bluuebunny/crossref_metadata_2025_split huggingface dataset:
8010 Potent MSB-61 as Type 1 Diabetes (T1D) therapy: mechanism of action in insulin secretion
Authors: Ajmal Nida , Bogart Maisy , Corbin Kathryn , Khan Palwasha , Shafqat Mariam , Bergmeier Stephen , Gu Guoqiang , Tong Xin , Nunemaker Craig S 
Published: October 2024

Abstract
Disclosure: N. Ajmal: None. M. Bogart: None. K. Corbin: None. P. Khan: None. M. Shafqat: None. S. Bergmeier: None. G. Gu: None. X. Tong: None. C.S. Nunemaker: None.
Type 1 diabetes (T1D) is a chronic autoimmune disorder caused by proinflammatory cytokines (Interleukin 1-beta; IL1-β, Tumor Necrosis Factor-alpha; TNF-α, and Interferon-gamma; IFN-ϒ) from immune cells that destroy insulin-producing beta cells in pancreatic islets and lead to hyperglycemia. The development of possible treatments to cure T1D is needed besides intensive insulin therapy that does not halt disease progression. We have identified a small molecule called MSB-61 that can protect islet cells from endoplasmic reticulum stressors (66% protection) and cytokines (33% protection) as measured by propidium iodide in islets isolated from mice using 50uM MSB-61. Importantly, we observed large increases in insulin secretion during overnight exposure to 50uM MSB-61. Insulin secretion began to increase in response to MSB-61 at ∼4h, reaching a plateau at ∼8h of greater than 4-fold insulin release compared to controls. The Kegg pathway analysis of RNA-seq data on MSB-61 suggested that multiple genes upregulated by MSB-61 are involved in insulin secretion through an amplifying pathway that includes cAMP/PKA and Pi3k/Akt signaling cascades. Based on RNA sequencing data, this study aimed to test MSB-61 for identifying pathway by which it potentiates insulin secretion. Islets from CD-1 mice and mouse insulinoma Min-6 cell lines were used to test amplifying pathways by using cAMP/PKA and Pi3k/Akt analogs and antagonists with and without MSB-61, and overnight insulin secretion and insulin content will be measured by enzyme-linked immunosorbent assay (ELISA). MSB-61 showed no potential effects on insulin secretion when tested for Pi3k/Akt pathway in the presence of analogs and antagonists such as 740-Y-P and wortmannin. It further suggests MSB-61 might potentiate insulin secretion through the cAMP/PKA pathway, which is still under investigation. RNA sequencing analysis of mouse islets showed several genes that belong to Ras family member-2 and have GTPase activity. Genes with GTPase activity will be further investigated to help identify if MSB-61 stimulates insulin secretion through an amplifying pathway involving the cAMP/PKA downstream signaling cascade. Identifying the mechanism of action and signaling pathway by which MSB-61 potentiates insulin secretion will open new ways of identifying T1D therapeutic interventions that would help replace standard insulin therapy.
Presentation: 6/3/2024
8473 Prediabetes As A Risk Factor For All-Cause And Cause-Specific Mortality In 117,227 Diabetes-Free Adults In Mexico City
Authors: Fermin-Martinez Carlos Alberto , Bello-Chavolla Omar Yaxmehen , Antonio-Villa Neftali Eduardo , Garcia Daniel Ramirez , Seiglie Jacqueline A 
Published: October 2024

Abstract
Disclosure: C.A. Fermin-Martinez: None. O.Y. Bello-Chavolla: None. N.E. Antonio-Villa: None. D. Ramirez Garcia: None. J.A. Seiglie: None.
Background: Prediabetes has been consistently linked to high risk of diabetes progression, cardiovascular disease, and all-cause mortality. However, no large-scale studies have been conducted in Mexico or Latin America examining these associations despite the growing prevalence of this condition in low- and middle-income countries. Methods: We analyzed data from 117,227 adults without diabetes aged ≥35 years who participated in the Mexico City Prospective Study (1998-2004). Individuals with self-reported chronic comorbidities at baseline were excluded to mitigate reverse causation. Participants were followed-up until January 1st, 2021 for cause-specific mortality. We defined prediabetes according to the American Diabetes Association (ADA, HbA1c ≥5.7%) and the International Expert Committee (IEC, HbA1c ≥6.0%) definitions. Cox regressions were used to estimate prediabetes-related risk for all-cause and cause-specific mortality, stratified by sex and age-at-risk and adjusted for municipality of residence, education level, physical activity, smoking, alcohol consumption, and adiposity markers. Results: Compared to individuals with normoglycemia, participants with IEC-defined prediabetes had a higher risk of all-cause (HR 1.16, 95%CI 1.05-1.27), cardiac (HR 1.29, 95%CI 1.05-1.59), renal (HR 1.59, 95%CI 1.14-2.23), and acute diabetes-related (HR 2.60, 95%CI 1.52-4.43) mortality at ages 40-74 years compared to normoglycemic participants. HRs were attenuated at older ages. Results were broadly similar irrespective of the definition of prediabetes except for cardiac deaths, in which the risk was non-significant using the ADA cutoff (HR 1.14, 95%CI 0.99-1.31). Long-term effects of prediabetes (IEC-defined) accounted for ∼37% of renal deaths and ∼61% of acute diabetes-related deaths in Mexican adults without diabetes at baseline. Conclusion: Prediabetes is an important risk factor that accounts for a significant fraction of all-cause, cardiac, renal, and acute diabetes-related deaths among Mexican adults, particularly when using the higher threshold of IEC-defined prediabetes. Endpoint-driven definitions of prediabetes should be considered for widespread implementation of screening and preventive strategies that minimize overdiagnosis and improve cardiometabolic outcomes in this population.
Presentation: 6/1/2024
6608 Racial Disparities In Outcomes of Hyperosmolar Hyperglycemic State- A National Inpatient Sample Analysis
Authors: Karki Sunita , Neupane Shila , Neupane Binita , Chavez Luis F 
Published: October 2024

Abstract
Disclosure: S. Karki: None. S. Neupane: None. B. Neupane: None. L.F. Chavez: None.
Introduction: Numerous studies have explored variations in access to healthcare among racial and ethnic groups, revealing disparate challenges in insurance coverage and other healthcare services. Hyperosmolar Hyperglycemic State (HHS) or Hyperosmotic Hyperglycemic Nonketotic State (HHNK) represents a severe complication associated with type 2 diabetes mellitus. Objective of the study:To investigate if there are any racial disparities between white and black populations with the diagnosis of HHS, focusing on outcomes such as mortality rates, length of stay (LOS), hospital costs, and other outcomes. Methods: Retrospective data encompassing adult patients (age &gt;18) with HHS between 2017 and 2020 were extracted from the National Inpatient Sample (NIS). Employing STATA as the data analysis tool, the International Classification of Diseases (ICD-10) was utilized to select disease and outcome codes. Multivariate regression analysis adjusted for relevant variables determining the adjusted odds ratio (aOR). Proportions were compared using the Fisher exact test, while continuous variables were assessed via the student t-test. The study's primary outcome was mortality, with secondary outcomes including LOS, total hospitalization costs, Acute Coronary Syndrome (ACS), septic shock, pulmonary edema, Acute Respiratory Failure (ARF), mechanical ventilation, Acute Respiratory Distress Syndrome (ARDS), Acute Kidney Injury (AKI), and Cerebrovascular Accident (CVA). Results: Among 181,720 HHS-diagnosed patients, 84,140 were white, and 58,645 were black. White patients exhibited a $2,741 higher total hospital expenses compared to their black counterparts. Rates of septic shock (aOR=0.78, 5.26% vs. 4.1%, p&lt;0.001) and ARF (aOR=0.83%, 10.54 vs. 9%, p&lt;0.001) were elevated in whites compared to blacks. Conversely, rates of AKI were higher in blacks (aOR=1.48, 58.29% vs. 50.58%, p&lt;0.001) compared to whites. No statistically significant differences in mortality rates, mean LOS, ACS, pulmonary edema, mechanical ventilation, ARDS, and CVA were observed. Conclusion: Whites demonstrated increased rates of total hospital expenses, septic shock, and ARF compared to blacks, while blacks exhibited higher rates of AKI. No significant differences were observed in mortality rates, LOS, ACS, pulmonary edema, mechanical ventilation, ARDS, and CVA.
Presentation: 6/2/2024
6698 Rapidly Progressive Type 1 Diabetes Mellitus Complicated By Hyperglycemic Crisis And Bowel Ischemia
Authors: Bondarenko Darya , Deyar Dylan , Nadeem Ramsha , Herrera Melanie , Arzeno Luis Enrique 
Published: October 2024

Abstract
Disclosure: D. Bondarenko: None. D. Deyar: None. R. Nadeem: None. M. Herrera: None. L.E. Arzeno: None.
Introduction: Type 1 diabetes mellitus (T1DM) stems from insulin deficiency due to islet-related autoantibodies. Misclassification of T1DM as type 2 diabetes mellitus (T2DM) occurs in 40% of those developing T1DM after age 30. Fulminant T1DM (FT1DM), described in East Asia, exhibits rapid progression and is diagnosed by ketosis, blood glucose ≥288 mg/dL, HgbA1c &lt;8.7%, and fasting C-peptide &lt;0.3 ng/mL. We present a case of rapidly progressing T1DM in a white male presenting as a hyperglycemic crisis (HC) complicated by multiorgan failure and bowel ischemia. CASE:A 52-year-old male, T2DM diagnosed by HgbA1c of 8% (normal &lt;5.7%) 1 month prior, presented to the emergency room obtunded with two days of nausea and vomiting. Vital signs were normal other than tachycardia and tachypnea. Blood work showed pH 7.0 (normal 7.31-7.41), creatinine 4.58 mg/dL (0.7-1.3 mg/dL), glucose &gt;1500 mg/dL (normal 65-139 mg/dL), beta-hydroxybutyrate 114.7 mg/dL (normal 0.2-2.8 mg/dL), lactate 5.7 mmol/L (normal 0.5-2 mmol/L), serum osmolarity 438 mOsmol/kg (normal 275-295 mOsmol/kg), WBC 26.2 B/L (4-11 B/L) and 4% bands (normal 0%), Hgb A1c 17.1% , C-peptide 0.11 ng/mL (0.8 - 3.85 ng/mL), GAD65 1:600 - 1:1200 (normal &lt; 1:600). He was intubated Day 1-5. HC was treated with intravenous (IV) fluids and IV insulin infusion. He transitioned to subcutaneous insulin by Day 2. 10 days hemodialysis achieved renal recovery. He was diagnosed with latent autoimmune diabetes of adult (LADA). No triggers were identified for his HC. From Day 1, his abdominal exam was notable for guarding. Initial abdominal computed tomography (CT) was normal. Abdominal pain and distension persisted despite normalized blood work. Repeat CT showed ileus vs obstruction. Surgery on Day 12 showed multifocal bowel ischemia requiring surgical resection. Conclusion: FT1DM is a subtype of T1DM seen in Asia characterized by rapid β-cell destruction with hyperglycemia and ketoacidosis. LADA subset of T1DM manifests in adults and may take up to three years to progress to insulin dependence. Triggers for both include autoimmunity, infections, and pregnancy. HC has been associated with increased risk of occlusive and nonocclusive bowel ischemia. While this case does not meet all criteria of FT1DM, the rapid progression of the HgbA1c and disease severity is an unusual presentation of LADA. Raising awareness of the complications of this severe metabolic disorder can improve timely interventions and medical outcomes.
Presentation: 6/1/2024
7800 Real World Incidence Of Urinary Tract Infections (UTI) & Genital Tract Infections (GTI) With SGLT2 Inhibitors Alone Or In Combination With DPP4 Inhibitors In Patients With T2D In India
Authors: Gupta Arvind , Singh Nagendar Kumar , Phatak Sanjeev , Singh Akashkumar Navinprakash 
Published: October 2024

Abstract
Disclosure: A. Gupta: None. N. Singh: None. S. Phatak: None. A.N. Singh: None.
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are associated with urinary and genital tract infections (UTI and GTI), as they increase glucose availability in these areas, fostering bacterial growth. A study found a 26% lower occurrence of UTI and GTI in patients using a combination of Dipeptidyl Peptidase-4 inhibitors (DPP4i) and SGLT2i compared to those on SGLT2i alone. (1) The present study assessed whether patients receiving SGLT2i were at increased risk of significant UTIs & GTIs compared with those using a combination of SGLT2i & DPP-4i. A cross-sectional, multicenter, real-world study was conducted that enrolled patients with Type 2 Diabetes Mellitus (T2D) from 15th June to 30th September 2023 across 42 sites in India. The recorded data encompassed demographic information, glycemic parameters, medication use & information on hygiene practices. The sample considered for this analysis is those on SGLT2i & with or without DPPi. [Note – all patients are on other OHAs besides SGLT2i or DPP4i]. Of 10,179 patients, 2,123 were on only SGLT2i (Group A), and 8,052 were on SGLT2i and DPP4i (Group B). Group A showed a significantly higher incidence of UTI (9.09% vs. 6.11%) and GTI (6.64% vs. 5.2%). Elderly patients, especially those aged 60-69 and &gt;70, exhibited higher UTI and GTI rates in Group A. In both genders, the incidence of UTI was higher in Group A (7.93%-males & 10.53%-females) than in Group B (5.41%-males & 7.11%-females). Amongst males, the incidence of GTI was significantly higher in Group A (5.63%) than in Group B (4.12%). In females, no significant difference was noted. Two models were developed to assess the impact of SGLT2i and insulin usage on UTI and GTI likelihood. Propensity score matching addressed confounding variables like age, gender, BMI, and comorbidities. Subsequently, logistic regression analysis focused solely on medication variables. The odds of developing UTI were calculated for various medication possibilities. As against ‘No SGLT2i’, Group A has 2.24 (CI 1.69-2.96) times higher odds of UTI, while Group B has 1.45 (CI 1.15-1.72) times. or GTI, Group A shows 3.18 (CI 2.23-4.53) times higher odds, and Group B has 2.48 (CI 1.90-3.25) times, as against ‘No SGLT2i’. In summary, DPP-4 & SGLT2 inhibitors combination therapy decreases the incidence of UTI & GTI linked to SGLT2i. Reference: (1) Fadini et al. DPP4i moderate the risk of GTI & UTI associated with SGLT2i. Diab Obes Metab. 2018 Mar;20(3):740-744.
Presentation: 6/2/2024
6774 Recurrent Hypoglycemia In Malignant Insulinoma With Multiple Liver Metastases Successfully Managed With Octreotide
Authors: Kim Keun Young , Mascarell Susana 
Published: October 2024

Abstract
Disclosure: K. Kim: None. S. Mascarell: None.
Introduction: Insulinoma is a rare functional pancreatic neuroendocrine tumor (pNET) with the incidence of 1-4/million person-years. Malignant insulinomas with locoregional invasion or metastases consist 10% among insulinomas. While the treatment of a single insulinoma is surgical resection, treatment of malignant insulinoma requires a comprehensive approach. Due to the low prevalence of the disease, data on therapeutic modalities of malignant insulinomas are limited. We hereby present a case of malignant insulinoma in which recurrent hypoglycemia was successfully managed with octreotide. Case: A 36 year old female diagnosed with grade III well differentiated pNET with multiple metastases to the liver and abdominal lymph nodes 1 year ago was admitted for recurrent hypoglycemic episodes. She reported progressively worsening hypoglycemia for the past 1 month. She was eating every 2 hours including her sleeping hours to prevent hypoglycemia. Due to recurrent hypoglycemia she required hospitalization with IV dextrose. After 13 hours of fasting in the ICU, hypoglycemia due to insulin hypersecretion was confirmed with blood glucose 51 mg/dL and elevated serum insulin 51.11 uIU/mL (1.9-23uIU/mL). She underwent the short octreotide test which showed suppressed insulin (5.25 uIU/mL) 6 hours after receiving 100 mcg of octreotide. She was started on octreotide 50 mcg every 12 hours and monitored for further hypoglycemic episodes. She tolerated octreotide without any side effects including hypoglycemia. She was discharged home with a continuous glucose monitor (CGM) and transitioned to intramuscular lanreotide 20mg injections every 4 weeks as an outpatient. No further hypoglycemic episodes occurred. Discussion: Few cases report treatment of hypoglycemia in malignant insulinoma with octreotide. Octreotide has the dual effect of suppressing insulin secretion and tumor growth on insulinomas that express SSTR2 receptors. However, because somatostatin agonists also inhibit the secretion of glucagon, in insulinomas without SSTR2 expression, octreotide can aggravate hypoglycemia. This was especially a concern for our patient with a large tumor burden. Thus the short octreotide test was conducted. We suggest that the octreotide test of 100 mcg SQ octreotide injection followed by hourly measurements of glucose and insulin levels is a useful and convenient test to predict efficacy while monitoring for octreotide induced hypoglycemia. Finally the use of CGM in the outpatient setting enabled successful transition to octreotide LAR which improved the patient’s quality of life greatly by enabling once a month injections.
Presentation: 6/3/2024
8537 Refractory Hypoglycemia Secondary To Metastatic Insulinoma Treated With Novel Insulin Receptor Antibody - A Case Report
Authors: Lloyd J , Abu Omar S , Lester L , Wilson L 
Published: October 2024

Abstract
Disclosure: J. Lloyd: None. S. Abu Omar: None. L. Lester: None. L. Wilson: None.
Introduction: Insulinoma is the most common functional pancreatic neuroendocrine tumor, characterized by hypersecretion of insulin, causing hypoglycemia. Insulinomas are mostly benign, however malignant neoplasms account for 5-10 % of cases. Surgical resection is the preferred treatment for solitary tumor, however metastatic insulinoma requires a more aggressive approach with medications to prevent hypoglycemia, resection of primary tumor, resection of metastasis, and chemoembolization. We describe a case of metastatic insulinoma with refractory hypoglycemia despite treatment with multiple medications, surgical resection of tumor, embolization of liver metastasis and successfully treated with a novel monoclonal antibody that blocks insulin receptor. Clinical Case: 43-year-old female was initially diagnosed with metastatic insulinoma in 2021. The primary tumor was pancreatic with metastasis to the liver. She was treated with surgical resection of the primary tumor and three hepatic embolizations for liver metastasis. She required a progressive number of medications to treat frequent, debilitating hypoglycemia. These medications included diazoxide, verapamil, lanreotide then changed to pasireotide, everolimus, and dexamethasone. Despite these treatments, she experienced refractory hypoglycemia and was admitted to the hospital. She required continuous dextrose infusion up to 100ml/hr of D50. Due to the large volume of fluid from dextrose infusion and other medications, she developed severe edema and AKI and required aggressive diuretic regimens and briefly intermittent CRRT. As there were no additional medications to add and prospects for future liver embolization were limited, we requested use of RZ358 through the manufacturer’s Expanded Patient Access program. This medication is a monoclonal antibody that blocks the insulin receptor to counteract the effects of insulin and thereby reduce hypoglycemia. This mechanism of action is unique from medications used to manage insulinoma induced hypoglycemia. She received her first infusion of RZ358 which she tolerated well. She had baseline elevation of ALP due to liver metastasis with further rise after liver embolizations, most recently 4 weeks prior. There was a rise in ALP levels which stabilized after 3 days. She experienced no significant side effects. For the first time in two months, five days after her first infusion of RZ358, the dextrose infusion could be stopped. She received her second infusion of RZ358 one week after first infusion. She was discharged home in a stable condition shortly after the second infusion. Conclusion: The Insulin receptor blocking monoclonal antibody, RZ358, offers a promising approach to patients with metastatic insulinoma who have refractory hypoglycemia despite maximal medical and surgical therapy.
Presentation: 6/1/2024
5154 Regulation Of T2D Genes In Human Adipocytes
Authors: Zhang Qianbin 
Published: October 2024

Abstract
Disclosure: Q. Zhang: None.
Type 2 diabetes (T2D) is a chronic disease that affects 415 million people around the world and was the fourth leading cause of death (2015). Insulin resistance (IR), one of the major pathophysiological mechanisms that characterize T2D, is defined as the state in which cells, tissues, or organisms no longer respond appropriately to endogenous or exogenous insulin. We have generated detailed transcriptomes and chromatin state maps from the isolated adipocytes of insulin sensitive (IS) and insulin resistant (IR) human subjects. Mapping IR/IS differentially enriched H3K27ac peaks onto T2D GWAS SNPs suggested several loci as noncoding regulatory elements (REs) of human IR. We focused on the IRS1 gene, a known T2D related locus that encodes a critical protein in the insulin signaling cascade. We developed a CRISPRi-based assay that enabled us to determine which noncoding regulatory elements are required for normal IRS1 expression in human adipocytes. Our data indicate that many IR/IS differentially regulated H3K27ac peaks are critical regulatory elements for IRS1 transcription, although we did not observe that peaks that were increased in the IS state had a larger effect, as predicted. Overall, we have developed a CRISPRi-based screening system for noncoding elements in human adipocytes, which can be deployed to study many different loci related to metabolic disease.
Presentation: 6/2/2024