630 and an odds ratio of 0.564. For the GLP-1 vs. DPP4i comparison, the GLP-1 group's AP recurrence risk was 14.4%, lower than the 23.3% in the DPP4i group. This difference (-8.9%, 95% CI: -0.108 to -0.071) was also significant, with a risk ratio of 0.616 and an odds ratio of 0.552. For the GLP-1 vs. no medication (GLP-1RA, DPP4i, and SGLT2i) comparison, the GLP-1 group's AP recurrence risk was 14.5%, lower than the 51.6% in the comparison group. This difference (-37.1%, 95% CI: -0.388 to -0.353) was also significant, with a risk ratio of 0.282 and an odds ratio of 0.16. Conclusion: Our research showed that starting GLP-1 RA therapy in people who have had a history of AP does not increase and may potentially lower the risk of recurrence of AP than starting SGLT2i or DPP4i therapy and no medication group. These findings highlight the potential of GLP-1 RA therapy as a safer therapeutic option in this patient population, which requires further investigation.
Presentation: 6/1/2024
8626 Associations Between Low Serum Bilirubin Levels and the Progression of Diabetic Kidney Disease in Individuals with Type 2 Diabetes, Including Those in a Normoalbuminuric State
Authors: Kim Eun Sook , Cho Yunjung , Hong Oak-Kee , Jo Kwanhoon , Han Je-Ho , Moon Sungdae 
Published: October 2024

Abstract
Disclosure: E. Kim: None. Y. Cho: None. O. Hong: None. K. Jo: None. J. Han: None. S. Moon: None.
Objective: This study aimed to investigate the potential correlation between serum bilirubin levels and the progression of diabetic nephropathy, assessing whether low serum bilirubin levels are associated with a decline in renal function, while considering the baseline albumin excretion status. Methods: The longitudinal observation, spanning 11 years, involved 1167 Korean subjects aged 20 years or older, diagnosed with type 2 diabetes mellitus (T2DM), and having a baseline estimated glomerular filtration rate (eGFR) greater than 60 ml/min per 1.73 m2. Albuminuria was assessed by the 24-hour urinary albumin to creatinine excretion rate (ACR) and categorized into normoalbuminuria (ACR &lt;30 mg/g), micro- or macroalbuminuria (ACR &gt;300/g). Cox regression analysis was employed to explore connections between serum bilirubin levels and eGFR decline ≥40%, with adjustments for potential confounding variables. Results: Over a median follow-up of 8.2 years, 128 individuals experienced a decline in eGFR &gt;40%. The hazard ratio (HR) of incident GFR decline was 1.72 (95% CI: 1.04-2.85, P=0.036) in the lowest total bilirubin (TB) tertile compared to the highest TB tertile after multivariable adjustment. When stratified by baseline albuminuria status, low bilirubin levels were significantly associated with eGFR decline, even in the normoalbuminuria group (HR: 2.21, 95% CI: 1.26-3.90, P=0.006), with a gradually increasing risk according to the absence of low TB levels and albuminuria (HR: 2.92, 95% CI: 1.65-5.19, P&lt;0.001), and low TB levels and albuminuria (HR: 3.01, 95% CI: 1.65-5.46, P&lt;0.001). Conclusion: Low serum TB levels are associated with an increased risk of rapid GFR decline in Korean patients with T2DM. Serum bilirubin levels may serve as a prognostic marker for the development and progression of diabetic kidney disease.
Presentation: 6/1/2024
9332 Breathless Struggle: Unraveling The Interplay Between DKA And Acute Respiratory Distress Syndrome
Authors: Zahra Sundas , Subramani Rashmi , Abbas Mubashir , Hasan Khwaja Yusuf , Manas F N U , Bajracharya Charu 
Published: October 2024

Abstract
Disclosure: S. Zahra: None. R. Subramani: None. M. Abbas: None. K.Y. Hasan: None. F. Manas: None. C. Bajracharya: None.
Introduction: Diabetic Ketoacidosis (DKA) is a life threatening emergency with mortality rate of 0.15%-0.30%. Acute Respiratory Distress Syndrome (ARDS) is a rare complication of DKA which presents as a sudden onset of dyspnea and progressive hypoxia. It is an inflammatory process that damages the alveolar-capillary membrane leading to the fluid leakage into the alveolar space. The incidence of ARDS in DKA remains unknown. It is more commonly seen in adolescents and young adults. The exact pathogenesis of ARDS in DKA is currently unknown. Some proposed mechanisms are that a severe metabolic acidosis in DKA along with increased cytokines production due to long standing hyperglycemia leads to increased capillary membrane permeability allowing fluid to accumulate in the alveolar space. TNF-a and IL-6 along with other pro-inflammatory cytokines are known to cause endothelial damage and increase pulmonary permeability leading to pulmonary edema. However most DKA patients with severe metabolic acidosis do not develop ARDS. Case Presentation:Case 1: A 19 year old male with uncontrolled type I diabetes mellitus presented with altered mental status. On examination, he was tachycardic and tachypneic with dry mucous membranes. Lab workup revealed leukocytosis, severe hyperglycemia, and severe anion gap metabolic acidosis with beta hydroxybutyrate level of 14.20 mmol/L (normal: 0.02-0.27 mmol/L). He was diagnosed with DKA and started on intravenous fluids, and insulin as per institutional DKA protocol. Approximately 12 hours post-admission, the patient experienced sudden-onset dyspnea with deteriorating hypoxia, necessitating emergent intubation and mechanical ventilation. Chest radiography displayed bilateral patchy ground-glass opacifications consistent with acute respiratory distress syndrome (ARDS). Despite the administration of 8 liters of intravenous fluids, the patient exhibited a negative net fluid balance of 2.3 liters, implicating fluid shift. Further investigations, including bronchoscopy and bronchoalveolar lavage, revealed an unobstructed airway, minimal secretions, and no evidence of hemorrhage or infection. Comprehensive infectious work-ups yielded negative results as well, reinforcing the diagnosis of DKA as the underlying cause of ARDS. Conclusion: Acute Respiratory Distress Syndrome is a rare but potentially fatal complication of Diabetic Ketoacidosis. Early recognition of this serious pulmonary complication of DKA and its prompt management is essential to prevent respiratory failure and mortality.
Presentation: 6/1/2024
12340 Cardiovascular Risks With Testosterone Replacement Therapy In Patients With Type 2 Diabetes Mellitus
Authors: Gupta Archit , Nassar Mahmoud , Ghanim Husam 
Published: October 2024

Abstract
Disclosure: A. Gupta: None. M. Nassar: None. H. Ghanim: None.
Background: Concerns have been raised about testosterone replacement therapy (TRT) in hypogonadism patients, particularly regarding cardiovascular disease (CVD) risk. Despite some studies showing TRT's non-inferiority to placebo in men at high CVD risk, its impact on patients with type 2 diabetes mellitus (T2DM) remains uncertain. This study examines the incidence of cardiovascular events in patients with T2DM on TRT, with a focus on the first four years of treatment. Methods: Utilizing the TriNetX electronic health records network, this retrospective cohort study targeted patients with T2DM with testosterone levels &lt;300 ng/dl or diagnosed hypogonadism. Patients were divided into two main groups based on their CVD history and TRT status. We conducted a comparative analysis between each cohort and a control group of patients who did not get testosterone replacement therapy (TRT). Matching for age, HbA1C, and BMI created balanced cohorts for comparison: 39,589 in each of the non-CVD event cohorts and 16,065 in each of the CVD event cohorts. Results: In patients without prior CVD, TRT significantly reduced the risk of acute myocardial infarction (MI) (risk ratio: 0.765, p &lt;0.0001), with no significant difference in cerebral infarction risk. Conversely, TRT increased the risk of acute MI (risk ratio: 1.164, p &lt; 0.0001) and cerebral infarction (risk ratio: 1.177, p &lt; 0.0001) in patients with a history of CVD.Discussion: TRT may decrease acute MI risk in patients with T2DM without prior CVD but elevate acute MI and stroke risks in those with a CVD history. These findings suggest the need for cautious TRT consideration in patients with T2DM with differing cardiovascular histories. Conclusion: This analysis reveals that TRT is associated with a decreased risk of acute myocardial infarction in patients with T2DM without a history of CVD, suggesting a potential protective effect in this subgroup. However, TRT increases the risk of both myocardial infarction and stroke in patients with a prior history of CVD, indicating the need for careful patient selection and monitoring. These findings highlight the significance of personalized evaluation in the administration of TRT, particularly in patients with T2DM who have different cardiovascular backgrounds, to balance benefits against potential risks.
Presentation: 6/2/2024
8150 CD1a Lipid Presentation Contributes to T2D Phenotype in DIO Mouse Model
Authors: Ayala Angulo J A , Wiggins K D , Lopez M , Nicholas D 
Published: October 2024

Abstract
Disclosure: J.A. Ayala Angulo: None. K.D. Wiggins: None. M. Lopez: None. D. Nicholas: None.
Type 2 Diabetes’s complex etiology, progression, and comorbidities are not fully explained by current models. Elevation of inflammatory markers and immune cell infiltration into tissues of T2D patients has been described in the literature extensively, but no clear answers as to what antigens are driving this response and how these observations contribute to disease progression exist. Recently, CD1a has been shown to present lipids to T cells and induce a memory response. Our previous work shows that T2D patients produce anti-lipid antibodies likely derived with T cell help, not present in healthy patients. Together, these data suggest a potential role for lipid-specific T cell responses to drive T2D progression through inflammatory stress, antibody production, and tissue infiltration. Current work with human CD1a transgenic B6 mice points to elevated liver steatosis and hepatitis along with higher glucose levels relative to low fat diet controls. CD1a mice show smaller islets suggesting pancreatic atrophy. This validates the CD1a-T cell mechanism as a potential contributor to T2D but also introduces a more physiologically relevant mouse model of T2D.
Presentation: 6/1/2024
9271 Cholinergic Signaling in the Mouse Embryonic Pancreas Targets Early Endocrine Cells
Authors: Duarte Carolina , Panzer Julia Katharina , Borowsky Nicholas , Caicedo Alejandro 
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
7890 Combination of Dorzagliatin and Canagliflozin Improves β-cell Function and Alleviates Hepatic Steatosis in db/db Mice
Authors: Zhang Ziyue , Chen Shanshan , Ji Shuhui , Zhao Qinying , Qiao Jingting , Liu Ming 
Published: October 2024

Abstract
Disclosure: Z. Zhang: None. S. Chen: None. S. Ji: None. Q. Zhao: None. J. Qiao: None. M. Liu: None.
Introduction: Early combination of anti-hyperglycemic medications with different targets is an optimal choice for patients with type 2 diabetes (T2D) who do not achieve targeted HbA1c with monotherapy. Dorzagliatin is a novel dual-acting glucokinase activator that has been shown to be effective in both drug-naive and metformin-treated patients with T2D. However, the effect of combination of dorzagliatin and sodium-glucose cotransporter-2 inhibitor (SGLT2i) remains unknown. Methods: Ten-week-old db/db mice were treated daily with either dorzagliatin (30mg/kg of body weight) alone, or canagliflozin (30mg/kg of body weight) alone, or dorzagliatin plus canagliflozin, or vehicle only by gavage for 6 weeks. Body weight and fasting blood glucose were monitored weekly. Plasma insulin, triglyceride, and cholesterol were measured every two weeks. The morphology of islets and liver was evaluated by chemical staining and immunofluorescence. Results: The 6-week treatment of dorzagliatin had no significant effect on fasting blood glucose and fasting plasma insulin but reduced body weight in db/db mice compared to those treated with vehicle. It also caused a significant decrease of islet size and β-cell number. Surprisingly, dorzagliatin alleviated hepatic steatosis but did not affect serum lipid levels. The combination of dorzagliatin and canagliflozin lowed fasting blood glucose and improved glucose tolerance without affecting bodyweight, and the anti-diabetic effect was stronger than the canagliflozin-only treatment group. Combination treatment group also showed an increased islet size and β-cell number, and alleviated liver steatosis compared with vehicle group. Conclusion: The combination of dorzagliatin and canagliflozin had better antidiabetic effects than single-agent administration, providing clinical guidance for the combination therapy of dorzagliatin and SGLT2i in the treatment of type 2 diabetes.
Presentation: 6/2/2024
6844 Comparison of Lactated Ringers and Normal Saline in the Treatment of Diabetic Ketoacidosis
Authors: Johnson Jake N , Drincic Andjela T , Nein Kaitlyn , Buddenhagen Emma , Samson Kaeli , Langenhan Trek 
Published: October 2024

Abstract
Disclosure: J.N. Johnson: None. A.T. Drincic: None. K. Nein: None. E. Buddenhagen: None. K. Samson: None. T. Langenhan: None.
Background: Current guidelines recommend normal saline (NS) for fluid resuscitation in the management of patients presenting with diabetic ketoacidosis (DKA). However, previous prospective studies have demonstrated improvement in patient specific outcomes, including time to DKA resolution, when balanced crystalloid fluids are used. We hypothesized that the use of LR compared to NS for volume management in DKA will shorten time to DKA resolution, reduce time to DKA associated protocol insulin infusion discontinuation, and result in lower post-intravenous fluid resuscitation chloride values. Methods: We conducted a single institution, retrospective cohort study of patients admitted with the diagnosis of DKA following our institution’s transition from NS to lactated ringers (LR) as the default resuscitative and maintenance fluid in our DKA management protocol. Adult patients admitted with DKA before and after the protocol change were identified. The primary outcome was time from DKA clinical presentation until DKA resolution. The secondary outcome was time to discontinuation of DKA protocol continuous insulin infusion. Results: Of 246 patients meeting inclusion criteria, 119 were stratified to the NS group (pre-protocol change) and 127 to the LR group (post-protocol change). T-test analysis revealed decreased time to DKA resolution in the LR group (mean 17.1 hours; SD 11.02) relative to the NS group (mean 20.6 hours; SD 12.22; p = .02). Duration of DKA protocol continuous intravenous insulin was shorter in the LR group (mean 16.0 hours; SD 8.72) compared to the NS group (mean 21.4 hours; SD 12.50; p = 0.0001). Conclusions: In this retrospective cohort study, protocolized DKA intravenous fluid management with LR resulted in shorter time to resolution of DKA and reduced duration of DKA protocol continuous insulin infusion.
Presentation: 6/2/2024