bluuebunny/crossref_metadata_2025 huggingface dataset:
12505 Prevalence Of Mody Diabetes Polymorphism Of Thai Urban Families By Targeted Next Generation Sequencing Of Diabetes Polymorphism
Authors: Niramitmahapanya Sathit
Published: October 2024

Disclosure: S. Niramitmahapanya: None.

Prevalence of MODY diabetes polymorphism of Thai Urban families by targeted next-generation sequencing in diabetes polymorphismObjective: To study the prevalence between single nucleotide polymorphism of urban diabetes (UD) and non-diabetes (noD) in Thai population. Method: Cross-sectional study was collected 240 participant samples; 60 from UD, 60 from RnoD, 60 from non-relative, non-diabetes (noRnoD) and 60 diabetes, non-relatives (noRD). And generated diabetes variant frequency in Thai population by targeted next-generation sequencing. Result; Among group of UD and RnoD found that age, fasting blood glucose (FBG), HbA1c and LDL level were statistic significant all parameter by p<0.001. Age in UD was 64.15±10.74 vs. 43.43±12.46 in RnoD, FBs in UD was 129.39±44.91 vs. 99.74±39.75 in RnoD, A1c in UD was 8.26±4.76 vs. 6.17±1.35 in RnoD and LDL level in UD was 98.28±38.52 vs. 129.35±39.75 in RnoD.In subgroup analysis of diabetes variant, we designed Ion AmpliSeq On-Demand Panels (25 genes related diabetes) for targeted sequencing. We didn’t found statistic significant between UD and RnoD group by p-value =0.998 (23 genes; ABCC8, FGA, SELE, PAX4, HNF1A, BLK, LOC10028732, NEUROD1, KCNJ11, MMP2, APPL1, LPL, CAT, CEL, HNF1A, HNF1B, ICAM1, INSR, SOD, GCK, INS and UCP3). We identified 12 mutations of MODY in UD, the most polymorphism was HNF1a and ABCC8 that found 16.4%, PAX4 found 13.1%, APPL1 found 11.5%, KCNJ11 and NEUROD1 found 8.2%, BLK 6.6% and other less polymorphism that found <5% (HNF1B, HNF4a, CEL, GCK, INS). Conclusion; From the study, we analyzed genetic data from 12 genes that involved pathogenesis for diabetes polymorphism between UD and noD groups. We focus on diabetes variant frequency. We found that 5 pathogenic polymorphism such as HNF1a, GCK, CEL, INS and APPL1. Further study needs to evaluate correlation diabetes polymorphism and their treatment protocols. Keywords; Thai urban diabetes, first degree relatives and MODY diabetes polymorphism

Presentation: 6/1/2024
8132 Prolonged Refractory Hypoglycemia For Seven Days After Discontinuation Of Neutral Protamine Hagedorn (NPH) Insulin And Injectable Semaglutide
Authors: Musleh Anisa , Rauf Mohammad Talha , Afroze Eman , Al-Bacha Souad
Published: October 2024

Disclosure: A. Musleh: None. M.T. Rauf: None. E. Afroze: None. S. Al-Bacha: None.

A 75-year-old male with Type 2 Diabetes was brought to the emergency department (ED) by emergency medical services (EMS) due to altered mentation. The patient’s wife found him unresponsive with seizure-like activity. EMS was called to the scene and obtained a capillary blood glucose reading of 31 mg/dL. Despite initial treatment with 50% dextrose the patient’s capillary blood glucose came down to 21 mg/dL in the ED and was confirmed by venous glucose. Workup including Computed Tomography (CT) imaging was inconsistent with a cerebrovascular accident. Given refractory hypoglycemia and delirium, the patient was started on a dextrose 10% infusion at 150 milliliters per hour. He was admitted to the intensive care unit for closer monitoring. His wife states that the patient had a few episodes of mild hypoglycemia overnight for the past several weeks, which improved after eating. His home medications included NPH insulin 46 units twice daily, empagliflozin 25 mg once daily, and injectable semaglutide 2 mg once weekly. The last dose of NPH insulin was the night before the presentation and the last dose of semaglutide was 5 days prior to admission. Serum creatinine levels were stable at 1.3-1.5 mg/dL throughout the hospitalization, which was below his baseline creatinine of 1.7 mg/dL. Laboratory results were as follows: hemoglobin A1c 5.9%, c-peptide level was 0.3 ng/mL (normal range 0.8-3.9 ng/mL) with a glucose of 68 mg/dL (normal range 70-100 mg/dL), insulin 203.8 mcIU/mL (normal range less than 24 mcIU/mL), proinsulin 3.2 pmol/L (normal range less than or equal to 8 pmol/L), beta-hydroxybutyrate 0.06 mmol/L (normal range 0.02-0.27), cortisol 66.6 mcg/dL (normal range 6.7-22.6 mcg/dL), insulin-like growth factor 1 123 ng/mL (normal range 53-222), and hypoglycemic agent panel was negative. On ICU Day 2, his mentation improved, he was allowed to eat but continued to require dextrose infusion to prevent hypoglycemia. Repeat fasting insulin levels even four days from prior showed an incremental decrease to 59.4 mcIU/mL with a glucose of 77 mg/dL. It took 7 days before the patient was able to maintain glucose above 70 mg/dL off of dextrose infusion. After which he had hyperglycemia requiring gradual reintroduction of his diabetes medicines other than insulin. It is rare to see such prolonged refractory hypoglycemia from an exogenous source of insulin as exhibited in this case. Notably, the patient was on semaglutide and had stable chronic kidney disease without acute kidney injury. Although multiple mechanisms explain the prolonged insulin duration of action in kidney disease, the effects of semaglutide on insulin action are unknown.

Presentation: 6/3/2024
9343 Protection Against Type 1 Diabetes Development In Mice With 4E-BP2 Deletion
Authors: Pita Grisanti V , Pecanha F , Louzada R , Blandino M , Jaramillo C , Arenas N , Bayer A , Bernal-Mizrachi E
Published: October 2024

Disclosure: V. Pita Grisanti: None. F. Pecanha: None. R. Louzada: None. M. Blandino: None. C. Jaramillo: None. N. Arenas: None. A. Bayer: None. E. Bernal-Mizrachi: None.

Type 1 diabetes is an autoimmune disease characterized by β-cell destruction promoted by autoreactive T cells that acquire an effector inflammatory phenotype. 4E-BP1/2 proteins are translational repressors and downstream targets of mTORC1, a key regulator of metabolism. mTORC1 signaling disruption is implicated in human diseases including diabetes. Activation of 4E-BP2/eIF4E pathway by 4E-BP2 deletion promotes translation initiation, which induces β-cell expansion and proliferation and is crucial for the regulation of adaptive immunity. However, the involvement of 4E-BP2 in type 1 diabetes development has not been explored. Therefore, this study aimed to determine the role of 4E-BP2/eIF4E signaling in type 1 diabetes prevention by regulation of β-cell survival and immune modulation. To investigate the role of 4E-BP2/eIF4E axis in diabetes pathogenesis, we used the non-obese diabetic (NOD) mouse model as a type 1 diabetes model, and generated mice with global deletion of 4E-BP2 in the NOD background (4E-BP2KONOD). We assessed type 1 diabetes development, glucose homeostasis, pancreas morphometry and immune responses in male and female 4E-BP2KONOD and control NOD mice. We found that 4E-BP2KONOD exhibited reduced diabetes incidence in male but not female mice. Reduction in diabetes incidence in 4E-BP2KONOD male mice was associated with comparable degree of insulitis and β-cell proliferation, and with preserved β-cell mass compared to the control NOD mice. Glucose-stimulated insulin secretion of the islets, assessed in vitro by static incubation, was significantly higher in the 4E-BP2KONOD compared to the NOD control. Autoimmune responses were also evaluated by assessment of insulitis and characterization of T cell compartments, which showed a decrease in splenic CD8+ cytotoxic T cells and an increase in pancreatic regulatory T cell (Treg) infiltration mainly by increased Treg survival in 4E-BP2KONOD mice compared to control NOD. Finally, adoptive transfer studies demonstrated that lymphocytes derived from male 4E-BP2KONOD mice were less diabetogenic than those derived from control NOD mice. In conclusion, this study showed that activation of 4E-BP2/eIF4E axis in 4E-BP2KONOD male mice protects against type 1 diabetes development by dampening autoimmune responses and preserving β-cell mass. Targeting 4E-BP2 may provide a potential treatment for type 1 diabetes.

Presentation: 6/1/2024
7484 Pseudohypoglycemia In A Patient With Raynaud’s Phenomenon
Authors: Fedorko J , Subarajan P , Amblee A P , Poku C A
Published: October 2024

Disclosure: J. Fedorko: None. P. Subarajan: None. A.P. Amblee: None. C.A. Poku: None.

Background: The term ‘pseudohypoglycemia’ is used to describe the disparity between actual and measured capillary glucose and clinical presentation. It has been used to describe situations when a patient has the characteristic symptoms of low blood glucose (BG) Whipple’s triad), but the patient’s BG levels are within normal limits. Alternatively, this term can also be used to describe falsely low BG levels on finger-stick (capillary) readings in a patient with normal serum glucose levels and without the characteristic Whipple’s triad. Case: A 55-year-old female with Raynaud’s phenomenon was seen in Endocrine clinic with persistent hypoglycemia noted on finger-stick glucose readings. Her finger-stick glucose reading was 43, and was subsequently given 24 grams of glucose gel. Ten minutes later, a repeat finger stick BG was 44. She had no weakness, tremors, shakiness, vision changes, confusion, seizures, lightheadedness, dizziness, tachycardia, palpitations, nervousness, hunger, paresthesias irritability, confusion, seizures, loss of consciousness, or any other symptoms or signs of hypoglycemia. She had no such previous episodes and her fasting BG ranged from mid-70s to 80, with post-meal BG ranging from 100 to mid-100’s. Her most recent hemoglobin A1c was 5.5. She regularly experiences cyanosis of fingers consistent with Raynaud’s phenomenon, triggered by cold air in winter and air conditioners in summer. She does not take any medications for these episodes. Given the absence of classic Whipple triad and normal BG from peripheral blood draw, the patient’s low finger stick BG readings were attributable to Raynaud’s phenomenon. It is postulated to be secondary to decreased perfusion in the digital microcirculation and increased blood transit time in the fingers, resulting in a local increase in glucose consumption and thus low capillary finger stick BG levels. Simultaneously done serum glucose levels are usually normal. Conclusion: Pseudohypoglycemia can occur in patients with impaired peripheral circulation such as Raynaud’s phenomenon, acrocyanosis, peripheral vascular disease, shock, or with increased glycolysis by blood cells like in leukemia, polycythemia and rare infections like African trypanosomiasis, hyperviscosity syndromes like Waldenstrom’s and monoclonal gammopathy of undetermined significance. In patients with low finger-stick (capillary) glucose levels who do not display Whipple’s triad, and have comorbid conditions that might interfere with the BG reading, it is important for clinicians to recognize the difference between true and pseudohypoglycemia. This can be confirmed with a simultaneously done normal serum glucose level and will prevent unnecessary investigations or excessive treatment.

Presentation: 6/3/2024
8654 Real-World Performance Of The Medtronic Extended Infusion Set In The United States
Authors: Kwa Timothy , Zhang Gina , Kiehl Justin , Putcha Venkat , Patel Anuj , Chattaraj Sarnath , Cohen Ohad , Vigersky Robert Alan
Published: October 2024

Disclosure: T. Kwa: Employee; Self; Medtronic Minimed. G. Zhang: Employee; Self; Medtronic Minimed. J. Kiehl: Employee; Self; Medtronic Minimed. V. Putcha: Employee; Self; Medtronic Minimed. A. Patel: Employee; Self; Medtronic Minimed. S. Chattaraj: Employee; Self; Medtronic Minimed. O. Cohen: Employee; Self; Medtronic Minimed. R.A. Vigersky: Employee; Self; Medtronic Minimed.

Real-World Performance of the Medtronic Extended Infusion Set in the United States Objective: The Medtronic extended infusion set (EIS) is the first and only infusion set approved for up to 7-day use and its pivotal trial established clinical safety and efficacy.[1] The purpose of this retrospective analysis was to assess real-world EIS performance and overall glycemic outcomes based on United States (US) data uploaded by MiniMed™ 770G system (MM770G) users at an aggregate level. Methods: Infusion set occlusion alarm events and time in (TIR, 70-180 mg/dL), below (TBR, <70 mg/dL) and above (TAR, >180 mg/dL) range of EIS-MM770G users (N=393) with >30-day device use in the U.S. were analyzed and compared against the data of a cohort of the same median age of 50 years (N=77219) using the MM770G with a standard 2/3-day infusion set (at an aggregate level). Results: EIS users experienced a lower occlusion alarm rate (median 0.011 alerts/patient day) compared to 0.016 alerts/patient day with the standard set (p = 0.005). TIR for EIS users was 69.4%, which was numerically greater than the 69.1% for standard set users (p = 0.258). While TAR was not significantly different (28.9% for EIS and 29.0% for standard set, p = 0.995), TBR was significantly lower (0.5% for EIS and 1.3% for standard set, p = 0.000). The difference in the total daily dose (TDD) of insulin between the two groups (53.0 units for EIS, 49.4 units for standard set) was not statistically significant (p = 0.961). Conclusion: Since the U.S. launch, the EIS has continued to perform similarly to the pivotal trial results and an early real-world analysis of EIS use outside of the US.2 The decreased burden of fewer set changes comes with a lower occlusion alarm rate and does not compromise time spent in target range. References: 1.Brazg R, et al. Diabetes Technol Ther. 2022;24:535-543. 2.Kwa T, et al. Diabetes. 2023;72(Supplement_1):910-P.

Presentation: 6/1/2024
12421 Reduced ZMPSTE24 Expression Leads To Prelamin Accumulation And Development Of Steatosis In MASLD Patients
Authors: Schinderle Joseph , Bochkis Irina , Wu Anqi
Published: October 2024

Disclosure: J. Schinderle: None. I. Bochkis: None. A. Wu: None.

Reduced ZMPSTE24 expression leads to prelamin accumulation and development of steatosis in MASLD patients. Joseph D. Schinderle[1],[2], Anqi Wu[1],[2], Irina M. Bochkis[1],[2]* [1] Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261 [2] Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261 We have previously observed changes at the nuclear lamina in MASLD patients that led to redistribution of lamina-associated domains and reshaping of FOXA2 binding with progression of steatosis. Here we report that the changes at the nuclear envelope are caused by downregulation of ZMPSTE24, an enzyme that processes prelamin to mature lamin A, leading to accumulation of prelamin in MASLD patients. Mutations of LMNA and ZMPSTE24 have been associated with fatty liver. In addition, Zmpste24 mutant mice develop hepatic steatosis and Zmpste24 deficiency is linked to upregulation of p53 target genes. Ingenuity Pathway Analysis determined upregulated p53 activity in genes differentially expressed in both male and female MASLD patients. Furthermore, upstream analysis identified p53 as a regulator of genes bound by FOXA2 in these individuals, corresponding to observations in Zmpste24 knockout animals. Additional regulator analysis of RNA-Seq determined that genes regulated by glucose and insulin to be downregulated in MASLD patients, suggesting altered glucose metabolism and insulin resistance, hallmarks of type 2 diabetes (T2D). Hence, our genomics data shows that MASLD patients with severe steatosis that have yet to progress to MASH are already suffering from severe metabolic consequences and underscores the need for treatment at this stage of the disease.

Presentation: 6/2/2024
8016 Resolution of Refractory Hypoglycemia Following Pancreatic Solitary Fibrous Tumor Resection
Authors: Horowitz Maxwell Ethan , Stefan Simona
Published: October 2024

Disclosure: M.E. Horowitz: None. S. Stefan: None.

Introduction: Solitary fibrous tumors (SFT) are exceptionally rare mesenchymal tumors, accounting for only 3.7% of all cases of soft-tissue sarcoma with an incidence of 0.35 cases per 100,000 persons per year. SFT may arise in various anatomical locations, approximately 30% occuring in the abdomen. SFT can manifest with paraneoplastic syndromes, with the most commonly described being non-islet cell hypoglycemia. We present a case of refractory hypoglycemia which resolved following the resection of a large pancreatic SFT. Clinical Case: A 75-year-old male with a history of hypertension presented from oncology clinic with hypoglycemia. Two weeks prior, a 26cm mass of the pancreatic head was identified after he presented to the hospital for one month of abdominal pain and distention, and biopsy of the mass confirmed an SFT. The patient complained of nighttime weakness, confusion, nausea, vomiting, and urinary incontinence for two nights prior to arrival. During this time, the patient had multiple fingersticks showing hypoglycemia below 70 mg/dL, the lowest at 37 mg/dL. On arrival, fingerstick glucose was 38 mg/dL and serum glucose was 27 mg/dL, with a c-peptide level of 0.28 ng/mL (1.00-4.00 ng/mL). Despite hypoglycemia, he was asymptomatic at the time of presentation, indicating hypoglycemia unawareness. Investigation into the cause of hypoglycemia included normal morning cortisol levels, normal thyroid function tests, and normal liver and renal function tests. Further assessment for paraneoplastic disease was conducted, revealing an IGF1 level of 36 ng/dL (5-34 ng/dL) and IGF2 241 ng/dL (267-616 ng/dL), with a ratio of IGF2:IGF1 of 6.7:1. He underwent surgical removal of the large abdominal mass with distal gastrectomy and Billroth-I reconstruction. Pathology was consistent with a 34cm retroperitoneal SFT, STAT6 positivity, and negative margins. Following surgery, the patient did not experience any further hypoglycemia or related symptoms, and glucose ranged 78-135 mg/dL through discharge. Clinical Lessons: Refractory hypoglycemia resulting from a tumor's production of IGF2 is a rare paraneoplastic syndrome known as Doege-Potter Syndrome. This syndrome is observed in fewer than 5% of patients with SFT. The first documented case of hypoglycemia in a patient with "fibrous sarcoma" dates back to 1930. To establish a diagnosis, a ratio of IGF2:IGF1 exceeding 3:1 is suggestive of tumor-mediated production, while a ratio exceeding 10:1 is considered diagnostic. A positive immunohistochemical stain for STAT6 confirms the diagnosis. Patients with these tumors should be routinely monitored for hypoglycemia and related symptoms.

Presentation: 6/3/2024
8327 Risk Of Chronic Kidney Disease In Subjects With Metabolic Dysfunction-Associated Fatty Liver Disease Or Metabolic Dysfunction-Associated Steatotic Liver Disease: A Retrospective Study
Authors: Rhee E J , Kwon H , Park S , Lee W Y
Published: October 2024

Disclosure: E. Rhee: None. H. Kwon: None. S. Park: None. W. Lee: None.

Background: Recently, the term non-alcoholic fatty liver disease (NAFLD) is replaced by a new term, metabolic dysfunction-associated liver disease (MASLD), with a new definition made by a modified Delphi process led by three large pan-national liver associations. In this study, we aimed to analyze the risk for chronic kidney disease (CKD) development in those with MASLD defined by the new definition and metabolic dysfunction-associated fatty liver disease (MAFLD). Methods: Among 52,606 participants (mean age 35.4 years) in the health checkup program from 2002 to 2019, in whom at least 10 health checkups were performed, after strict exclusion, 48,751 participants were enrolled and analyzed the development of CKD defined by estimated glomeruls filtration lower than 60 mL/min/1.73m2) during a median of 14.7 years of follow-up. The presence of MAFLD was defined by presence of hepatic steatosis plus one of the three criteria of overweight or obese, type 2 diabetes or presence of ≥2 metabolic risk abnormalities. MASLD was defined by presence of hepatic steatosis plus at least 1 of 5 cardiometabolic risk factors. Results: At baseline, 12,773(26.2%) participants had MAFLD and 35,359(74.58%) had MASLD. During the follow-up period, 849(1.7%) participants developed CKD. In participants with MAFLD, 345(2.7%) participants developed CKD, and in participants with MASLD, 609(1.7%) developed CKD. After adjustment for age and sex, the hazard ratio(HR) of CKD was 1.44 (95% confidence interval [CI] 1.25-1.66) for MAFLD, and 1.25(95% CI 1.07-1.47) for MASLD. Both definition predicted development of CKD nicely (Harrell’s C-index: 0.79(0.77-0.81) for MAFL and MASLD) Conclusions: The participants with MAFLD and MASLD showed significantly increased risk for CKD during a median of 15 years of follow-up. Both criteria showed nice predictability for CKD.

Presentation: 6/1/2024
9215 Role Of Insulin/IGF1 Signaling And FoxO Transcription Factors In Satellite Cell And Skeletal Muscle Development And Senescence
Authors: Yu Yingying(Joy) , Wang Guoxiao , O'Neill Brian Timothy , Kahn Carl Ronald
Published: October 2024

Disclosure: Y. Yu: None. G. Wang: None. B.T. O'Neill: None. C.R. Kahn: None.

Aging is associated with loss of skeletal muscle mass, deficiency of satellite cell (SC) function, and increase in intramuscular adipose tissue (IMAT) and insulin resistance posing threats to health and quality of elder life. Insulin / IGF1 signaling and their downstream signaling pathways play crucial roles in muscle function, as well as longevity a broad range of species. To identify the role of Insulin / IGF1 signaling in skeletal muscle homeostasis and aging/senescence, we took advantage of Cre-loxp mouse model using Pax7-Cre or HAS-Cre mice cross with insulin receptor (IR) and IGF1 receptor (IGF1R) double flox mice to create IR/IGF1R double knockout mice in both muscle progenitors (satellite cells) and mature skeletal muscle cells. We refer to the PaxCreIRIGF1RKO as the P7DKO and HSACreIRIGF1RKO as simply the DKO. Both P7DKO and DKO mice show severe loss of skeletal muscle with increased markers of cellular senescence and increased IMAT infiltration. This was indicated by a 60% loss of muscle mass, morphological evidence of skeletal muscle with atrophy and increased adipocyte infiltration, with a >6-fold increase of adipocyte marker Perlipin1. The muscle also exhibited 2- to 10-fold increases of cellular senescence and senescence-associated secretory markers, including Cdkn1a, Cdkn2a, Trp53, CD68, Cxcl14, and Ccr2. Both the whole skeletal muscle and primary satellite cells isolated from P7DKO mouse muscle show a higher level of senescence-associated beta-galactosidase, as compared to the cells from littermate controls. This was accompanied by a deficiency of proliferation and differentiation of the satellite cells. Interestingly, simultaneous knockout of Foxo1/3/4 in the DKO mouse muscle rescued the muscle atrophy, reduced IMAT infiltration and reduced skeletal muscle cell senescence. Thus, insulin/IGF1 signaling in satellite cells and mature muscle cells plays not only an important role in skeletal muscle development, but also skeletal muscle cell senescence, and this is mediated, in large part, through FOXO transcription factors. This pathway and these proteins provide both new insights and potential targets for improving skeletal muscle homeostasis and function in the elderly.

Presentation: 6/2/2024
7897 Role Of Insulin/IGF1 Signaling And FoxO Transcription Factors In Satellite Cell And Skeletal Muscle Development And Senescence
Authors: Yu Yingying(Joy) , Wang Guoxiao , O'Neill Brian Timothy , Kahn Carl Ronald
Published: October 2024

Disclosure: Y. Yu: None. G. Wang: None. B.T. O'Neill: None. C.R. Kahn: None.

Aging is associated with loss of skeletal muscle mass, deficiency of satellite cell (SC) function, and increase in intramuscular adipose tissue (IMAT) and insulin resistance posing threats to health and quality of elder life. Insulin / IGF1 signaling and their downstream signaling pathways play crucial roles in muscle function, as well as longevity a broad range of species. To identify the role of Insulin / IGF1 signaling in skeletal muscle homeostasis and aging/senescence, we took advantage of Cre-loxp mouse model using Pax7-Cre or HAS-Cre mice cross with insulin receptor (IR) and IGF1 receptor (IGF1R) double flox mice to create IR/IGF1R double knockout mice in both muscle progenitors (satellite cells) and mature skeletal muscle cells. We refer to the PaxCreIRIGF1RKO as the P7DKO and HSACreIRIGF1RKO as simply the DKO. Both P7DKO and DKO mice show severe loss of skeletal muscle with increased markers of cellular senescence and increased IMAT infiltration. This was indicated by a 60% loss of muscle mass, morphological evidence of skeletal muscle with atrophy and increased adipocyte infiltration, with a >6-fold increase of adipocyte marker Perlipin1. The muscle also exhibited 2- to 10-fold increases of cellular senescence and senescence-associated secretory markers, including Cdkn1a, Cdkn2a, Trp53, CD68, Cxcl14, and Ccr2. Both the whole skeletal muscle and primary satellite cells isolated from P7DKO mouse muscle show a higher level of senescence-associated beta-galactosidase, as compared to the cells from littermate controls. This was accompanied by a deficiency of proliferation and differentiation of the satellite cells. Interestingly, simultaneous knockout of Foxo1/3/4 in the DKO mouse muscle rescued the muscle atrophy, reduced IMAT infiltration and reduced skeletal muscle cell senescence. Thus, insulin/IGF1 signaling in satellite cells and mature muscle cells plays not only an important role in skeletal muscle development, but also skeletal muscle cell senescence, and this is mediated, in large part, through FOXO transcription factors. This pathway and these proteins provide both new insights and potential targets for improving skeletal muscle homeostasis and function in the elderly.

Presentation: 6/2/2024
7967 Ruxolitinib Prevents Immune-Checkpoint Inhibitor-Related Diabetes Mellitus Via Inhibition Of Pathogenic IL-21 And IFNγ-Producing CD4+ T Cells
Authors: Huang N L , Ortega J , Wang S J , Scott L N , Kimbrell K , McCarthy E , Olay J , Nguyen J N , Kim K , Lee J , Lechner M G
Published: October 2024

Disclosure: N.L. Huang: None. J. Ortega: None. S.J. Wang: None. L.N. Scott: None. K. Kimbrell: None. E. McCarthy: None. J. Olay: None. J.N. Nguyen: None. K. Kim: None. J. Lee: None. M.G. Lechner: None.

The use of immune checkpoint inhibitor (ICI) therapy has revolutionized the treatment landscape for many advanced cancers by leveraging immune activation through the blockade of checkpoint proteins, including programmed death protein-1 (PD-1). Unfortunately, autoimmune attack of healthy tissue can occur in up to 60% of patients. ICI-induced Type 1 diabetes mellitus (ICI-T1DM) is a rare but life-threatening adverse event during ICI therapy that leads to rapid destruction of pancreatic islets, hyperglycemia, and lifetime dependence on insulin. While cytotoxic CD8+ T cells are recognized as important players in ICI-T1DM, the role for CD4+ helper T cells in disease pathogenesis is less well understood. Using a mouse model of ICI-autoimmunity, in which male and female NOD mice treated with anti-PD-1 (10mg/kg/day, i.p., twice weekly) develop multi-organ autoimmune infiltrates including insulitis and DM, we identified interleukin-21 (IL-21) and interferon gamma (IFNγ) CD4+ T cells as key contributors to ICI-T1DM. Antibody depletion of CD4+ T cells in NOD mice significantly delayed the onset of ICI-T1DM. Immunophenotyping of pancreatic islet infiltrates in ICI-treated mice revealed increased IL-21+ IFNγ+ CD4+ T follicular helper (Tfh; ICOS+ PD1+ CXCR5+) and T peripheral helper (Tph; ICOS+PD1+ CXCR5- CXCR6+) cells. In vitro, IL-21 increased effector CD8+ T cell function and IFNγ promoted production of T cell-attracting chemokines CXCL9, CXCL10, and CXCL16 by macrophages. Given the potential role for IL-21 and IFNγ to amplify ICI-DM progression, we sought to target these signaling pathways as potential interventions. Genetic inhibition of IL-21 or IFNγ signaling in NOD mice reduced insulitis and DM in anti-PD-1 treated mice. Considering that IL-21 and IFNγ act through JAK/STAT signaling in immune cells, we proposed to block this pathway to prevent ICI-DM using ruxolitinib, a clinically available JAK1/2 inhibitor. Indeed, ruxolitinib blocked STAT3 and STAT1 phosphorylation in mouse splenocytes in response to IL-21 or IFNγ, respectively, and completely protected ICI-treated NOD mice from DM. Finally, in a syngeneic tumor model, use of ruxolitinib after initiation of anti-PD-1 therapy did not abrogate ICI anti-tumor effects. Taken together, these data suggest that IL-21 and IFNγ producing CD4+ T cells are important drivers of ICI-T1DM, and that the use of JAK inhibitors may be a promising clinical intervention to reduce ICI-T1DM toxicities in patients.

Presentation: 6/2/2024
8035 Severe Hyperglycemia Induced By Enfortumab Vedotin (EV) Treatment For Urothelial Carcinoma
Authors: Semreen Noura , Goldberg Michael David
Published: October 2024

Disclosure: N. Semreen: None. M.D. Goldberg: None.

Introduction: Immunotherapy has revolutionized cancer treatment, but it has a wide range of adverse events including endocrinopathies. Here we present a case of severe hyperglycemia induced by enfortumab vedotin (EV) treatment for advanced urothelial carcinoma. Clinical Case: A 56-year-old male was admitted to our hospital with a painful rash in sun-exposed areas. He had metastatic urothelial carcinoma, with progression of disease after platinum-based chemotherapy, radiation therapy, and pembrolizumab, and had begun treatment with EV six weeks prior to presentation. He also had type 2 diabetes mellitus, with a recent A1c of 6.1% on metformin monotherapy, and obesity (BMI, 31 kg/m2). His blood glucose on admission was 600 mg/dL, and insulin therapy was initiated. There was no evidence for DKA or HHS. Over the course of his 9-day admission he required approximately 200 units of insulin per day to control his glucose. A fasting C-peptide level was 6.89 ng/mL (0.81-3.89 ng/mL) concurrent with a glucose of 181 mg/dL. Skin biopsy revealed erythema multiforme, which represented a grade 4 toxicity of EV treatment, and the EV was discontinued. Symptoms improved with oral glucocorticoids. The patient was discharged on multiple daily injections of insulin in addition to metformin. His insulin requirements fell rapidly, and one month later he was able to discontinue insulin completely. He was started on sacituzumab for his cancer treatment. Discussion: EV is a first-in-class antibody-drug conjugate directed against Nectin-4, which was approved in 2019 for previously treated locally advanced or metastatic urothelial carcinoma. Hyperglycemia was reported in 6.4% of patients receiving EV in the initial phase III study; BMI ≥ 30 kg/m2 and pretreatment A1c ≥ 6.5% were identified as risk factors. In a 24-month follow-up analysis, the incidence of grade ≥ 3 hyperglycemia was 4.4%, and the median time to onset of hyperglycemia was 19 days. There have been postmarketing reports of EV-induced DKA, as well as cases of refractory hyperglycemia requiring more than 1,000 units of insulin daily. The mechanism explaining the hyperglycemia is not yet defined, but in the prior case reports, as well as the current case, C-peptide levels have been elevated. It is assumed, therefore, that the mechanism involves insulin resistance as opposed to insulin deficiency. The marked hyperglycemia appears to be reversible once EV therapy is discontinued. In 2023, EV was approved in combination with pembrolizumab for first-line therapy of locally advanced or metastatic urothelial cancer, as an alternative to platinum-based chemotherapy. With this expanded indication, providers should be aware of the risk of hyperglycemia, which in some cases may be severe.

Presentation: 6/3/2024
6524 Sex-Specific Single Cell Genetic Architecture Of Human Islets With And Without Type 2 Diabetes
Authors: Qadir M , Elgamal R M , Kudtarkar P , Gaulton K J , Mauvais-Jarvis F
Published: October 2024

Disclosure: M. Qadir: None. R.M. Elgamal: None. P. Kudtarkar: None. K.J. Gaulton: None. F. Mauvais-Jarvis: None.

Type 2 diabetes (T2D) is a heterogeneous disease and biological sex affects its pathogenesis including the development of adiposity, insulin resistance, and β cell failure. For example, ketosis-prone diabetes is a phenotypically-defined form of T2D with acute β cell failure and severe insulin deficiency, predominantly observed in men. However, what mechanisms drive male predominance in β cell failure is unknown. To fully understand the sex-based pathogenesis of islet failure in diabetes, the study of sex differences in human islet biology and dysfunction is essential. To decipher sex differences in human islets genetic architecture and function, we performed an orthogonal series of experiments from 15 islets of non-diabetic (ND) donors, using single cell RNAseq (scRNAseq) and single nucleus assay for transposase-accessible chromatin sequencing (snATACseq). We also leveraged 37 ND and T2D donors for scRNAseq data from the human pancreas analysis program (HPAP) dataset. We studied over 200,000 single cells spanning the accessible genome and transcriptome. It is the largest study of sex-based single-cell genomics and transcriptomics of human islets to date. We observe that in cultured human ND islets, in the absence of the in vivo hormonal environment, islet cell transcriptome, and genome accessibility across coding regions are predominantly limited to sex chromosome genes. Of particular interest are sex differences in gene accessibility and expression of the X-linked KDM6A and Y-linked KDM5D demethylase genes in female (F) and male (M) islet cells respectively. Furthermore, analysis of T2D islets revealed a greater number of autosomal differentially expressed genes (DEGs) in F (721 upregulated and 1164 downregulated, FDR < 0.01) compared to M β cells (111 upregulated and 99 downregulated, FDR < 0.01). M β cell DEGs over-representation analysis revealed suppressed insulin secretion and processing pathways, while F β cell DEGs exhibited suppression of oxidative phosphorylation and electron transport chain pathways. Thus, although, sex differences in gene expression and accessibility of cultured ND human islets are restricted to sex chromosome genes, during the transition from ND to T2D, major sex differences in autosomal DEGs appear, with a greater number of autosomal DEGs in F compared to M T2D islets.

Presentation: 6/3/2024
7578 SGLT2 Inhibitor Is Associated With A Decreased Risk Of Cerebrovascular Events And Dementia Compared To Thiazolidinedione In Subjects With Type 2 Diabetes
Authors: Park Hyeong-Kyu , Park Sang Joon , Kim Hye Jung , Byun Dong Won
Published: October 2024

Disclosure: H. Park: None. S. Park: None. H. Kim: None. D. Byun: None.

Subjects with type 2 diabetes (T2D) are at higher risk of developing cerebrovascular disease, cognitive decline, and dementia. Hyperinsulinemia and insulin resistance in the brain have been linked to amyloid beta metabolism, raising the risk of Alzheimer's dementia. Recently, several clinical studies have shown potential beneficial effects of sodium glucose co-transporter-2 (SGLT2) inhibitors, and thiazolidinediones, in the risk of cerebrovascular events and dementia in T2D. This study was aimed to investigate the comparative efficacy of SGLT2 inhibitors and thiazolidinediones in modifying the risk of cerebrovascular events, dementia, and Alzheimer's dementia. Using the common data model, we analyzed patients from December 31, 2011 to December 30, 2022 from 15 hospitals in South Korea. Clinical outcomes between SGLT2 inhibitors and thiazolidinediones were compared using hazard ratios (HRs), with large-scale propensity score matching and a random-effects model applied. Our analyses showed that subjects on SGLT2 inhibitors had a significantly reduced rate of cerebrovascular events (HR 0.2787, 95% CI 0.1882-0.4127, p<0.00001), dementia (HR 0.5395, 95% CI 0.3824-0.7614, p=0.0004), and Alzheimer's dementia (HR 0.586, 95% CI 0.4634-0.7411, p<0.00001), compared to those on thiazolidinediones. In summary, these results suggest that SGLT2 inhibitor administration is associated with a lower risk of cerebrovascular events, dementia, and Alzheimer's dementia compared to thiazolidinedione in subjects with T2D. Further studies are warranted to confirm our findings and elucidate the underlying mechanisms.

Presentation: 6/3/2024
7568 Sickle Cell Variant Promotes Glycemic Dysregulation In A Mouse Model Of Human Sickle Cell Trait And Sickle Cell Disease
Authors: Zapater Joseph L , Layden Brian T
Published: October 2024

Disclosure: J.L. Zapater: None. B.T. Layden: None.

Since cases of type 2 diabetes mellitus (T2DM) are rising due to environmental and societal factors, it is estimated that in the coming decades that T2DM will affect twenty percent of the United States population and that mortality from diabetic complications will continue to rise. It is therefore critical to accurately diagnose and treat T2DM early, however this proves difficult in certain populations. Sickle cell anemia is a common hemoglobinopathy in which changes in red blood cell turnover lead to inaccurate measurement of hemoglobin A1c and incongruencies between this and other glucose measures, making it difficult to establish a diagnosis of T2DM. The sickle cell variant has been linked to higher hemoglobin A1c, and with 1-in-10 African Americans having the sickle cell trait (SCT), an increasing prevalence of sickle cell disease (SCD), and a higher risk of diabetic complications in those with SCT or SCD, it is critical that we elucidate the precise mechanisms by which the sickle cell variant affects glycemic homeostasis. In this work, we utilized a mouse model of human sickle cell anemia to begin to determine the biochemical mechanisms governing glucose handling in the presence of the sickle cell variant by examining glycemic homeostasis under normal and obesogenic conditions. Townes sickle cell mice containing human hemoglobin with either two normal β-globin chains (littermate controls) or one normal and one sickle β-globin chain (SCT) were placed on either a normal chow diet or on a high fat diet (HFD) until 20 weeks of age to induce an obesogenic state. Although no overt glycemic phenotype was noted, 20-week-old HFD-fed SCT mice exhibited an increased glucose excursion following an oral glucose load compared to littermate controls. Though serum insulin levels were comparable, HFD-fed SCT mice also exhibited a reduced whole-body insulin sensitivity during insulin tolerance testing compared to controls, correlating with the noted increased glycemic excursion. With these findings, we have initiated work with Townes mice containing two normal α-chains and two sickle β-chains (SCD), which is found in human sickle cell anemia. Early results show that chow-fed SCD mice exhibit greater random and fasting glucose levels at 8 and 12 weeks of age, despite similar fasting insulin levels. These findings suggest that the presence of one sickle β-globin chain, as in SCT, promotes hyperglycemia in the obesogenic state through reduction of whole-body insulin sensitivity. Furthermore, the presence of two sickle β-globin chains, as in SCD, is sufficient to dysregulate glycemic control under normal conditions. In total, these findings demonstrate that the presence of the sickle cell variant promotes glucose dysregulation and hyperglycemia, meaning that it is essential to understand the glycemic regulation in patients with sickle cell trait and sickle cell anemia.

Presentation: 6/1/2024
8413 Skeletal Muscle Mass, Insulin Sensitivity, And Beta-Cell Function In The Development Of Type 2 Diabetes: A 16-Year Prospective Cohort Study
Authors: Mun H , Lee S , Kim S , Yoo S J , Son J
Published: October 2024

Disclosure: H. Mun: None. S. Lee: None. S. Kim: None. S. Yoo: None. J. Son: None.

Background: The relationship of relative muscle mass with beta-cell dysfunction and insulin resistance in the development of type 2 diabetes is unclear. We therefore aimed to evaluate longitudinal changes in glycemia, insulin sensitivity, and beta-cell function according to muscle mass. Methods: We prospectively evaluated 7090 middle-aged and older participants without diabetes at baseline every 2 years with oral glucose tolerance tests for 16 years in the Korean Genome Epidemiology Study. Weight-adjusted appendicular skeletal muscle mass was used to derive the muscle mass index (MMI). Using linear mixed-effect models, we assessed trajectories of fasting and 2-hour post-load glucose (2hPG), the composite insulin sensitivity index (ISIcomp), the 60-minute insulinogenic index (IGI60), and the disposition index (DI) according to sex-specific MMI tertiles before diagnosis with type 2 diabetes or the completion of follow-up. Results: During a median follow-up of 13.9 years, 1742 (24.5%) participants were diagnosed with type 2 diabetes. The risk of developing type 2 diabetes gradually increased as MMI decreased (multivariable-adjusted hazard ratio 1.36; 95% CI 1.29; 1.44 per SD decline in MMI). After age- and sex adjustment, significant differences were found in fasting and 2hPG trajectories between low and high MMI tertiles during follow-up (p < 0.001 for group-by-time interaction). The low MMI tertile showed significantly lower ISIcomp and DI at baseline compared to the high MMI tertile. The rate of increase in IGI60 was significantly lower in the low MMI tertile than in the high MMI tertile (0.0021 vs. 0.0191; p < 0.001) despite a progressive decline in ISIcomp during follow-up. The rate of decrease in DI was significantly greater in the low MMI tertile than in the high MMI tertile (-0.0228 vs. -0.006; p < 0.001). Conclusion: Sufficient muscle mass in middle-aged and older adults could protect against incident type 2 diabetes by preserving beta-cell function to compensate for aging-induced reductions in insulin action, independent of obesity.

Presentation: 6/1/2024
6765 Surveillance For Side Effects Of Glycemic Control: Von Gierke Disease And Recurrent Diarrhea With Hospitalized Approach
Authors: Gone Jayanthraj , Fegahli Elie , Thompson Trevor
Published: October 2024

Disclosure: J. Gone: None. E. Fegahli: None. T. Thompson: None.

Background: Von Gierke disease is an autosomal recessive disorder leading to the inability to break down glycogen. Clinical features manifest at 3-6 months including symptoms of hypoglycemia, short stature, thin legs, round face, protruding abdomen, muscular hypotonia, and psychomotor retardation. Workup shows hypoglycemia, lactic acidosis, hyperuricemia, hyperlipidemia, anemia, hepatomegaly, and renomegaly. Patients may develop inflammatory bowel disease, osteopenia, renal failure, hepatic tumors, and pulmonary hypertension. Molecular sequencing confirms the diagnosis. Feeding glucose at regular intervals prevents hypoglycemia. One should avoid fructose, lactose, sucrose, and galactose. Oral citrate or bicarbonate is used to treat lactic acidosis. Gout, hyperlipidemia, anemia, IBD and osteoporosis are managed accordingly. Regular screening for osteoporosis, renal failure, hepatic tumors, and pulmonary hypertension is recommended. Liver transplantation results in optimal management. Gene therapy clinical trials are underway. Clinical Case: We present a case of von Gierke disease in a 20-year-old male presenting to the Emergency Department for recurrent nausea, emesis, poor oral intake, water diarrhea and subjective fever. Inpatient workup showed lactic acidosis, hyperuricemia, hypertriglyceridemia, transaminitis, and fibrofatty hepatomegaly. Intravenous fluids, antiemetics and cornstarch were given. Symptoms including nausea, emesis, and diarrhea improved, most notably after adjustments made to cornstarch dosage and frequency. The patient was discharged with an antiemetic and an antidiarrheal and with recommendations to continue scheduled cornstarch. Patient was educated about the importance of proper diet compliance and close outpatient follow up. Hence, management of von Gierke disease should include not only strict glycemic control but also close surveillance for possible side effects, such as diarrhea. Moreover, future studies are necessary to support empiric modifications in management despite a basis of a hypothetical rationale. Conclusion: An essential goal of managing GSD-1 is not only strict glycemic control but also close surveillance for possible side effects, such as diarrhea. Adjustments to maintaining normoglycemia may be mandatory by manipulating factors including dosage and frequency of oral carbohydrates, such as cornstarch, to reduce the recurrence of side effects as much as possible. Treatment regimens should be individualized to each case because the initial presentation and response to treatment in every patient can be different, whether it is minor or major. Future studies about the mechanisms regarding possible side effects of treatment, such as diarrhea, are warranted to corroborate empiric changes in management, like adjusting dosage and frequency or medications, despite having a hypothetical rationale.

Presentation: 6/1/2024
7501 The Effect Of Liraglutide On Postprandial Hypoglycemia In Non-Bariatric Surgery Patients; A Case Series And Review Of Literature
Authors: Almistehi Wael Mohammad , Alatawi Jamilah Atallah , AlJalal Wesam Abdullah
Published: October 2024

Disclosure: W.M. Almistehi: None. J.A. Alatawi: None. W.A. AlJalal: None.

Background: Postprandial hypoglycemia is not an uncommon symptom with various causes and pathophysiology, including exaggerated insulin response related to rapid glucose absorption like in patients with dumping syndrome post-bariatric, Impaired glucagon sensitivity, Insulin resistant-related hyperinsulinemia, Alcohol, and idiopathic. It affects the patient's quality of life, causing autonomic and neuroglycopenic symptoms. In extreme cases, it might be fatal as well. To our knowledge, there are no published studies on using Liraglutide in patients with postprandial hypoglycemia without a history of bariatric surgery. Methods: This case series involved six patients who share a similar presentation to the endocrine clinic in the Obesity, Endocrine and Metabolism Center in King Fahad Medical City-Riyadh, Saudi Arabia. All patients with adrenergic symptoms and hypoglycemia documented less than 65 mg/dl, mainly post-meal, within 3-4 hours. We prescribed Liraglutide and other medical treatment regimens to improve their symptoms and follow them up for up to two years. Results: There are six patients, five females and one male, aged between 22 and 55 years old. They presented with adrenergic symptoms such as sweating, dizziness, hunger, shivering and blurring of vision with documented hypoglycemia less than 65 mg/dl that improved with meal. Of the six patients, four had symptoms triggered by eating, one reported symptoms mainly after stress, and the last had no specific trigger factor. Two patients were started on Acarbose and Diazoxide at doses of 50 mg twice daily and 100 mg Three times daily, respectively, with persistent adrenergic symptoms; those two patients started on Liraglutide 0.6 mg with titration up for a dose of 3 mg daily. Both had significant improvement in symptoms with decreased frequency and severity of hypoglycemia during the two-year follow-up. Another two patients had persistent symptoms while treated only with Acarbose 50 mg thrice daily. The first patient started on Liraglutide 0.6 mg daily and titrated to a dose of 1.8 mg daily for two years with no improvement of symptoms, but the patient was not compliant with the medication. The other patient reached 3 mg daily with partial improvement of symptoms at two years of follow-up. The last two patients started immediately on Liraglutide. The first one takes 1.8 mg daily and has significantly improved his symptoms since starting the medication until eight months follow up (up to date). The last case received 3 mg daily and showed improvement of his hypoglycemia up to two years follow up. Conclusion: Liraglutide might be a good option for treating postprandial hypoglycemic patients with good clinical outcomes. However, more publications are needed to evaluate the efficacy and long-term follow-up in treating this group of patients.

Presentation: 6/3/2024