bluuebunny/crossref_metadata_2025_split huggingface dataset:
8114 The Need For Autoantibody Screening And Diagnostic Criteria For Immune-Checkpoint Inhibitor-Induced Type 1 Diabetes
Authors: Gupta Ashna , Sanekommu Harshavardhan , Ravin Andrew B , Akula Monica , Cheng Jennifer 
Published: October 2024

Abstract
Disclosure: A. Gupta: None. H. Sanekommu: None. A.B. Ravin: None. M. Akula: None. J. Cheng: None.
Background: Immune-checkpoint inhibitors (ICIs) such as Nivolumab have been extensively studied, especially in relation to their side-effect profiles. Patients on Nivolumab are prone to immune-related adverse events (irAEs) including type 1 diabetes mellitus, thyroiditis, and hypopituitarism. Prior studies have indicated that ICIs can unmask existing diabetic autoimmunities, but currently no specific guidelines exist for autoantibody screening prior to initiating treatment. We report a unique case of a young patient with newly diagnosed immune-checkpoint inhibitor-induced type 1 diabetes (ICI-T1DM) who was found to have mixed autoantibody results. Clinical Case: This is a 31-year-old male who was diagnosed with fibrolamellar hepatocellular carcinoma (pT23N0) and underwent partial hepatic resection later that year. Repeat imaging showed new hepatic lesions, thus Nivolumab was initiated. He received a total of three cycles, after which he presented to the hospital with symptoms of fever and nausea; labs were consistent with diabetic ketoacidosis (DKA) for which he was treated with IV insulin and aggressive hydration with successful resolution. Nivolumab was stopped and the patient was discharged on a basal-bolus insulin regimen. Further outpatient workup was significant for A1c 5.9% (n&lt;5.7%), C-peptide (with glucose 220mg/dL) 0.7 (n=0.8-3.9ng/mL), glutamic acid decarboxylase autoantibody (GAD Ab) 11 (n&lt;5.0U/mL). Insulin antibody and islet cell antibody IgG were negative. Due to the acute onset in the presentation and the recent use of Nivolumab, the patient was diagnosed with ICI-T1DM. He remained insulin-dependent after discharge. Unfortunately, soon after, he began showing signs of liver failure and ultimately underwent liver transplantation. Conclusion: This case highlights two crucial aspects - the importance of screening for autoantibodies prior to initiating an ICI and the necessity for guidelines in diagnosing ICI-T1DM. Given the evidence linking positive GAD Ab to a higher risk of developing DKA and earlier onset ICI-T1DM, it is beneficial to screen patients for these autoantibodies prior to ICI initiation to identify those more susceptible to developing ICIDM1. It may also be beneficial to obtain a C-peptide level prior to initiation to evaluate for endogenous insulin production. Additionally, while several factors support the diagnosis of ICI-T1DM such as recent ICI use, acute DKA presentation, low C-peptide levels, and the need for exogenous insulin, there is currently no specific criteria for the formal diagnosis of ICI-T1DM. Consequently, the decision to continue an ICI remains uncertain until specific diagnostic criteria are established for healthcare providers.
Presentation: 6/2/2024
7971 The Role of PDX1 In Beta Cell Response To GLP1
Authors: Bheeman Chandni , Vann Kenji , Astapova Olga 
Published: October 2024

Abstract
Disclosure: C. Bheeman: None. K. Vann: None. O. Astapova: None.
Mature Onset of Diabetes of the Young Type 4 is a rare form of diabetes mellitus caused by a defect in the Pancreatic and Duodenal homeobox 1 (PDX-1) gene, which is predominantly expressed in β-cells and is an important factor in insulin gene transcription. We aim to study the impact that a PDX1 mutation (modeled after a patient) has on the beta cell response to GLP1. This was a 33-year-old nonobese man who presented to the clinic with new onset diabetes without ketosis. He was treated with insulin and metformin and his hemoglobin A1c decreased from 16% to 6.1% in six months. Other labs showed c-peptide of 8.9 ng/mL in setting of a blood glucose of 231 mg/dL, negative islet cell antibodies and glutamic acid antibodies. Of note, patient also had significant family history of diabetes. Due to high probability of MODY, genetic testing was obtained. He was found to have a heterozygous frameshift mutation in codons 228 -233 leading to a 17 base pair deletion in the PDX1 gene causing replacement of the 56 C- terminal amino acids with a shorter, missense C-terminal tail. Patient was started on dulaglutide 0.75 mg weekly but was hypoglycemic on the smallest dose so he was then switched to Semaglutide and has been maintained on less than 0.25 mg weekly. The clinical question we aim to answer was why was this patient so sensitive to GLP1 agonist activity. To study how the mutation affects response to GLP1 we are using mouse beta-TC-6 cell as they are insulin secreting, and regulated by glucose. The PDX-1 gene is highly conserved among species and the mouse PDX gene is comparable to the human gene. We used CRISPR-Cas9 to introduce the same 17 base-pair deletion into the mouse PDX-1 gene in beta-TC-6 cells. We first measured the glucose stimulated insulin secretion in control cells to examine first and second phases of insulin secretion, determining that the first phase of insulin occurs in twenty minutes and the second phase starts at about two hours. We also evaluated if these cells responded GLP-1 by increasing insulin secretion. We found that these cells respond to glucose and GLP1 in an additive manner. Insulin was measured by enzyme-linked immunosorbent assay (ELIZA). In the next phase of the experiment we aim to determine the effect of the GLP-1 in cell lines with the PDX1 deletion mutation as compared to control cell line. We will measure insulin secretion by ELISA in both mutant and the control cells treated with and without glucose and GLP1. We will measure insulin at 0 minutes and 30 minutes and insulin mRNA at 0 minutes and 6 hours to determine the first and second phases of insulin production. Our results will help guide personalized treatment for patients with MODY type 4 and improve our understanding of beta cell response to GLP1.
Presentation: 6/2/2024
8527 The Role Of SGLT2 Inhibitors In Outcomes After LVAD Implantation
Authors: Carafone Lindsay , McNitt Scott , Goldenberg Ilan , Alexis Jeffrey 
Published: October 2024

Abstract
Disclosure: L. Carafone: None. S. McNitt: None. I. Goldenberg: None. J. Alexis: None.
Introduction: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are important medications in the treatment of diabetes mellitus, however they offer several additional benefits, including improved heart failure outcomes in patients with and without diabetes. The role of SGLT2i in heart failure outcomes for patients who receive left ventricular assist device (LVAD) implantation is not known. Right heart failure, in particular, is a frequent complication and major contributor to morbidity and mortality after LVAD implantation. SGLT2i have been increasingly used in patients who undergo LVAD implantation, however it is unknown whether right heart failure events post-LVAD implantation are meaningfully impacted by SGLT2i use. Objective: The purpose of this study was to evaluate the role of SGLT2i in outcomes after LVAD implantation. The primary endpoint was the onset of a first right heart failure (RHF) event following LVAD implantation. Secondary endpoints included recurrent RHF, first and recurrent hospitalization for RHF, and all-cause mortality. Methods: The study population comprised all consecutive patients who received a HeartMate 3 LVAD implantation at the medical center from 9/25/2015 through 9/1/2023 who are included in the institution’s LVAD Database. Both patients who received and did not receive a SGLT2i were included. A time-dependent model was used to evaluate treatment with SGLT2i as a time-dependent variable. Multivariable propensity score matching was used in the analysis of outcomes. Results: A total of 399 patients were analyzed, which included 175 patients who received SGLT2i and 224 patients who did not receive SGLT2i. Cox proportional hazards regression, employing propensity score stratification, demonstrated SGLT2i use was not associated with a statistical significant effect in the primary endpoint of a first occurrence of RHF event (HR = 1.41, 95% CI = 0.77-2.61, p = 0.268). Similarly, SGLT2i use was not associated with secondary outcomes, including recurrent RHF (HR = 1.28, 95% CI = 0.76-2.16, p = 0.360), first or recurrent hospitalization for RHF (HR = 0.38, 95% CI = 0.11-1.33, p = 0.131 and HR = 0.63, 95% CI = 0.27-1.46, p = 0.285, respectively), and all-cause mortality (HR = 0.90, 95% CI = 0.44-1.83, p = 0.771). Presence or absence of diabetes diagnosis did not significantly impact outcomes. Conclusions: The observational data in this study suggest no incremental benefit of SGLT2i for right heart failure or mortality outcomes after LVAD implantation, however large-scale prospective studies are needed to evaluate the role of SGLT2i in this setting. Further elucidating the role of these medications in LVAD outcomes will be critical in clinical decision-making regarding use of SGLT2i in this population.
Presentation: 6/1/2024
12443 Thioredoxin Interacting Protein (Txnip) Regulates Cellular Senescence And Lifespan
Authors: Abubaker Mohammed , Xia Ling , George Fantus I 
Published: October 2024

Abstract
Disclosure: M. Abubaker: None. L. Xia: None. I.G. Fantus: None.
Thioredoxin-interacting protein (Txnip) is a ubiquitously expressed protein that belongs to the α-arrestin family. It is unique among α-arrestin proteins in its ability to bind and inhibit thioredoxin (Trx), a major endogenous antioxidant. In the context of diabetes, hyperglycemia upregulates Txnip, which in turn promotes oxidative stress and apoptosis, and has been associated with progression of diabetes and its microvascular complications. Paradoxically, TXNIP also acts as a tumor suppressor, as evidenced by the development of hepatocellular carcinoma in Txnip knockout (KO) mice. Loss of Txnip is associated with enhanced glucose uptake but a shift in cellular metabolism towards glycolysis and lactate accumulation reminiscent of the Warburg effect seen in cancer cells. In our studies of glomerular mesangial cells (MC) we observed that late-passage cells (25 passages) exhibited significantly reduced Txnip expression (p&lt;0.05) coinciding with the development of senescence, consistent with “replicative” senescence. To explore the role of Txnip, we compared primary mouse MC obtained from wild-type (WT) and Txnip KO mice at early passages (5-7). Txnip KO MCs displayed significantly increased expression of senescence markers P53 and P16, as well as enhanced senescence-associated beta-galactosidase staining (p&lt;0.05), confirmed in kidney cortex of KO mice. Txnip KO MCs exhibited higher activation of Akt associated with lower PTEN activity compared to WT. Activation of Akt is known to stimulate the generation of reactive oxygen species (ROS). ROS (DCF fluorescence) were significantly elevated in Txnip KO MCs (p&lt;0.05). While mitochondrial ROS generation (mitosox) was not altered, there was an increase in the expression of NADPH oxidase 4 (NOX4). Additionally, Txnip KO MCs showed increased activation of the oncogene RAS and reduced apoptosis. Inhibition of Akt rescued the senescence phenotype in Txnip KO MCs, accompanied by reduced total ROS and NOX4 expression. Accumulation of senescent cells is a hallmark of organismal aging. Using a Y-maze apparatus, we assessed spatial memory in 21-month-old mice. KO mice exhibited compromised memory function compared to their WT counterparts. Significantly, Txnip KO mice, male and female, showed a shortened lifespan (median WT 28 m; KO 20.3 m; and Maximum WT 38 m; KO 29.5 m; Kaplan-Meier p&lt;0.001) and increased susceptibility to tumor growth at later ages. Our findings demonstrate for the first time that loss of Txnip contributes to cellular senescence through mechanisms consistent with oncogene-induced senescence, including increased Akt and RAS activation. These findings highlight the potential importance of Txnip in age-related diseases and tumorigenesis. Considering Txnip as a potential therapeutic target in diabetes, our data emphasize caution since overexpression and under-expression of TXNIP can both have adverse health consequences.
Presentation: 6/3/2024
8591 Tight Blood Glucose Control In Patients With Diabetes In The Icu Does Not Decrease Mortality: A Systematic Review And Meta-Analysis
Authors: Defante M L , Ximenes B X , Morais B A , Martins O C , Prizão V M , Correa T L , de Souza M M 
Published: October 2024

Abstract
Disclosure: M.L. Defante: None. B.X. Ximenes: None. B.A. Morais: None. O.C. Martins: None. V.M. Prizão: None. T.L. Correa: None. M.M. de Souza: None.
Tight Blood Glucose Control in Patients with Diabetes in the ICU Does Not Decrease Mortality: A Systematic Review and Meta-Analysis Background: Dysglycemia is a common complication in critically ill patients admitted to the Intensive Care Unit (ICU). However, there is controversy among clinical trials and a lack of evidence for patients with diabetes on this matter. Therefore, we aimed to perform a meta-analysis comparing tight with liberal blood glucose control among patients with diabetes in the ICU. Hypothesis: Among patients with diabetes, tight blood glucose control is a safe option in the ICU to avoid hyperglycemia episodes. Methods: We searched PubMed, Cochrane Central, and EMBASE for studies comparing tight with liberal blood glucose control in critically ill patients with diabetes in the intensive care unit. The main outcome was mortality. Statistical analysis was performed using Review Manager 5.17 (Cochrane Collaboration) and RStudio 2023.12.0. Heterogeneity was assessed with I² statistics and Cochran's Q test. Quality assessment was performed with the Cochrane tool for assessing the risk of bias in randomized trials. Results: 6 randomized clinical trials with 3,775 patients were included. The frequency of mortality showed no statistically significant difference between patients under tight blood glucose control (385/1872; 20.56%) compared to those under liberal blood glucose control (345/1903; 18.12%) (OR 1.16; 95% CI 0.98-1.37; p= 0.09; I²= 0%). No further analysis was conducted due to a lack of outcome data for patients with diabetes in the trials. All studies were considered at low risk of bias. The funnel-plot showed no evidence of publication bias despite the small number of studies. Conclusion: The mortality outcome showed no statistically significant difference between the intervention and control groups. Observational studies suggest that hyperglycemia and hypoglycemia may have different physiological implications in patients with diabetes, making them poor markers of physiologic stress and risk of mortality. More randomized clinical trials are needed to make it possible to run more robust meta-analyses and clarify this clinical question.
Presentation: 6/2/2024
7700 Two Years Of Testosterone Therapy Reduces Glycemia In Males At High Risk Of Type 2 Diabetes Without Affecting Beta Cell Function: Results From A Randomised Controlled Trial And Cellular Model
Authors: Umapathysivam M , Nawaz S , Robledo K , Allan C A , Bracken K , Grossmann M , Handelsman D J , Inder W J , Jesudason D , Stuckey B , Yeap B , Januszewski A , Jenkins A , Conway A , Hastoy B , Wittert G A 
Published: October 2024

Abstract
Disclosure: M. Umapathysivam: None. S. Nawaz: None. K. Robledo: None. C.A. Allan: None. K. Bracken: None. M. Grossmann: None. D.J. Handelsman: None. W.J. Inder: None. D. Jesudason: None. B. Stuckey: None. B. Yeap: None. A. Januszewski: None. A. Jenkins: None. A. Conway: None. B. Hastoy: None. G.A. Wittert: Consulting Fee; Self; I-Nova. Grant Recipient; Self; Lawley pharmaceuticals, Bayer, Weight Watchers, Eli Lilly & Company. Speaker; Self; Bayer, Inc., Amgen Inc, Besin Health Care.
Background: In the Testosterone for the prevention of type 2 diabetes (T4DM) Study, treatment with testosterone (T)-undecanoate (1000 mg IM 3 monthly) vs placebo decreased fat mass and reduced the risk of T2D by 40% after 2 years. However, the mechanism(s) by which T therapy prevents or reverts T2D remain unclear. Aim: To assess (1) the impact of T treatment on insulin resistance (IR) and beta-cell function in the T4DM study and (2) the in-vitro effect of graded T exposure on glucose stimulated insulin secretion (GSIS) from the human beta-cell line EndoC-βH1. Methods: (1) T4DM study: Men (n= 1007) from the T4DM study aged, 50-74 years, waist circumference (WC) &gt;95cm, with prediabetes, or newly diagnosed T2D (by OGTT) and serum testosterone (T) ≤ 14 nmol/L (chemiluminescent assay) treated with T-undecanoate (1000 mg IM 3 monthly) or placebo for 2 years. Men were included if they had fasting bloods at baseline, weeks 18, 66, and 102 (N=743). We compared the change in glycated albumin, and derived measures of beta-cell function (HOMA2-B) and insulin resistance (HOMA-IR) using fasting glucose and c-peptide in T and placebo treated men using linear regression models.(2) EndoC-βH1 were incubated with T 5nM, 10nM and 15nM for 20 min and 15nM T for 2-days. Insulin secretion and content were measured at baseline (1mM glucose) and after 20 min exposure 20mM glucose. Results: Treatment with T compared to placebo reduced glycated albumin (-3.4 umol/L; 95%CI:1.4-5.4, p&lt;0.001) maximally at week 66, along with C-peptide (corrected for baseline C-peptide and change in fasting glucose) (-0.12 nmol/L;-0.22,-0.02; p=0.01), HOMA2-B (-6.1; 95%CI: -16, 3.7; p=0.2) and HOMA-IR (-0.20; 95%CI: -0.59,0.20; p=0.3). In-vitro, acute exposure of EndoC-βH1 to 5nM and 10nM of T had no effect on GSIS, and 15nM T reduced GSIS (&lt;20%, p=0.002). T, at 15nM for 2 days was without effect on GSIS. EndoC-βH1 insulin content was not altered at any concentration or timeframe of T exposure. Conclusion: In men with pre-diabetes or early T2D, T treatment reduces glycemia without evidence either in vivo or in-vitro of an affect to increase insulin secretion.
Presentation: 6/1/2024
7184 Type 2 Diabetes As An Independent Risk Factor For Increased Incidence Of Cardiovascular Events In Patient With Nonalcoholic Fatty Liver Disease
Authors: Roh E , Son K , Jung H , Huh J , Lee S , Ihm S H , Han K D , Kang J 
Published: October 2024

Abstract
Disclosure: E. Roh: None. K. Son: None. H. Jung: None. J. Huh: None. S. Lee: None. S. Ihm: None. K. Han: None. J. Kang: None.
Background: Although coexistence of type 2 diabetes (T2DM) and non-alcoholic fatty liver disease (NAFLD) has been linked to unfavorable metabolic profile and an increasing cardiovascular risk, the impact of T2DM on the risk of developing CVD within the context of NAFLD remains unclear. This study aimed to investigate long-term CVD outcomes in patients with NAFLD according to glycemic status using nationwide cohort of Korean adults. Methods: This retrospective, longitudinal study included 1,057,775 patients with NAFLD, who had participated in the national health screening in 2009 and were followed up until 2020. The baseline glycemic status was divided into three categories [normal fasting glucose (NFG), impaired fasting glucose (IFG) and T2DM]. Cox proportional hazards models were used to assess the association of glycemic status with incident CVD. Results: During a median follow-up period of 10.3 years, 26,491 cases of MI, 55,791 cases of stroke, and 11,147 cases of CV death were identified. After adjusting for possible covariates, participants with T2DM had a higher risk of CVD, with hazard ratios of 1.394 (95% CI 1.351−1.439) for MI and 1.391 (95% CI 1.362−1.420) for stroke, and 1.457 (95% CI 1.392−1.524) for CV mortality, compared to those with NFG. The increased risk of CVD attributable to T2DM was more profound among individuals with fewer conventional CVD risk factos, including younger age, not obese, and the absence of hypertension. Conclusions: These results suggest that the identification of T2DM in individuals of NAFLD may help the prediction of future progression of CVD.
Presentation: 6/3/2024
8145 Type 2 Diabetes In A Patient With IMAGe Syndrome
Authors: Mulpuri Neha , Mirfakhraee Sasan , Abramowitz Jessica 
Published: October 2024

Abstract
Disclosure: N. Mulpuri: None. S. Mirfakhraee: None. J. Abramowitz: None.
Background: Individuals with mutations that lead to deficiency of POLE1 (a catalytic subunit of polymerase epsilon) may have clinical features of IMAGe syndrome (intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenital, and genitourinary anomalies) in addition to distinctive facial features and variable immunodeficiency. Of 15 reported cases in the literature, none were previously characterized with type 2 diabetes mellitus (T2DM). Clinical case: This is a 25-year-old woman with a history of IMAGe syndrome (confirmed mutation in the POLE gene). With regards to IMAGe syndrome history, during the prenatal period, she had growth restriction in the third trimester with delivery at 38 weeks. At 4 years-old, she presented with adrenal crisis and was started on glucocorticoid and mineralocorticoid therapy, now taking hydrocortisone 2.5mg three times daily (8.6 mg/m2/day) and fludrocortisone 0.05mg daily. Initial labs in the adult endocrine clinic were notable for serum glucose 339 mg/dL (65-99 mg/dL), undetectable estradiol (&lt; 15 pg/ml) with FSH 6.8 mIU[JA1] /mL and LH 2.0 mIU/mL, TSH 1.25 mIU/L (0.40-4.50 mIU/dL), FT4 0.7 ng/dL (0.8-1.8 ng/dL). The patient denied any history of T2DM. She also denied polyuria, polydipsia, or weight loss. There was no stigmata of peripheral insulin resistance on exam. Subsequent labs included HbA1c 8.9%, fructosamine 417 mcmol/L (200-285 mcmol/L), insulin 18.4 mcIU/mL (2.6-24.9 mcIU/mL), and C-peptide 3.9 ng/dL (1.1-4.4 ng/dL) with serum glucose 164 mg/dL. Islet cell, insulin, and GAD-65 antibodies were undetectable. CT abdomen/pelvis did not show any pancreatic mass or anomalies. Initially, prandial insulin (lispro 3 units prior to each meal) was initiated given post-prandial hyperglycemia noted on continuous glucose monitoring. Low-dose levothyroxine, 25 mcg daily, was initiated given concern for secondary hypothyroidism, with subsequent normalization of serum thyroxine. HbA1c improved to 7.4% six months later. Ultimately, she transitioned to sitagliptin 25 mg daily and her latest HbA1c was 6.2% three years after initial diagnosis of T2DM. Conclusion: Of the 15 cases of IMAGe syndrome with mutations in POLE described in Logan et al, none were noted to have diabetes. The patient described above was diagnosed with new-onset diabetes at age 21, presumably T2DM in the context of undetectable antibodies and high-normal C-peptide. Interestingly, she did not have any typical stigmata of peripheral insulin resistance. Glucocorticoids used for the treatment of adrenal insufficiency in patients with IMAGe syndrome can contribute to development of T2DM. Patients with IMAGe syndrome on chronic glucocorticoids should be monitored for hyperglycemia and diabetes. Additionally, glucocorticoid doses should be optimized to balance mitigating side effects such as hyperglycemia and osteoporosis while preventing adrenal crisis.
Presentation: 6/3/2024