bluuebunny/crossref_metadata_2025_split huggingface dataset:
12388 MALA: A Severe Nonfatal Case Report
Authors: Matos-Chaparro Jeysla Marie , Martinez-Aponte Victor , Velez-Maymi Sharon 
Published: October 2024

Abstract
Disclosure: J.M. Matos-Chaparro: None. V. Martinez-Aponte: None. S. Velez-Maymi: None.
Metformin associated lactic acidosis (MALA) is defined as altered lactate and hydrogen metabolism with pH &lt;7.35, lactate &gt;5 mmol/L in a patient using metformin chronically or with an overdose. MALA carries a significant mortality rate of up to 50% in metformin consumers. This is a case report of a severe non-fatal MALA that responded successfully to renal replacement therapy. We report the case of a 83-year-old female with past medical history of DMT2 and hypertension, who arrived at the urgency room due to anuria and non-radiating, lower back pain, 9/10 in intensity, with associated anorexia and general weakness, of two days of evolution. Review of systems was negative for nauseas, vomiting, and urinary symptoms. Medical reconciliation remarkable for metformin 1000 mg orally daily and losartan 100 mg orally daily. Patient was admitted to the ICU after chemistry remarkable for creatinine 6.25 mg/dL and BUN 85 mg/dL (CrCl 7 ml/min and GFR 6 ml/min). Creatine level more than 3-fold of her baseline (1.20 mg/dL). Electrolyte disturbances remarkable for severe hyperkalemia 7.30 mmol/L with peaked T waves on EKG, isotonic moderate hyponatremia (Na 128 mmol/L) and a pronounced acidosis (pH 7.28, pCO2 35, HCO3 16.20). Also, a hyperlactatemia of 9.8 mmol/L. Despite discontinuation of metformin and aggressive fluids therapy the patient progress to an oliguric state with worsening renal function (creatine 7.08 mg/dL). As per nephrology recommendations emergent renal replacement therapy was initiated. Patient underwent three consecutive days of hemodialysis that resulted in a significant improvement of renal function as well as resolution of electrolyte disturbances. The patient was transitioned to subcutaneous (Lantus) and oral therapy (Tradjenta) for DMT2 outpatient management. This case illustrates the potential for severe lactic acidosis induced by metformin toxicity. Even though most patients respond to aggressive fluid therapy and discontinuation of medication, in this case emergency hemodialysis was indicated as patient with multiple electrolyte disturbances and oliguric state. Measurements of biological parameters blood concentrations showed the effectiveness of repeated hemodialysis sessions on metformin elimination and acidosis. Patient admission was shortened due to early recognition and prompt initiation of hemodialysis, reducing hospital associated complications and cost. MALA is a fatal complication commonly seen on elderly patients on high doses of metformin. Accurate recognition and prompt initiation of dialysis and close observation in an intensive care unit leads to rapid recovery and favorable outcomes. On literature review, most cases reported with severe MALA were associated with a high mortality rate. This is a severe case of MALA with a favorable outcome due to prompt recognition and treatment with renal replacement therapy.
Presentation: 6/1/2024
8761 Marchiafava-Bignami Syndrome in a Diabetic Patient
Authors: Garg Ayushi , Chalasani Pranav , Kulairi Zain , Lawrence Lima , Sharza Jeffrey 
Published: October 2024

Abstract
Disclosure: A. Garg: None. P. Chalasani: None. Z. Kulairi: None. L. Lawrence: None. J. Sharza: None.
Introduction: Marchiafava-Bignami Syndrome (MBS), described as demyelination and necrosis of the corpus callosum, is a rare and fatal neurological disorder commonly caused by chronic alcoholism and malnutrition. However, there have been isolated cases of MBS reported in non-alcoholic patients, including those with uncontrolled diabetes mellitus. We report a diabetic patient who presented with anoxic hypoglycemic encephalopathy, subsequently diagnosed with MBS without a preceding history of chronic alcoholism or malnutrition. Clinical Presentation: A 56-year-old male with a past medical history of longstanding, uncontrolled type 2 diabetes mellitus, hypertension, pulmonary hypertension, congestive heart failure, chronic kidney disease(CKD), and class 3 obesity with a BMI of 43 kg/m2 was hospitalized for unresponsiveness. On arrival to the ED, his blood glucose was 37 mg/dl, and he received 1 amp of dextrose. On examination, Glasgow Coma Scale was 6 and the patient was intubated and transferred to intensive care. Labs were remarkable for hemoglobin A1c 7.0% in the setting of anemia with hemoglobin 10.4 g/dL (12.0-15.5), C-peptide 14.3 ng/ml (1.1-4.4), and insulin 4.0 uIU/mL (&lt 25), with a corresponding blood glucose of 141 mg/dl. MRI brain revealed necrosis and demyelination of the splenium of the corpus callosum, consistent with MBS. The patient was found to be persistently hypoglycemic, requiring IV dextrose infusion and octreotide for sulfonylurea-induced hypoglycemia, in the setting of renal dysfunction. The patient’s family corroborated noncompliance with diabetes medications. Extensive tests including CSF analysis for various infections and malignancies yielded no results. The patient was eventually transferred to hospice care and expired, after prolonged hospitalization. Conclusion: The etiology of MBS is most commonly alcoholism and malnutrition; however, there are rare case reports of MBS in patients with poorly controlled diabetes who are not alcoholic or malnourished. Wide glycemic fluctuations and subsequent osmotic changes are thought to contribute to the pathophysiology of MBS in diabetic patients. Hypoglycemia can induce osmotic stress in oligodendroglial cells, leading to the structural and functional abnormalities seen in MBS. In this patient with longstanding uncontrolled diabetes and medication noncompliance, in the setting of CKD and sulfonylurea use, wide glycemic fluctuations likely contributed to the development of this atypical case of MBS. Reference: Marchiafava-Bignami disease triggered by poorly controlled diabetes mellitus A.I. Pérez Álvarez, C. Ramón Carbajo, G. Morís de la Tassa, J. Pascual Gómez https://www.elsevier.es/en-revista-neurologia-english-edition--495-articulo-marchiafava-bignami-disease-triggered-by-poorly-S2173580816300633
Presentation: 6/1/2024
12449 Mechanisms Underlying Progressive Loss Of Sulfonylurea Sensitivity In T2D In Vivo
Authors: Patel S , Yan Z , Remedi M S 
Published: October 2024

Abstract
Disclosure: S. Patel: None. Z. Yan: None. M.S. Remedi: None.
Type 2 Diabetes (T2D) is characterized by a gradual loss of functional pancreatic β-cell mass, along with insulin resistance in peripheral tissues. Sulfonylureas (i.e. glibenclamide/glyburide) have long been used to treat T2D because of their ability to inhibit pancreatic β-cell KATP channels and therefore enhance insulin secretion. Although initially beneficial, sulfonylureas inevitably fail as sole therapy for unknown reasons. To determine the mechanisms underlying this secondary failure, slow-release sulfonylurea glibenclamide pellets (2.5 mg/pellet, 60-day release) were implanted in 6-week-old KK mouse model of polygenic T2D. As expected, KK mice implanted with placebo pellets (KK-Placebo) spontaneously develop hyperglycemia (230 mg/dL), glucose intolerance, impaired insulin secretion and insulin resistance. Interestingly, KK mice chronically treated with glibenclamide (KK-Glib) did not show improvement in blood glucose levels over time, nor in glucose tolerance at day 28 and 42 post treatment. Fed plasma insulin levels were decreased in KK-Glib mice compared to KK-Placebo mice. Moreover, KK-Glib mice did not show increase in plasma insulin in response to glucose challenge during glucose tolerance test at either 28- or 42-days post-treatment. Intriguingly, KK-Glib mice demonstrated improvement in insulin sensitivity at day 30 of treatment, but surprisingly not at day 45 of treatment. Fasting-refeeding study further showed decreased insulin secretion after 2 hours of feeding in KK-Glib mice compared to the KK-Placebo mice. KK-Glib mice demonstrated islet hypertrophy, and reduced β-cell number, which drive the increase in α:β cell ratio. Strikingly, islets from the KK-Glib mice showed a marked increased expression of α-cell identity markers: Gcg, Irx2, MafB and Arx with respect to KK-Placebo mice. While β-cell identity markers did not change in islets from KK-Glib mice with respect to KK-Placebo, there was a significant increase in Ngn3 mRNA levels in islets from KK-Glib mice, suggestive of β-cell dedifferentiation. Importantly, while glucose stimulated glucagon secretion was unchanged between KK-Glib and KK-Placebo islets, glucagon content was significantly increased in islets from KK-Glib mice. These findings show that secondary failure to sulfonylureas could be partly due to the increased turnover of α-cells upon treatment.
Presentation: 6/2/2024
6817 Metabolomics Analysis Reveals Disordered Serotonin Metabolism as a Novel Therapeutic Target for Post-Bariatric Hypoglycemia
Authors: Ferraz-Bannitz R , Ozturk B , Cummings C , Efthymiou V , Wang H , Navarrete V , Saeed H , Mulla C M , Sandoval D , Pan H , Dreyfuss J M , Patti M E 
Published: October 2024

Abstract
Disclosure: R. Ferraz-Bannitz: None. B. Ozturk: None. C. Cummings: None. V. Efthymiou: None. H. Wang: None. V. Navarrete: None. H. Saeed: None. C.M. Mulla: None. D. Sandoval: None. H. Pan: None. J.M. Dreyfuss: None. M. Patti: Advisory Board Member; Self; Fractyl Health. Consulting Fee; Self; AstraZeneca, Hamni, MBX Biosciences. Grant Recipient; Self; Dexcom.
Bariatric surgery is a potent approach for obesity and type 2 diabetes but can be complicated by post-bariatric hypoglycemia (PBH). PBH typically occurs 1-3 hours after meals, in association with exaggerated postprandial levels of incretins and insulin. To identify mediators of disordered metabolism in PBH, we analyzed the plasma metabolome in the fasting state and 30 and 120 minutes after an oral mixed meal in 3 groups: PBH (n=13), asymptomatic post-RYGB (n=10), and non-surgical controls (n=8). In the fasting state, multiple tricarboxylic acid cycle intermediates and the ketone beta-hydroxybutyrate were increased by 30-80% in PBH vs. asymptomatic. Conversely, multiple amino acids (BCAA, tryptophan) and polyunsaturated lipids were reduced by 20-50% in PBH vs. asymptomatic. Tryptophan-related metabolites, including kynurenate, xanthurenate, and serotonin, were reduced by 2-10-fold in PBH in the fasting state (p&lt;0.01 for all). Serotonin patterns in response to meal ingestion were distinct in PBH. ELISA analysis of serotonin levels revealed 1.9-fold increase at 120 minutes after the meal (p&lt;0.001); by comparison, serotonin levels decreased by 1.6 to 1.4-fold over the same time course in asymptomatic and nonsurgical groups (p&lt;0.001 for both). To determine whether serotonin could modulate glucose levels, we injected wild type C57BL/6J mice with serotonin (20 mg/kg, intraperitoneal) or vehicle. Glucose levels were 39-43% lower in serotonin-injected mice (p&lt;0.01 at 15-60 minutes). Serotonin administration also significantly increased plasma insulin by up to 5-fold at 30 minutes (p=0.004) and increased plasma GLP1 by up to 2-fold (p&lt;0.001). Moreover, serotonin-induced hypoglycemia after mixed meal in mice was blocked by the serotonin antagonist cyproheptadine. Together these data suggest that increased postprandial serotonin may contribute to the pathophysiology of PBH and provide a new therapeutic target.
Presentation: 6/1/2024
7309 Moderate ER Stress, Facilitated by IL-1β, Initiates Protective Mechanisms in Pancreatic β-Cells Ameliorating Dysfunction and Diminishing Death Induced by Inflammatory Cytokines
Authors: Sétula C , Orellano M S , Argañarás M , Scelza-Figueredo A , Spinedi E , Andreone L , Perone M J 
Published: October 2024

Abstract
Disclosure: C. Sétula: None. M.S. Orellano: None. M. Argañarás: None. A. Scelza-Figueredo: None. E. Spinedi: None. L. Andreone: None. M.J. Perone: None.
Type 1 and type 2 diabetes share common features, encompassing islet inflammation, β-cell dysfunction and the eventual reduction in both the number and mass of β-cells. The organism's resilience against higher doses of a harmful substance can be bolstered through the induction of mild stress responses, achieved by exposing it to low concentrations of the said agent. Our objective was to evaluate whether physiological concentrations of IL-1β prompt adaptive mechanisms that protect β-cells from the distinctive inflammatory milieu associated with diabetes.We employed INS-1E insulinoma and isolated mouse islets and measured NO by Griess, cell viability (MTT) and death (Hoechst/PI, microscopic fluorescence and Annexin V-PE/7-AAD, flow cytometry), mRNA by RT-qPCR, NF-κB (immunofluorescence), insulin (ELISA) and proteins by Western blot (WB). GSIS (glucose-stimulated insulin secretion) index was calculated as the ratio of insulin released during 1h under stimuli of 20mM/2mM glucose. Results are presented as mean ± SD, n≥3 independent experiments. Comparison between groups was carried out using paired or unpaired Student's t-test or ANOVA followed by Bonferroni's multiple comparison test, as appropriate. Mild endoplasmic reticulum (ER) stress was induced in β-cells through a 72h incubation with 10 pg/ml IL-1β (IL-1βlow). Cytokine-induced damage was triggered by 100 pg/ml IL-1β + 5 ng/ml IFNγ for 16h (CYT). IL-1βlow protects INS-1E from the decrease in mitochondrial reduction potential triggered by CYT, diminishes cell death (p&lt;0.05 vs CYT) and improves GSIS (p&lt;0.05 vs CYT), the latter in pancreatic islets as well (p&lt;0.05 vs CYT). IL-1βlow reduces NO production (p&lt;0.001 vs CYT) through a decrease in iNOS mRNA (p&lt;0.01 vs CYT) and its protein expression (p&lt;0.01 vs CYT). IL-1βlow reduces CYT-triggered NF-κB nuclear translocation (p&lt;0.05 vs CYT). IL-1βlow hampers the increase in CHOP expression (p&lt;0.001 vs CYT; by WB), decreases the mRNA expression of DP5 (p&lt;0.05 vs CYT), PUMA (p&lt;0.05 vs CYT), Bax/Bcl-2 ratio (p&lt;0.01 vs CYT) and cleaved caspase-3 (p&lt;0.001 vs CYT; by WB). Our study demonstrates that β-cells possess the capability to activate an adaptive stress response mediated by IL-1β in response to inflammatory stimuli. Approaches aimed at bolstering this resilient response provide a novel therapeutic avenue to enhance the functionality and viability of β-cells, ultimately mitigating the adverse inflammatory conditions associated with diabetes.Supported by ANCYPT-FONCYT (PICT -2018-1577 / -2018-0719), and partially by FPREDM 2023.
Presentation: 6/2/2024
12622 Molecular Physiology And Compensatory Response In Maladapted Pancreatic Islets Of Humanized Mice Model For Type 1 Diabetes
Authors: Hussain Ashaq , Aldasouqi Ahmad , Rafiqi Shafiya Imtiaz , Khan Saira Saeed , Paparodis Rodis , Jaume Juan Carlos , Imam Shahnawaz 
Published: October 2024

Abstract
Disclosure: A. Hussain: None. A. Aldasouqi: None. S. Rafiqi: None. S.S. Khan: None. R. Paparodis: None. J.C. Jaume: None. S. Imam: None.
Genetic predisposition linked with specific HLA (DR and DQ) alleles, environmental factors, and other uncharacterized physiological aberrations triggers an autoimmune attack and depletion of β cells in pancreatic islets, leading to decreased insulin secretion and diabetes. Our laboratory has generated humanized mice carrying the antigen-presenting HLA-DQ8 diabetes-linked haplotype and expressing the human autoantigen GAD65 in pancreatic beta cells. These humanized mice spontaneously develop type 1 diabetes (T1D) and represent the full spectrum of pathophysiological conditions experienced in T1D. Using humanized mice as a model of study, we studied the molecular physiology and compensatory response in maladapted pancreas under normal physiological conditions and hyperglycemic stress of T1D. We studied the differential expression of some important genes by quantitative PCR in maladapted islets to identify the physiological processes affected during the initial oxidative stress exerted by autoimmune conditions. Our results confirmed that levels of cyclin B, cMyc, Cyc D, Cyc E, PDGFRA, and NOTCH are reduced during autoimmune insult, reflecting the poor regenerative capacity of islet cells. However, Cyc A has an elevated expression, reflecting that islet cells, particularly the β cells of Type 1 diabetic mice, may have regenerative potential that may be explored. The genes for Desmin and Survivin showed decreased expression, whereas genes for Smad and Synuclein displayed increased expression. The genes for insulin and somatostatin showed elevated expression, whereas the gene for glucagon displayed reduced expression. The results suggest that during autoimmune insults, the β cells moderately whip up the synthesis of insulin-specific RNA to maintain the requirements. Among the endoplasmic reticulum-specific molecular chaperones, Calnexin showed an elevated expression, whereas calreticulin displayed a reduced expression. Among the genes involved with the architecture of the islet, Lamin and Integrin both display increased expression, reflecting the dynamic change in islet architecture during the autoimmune depletion of β cells. We also investigated the expression of ER-specific stress genes both at RNA and protein levels. Our preliminary results have confirmed that ER-specific stress genes showed an elevated expression during oxidative stress mediated by autoimmune T1D conditions.
Presentation: 6/3/2024
6684 Multi-Dose BCG Vaccination for Protection Against COVID-19 Disease and Other Respiratory Infections in Subjects with Type 1 Diabetes Late in the US Pandemic
Authors: Kühtreiber Willem , Hostetter Emma , Wolfe Grace E , Vaishnaw Maya , Goldstein Rachel , Bulczynski Emily , Hullavarad Neeshi , Braley Joan E , Zheng Hui , Faustman Denise L 
Published: October 2024

Abstract
Disclosure: W. Kühtreiber: None. E. Hostetter: None. G.E. Wolfe: None. M. Vaishnaw: None. R. Goldstein: None. E. Bulczynski: None. N. Hullavarad: None. J.E. Braley: None. H. Zheng: None. D.L. Faustman: None.
A Phase II clinical trial previously reported that multiple doses of the bacillus Calmette-Guerin (BCG) vaccine, originally developed for tuberculosis prevention, could protect at-risk individuals with type 1 diabetes (T1D) against COVID-19 disease and infectious diseases early in the pandemic in the United States (US) (Cell Rep Med 2022). As SARS-CoV-2 evolved, COVID-19 disease became more transmissible, but less lethal. In a new, Phase III, randomized, double-blinded, placebo-controlled trial, we tested whether at-risk individuals with T1D given multi-dose, intradermal BCG would be protected against COVID-19 and other infectious diseases (2:1 randomization; BCG: n=93; placebo: n=48). The trial was conducted late in the COVID-19 pandemic during sequential dominance of Beta, Gamma, Delta and Omicron variants. All participants were US citizens and were negative for prior BCG vaccination and negative for tuberculosis. Two co-primary endpoints were protection from COVID-19 disease and platform protection from all infectious diseases. From April 2021 to November 2022, Tokyo-strain BCG vaccination provided significant protection against COVID-19 disease (p=0.023) and strong platform protection against all infectious diseases (p&lt;0.0001). Over the 19-month course of the study, commercial COVID-19 vaccines were rolled out. An observational analysis of the placebo control group (i.e., no BCG vaccination) showed that COVID-19 mRNA vaccination alone provided no protection from COVID-19 disease in the enrolled population (p=0.43). BCG vaccination efficacy against COVID-19 and infectious disease in T1D was unaffected by concurrent COVID-19 vaccinations (observational analysis). These data suggest that BCG has efficacy against a range of SARS-CoV-2 variants, in contrast to current COVID-19 vaccines, which have narrow efficacy against specific viral variants. Further, it shows that individuals with T1D represent a vulnerable population for whom BCG appears to be the only effective vaccine against COVID-19 disease and confirms that, in the US, BCG vaccination protects against infectious disease as well.
Presentation: 6/3/2024
6536 National Trends in Prevalence of Prediabetes and Diabetes Among Women With Low Bone Mineral Density: 2009-2018
Authors: Atri Avica , Anastasopoulou Catherine 
Published: October 2024

Abstract
Disclosure: A. Atri: None. C. Anastasopoulou: None.
Introduction: In recent years, bone fragility has emerged as a complication of prediabetes (preDM) and diabetes mellitus (DM), resulting in reduced bone mass and increased fracture risk, and is an important, though under-studied risk factor for osteoporosis. However, the converse relationship, trends in prevalence of preDM and DM in women with low bone mineral density (BMD) in the United States, are not well established. Methods: We used data from the National Health and Nutrition Examination Survey (NHANES) for the years 2009-10, 2013–14 and 2017–18 to include U.S. women aged ≥ 50 years with T-score ≤ -1. Osteoporosis assessment in NHANES was not completed in 2011–12 and 2015–16, and therefore not included in the analysis. Osteopenia and osteoporosis were defined by a femoral neck BMD ≤1 to 2.5, and ≤2.5 standard deviations (SDs) below the BMD of a young female adult mean (T-score). Femur neck BMD was measured by dual energy x-ray absorptiometry (DEXA). PreDM and DM were defined using HbA1c values of 5.7 - 6.4% and ≥ 6.5% respectively. Participants with missing HbA1c and BMD data were excluded. Descriptive statistics were used for comparing means and medians. The Cochran-Armitage test was utilized for trend analysis. Results: In this nationally representative sample of US women with low BMD, the median (IQR) T-score at femoral neck worsened from -1.74 (-1.4 to -2.17) in 2009-10 to -1.87 (-1.43 to -2.32) in 2017-18 (trend p = 0.001). Similarly, the prevalence of osteoporosis increased from 13.7% to 16.9% (trend p = 0.001). Overall, in this cohort, the national prevalence of both preDM and DM decreased from 40% to 32.9% and 9.6% to 9%, respectively (trend p = 0.001). Along with a reduction in the overall prevalence of osteopenia (86.3% to 83.1%, p=0.001), the prevalence of both preDM and DM decreased from 39.2% to 32.6% and 10% to 9% (p = 0.001). In those with osteoporosis, the prevalence of preDM decreased from 45.2% to 34.4% (p trend=0.001), however, the prevalence of DM increased from 7.5% to 8.7% (p trend =0.001). Overall rates of uncontrolled DM (HbA1c &gt; 7%) in women with osteoporosis showed significant improvement (5.8% to 3.5%, p = 0.001). Discussion Despite worsening trend in femoral neck BMD among US women age ≥ 50 years from 2009-10 to 2017-18, the overall prevalence of preDM and DM improved by 7.1% and 0.6% respectively. However, this favorable trend was not observed among women with osteoporosis, where the overall prevalence of DM increased by 1.2%, though the rate of uncontrolled DM significantly decreased by 2.3%. Targeted interventions to improve blood glucose control among women with low BMD, especially those with osteoporosis are warranted, to improve bone health, as well as reduce fall and fracture risk.
Presentation: 6/2/2024