bluuebunny/crossref_metadata_2025 huggingface dataset:
OR23-01 The Nonredundant Role Of Beta-Amyloid In Mediating Tonic PTH Secretion In Physiological And Pathological States
Authors: Tu Chia-Ling , Cheng Zhiqiang , Alejandra Pena Karina , Szeto Nicholas , Ann Sosa Julie , Vilardaga Jean-Pierre , Koh James , Chang Wenhan
Published: October 2023

Disclosure: C. Tu: None. Z. Cheng: None. K.A. Pena: None. N. Szeto: None. J.A. Sosa: None. J. Vilardaga: None. J. Koh: None. W. Chang: None.

Understanding the mechanisms driving parathyroid hormone (PTH) hypersecretion in primary hyperparathyroidism (PHPT) is essential for better management of this common endocrinopathy. Prior studies showed that reduced Ca2+-sensing receptor (CaSR) expression and the subsequent increases in heterodimerization of the CaSR with the type B γ-aminobutyric acid receptor 1 (GABAB1R) are causally linked to PTH hypersecretion in PHPT mouse models (Nat Metab 2:243-255). We further showed that expression of the putative GABAB1R ligands, amyloid precursor protein (APP) and its proteolytic product, β-amyloid (Aβ1-42), is significantly upregulated in adenomas of PHPT patients associated with vitamin D insufficiency/deficiency when compared to normal donor controls. The current study aims to delineate the actions of Aβ1-42 in promoting tonic PTH secretion and its interactions with vitamin D receptor (VDR) signaling in parathyroid glands (PTGs) in basal and PHPT states. We show that Aβ1-42 (200 nM) stimulated tonic PTH secretion in cultures of normal human PTGs without shifting the calcium/PTH secretion setpoint (Ca2+-setpoint). In contrast, conditional knockout (KO) of the App gene in the parathyroid cell (PTC) of PTCAppΔflox/Δflox mice significantly reduced serum PTH levels (KO: 64±13 pg/ml vs Control: 109±12 pg/ml; p<0.05, n=8) despite hypocalcemia, indicating hypoparathyroidism. In PTGs cultured from the PTCAppΔflox/Δflox mice, supplementation of Aβ1-42 dose-dependently (EC50=5.6 nM, p<0.001) increased PTH secretion without altering the Ca2+-setpoint. However, the stimulatory effects of Aβ1-42 on tonic PTH secretion were completely abrogated in the PTGs with concurrent deletions of App, Casr and Gabbr1 genes, supporting a direct action of Aβ1-42 on CaSR and/or GABAB1R. The latter notion is further supported by the ability of Aβ1-42 to stimulate cAMP production in cells co-expressing CaSR and GABAB1R. PTC-specific deletion of the Vdr gene in the PTCVdrΔflox/Δflox mice led to elevated serum PTH levels in vivo and increased tonic PTH secretion with unaffected Ca2+-setpoint in PTGs in vitro. Concurrent ablation of the App gene completely normalized serum PTH levels in the PTCVdrΔflox/Δflox mice and prevented PTH hypersecretion in their PTGs in culture. These findings support a critical role of the APP-derived Aβ1-42 in mediating tonic PTH secretion in the normal physiological state and suggest a new mechanism driving PTH hypersecretion in PHPT due to vitamin D deficiency.

Presentation: Saturday, June 17, 2023
THU583 Cardioprotection By Nitric Oxide Is Mediated Via Mitochondrial Function In Rodents
Authors: Islam Kazi , Islam Rahib , Draper Alexis
Published: October 2023

Disclosure: K. Islam: None. R. Islam: None. A. Draper: None.

Background: Reduced nitric oxide (NO)bioavailability and decreased expression of mitochondrial transcription factor A (TFAM) occurs in the setting of heart failure (HF). TFAM promotes transcription of mitochondrial DNA, mitochondrial biogenesis, respiratory chain activity, and ATP synthesis. We investigated the effects of oral NaNO2therapy to increase NO in chronic HF following acute myocardial infarction and examined the effects of NaNO2 on the activation of TFAM, mitophagy, and antioxidant signaling pathways. Methods: Male C57/BL6J mice underwent 60 minutes of myocardial ischemia (MI) induced by left coronary artery (LCA) occlusion followed by 4 weeks of reperfusion. NaNO2 or saline vehicle (VEH)was administered at a dose of 165 µg/kg at reperfusion and then daily for 4weeks in the drinking water (100 mg/L). Left ventricular ejection fraction (LVEF) was determined at baseline and at 4 weeks of reperfusion. At 4 weeks of reperfusion myocardial tissue samples were collected and analyzed by RT-qPCR, immunoblot, oxidative stress assay, and protein sulfhydration assay. Results: NaNO2 administration markedly preserved left ventricular ejection fraction (LVEF) and improved left ventricular diastolic and systolic dimensions at 4 weeks as compared to VEH. Mitochondrial antioxidant proteins, SOD2 (MnSOD), peroxiredoxin-3 (Prx-3) and thioredoxin 2 (TXN2) (p < 0.05) were markedly increased in NaNO2treated mice compared to VEH. Expression of mitophagic markers, p62 (p <0.05) and Map1lc3 (p < 0.05) were significantly increased in NaNO2treated HF mice as compared to VEH. Expression of mitochondrial quality control such as PINK1 and PARKIN2 were also markedly increased HF mice after treated with nitrite therapy as compared with VEH. Marked induction of sulfhydration of interferon regulator factor 1 (IRF-1) as well as upregulation of mitochondrial transcription factor A (TFAM) (p < 0.05) and suppression of DNA methyltransferase3a (Dnmt-3a) (p < 0.05) were observed in NaNO2 treated ischemic HF mice as compared with VEH. Conclusions: Our results clearly demonstrate thatNaNO2 therapy improves left ventricular function during ischemic HF through induction of antioxidant signaling, mitophagy, sulfhydration of IRF-1and TFAM resulting in increased mitochondrial biogenesis.

Presentation: Thursday, June 15, 2023
FRI091 Treatment Of Secondary Hyperlipidemia Due To Nephrotic Syndrome
Authors: Girard Jeanette , Quadri Hamza , Jiang Bryan , Kapoor Force Bahar , Abushamat Layla , Schneider Aguirre Rebecca
Published: October 2023

Disclosure: J. Girard: None. H. Quadri: None. B. Jiang: None. B.K. Force: None. L. Abushamat: None. R.S. Aguirre: None.

Introduction: Secondary Hyperlipidemia associated with nephrotic syndrome contributes to significant cardiovascular morbidity. The elevated atherogenic lipoprotein levels are caused by upregulation of HMG-CoA reductase and downregulation of lipoprotein lipase. More recently, studies in mice have linked PCSK9 and Inducible Degrader of the LDL Receptor (IDOL) as primary contributors to hypercholesterolemia in nephrotic syndrome due to the decrease in LDL receptor recycling (1). Treating nephrotic syndrome is the first-line treatment for the associated secondary hyperlipidemia. Since exposure time to atherogenic lipoproteins matters in the development of cardiovascular disease, statins, with or without ezetimibe, are utilized. PCSK9 inhibitors are initiated if LDL remains elevated despite these measures. This case report highlights a severe case of hypercholesterolemia associated with nephrotic syndrome and treatment response. Clinical Case: A 55-year-old male with no significant past medical history presented to the emergency department with shortness of breath and lower extremity edema. He denied a family and personal history of premature cardiovascular disease. Initial evaluation revealed a serum total cholesterol on 10x dilution of 833.9 (</=200mg/dL), calculated LDL 718mg/dL (<100mg/dL), triglycerides 381mg/dL (<150mg/dL), HDL 39.3mg/dL (40-60mg/dL), Apo B >400mg/dL (<90mg/dL), and Lp(a) 17.5mg/dL (<75mg/dL). His serum albumin was <1.5g/dL (4.2-4.5g/dL), creatinine 2mg/dL (0.7-1.3mg/dL), and 24-hour calculated urinary protein level 10,294mg/24-hour (30-150mg/24-hour). A kidney biopsy revealed a mixed Type III and Type V Lupus Nephritis. The patient started lupus treatment along with atorvastatin 80mg qHS, fenofibrate 45mg daily, and ezetimibe 10mg daily. His LDL decreased to 418mg/dL (<100mg/dL) after 15 days. The patient continued to have undetectable albumin although kidney function improved after 2 months. We planned to initiate PCSK9 inhibitor treatment for further LDL reduction pending treatment of lupus, but patient died from septic shock prior to initiation. Conclusion: This case illustrates that extremely elevated LDL levels from nephrotic syndrome resulted in a nearly 60% reduction of LDL with statin and ezetimibe treatment. Statins, ezetimibe and PCSK9 inhibitor therapy should be considered stepwise when treating secondary hyperlipidemia from nephrotic syndrome. 1. LIU S, VAZIRI ND. ROLE OF PCSK9 AND IDOL IN THE PATHOGENESIS OF ACQUIRED LDL RECEPTOR DEFICIENCY AND HYPERCHOLESTEROLEMIA IN NEPHROTIC SYNDROME. NEPHROL DIAL TRANSPLANT. 2014 MAR;29(3):538-43. DOI: 10.1093/NDT/GFT439. EPUB 2013 OCT 28. PMID: 24166456

Presentation: Friday, June 16, 2023
FRI106 Outcomes Of SGLT2 Inhibitors In Patients With Heart Failure With Or Without Diabetes In A Tertiary Care Center In Saudi Arabia
Authors: Alqifari Saleh F , Mohammed Adil , Anwar Eman , Niazi Kashan , Aldawish Rahaf , Mutlaq Mai , Binsaqr Maha , Khojah Asmaa , Albahli Rand , Amirthalingam Palanisamy , Aljabri Ahmed , Ziada Shimaa , Alshaye Bshaier , Almlkhlef Salman
Published: October 2023

Disclosure: S.F. Alqifari: None. A. Mohammed: None. E. Anwar: None. K. Niazi: None. R. Aldawish: None. M. Mutlaq: None. M. Binsaqr: None. A. Khojah: None. R. Albahli: None. P. Amirthalingam: None. A. Aljabri: None. S. Ziada: None. B. Alshaye: None. S. Almlkhlef: None.

Objectives: The role of Sodium-glucose cotransporter 2 (SGLT2) inhibitors in the reduction of renal complications, death, and hospitalization in patients with heart failure has been highlighted in recent trials. However, real-world evidence is lacking, especially in the Middle East. This study aims to examine SGLT2 inhibitors outcomes in patients with heart failure with or without diabetes mellitus. Materials and Methods: This is a retrospective single-center study conducted in Saudi Arabia that reviewed patients’ data from July 2021 to June 2022. We included adults (≥18 years) diagnosed with heart failure and treated with Empagliflozin for a minimum of 3 months. Results: A total of 45 patients were included in the study. A significant difference was detected among the group of patients with diabetes and no diabetes in baseline diastolic blood pressure (DBP), baseline left ventricular ejection fraction (LVEF), and the use of diabetic medications (p= 0.008, <0.001, 0.008), respectively. SGLT2 inhibitors use signaled a trend towards improvement in HbA1C, LVEF, and ED visits frequency in both groups, however, findings were non-statically significant. Conclusions: Although the use of SGLT2 inhibitors for at least 3 months improved HbA1C, LVEF, and ED visit frequency in both groups, results were not statistically significant. These findings warrant larger studies to further evaluate the clinical outcomes of SGLT2 inhibitors in Saudi patients.

Presentation: Friday, June 16, 2023
FRI119 Cardiac Biomarkers In Fabry Disease Exhibit Distinct Associations With Cardiovascular Outcomes: A (Rare) Prism For Cardiovascular Endocrinology
Authors: Shemesh Elad , Rusk Rosemary , Feigin Paul , Deegan Patrick
Published: October 2023

Disclosure: E. Shemesh: None. R. Rusk: None. P. Feigin: None. P. Deegan: None.

Background: Fabry disease (FD) (OMIM 301500) is a rare x-linked metabolic disorder. Cardiovascular involvement in this rare metabolic disorder is common, including hypertrophy, fibrosis, heart failure and arrythmias. Troponin concentrations are often continuously elevated in FD patients, which at times may lead to false assumptions and unnecessary invasive investigations. Furthermore, while nt-proBNP, another cardiac biomarker, is regarded by some as a valuable biomarker in FD, its concentrations might be falsely high due to renal involvement in the disease. We sought to explore the associations between these cardiac biomarkers with myocardial architecture and clinical outcomes in patients with FD. Hypothesis: Biomarkers in FD associate similarly with myocardial architecture and clinical outcomes. Results: 107 patients from a tertiary referral center in the United Kingdom were included in this study. Mean age at first visit was 44.5±17 years. Study population was composed of 40 males and 67 females. Twenty males and 43 females carried a classic mutation. At baseline, 27% had elevated troponin concentrations and 30% of patients had elevated nt-proBNP concentrations. Throughout follow-up, 17 cardiac-related hospitalizations were recorded, and 12 cardiac-related deaths occurred. While troponin and nt-proBNP concentrations at baseline were closely related (r= 0.5, p < 0.05), distinct associations with future occurrence of cardiac architecture pathologies were noted: elevated troponin concentrations associated with presence of late gadolinium enhancement and left ventricular hypertrophy in a statistically significant manner (late gadolinium enhancement: r=0.54, p<0.05; hypertrophy: r-0.45, p<0.05), but nt-proBNP did not. However, both biomarkers associated with adverse clinical outcomes, and nt-proBNP displayed stronger correlation with future heart failure events than troponin (r= 0.52, p<0.05 vs r=0.3, p<0.05). Neither troponin nor nt-proBNP baseline concentrations associated with the implantation of cardiac device (defibrillator or pacemaker). Conclusions: Cardiac biomarkers associate differently with myocardial architecture pathologies, but similarly with clinical outcomes in FD. Our results imply distinct roles for troponin and nt-proBNP in adverse cardiac events in FD.

Presentation: Friday, June 16, 2023
FRI126 Autoreactive T Cells To Angiotensin II Type 1 Receptor In Salt-dependent Hypertension Due To Primary Aldosteronism
Authors: Scarpa Riccardo , Piazza Maria , Caroccia Brasilina , Carraro Samuela , Vianello Fabrizio , Cinetto Francesco , Agostini Carlo , Seccia Teresa M , Paolo Rossi Gian
Published: October 2023

Disclosure: R. Scarpa: None. M. Piazza: None. B. Caroccia: None. S. Carraro: None. F. Vianello: None. F. Cinetto: None. C. Agostini: None. T.M. Seccia: None. G. Rossi: None.

Compelling evidence suggested a role of acquired immunity in hypertension and hypertension-mediated organ damage (HMOD), but the pathogenic role of this acquired immunity is still unknown. Primary Aldosteronism, the paradigm of salt-dependent hypertension, is characterised by a more prominent HMOD than primary (‘essential’) hypertension and by high titer of autoantibodies against the type 1 angiotensin receptor (AT1R). As T cells are broadly recognised as HMOD-mediators, we aim to investigate: 1) the presence of AT1R-autoreactive T cells in PA; 2) aldosterone rapid and chronic effect on AT1R-autoreactive T lymphocytes; 3) the presence and functional role of know aldosterone receptors on T lymphocytes. The presence of AT1R-autoreactive T cells in 11 PA patients was investigated by flow cytometry after stimulation with pool of peptides spanning the full length of AT1R. The expression of mineralocorticoid receptor (MR) and G Protein-Coupled Estrogen Receptor (GPER) on T cells was tested by measuring mRNA copy number by droplet digital PCR and immunoblotting from healthy donors (HD) subjects and PA patients. Peripheral blood mononuclear cells (PBMCs) from PA patients were exposed to aldosterone 10-10 M with or without MR antagonist (canrenone) and GPER agonist (G1) and antagonist (G36). We evaluated the effect of aldosterone on CD8+ T cells by measuring IFNɣ release with flow cytometry. PA patients were found to have CD8+ AT1R-autoreactive T cells after activation of PBMC with AT1R peptides. MR and GPER were detected both at mRNA and protein level in CD4+ and CD8+ T cells with the following rank of expression GR>MR>>GPER. Aldosterone significantly increased IFNɣ release in CD8+ T-cell both under chronic and acute stimulation. Chronic exposure to aldosterone increased IFN-γ production by CD8+ T cells by acting via the MR, as it was prevented (p < 0.004) by canrenone, while the rapid aldosterone action was MR and GPER mediated, as it was reduced by canrenone (p < 0.003), but also by G36 (p < 0.02), and mimicked by G1. These results showed the presence of AT1R-autoreactive T cells in patients with PA. Moreover, upon of MR and GPER receptor stimulation with aldosterone, AT1-R specific CD8+ T cells undergo profound changes that mediated a strong cytotoxic response towards AT1-R-expressing organs.

Presentation: Friday, June 16, 2023
FRI134 Transcriptomic Profiling Of Monocytes To Seek A Potential Biomarker For Primary Aldosteronism
Authors: Libianto Renata , Karthigan Nikshay , Morgan James , Powell David , Fuller Peter J , Jennifer Young Morag , Yang Jun
Published: October 2023

Disclosure: R. Libianto: None. N. Karthigan: None. J. Morgan: None. D. Powell: None. P.J. Fuller: None. M.J. Young: None. J. Yang: None.

Primary aldosteronism (PA), the most common endocrine cause of hypertension, is associated with increased cardiovascular risk compared with essential hypertension. The diagnosis of PA currently relies on measurements of plasma aldosterone and renin levels which can be compromised by patient- or assay-related issues and relies on arbitrary thresholds. A cellular marker that reflects excess endogenous aldosterone activity could enhance the diagnostic process. Mineralocorticoid receptor (MR) activation in macrophages has previously been shown to play a key role in mediating cardiovascular injury. Macrophage precursors, the monocytes, also express MR and can be easily isolated from circulation. We therefore sought to identify unique transcriptomic markers of aldosterone excess in peripheral blood monocytes. Monocytes were isolated from nine male patients with unilateral PA before and 3 months after curative adrenalectomy. Each patient’s post-adrenalectomy samples served as the control for comparison with the pre-adrenalectomy samples. RNA sequencing (RNA-seq) was performed on monocyte RNA samples to identify differentially expressed genes (DEGs), followed by evaluation using a second method by real-time quantitative PCR (RT-qPCR). Distinct clustering of gene expression was observed between the “before” and “after-surgery” samples with 1679 significantly differentially expressed (false discovery rate <0.05). The top 26 DEGs were selected for evaluation by RT-qPCR. Differences were observed in the relative expression of phosphoglycerate mutase 1 (PGAM1), ferrochelatase (FECH), and nuclear enriched abundant transcript 1 (NEAT1) genes pre- and post-surgery. The ratios of the relative expression of these genes accentuated the difference between the before- and after-surgery samples. In conclusion, differential gene expression was found between monocytes of patients with unilateral PA before and after adrenalectomy. Further validation studies are needed in female patients and those with bilateral PA and essential hypertension. These transcriptomic markers or their ratios have the potential to serve as novel biomarkers of aldosterone excess.

Presentation: Friday, June 16, 2023
FRI136 Adrenal Venous Sampling Criteria For Chemiluminescent Enzyme Immunoassay
Authors: Nakai Kazuki , Tsurutani Yuya , Irie Koki , Teruyama Kyoko , Saito Jun , Omura Masao , Nishikawa Tetsuo
Published: October 2023

Disclosure: K. Nakai: None. Y. Tsurutani: None. K. Irie: None. K. Teruyama: Employee; Self; Fujirebio Inc. J. Saito: None. M. Omura: None. T. Nishikawa: None.

Objective: In primary aldosteronism (PA), plasma aldosterone concentration (PAC) was measured by radioimmunoassay (RIA), but the supply of the RIA kit was discontinued in March 2021 in Japan. The Japan Endocrine Society's 2021 Clinical Practice Guideline for the Diagnosis and Management of PA recommends that PAC measured by chemiluminescent enzyme immunoassay (CLEIA), which yields standardized LC-MS/MS compliant measurements, be used for clinical judgment. Because CLEIA shows a lower PAC than RIA, various cutoff values for PA need to be revised. Although conversion formulas for RIA and CLEIA for various kits have been provided, these conversions were studied mainly using samples representing aldosterone concentrations in peripheral blood; thus, it is unclear whether the same conversion formula can be used for samples obtained by adrenal venous sampling (AVS). In this study, we examined PAC conversion in AVS samples and the criteria for AVS when measured using CLEIA. Methods: PAC of 415 adrenal venous blood samples from AVS (including segmental AVS) from 63 patients with PA, were measured using RIA and CLEIA methods. The established conversion formula for PAC in peripheral blood samples was PAC (CLEIA) = 0.852 × PAC (RIA) − 36.0. PAC and aldosterone/cortisol ratio (A/C ratio) conversion formulas were determined between the two assays for AVS samples. Moreover, the CLEIA conversion value, which corresponds to the AVS criteria of conventional RIA, was obtained. Results: The median [interquartile range] PAC (CLEIA) in the samples was 9823.3 [3659.8-20600.5]. PAC measured using CLEIA was significantly correlated with RIA, and the correlation coefficient was 0.971. The PAC conversion formula determined was PAC (CLEIA) = PAC (RIA) × 0.7723 - 1199 pg/mL. PAC at 14,000 pg/mL in RIA was equivalent to 9,613 pg/mL in CLEIA. The correlation coefficient for the A/C ratio was 0.997, and the conversion formula was A/C (CLEIA) = A/C (RIA) × 0.7864 - 2.427. Discussion: Samples obtained from AVS had a much higher level of PAC than those obtained from peripheral blood. The PAC conversion formula for samples in AVS has a very large intercept compared with those in peripheral blood. Thus, the results of AVS tested by CLEIA should be interpreted with care because of the differences in the conversion formula. A different cut-off value may also be needed when evaluating the lateralization ratio because of the large intercept. Conclusion: PAC conversion formulas for AVS samples using CLEIA and RIA methods were obtained. The study outcomes are useful for interpreting AVS results using the CLEIA.

Presentation: Friday, June 16, 2023
FRI150 Individualized And Shorter Follow-up With Immunohistochemical Staining In Unilateral Primary Aldosteronism?
Authors: Gunnarsdottir Hrafnhildur , Agnarsson Bjarni A , Jonasdottir Sigurrós , Gudmundsson Jón , Birgisson Guðjón , Sigurjónsdóttir Helga Á
Published: October 2023

Disclosure: H. Gunnarsdottir: None. B.A. Agnarsson: None. S. Jonasdottir: None. J. Gudmundsson: None. G. Birgisson: None. H.Á. Sigurjónsdóttir: None.

Indroduction: Clinical significance of specific antibody staining (SAS) for unilateral primary aldosteronism (PA) has been unclear. Individualized follow-up of PA patients could be in sight. Long-term outcome of patients, classified based on immunohistochemical staining, needs further investigation. Aims: We aimed to assess long-term clinical outcome (using PASO criteria) for unilateral PA, classifying patients based on SAS. Methods: The study was a nationwide observational study, with up to 11 years follow-up, executed in 2007-2016 at Landspitali National University Hospital of Iceland, tertiary referral center. Patients were diagnosed and treated in line with the current guidelines. All unilateral PA patients, ( n=26) age 28-73 years, who underwent adrenalectomy in Iceland during the study period were included. H&E stained tissue slides were stained using specific CYP11B1 and -B2 antibodies. All cases were re-evaluated and classified as adenoma (APA) or non-adenoma (adrenal hyperplasia, unilateral adrenal micronodules (UMN) or aldosterone producing cell clusters (APCC)). Data collection consisted of aldosterone, renin and cortisol values, antihypertensive drug count, potassium supplementation, blood pressure and serum potassium pre-intervention and throughout follow-up and histopathology results post-adrenalectomy. Results: Following SAS, APA was seen in 21 adrenals, APCC in three and UMN in two. Immunohistochemical staining altered histopathological diagnosis in 27% of the patients. Around 80% of each subgroup had partial clinical success. No APA patient with complete clinical success at 12 months (n=4) relapsed during follow-up. Conclusions: We found SAS mandatory for accurate histopathological diagnosis of PA. Our results indicate that a subgroup of APA patients can be discharged safely early.

Presentation: Friday, June 16, 2023
OR24-05 High Waist Circumference Is Strongly Predictive Of Hepatic Steatosis And Significant Fibrosis
Authors: Janakiram Nikhila , Puri Sadhana , Thirumalai Arthi
Published: October 2023

Disclosure: N. Janakiram: None. S. Puri: None. A. Thirumalai: None.

Vibration-controlled transient elastography (TE) can measure controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) in non-alcoholic fatty liver disease (NAFLD) patients. A high skin-to-capsule distance can challenge the accuracy of this imaging technique. Therefore, high waist circumference (WC), a known risk factor for NAFLD, can hamper assessment in high-risk patients. Studies investigating the relationship between WC and TE measurements have yielded conflicting results. We used the 2017-2018 National Health and Nutrition Examination Survey (NHANES) data to explore this relationship in a large cohort of the general population. We hypothesized that high WC would be associated with (1) higher failure rate for completion of TE, (2) worse CAP and LSM measurements and (3) be predictive of presence of steatosis and significant fibrosis. We summarized the primary reason for incomplete TE in normal and high WC participants of male (M; WC ≥ 102 cm = high) and female (F; WC ≥ 88 cm = high) gender. We compared mean CAP and LSM between normal and high WC participants using unpaired t-tests. We calculated area under receiver operator curve (AUROC) for WC predicting presence of steatosis (CAP ≥248 dB/m) and significant fibrosis (LSM ≥8 kPa) and compared this with fibrosis-4 (FIB-4) and NAFLD fibrosis scores (NFS). We analyzed the 5757 patients (2880 F, 2877 M) with complete or partial TE status, based on WC. Proportion of patients with partial TE status was higher in those with high WC (8.9% F, 9% M) than normal WC patients (6.5% F, 6.4% M). We analyzed the 446 patients with partial TE status (231 F, 215 M) by cause. The proportion of patients who were unable to complete TE, either due to an IQR/medium > 30% or not having 10 valid measurements among the high WC population (66%) was significantly higher than those with normal WC (23%), in both women (X2 (1, n=231) = 29.63; p<.001) and men (X2 (1, n=215) = 49.43; p<.001).Among those with complete TE (n=2313; 1090 M, 1223 F), mean CAP was significantly higher (p<0.001) in high WC patients (308 dB/m M, 278 dB/m F) compared to normal WC patients (250 dB/m M, 225 dB/m F). Mean LSM was significantly higher (p<0.001) in high WC patients (6.8 kPa M, 5.7 kPa F) compared to normal WC patients (5.7 kPa M, 4.5 kPa F). The AUROC for WC predicting presence of steatosis was 0.77 in F and 0.80 in M (p<0.001 for both). The AUROC for WC predicting the presence of significant fibrosis (≥8 kPa) was 0.73 in F and 0.71 in M (p<0.001 for both). In AUROC analyses, WC performed better than FIB-4 and NFS in predicting presence of significant fibrosis and steatosis. Therefore, we conclude that high WC is more likely to result in an incomplete TE, but among those with a valid exam, it is highly predictive of presence of steatosis and significant fibrosis.

Presentation: Saturday, June 17, 2023
THU245 Association Between Sleep Duration And Incident Diabetes Mellitus In Healthy Subjects: A 12-year Longitudinal Cohort Study
Authors: Kim Wonjin , Hye Huh Ji
Published: October 2023

Disclosure: W. Kim: None. J. Huh: None.

Objective: Previous studies demonstrated that inadequate sleep, including the deprivation of absolute sleep duration and poor sleep quality, was associated with a higher risk of type 2 diabetes mellitus (DM) and obesity. This study aimed to investigate whether sleep duration and/or quality is associated with incident DM. Methods: The study population consisted of participants in the ongoing Korean Genome and Epidemiology Study (KoGES)-Ansung and Ansan Cohort Study, a rural, community-based, prospective study. A total of 8,816 of 10,030 healthy participants were enrolled in a prospective cohort study. DM was diagnosed as fasting glucose ≥126 mg/dL or 2-h post-loading glucose ≥200 mg/dL. Sleep du-ration and quality questionnaires were completed. Sleep duration was classified into four groups: 6 <, 6-7, 8-9, 9 h/day. Sleep quality was assessed in participants with sleep duration of < 10 h/day using the Epworth Sleepiness Scale (ESS) which measures an excessive daytime sleepiness in individuals. Results: During the 14-year follow-up period, 18% (1630/8816) were diagnosed with DM. A U-shaped relationship was observed between sleep duration and incident DM, with the highest risk observed when sleep duration was 10 ≥ h/day (Hazard ratios (HR) 1.65 [1.25–2.17]). This group exhibited decreased insulin glycogenic index, a marker of insulin secretory function, during the study period. Among study participants who slept less than 10 h/day, the risk of incident DM increased when the ESS score was > 10. Conclusion: We found that the association between sleep duration and incident DM was U-shaped; both short (≤5 h) and long (≥10 h) sleep duration were associated with an increased risk for the occurrence of incident DM. When sleep duration was 10 h or longer per day, there was a tendency to develop DM due to decreased insulin secretory function. Even if the sleep duration is less than 10 h, the likelihood of developing diabetes is greater when the quality of sleep decreases.

Presentation: Thursday, June 15, 2023
THU322 Lower HbA1c Is Associated With Lower In-Hospital Mortality In Patients With COVID-19
Authors: Tsikala Vafea Maria , Stefanovic-Racic Maja
Published: October 2023

Disclosure: M. Tsikala Vafea: None. M. Stefanovic-Racic: None.

Introduction/Aim: Diabetes has been proven to be a risk factor for worse outcomes in patients with COVID-19. Several studies have shown that poor glycemic control during hospitalization with COVID-19 is associated with higher mortality. However, the association between a long-term glycemic control and outcomes has yet to be clarified, with some studies reporting no association. The aim of this study is to determine the association between glycosylated hemoglobin (HbA1c) and in-hospital mortality in patients with COVID-19. Methods: Pubmed, Embase and Web of Science databases were searched until 11/15/2022, for studies examining the association between HbA1c level and mortality in hospitalized patients with COVID-19. A random-effects meta-analysis was performed. Heterogeneity was assessed using the I2 statistic. Publication bias was assessed using funnel plots. Results: Among 4,142 results, 22 studies were included in the final analysis with a total of 11,998 patients. In the primary analysis, in studies comparing outcomes in patients using HbA1c as a dichotomous variable using specific cutoff values, lower Hba1c was associated with lower in-hospital mortality [odds ratio (OR) 0.52, 95% confidence interval (CI) 0.37-0.72]. Heterogeneity was substantial (I2 78%). When only patients with diabetes were included in the analysis, the association remained statistically significant (OR 0.70, 95% CI 0.51-0.98). In the subgroup analysis, the association remained statistically significant in studies using as cutoff the HbA1c value of 6.5% (OR 0.34, 95% CI 0.15-0.77) and 7% (OR 0.54, 95% CI 0.32-0.90). The association did not remain statistically significant with greater HbA1c cutoff values; 7.5% (OR 1.09, 95% CI 0.91-1.30) and >= 8% (OR 0.78, 95% CI 0.33-1.82). In the secondary analysis, in studies using HbA1C as a continuous variable, HbA1c level did not have a statistically significant association with in-hospital mortality, either in univariate (OR 0.97, 95% CI 0.92-1.03) or multivariate analyses (adjusted OR 1.00, 95% CI 1.00-1.01). Conclusion: A better glycemic control prior to hospitalization, as reflected by lower HbA1c, is associated with lower in-hospital mortality in patients with COVID-19.

Presentation: Thursday, June 15, 2023
THU380 A Case Of Alpelisib Induced Diabetic Ketoacidosis (Dka) In A Patient With Type 2 Diabetes Mellitus And Rechallenge With SGLT2 Inhibitor
Authors: Sekar Vijaykumar , Shaik Shamsuddin
Published: October 2023

Disclosure: V. Sekar: None. S. Shaik: None.

Introduction: Alpelisib is a α-selective phosphatidylinositol 3-kinase (PI3K) inhibitor recently used in treatment of advanced breast cancer. Hyperglycemia is an expected adverse effect with the use of PI3K inhibitors. We report a case of Alpelisib induced worsening hyperglycemia in a patient with type 2 diabetes mellitus who developed DKA while on Empagliflozin and was rechallenged with Dapagliflozin to achieve better glycemic control. Case Description: 60-year-old female with known history of type 2 diabetes mellitus was referred to Endocrinology prior to the start of PI3K inhibitor, Alpelisib for metastatic breast cancer. On initial visit her Hemoglobin A1C was 7.4 % and she was on Empagliflozin 25 mg daily, Sitagliptin 100 mg daily, Metformin XR 500 mg daily and Insulin Glargine 30 units daily. Three weeks after initiation of Alpelisib, patient reported uncontrolled fasting and post-prandial hyperglycemia, therefore her basal insulin was up-titrated and added on prandial insulin. Sitagliptin was discontinued. Two weeks later patient was admitted with Euglycemic diabetic ketoacidosis (DKA) which was treated with IV insulin and IV fluids. Empagliflozin was stopped and discharged on basal bolus regimen. In the next 6 weeks basal bolus regimen was significantly up-titrated and added on correctional insulin along with increasing Metformin XR to 500 mg twice a day due to poor glycemic control. During this time patient was cautiously restarted on Dapagliflozin 5 mg daily after discussing the better outcomes for Alpelisib induced hyperglycemia versus risk of DKA with reuse of SGLT2 inhibitors. Since being on Dapagliflozin her blood sugars were better controlled and the insulin requirements plateaued. Patient was closely monitored, and she didn’t develop further episode of DKA. Discussion: The PI3K pathway controls the effect of insulin intracellularly and its activation promotes tumor development, spread and failure to anticancer treatment. PI3K inhibitor blocks the intracellular action of insulin which causes reversible insulin resistance and hyperglycemia which is the major side effect of this drug. Use of insulin to treat hyperglycemia was shown to partially reactivate the PI3K pathway in tumoral cells, leading to cellular proliferation. Therefore, insulin should be kept as the last line antihyperglycemic agent. Exploratory analysis of SOLAR-1* trial has shown better glycemic control with use of SGLT2 inhibitors in patient with Alpelisib induced hyperglycemia along with improved efficacy of Alpelisib against tumor growth. Both PI3K inhibitor and SGLT2 inhibitor has risk of causing DKA, but close monitoring and patient education helps to reduce the risk.

Reference *Study Assessing the Efficacy and Safety of Alpelisib Plus Fulvestrant in Men and Postmenopausal Women with Advanced Breast Cancer Which Progressed on or After Aromatase Inhibitor Treatment

Presentation: Thursday, June 15, 2023
THU381 A Case of Severe Type B Insulin Resistance Successfully Treated With Combined Immunosuppressive Therapy
Authors: Singh Sumal Amit Kartar , Santos Martinez Dorothy
Published: October 2023

Disclosure: A.K. Sumal: None. D.S. Martinez: None.

Background: Type B insulin resistance is a rare autoimmune disorder caused by autoantibodies against the insulin receptor and is characterized by markedly high insulin requirements, severe catabolism, and a mortality rate over 50%. Clinical Case: A 50-year-old woman with Sjogren’s syndrome and a one-year history of diabetes treated with insulin presented with diabetic ketoacidosis (DKA) and was found to have type B insulin resistance. Initial laboratory workup demonstrated DKA with a blood glucose of 464 mg/dL (n: 65–99 mg/dL), CO2 8 mmol/L (n: 20–30 mmol/L), anion gap 16 (n: 8–12), pH 7.08 (n: 7.30–7.40) on venous blood gas, 2+ ketonuria, and a hemoglobin A1c of 11.7% (n: <5.7%). Additional workup revealed negative glutamic acid decarboxylase-65, insulin antigen-2, and insulin antibodies, positive C-peptide 2.7 ng/mL (n: 1.1–4.3 ng/mL), and elevated adiponectin 41 ug/mL (n: 5–28 ug/mL). Her physical exam was notable for 100 lb weight loss and extensive acanthosis nigricans, facial acne, and hirsutism. She was started on IV insulin infusion with resolution of her DKA but required more than 5000 units of insulin per day to obtain glycemic control. Due to the suspicion of type B insulin resistance, she was treated with metformin 1000 mg twice daily and pioglitazone 45 mg daily to reverse her hypercatabolic state and combined immunosuppressive therapy consisting of 2 cycles of rituximab 750 mg/m2 infusion, cyclophosphamide 100 mg daily, and dexamethasone 40 mg for 4 days administered 14 days apart based on a 2018 NIH protocol. Her serum was sent for confirmatory insulin receptor autoantibody testing, which is pending. Over the next 30 days, her insulin requirements improved immensely, and she was ultimately discharged without insulin in clinical remission. To prevent recurrence and hypoglycemia associated with low titers of insulin receptor autoantibodies, she was started on azathioprine 100 mg daily as maintenance therapy. Three months later, she was seen in endocrine clinic in sustained remission with a hemoglobin A1c of 6.0% and resolution of her acanthosis nigricans and hyperandrogenism. Review of her continuous glucose monitor showed no episodes of hypoglycemia. Conclusion: This rare case demonstrates the successful treatment of type B insulin resistance using metformin, pioglitazone, and combination immunosuppressive therapy with rituximab, cyclophosphamide, and pulse-dose steroids, followed by maintenance azathioprine. With a mortality rate over 50%, the use of combined immunosuppressive therapy has transformed this condition into a curable form of diabetes and should be recommended in all patients with type B insulin resistance.

Presentation: Thursday, June 15, 2023
THU383 “My Hands Are Always Stiff”: A Common But Underrecognized Mimicker Of Inflammatory Arthritis.
Authors: Iqbal Iqra , Minalyan Artem , Alam Khan Muhammad Atique
Published: October 2023

Disclosure: I. Iqbal: None. A. Minalyan: None. M. Khan: None.

Introduction: Inflammatory arthropathies are often identified in patients by their characteristic patterns, including symmetric small joint involvement, joint stiffness that can improve with physical activity, and others. However, it is crucial to address comorbidities and their impact on symptom presentation when assessing these patients. Here we present a case of a relatively common but underrecognized mimicker of inflammatory arthropathies. Case: A 63-year-old man with Type 1 Diabetes Mellitus (DM1) and seronegative rheumatoid arthritis (RA) was referred to a rheumatology clinic by his family physician to manage RA. He was previously treated with prednisone and methotrexate for six months for presumed seronegative rheumatoid arthritis without any relief. He reported chronic pain and stiffness in his joints: wrists, metacarpophalangeal (MCP), proximal and distal interphalangeal (PIP and DIP) joints, ankles, and feet. His symptoms were worse in the morning. However, on further questioning, he admitted that the stiffness did not improve throughout the day. He denied joint swelling or redness over the affected joints. On exam, his hand joints had significant stiffness. We obtained hand radiographs which did not show erosive changes or significant joint space narrowing. He had negative rheumatoid factor (RF), normal anti-cyclic citrullinated peptide (CCP) antibodies, and antinuclear antibody (ANA) levels, which ruled out the diagnosis of rheumatoid arthritis. A detailed physical exam demonstrated a positive “prayer sign” and “tabletop sign.” Further lab review showed that his hemoglobin A1c (HbA1C) had been ranging between 8% to 10% over several years. Eventually, the patient was diagnosed with limited joint mobility due to the poorly controlled DM1. We discontinued his methotrexate and referred him to an endocrinologist to manage the uncontrolled DM1. He was referred to physical therapy for hand stretching exercises. After six months of treatment, his symptoms improved but did not resolve completely. Conclusion: It is essential to identify the impact of diabetes on the musculoskeletal system. Limited joint mobility, previously known as diabetic cheiroarthropathy (DCA), is a common but frequently missed manifestation of poorly controlled diabetes. It is characterized by a limited ability to flex or extend the MCP and IP joints. It may or may not be painful and can progress to fixed flexion contractures of the finger joints. Early recognition is essential for correct diagnosis. Treatment is with tighter glycemic control and physical therapy.

Presentation: Thursday, June 15, 2023
THU385 Refractory Hyperglycemia As Main Presenting Symptom In A Patient With Acromegaly
Authors: Rave Talia , Vidovic Jovana , Gu Yuwei
Published: October 2023

Disclosure: T. Rave: None. J. Vidovic: None. Y. Gu: None.

Acromegaly is a rare disorder caused by the overproduction of growth hormone (GH) from an anterior pituitary adenoma. GH regulates glucose control and about 10% of patients with acromegaly can have complications of hyperglycemia. GH stimulates hepatic release of insulin-like growth hormone-1 (IGF-1), which increases gluconeogenesis and lipolysis and decreases glucose uptake throughout the body. The increase in gluconeogenesis and decrease in glucose uptake results in hyperglycemia. The excess release of fatty acids increases insulin resistance. In this case report we present a case of hyperglycemia resistant to multiple modes of medical management with limited acromegaly features found to have acromegaly induced hyperglycemia. A 58-year-old male with a past medical history of type II diabetes mellitus, hypertension, and obesity presented to the endocrinology clinic with treatment resistant hyperglycemia. The patient also endorsed having progressive carpal tunnel symptoms. He had been using an insulin pump and requiring 3 or more boluses per day for the last 6 months. Trulicity was added in addition to current insulin pump therapy, however, sugars remained elevated with an unimproved A1c level of 9% and a fructosamine level of 538 µmol/L correlating to an A1c of 10.8%. An IGF-1 level was sent to rule out acromegaly in the setting of carpal tunnel symptoms. The IGF-1 resulted in 580 ng/mL with a z-score of +5.1. The patient underwent a GH suppression test with a glucose load which showed a significantly elevated nadir GH level of 26.3 ng/mL. Of note, the patient did not have other acromegaly symptoms such as frontal bossing, ring or shoe enlargement, coarse facial features, headaches or vision changes. An MRI pituitary was obtained which was notable for an enlarged pituitary gland with heterogeneous signal, measuring approximately 2.0cm CC x 1.5cm AP x 1.7cm TV, with the pituitary stalk deviated to the left. At this time the intervention for hyperglycemic therapy shifted. The patient was started on octreotide and referred to neurosurgery for transsphenoidal surgery. The pathophysiology of type II diabetes is complex and multifaceted. Additionally, secondary causes of hyperglycemia must be considered in refractory cases, such as in this patient. This case highlights the importance of considering acromegaly and other hormonal conditions in the treatment of patients with uncontrolled hyperglycemia, even in otherwise asymptomatic patients.

Presentation: Thursday, June 15, 2023
THU392 Type B Insulin Resistance: A Rare Cause Of Hypoglycemia
Authors: Zahoor Bhat Salman , Sidhaye Aniket , Hekmat Hamrahian Amir
Published: October 2023

Disclosure: S.Z. Bhat: None. A. Sidhaye: None. A.H. Hamrahian: None.

Introduction: Non-diabetic hypoglycemia in patients with diabetes mellitus is rare. Type B insulin resistance syndrome (TBIRS), caused by insulin receptor antibodies, presents with severe insulin resistance, but can uncommonly result in a hypoglycemic picture. Clinical Case: A 59-year-old woman with a history of SLE, T2DM, and primary hyperparathyroidism was admitted for acute confusion and found to have a POC glucose of 30 mg/dl. Her symptoms improved after IV glucose administration. She was on a stable basal-bolus insulin regimen of 0.8 U/kg/day and had unintentional 100-pound weight loss over 1 year. Significant exam findings included BMI of 29 kg/m2, gingival hyperplasia, and acanthosis nigricans. Aside from insulin, she took no medications strongly associated with hypoglycemia. Labs including CBC, CMP, TFTs, and morning cortisol were normal. HbA1C and adiponectin levels were 7.7%, and 28 µg/ml (5-28), respectively. Given the suspicion of exogenous insulin-mediated hypoglycemia, only correctional insulin was used during hospitalization. She had a repeat hypoglycemic episode on the 2nd day with minimal insulin use. A 72-hour fasting test showed a whole blood glucose of 44 mg/dL with concurrent serum C-peptide of 1.72 ng/mL, serum insulin 55 mIU/L and pro-insulin 21.9 pmol/L 12 hours into fasting. MRCP showed an 11 mm cystic lesion in the pancreas and widespread lymphadenopathy. The CGM noted significant fasting and post-prandial hypoglycemia. Diagnosis of insulinoma was considered unlikely due to persistent post-prandial hyperglycemia. Oral hypoglycemic panel and insulin autoantibodies were negative. The patient’s history of SLE, high-normal adiponectin, history of hyperglycemia and the presence of acanthosis nigricans favored work-up for insulin resistance syndromes. Due to the non-availability of insulin receptor antibody testing in the US, blood work was sent to Dr. Lutz Schomburg’s lab at Institute for Experimental Endocrinology, Berlin, Germany. The patient’serum was positive for insulin receptor antibodies, tested via an immunoassay technique, with elevated binding index (BI) of 248, 251 and 247 on 3 different samples of the patient, and normal binding index in the control sample, leading to the diagnosis of type B insulin resistance syndrome (BI >3 is positive, >10 indicates high positivity). The patient was treated with diet modification and CGM use, with improvement in the frequency of hypoglycemic episodes. She declined immunomodulation therapy. Conclusion: Hypoglycemia is an uncommon presentation of TBIRS and should be considered in the differential of non-diabetic hypoglycemia, particularly in patients with a history of auto-immune disease. The mechanism for hypoglycemia is purported to be an insulin-mimetic effect of insulin receptor antibodies at low titers.

Presentation: Thursday, June 15, 2023