bluuebunny/crossref_metadata_2025 huggingface dataset:
12331 Overcoming Limitations Of Identifying Proliferating β-cells In Dispersed Primary Islets Culture For Drug Discovery
Authors: Xu Haixia , Rebecca Schugar , Lee Sooyeon , Annes Justin P
Published: October 2024

Disclosure: H. Xu: None. S. Rebecca: None. S. Lee: None. J.P. Annes: None.

Tremendous efforts have been made with screening platforms to identify islet β-cell mitogens that may be used to treat diabetes. However, promising compounds induce profound proliferation of islet non-β-cells in available screening platforms, calling for both β-cell targeted drug discovery and rigorous identification of β-cell identity to reduce false positivity. First, we used an established drug discovery dispersed islet cell-based platform(2D) to test the replication-promoting activity of GNF2133, a selective DYRK1A inhibitor that promotes β-cell proliferation, in isolated islets from human, rat and mouse. After 72 h in vitro culture, replication of non-β cells (PDX/Insulin negative) contributed to over 60% of the total replicating cells (Ki67+) in all species (human: 64%, rat: 71%, mouse: 67%). Mouse islets, which exhibit the greatest non-β-cell replication response upon GNF2133 treatment (4-fold above baseline, [50 nM]), were selected for subsequent studies. Next, we evaluated identification efficiency of β cell markers in this image-based platform. β cells, selected by the quantification value of insulin intensity, comprised 60-70% of total cell population at 48 h, 50-60% at 72 h and 20-30% at 96 h (p< 0.0001 for both comparisons: 48 h vs 72 h, 72 h vs 96 h). Basal replication of β-cells (Insulin+Ki67+) was 2.80%, 2.32%, 0.85% at 48 h, 72 h and 96 h, respectively. By comparison, the proportion of non-β cells showed an increasing trend as 2.48%, 6.49%, 8.68%, correspondingly. Identification with PDX1, another β cell marker, exhibited the same findings. Prolonged culture of dispersed islet cells, as these results indicate, favors growth of non-β-cells over β-cells. In addition, proliferating β-cells express lower levels of differentiation markers makes their discernment from replicating non-β cells more challenging. 窗体顶端 To minimize the duration of monolayer culture, replication induction was measured using intact islets with addition of BrdU during the last 24 h of culture. Then, islets were either directly fixed (3D) or dispersed and cultured for an additional 36 hour before being fixed (3D+2D). Immunostaining showed 70-80% PDX1 positive cells from both methods, which resembles in vivo β cell distribution within primary mouse islets. Basal β-cell replication in 3D+2D method was 0.30%, similar to in vivo BrdU labelling level. Upon mitogen treatment, PDX1+BrdU+ cells increased to 6.57% in 3D+2D method, slightly lower than 10.02% in 3D assay (p<0.05) yet significantly higher than 1.15% in 2D assay (<0.01). In summary, we developed a 3D+2D assay that enhances β-cell survival and the β-cell replication-induction response. This platform, while offering reduced throughput, provides a robust platform for discovery of β-cell replication-promoting compounds. Further validation with human islets is needed.

Presentation: 6/2/2024
6411 Ozempic - Oh no! Acute Renal Failure Associated with Initiation of Semaglutide
Authors: Barney K , Tahir D , Pannu A , Saeed R
Published: October 2024

Disclosure: K. Barney: None. D. Tahir: None. A. Pannu: None. R. Saeed: None.

Background: Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist which has been proven to reduce weight in those with obesity and improve glycemic control in patients with type II diabetes mellitus. The effect of semaglutide on kidney function has not been well established. The phase 3b SUSTAIN trials revealed that when compared with other GLP-1 agonists, semaglutide exhibited more frequent acute kidney injuries [1-3]. The SUSTAIN 6 trial reported two instances of acute renal failure (ARF) in patients with chronic kidney disease, and one case of ARF in a patient with normal kidney function who was treated with semaglutide [3]. Despite these reports, the SUSTAIN 1-9 trials report no significant decline in kidney function associated with semaglutide [3-6]. Case: We present the case of a 58-year-old male with a past medical history of human immunodeficiency virus (HIV), type II diabetes mellitus, and hypertension who presented to the hospital with ARF after initiation of Ozempic (semaglutide) two months prior to presentation. On admission, vitals were stable and physical examination was benign. His pertinent labs were blood urea nitrogen (BUN) 55 mg/dL, creatinine 5.94 mg/dL (baseline 1.2 mg/dL), and urinalysis with 2+ protein. To determine the cause of his renal failure, urine sodium and creatinine were obtained to calculate his fractional excretion of sodium, which was found to be consistent with intrinsic renal disease. Further workup, including renal ultrasound, urine protein, urine eosinophils, complement and free light chain levels, and creatinine kinase, were unrevealing for cause of intrinsic renal injury. He was managed with intravenous fluids and his creatinine improved to 2.03 mg/dL. Given the acute onset of the patient’s renal failure and recent initiation of Ozempic, it was determined that this medication was the cause of his renal failure, and it was discontinued on discharge. He has since followed up with nephrology and endocrinology. He remains off Ozempic and is doing well. Conclusions: Our case highlights a rare but significant adverse effect of semaglutide on renal function. As the use of semaglutide has increased due to its rising popularity for weight loss and glycemic control in type II diabetes mellitus, the potential for renal injury should be considered and discussed with patients. Furthermore, it is imperative that semaglutide associated renal injury be considered as a cause for ARF in patients taking this medication. This case demonstrates that instances of ARF associated with semaglutide treatment are a cause for concern and further exploration.

Presentation: 6/1/2024
9334 Pancreatic Adenocarcinoma Presenting As Diabetic Ketoacidosis
Authors: Alvarez Julie , Horani Mohamad Hosam , Huynh Jacqueline , Huynh Jacqueline
Published: October 2024

Disclosure: J. Alvarez: None. M.H. Horani: None.

Background: Pancreatic adenocarcinoma is often diagnosed at an advanced stage due to late onset of clinical features including poor appetite, weight loss, weakness, epigastric pain, and rarely impaired glucose tolerance. In patients who present with impaired glucose tolerance or diabetic ketoacidosis without prior history of diabetes, pancreatic adenocarcinoma should be considered. Clinical Case: Patient is a 45-year woman with depression, HTN, irritable bowel syndrome who was found unresponsive by family and presented to the ED for acute encephalopathy. On exam, she was obtunded, tachypneic, with fruity-smelling breath and dry mucous membranes. Initial labs showed glucose of 950 mg/dL (70-99 mg/dL), lipase 539 U/L (8-78 U/L), lactic acid 4 mmol/L 0.5-2 mmol/L), ketone-BHB 170.75 mg/dL (0-2.81 mg/dL), A1c 16.5%. She had no prior history or family history of diabetes. She was admitted to hospital for DKA management.CXR to evaluate dyspnea showed bilateral opacities so CT chest/abdomen/pelvis without contrast was ordered. This showed bilateral multilobar pneumonia, trace pleural effusions, 6.7 x 3.8 cm lobulated fluid collection along pancreatic tail, 12.1 x 6.6 x 4.4 cm RLQ cystic lesion and 4.4 cm lesion vs loculation along the right pelvic sidewall.Initially, GI recommended repeat imaging of the pancreas in 4-6 weeks. OBGYN was consulted for pelvic masses and recommended IR-guided biopsy of right pelvic mass which showed rare mildly atypical mucinous epithelium present, cystic mucinous neoplasm cannot be excluded.CEA and CA125 tumor markers returned elevated. These biopsies showed adenocarcinoma (solid component) and rare atypical mucinous epithelium consistent with cystic mucinous neoplasm (cystic fluid). Patient was deemed medically stable for discharge with recommended follow-up to appropriate specialists. Following discharge, she was officially diagnosed with Stage III (cT4, cN0, cM0) pancreatic adenocarcinoma and started on appropriate chemotherapeutic regimen. Discussion: The current understanding is long-standing type 2 diabetes mellitus as a risk factor for pancreatic cancer based on previous studies.The inverse relationship of pancreatic cancer causing new onset diabetes is more rare, but if cancer is suspected in these patients it could potentially help in the diagnosis of early stage adenocarcinoma. Other case reports have suggested implementation of the enriching new-onset diabetes for pancreatic cancer (ENDPAC) score in addition to CT and EUS as screening for pancreatic cancer may help with earlier diagnosis. References: Menakuru, S. R., Priscu, A., Dhillon, V. S., & Salih, A. (2022). Diabetic Ketoacidosis as the Initial Presenting Symptom of Pancreatic Adenocarcinoma: A Discussion about Screening Utilizing ENDPAC Scoring Coupled with CT Scans and Endoscopic Ultrasound. Case Reports in Oncology, 15(3), 942-949. https://doi.org/10.1159/00052698

Presentation: 6/1/2024
8099 Pembrolizumab Induced Autoimmune Diabetes: An Abrupt Virulent Onset
Authors: Belal H F , Shaykh N , Rajesh A , Chehade J M
Published: October 2024

Disclosure: H.F. Belal: None. N. Shaykh: None. A. Rajesh: None. J.M. Chehade: None.

Background: Pembrolizumab is a programmed cell death protein 1 inhibitors (PD-1i) approved for the treatment of many solid cancers. Although thyroid abnormalities are among the most common endocrine adverse effects associated with PD-1i, insulin-dependent diabetes mellitus can also occur in up to 1% of patients treated with PD1-i.[1] Clinical Case: A 70-year-old female with past medical history of non-toxic multi-nodular goiter and surgical hypothyroidism was diagnosed with gastric cancer. She had no pancreatic abnormality on PET scan. Her management included four cycles of neo-adjuvant chemotherapy: fluorouracil, cisplatin, trastuzumab and pembrolizumab. She had no personal history of gestational diabetes. Prior to initiating neo-adjuvant chemotherapy her A1c was 5.9%. She was not prescribed any anti-diabetic medications. Her grandmother had type 2 diabetes mellitus. On exam her BMI was 23.73 kg/m². She had no acanthosis nigrans, skin tags or abdominal striae. Eighteen days after completing her second cycle of neo-adjuvant chemotherapy, she presented to the emergency department with nausea, vomiting, polyuria and confusion and was found to be in DKA. Her A1c during admission was 7.1%. Imaging revealed no pancreatitis. Labs showed suppressed C-peptide <0.1 ng/mL (1.1-4.4) in the setting of blood glucose 283 mg/dL (71-99). Her GAD-65 antibody was elevated at 902 U/mL (0.0-5.0). She was diagnosed with PD-1i induced autoimmune diabetes mellitus (PD-1i DM) and subsequently treated with basal and prandial insulin. Conclusion: The mechanism of PD-1i DM is unclear. A proposed mechanism is aberrant T cell activation towards pancreatic islet cells. One study found that 59% of patients with PD-1i DM presented with DKA.[1] In this study, the median time of PD-1i DM onset was 20 weeks after the first treatment cycle. Additionally, 40% of these patient had at least one positive pancreatic autoantibody. A recent meta-analysis found the relative risk of PD-1i DM to be 1.56 (95% CI = 0.95-2.57, P = 0.08).2 This relative risk increased to 2.06 (95% CI = 0.48-8.86, P = 0.33) when PD-1i were combined with cytotoxic T lymphocyte antigen-4 inhibitors. References: 1. Stamatouli AM, Quandt Z, Perdigoto AL, Clark PL, Kluger H, Weiss SA, Gettinger S, Sznol M, Young A, Rushakoff R, Lee J, Bluestone JA, Anderson M, Herold KC. Collateral Damage: Insulin-Dependent Diabetes Induced With Checkpoint Inhibitors. Diabetes. 2018 Aug;67(8):1471-1480. doi: 10.2337/dbi18-0002. Epub 2018 Jun 24. PMID: 29937434; PMCID: PMC6054443. 2. Vardarli I, Tan S, Brandenburg T, Weidemann F, Görges R, Herrmann K, Führer D. Risk and incidence of endocrine immune related adverse effects under checkpoint inhibitor mono or combination therapy in solid tumors: a meta-analysis of randomized controlled trials. J Clin Endocrinol Metab. 2023 Nov 15:dgad670. doi: 10.1210/clinem/dgad670. Epub ahead of print. PMID: 37967245.

Presentation: 6/2/2024
12380 Point Of Care Microscale Magnetic Resonance (µNMR) Effectively Monitors Mitigation Of Oxidative Stress By GLP-1 Treatment In A Preclinical Model Of Diabetic Nephropathy
Authors: Alves Andre Topa , Thamarath Smitha Surendran , Fjordside Simone , Sassower Stan , Rohr Rodolfo , Chambers Adam Paul
Published: October 2024

Disclosure: A.T. Alves: ; co-founder. ; LarmorBio. S.S. Thamarath: ; co-founder. ; LarmorBio. S. Fjordside: Employee; Self; Novo Nordisk. S. Sassower, MS.EE: ; Co-founder. ; LarmorBio. R. Rohr: ; co-founder,CEO. ; LarmorBio. A.P. Chambers: Employee; Self; Novo Nordisk.

Oxidative stress is a major driver in the pathogenesis of diabetes, obesity, and related (cardio-renal) disorders. Early detection and prevention of an oxidative stress overload can improve and potentially modify the long-term harmful outcomes associated with chronic hyperglycaemia. A novel assay was developed, that uses µNMR technology to directly monitor oxidative stress from 5 µL of plasma at the point of collection in less than 10 minutes. This assay is highly sensitive to redox changes in the blood microenvironment, including increased ferric iron (Fe3+), protein oxidation and lipid peroxidation. Here, we show the oxidative stress profiling of three groups of ZSF1 rats in a twelve week (11th -23rd week of age) observational study. Vehicle lean, vehicle obese, and glucagon-like-peptide-1 (GLP-1) treated obese ZSF1 rats (n = 8/group) were studied with the assay along with conventional diabetic/metabolic markers, blood glucose (BG), HbA1c, Albumin Creatinine Ratio (ACR). The kidney (immuno)histology studies, alpha-smooth muscle actin (aSMA) and leucocyte common antigen (CD45) were performed at the termination phase of the ZSF1 rats (23rd week of age). The results demonstrated that the assay distinguished obese rats from lean rats with statistical significance (P ≤ 0.01) independent of other in-life diabetic/metabolic markers. Significant correlations with urinary Albumin Creatinine Ratio (ACR, ρ = 0.64, P ≤ 0.0001) were established throughout the study. A positive quantitative association is highlighted with classic histological end points of organ damage, kidney fibrogenesis (aSMA, ρ = 0.23), and inflammation (CD45, ρ = 0.45). Moreover, the assay detected significantly reduced oxidative stress levels (e.g., P ≤ 0.01) in the GLP-1 drug treatment group at five weeks of follow-up. In summary, the µNMR assay effectively monitored oxidative stress and captured disease-modifying therapeutics.

Presentation: 6/1/2024
8071 Prevention Of Acute Kidney Injury By Reducing Mitochondrial Dysfunction In Diabetic Mice
Authors: Kim Min-Ji , Oh Chang Joo , Khang Ah Reum , Jeon Jae-Han , Lee In-Kyu
Published: October 2024

Disclosure: M. Kim: None. C. Oh: None. A. Khang: None. J. Jeon: None. I. Lee: None.

Background: Acute Kidney Injury (AKI) significantly contributes to the pathogenesis of diabetic kidney disease, often exacerbating chronic kidney disease (CKD) and accelerating the need for dialysis. Mitochondrial dysfunction, induced by an increase in reactive Oxygen Species (ROS) and inflammation, plays a crucial role in AKI. This study investigates the prevention of AKI by reducing mitochondrial dysfunction through pyruvate dehydrogenase kinase (PDK) inhibition in an ischemia-reperfusion (IR)-induced AKI model using streptozotocin (STZ)-induced diabetic mice. Methods: We utilized an IR-induced AKI model in STZ-induced diabetic C57BL6/J mice, subjecting them to IR by clamping both renal pedicles. Mitochondrial function tests, cellular apoptosis, and inflammatory markers were evaluated in NRK-52E cells and mouse primary tubular cells after hypoxia and reoxygenation using a hypoxia workstation. Results: In diabetic mice experiencing AKI following IR injury, there was a significant increase in pyruvate dehydrogenase E1α (PDHE1α) phosphorylation. This correlated with a notable increase in mitochondrial damage - TEM images of mice with IR-induced kidney injury revealed distension, loss of cristae, and fragmentation of the mitochondria. We also observed a decrease in oxygen consumption rate (OCR) accompanied by increased ROS, as well as increased production of inflammatory markers. Remarkably, the pan-PDK inhibitor, sodium dichloroacetate (DCA), mitigated apoptosis, attributable to the reduction of PDHE1α phosphorylation levels as well as normalized mitochondrial morphology and function. DCA treatment lessened oxidative stress and decreased the production of inflammatory markers following IR-induced AKI or hypoxia-reoxygenation injury. Conclusion: Restoration of mitochondrial function by DCA effectively alleviated renal injury by decreasing ROS production and inflammation, highlighting its critical role in IR-mediated damage. These results suggest another potential target for renal protection during AKI; therefore, the prevention of acute kidney injury through the inhibition of PDK could be a promising therapeutic approach for treating Diabetic Kidney Disease (DKD).

Presentation: 6/1/2024
7442 Racial Disparities On Outcomes Of Hypoglycemia
Authors: Neupane Shila , Neupane Binita , Karki Sunita , Farooq Umer , Quartuccio Michael
Published: October 2024

Disclosure: S. Neupane: None. B. Neupane: None. S. Karki: None. U. Farooq: None. M. Quartuccio: None.

Introduction: Numerous studies have been conducted on the differences in racial and ethnic groups' access to healthcare; some groups face greater challenges when it comes to insurance coverage and other healthcare services compared to others. Risk factors that may contribute to hypoglycemia include advanced age, concomitant conditions, aggressive hyperglycemia therapy, etc. Research on racial differences in hypoglycemia is limited. Objective:To investigate potential disparities in mortality rates, length of stay (LOS), and overall hospitalization costs between the white and black populations with the diagnosis of hypoglycemia. Methods: Using the National Inpatient Sample (NIS) for the years 2017 through 2020, we carried out a retrospective cohort study of adult patients (age >18) with a primary diagnosis of hypoglycemia. The disease and outcome codes were chosen using the International Classification of Diseases (ICD-10). The analysis was conducted using STATA. Adjusting for potential variables and calculating the adjusted odds ratio(aOR) were done using multivariate regression analysis. The student t-test was utilized to compare continuous variables, while the Fisher exact test was employed to compare proportions. Mortality was the primary outcome of the study; other secondary outcomes included LOS, total hospitalization costs, acute coronary syndrome (ACS), septic shock, pulmonary edema, acute respiratory failure (ARF), mechanical ventilation, acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), and cerebrovascular accidents (CVA). Results: There was a total of 804,164 patients with the diagnosis of hypoglycemia; out of them, 515,264 were white, 200,955 were black, and the rest were from other races besides white and black. Blacks had increased LOS than whites by 0.53 days, (6.92 days vs. 7.87 days, p<0.001) and rates of mechanical ventilation (11.96% vs.10.05%, p<0.001). There were other significant outcomes in rates of acute coronary syndrome (1.59% vs.1.38%, p<0.001), septic shock (10.07% vs. 9.90%, p=0.028), and ARF (16.10% vs. 15.27%, p<0.001) on white compared to black population. There was no significant difference in the outcomes of mortality rates, total hospitalization costs, pulmonary edema, ARDS, AKI, and CVA in white compared to black population. Conclusion: In comparison to the black population, the white population had an increase in rates of ACS, septic shock, and ARF. The overall rate of LOS and mechanical ventilation was higher in the black population than in the white population. The rates of mortality, total hospital costs, pulmonary edema, ARDS, AKI, and CVA did not differ between the two groups. To prevent poorer outcomes, more research is needed to understand the pathophysiology and underlying reasons for racial differences in hypoglycemia.

Presentation: 6/1/2024
6700 Risk Of Dementia According To The Reproductive Factors In Postmenopausal Women With Diabetes
Authors: Yu Jin , Han Kyungdo , Yun Jae-Seung , Lee Seung-Hwan
Published: October 2024

Disclosure: J. Yu: None. K. Han: None. J. Yun: None. S. Lee: None.

Risk of dementia according to the reproductive factors in postmenopausal women with diabetes Jin Yu[1], Kyungdo Han[2], Jae-Seung Yun[3], Seung-Hwan Lee[1],[4] [1]Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea[2]Department of Statistics and Actuarial Science, Soongsil University[3]Division of Endocrinology and Metabolism, Department of Internal Medicine, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea[4]Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea Background: Previous studies have suggested a possible association between endogenous estrogen exposure and decreased risk of cognitive impairment or dementia. We aimed to investigate the impact of reproductive factors on the risk of dementia in women with diabetes. Methods:166,245 postmenopausal women with type 2 diabetes aged over 40 who underwent health examination in 2009 were identified from the National Health Information Database. Information regarding reproductive factors were collected through self-administered questionnaires. Incident dementia was defined using diagnosis codes and anti-dementia drug prescription. Cox proportional hazards regression analyses were performed to evaluate the risk of all-cause dementia, Alzheimer’s disease, and vascular dementia according to reproductive factors including age at menarche, age at menopause, reproductive lifespan, parity, and use of hormone replacement therapy (HRT). Results: The mean age and reproductive lifespan were 64.5 ± 8.0 and 33.4 ± 4.7 years, respectively. During the median follow-up of 8.3 years, 25,330 cases of any dementia, including 20,817 cases of Alzheimer's disease and 2,756 cases of vascular dementia were developed. The hazard ratios (95% CI) of all-cause dementia were 1.28 (1.06-1.56) for age at menarche >16 years compared with ≤12 years, 0.71 (0.66-0.77) for age at menopause ≥55 years compared with <40 years, and 0.72 (0.68-0.76) for reproductive lifespan ≥40 years compared with <30 years, respectively. The risk of all-cause dementia was decreased by 11% in women with parity ≥2 compared with 0, and by 16% in women with HRT for more than 5 years compared without HRT. Similar findings were observed for Alzheimer’s disease and vascular dementia. Conclusion: Longer reproductive lifespan was associated with lower risk of dementia in postmenopausal women with diabetes.

Presentation: 6/2/2024
12591 Screening For Metabolic Dysfunction-Associated Steatotic Liver Disease In Diabetes Clinics
Authors: D’Annibale D , Mimoto M , Lis R , Deioma A , Patton H
Published: October 2024

Disclosure: D. D'Annibale: None. M. Mimoto: None. R. Lis: None. A. Deioma: None. H. Patton: None.

Screening for Metabolic Dysfunction-Associated Steatotic Liver Disease in Diabetes Clinics Background: The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) in patients with Type 1 (T1D) or Type 2 diabetes (T2D) is elevated, ranging from 22% in T1D to >55% in T2D. However, MASLD screening is not standard in diabetes clinics. The Fibrosis-4 (FIB-4) score and transient elastography (TE) are non-invasive tools to identify those at risk for MASLD and liver fibrosis. To identify at-risk individuals and determine the prevalence of undiagnosed MASLD in our Veterans with diabetes and elevated BMI, we developed a screening protocol using FIB-4 and TE. Methods: Veterans with T1D or T2D and elevated BMI seen in diabetes clinic were prospectively screened. Patients with prior TE or liver disease were excluded. In phase 1, patients were offered in-clinic TE during their visit. In phase 2, a FIB-4 determined referral to TE or hepatology. Results: 274 patients were screened over 8 months. Of 102 qualifying patients in phase 1, 28 had in-clinic TE; of these, 7 (25%) had a kPa of 8 or greater, indicating increased risk of fibrosis, and 16 (57.1%) had a CAP score >280, indicating severe steatosis.In phase 2, a FIB-4 was ordered in 157 qualifying patients. Of 110 completed tests, the FIB-4 was <1.3 (low risk), 1.3–2.6 (indeterminate risk) and >2.6 (high risk) in 61 (55.5%), 44 (40%) and 5 (4.5%), respectively. Patients were referred to TE (indeterminate) or hepatology (high risk). To date, 21 patients have undergone TE, 5 (23.8%) had a kPa of 8 or greater and 11 (52.4%) had a CAP score >280. Conclusions In Veterans with T1D or T2D and elevated BMI, both of our screening protocols identified those with severe steatosis (57.1% vs 52.4%) by TE at rates similar to those reported in the literature. Increased risk of fibrosis by TE was identified in ∼24-25% of our screened population. The high prevalence of undiagnosed MASLD in our Veteran population supports the need for screening in diabetes clinics. Increased provider awareness and point-of-care TE may increase access to screening and improve early diagnosis.

Presentation: 6/2/2024
8462 Synergistic Outcomes Of hCG And GLP1-RA Combination Therapy: Improved Body Composition And Carbohydrate Metabolism
Authors: Comite Florence , O’Malley Kaleigh
Published: October 2024

Disclosure: F. Comite: None. K. O'Malley: None.

Objective: Precision medicine prevents and reverses diseases of aging by way of systematic analysis of body composition and extensive blood biomarkers. Andropause, the age-related reduction of free testosterone (FT) in males, elicits symptoms primarily of muscle loss, decreased libido, and diminished energy. Exogenous testosterone therapy (TTx) subsequently increases lean body mass (LBM) and improves both libido and energy levels in affected males. More recently, stimulation of endogenous testosterone from the testes, human Chorionic Gonadotropin (hCG) has emerged as a compelling physiologic alternative to TTx. Common comorbidities to andropause are DMII and/or obesity. Recent literature surrounds the use of GLP-1 receptor agonists to improve insulin sensitivity in these disorders of carbohydrate metabolism. A primary benefit secondary to GLP-1 use is reduction of fat mass; however, concerns of this monotherapy surround loss of muscle.[1] Remarkably, when treated adjunctly with GLP-1s, hCG therapy significantly mitigates muscle loss while maintaining optimal carbohydrate biomarkers. The efficacy and benefits of hormonal optimization through hCG therapy simultaneous to GLP-1 intervention were investigated. Methods: In this retrospective analysis, a cohort of 20 males ≥30 years of age were reviewed at baseline timepoints and 18 months post treatment-initiation. Participants underwent biweekly hCG and weekly GLP-1 subcutaneous injections. Exclusion criteria restricted use of alternative GLP-1/GIP combination medication. Paired T-Tests were used to determine a relationship between LBM, FT, percent body fat (PBF), fasting glucose (FG), fasting insulin (FI), and HbA1c at each timepoint. Results: Body composition analysis as shown via bioelectrical impedance proved baseline PBF (mean=24.60) significantly reduced post-treatment (p<0.05, mean=18.08) for all participants. In addition, relevant carbohydrate metabolic biomarkers FG, FI, and HbA1c provided significant reductions (p<0.05). Initial FT (mean=67.76) and LBM (mean=150.36) increased significantly at follow-up (p<0.05) with values of 167.55 and 154.91, respectively. Discussion: Using metrics of precision medicine, our interpretation reveals a promising combination therapy for males experiencing andropause. The novel use of hCG to optimize FT levels enhances muscle, while simultaneously, fat loss and reversal of harmful carbohydrate metabolic markers resultant from GLP-1 therapy are achieved. Muscle loss due to overall weight loss is thus ameliorated. Our findings merit further investigation of the magnitude of downstream improvements, particularly in energy and libido. References: John P.H. Wilding, e. a. (2021). Once-Weekly Semaglutide in Adults with Overweight or Obesity. The New England Journal of Medicine.

Presentation: 6/3/2024
8439 Targeting Interferon Gamma-Mediated CXCL16-CXCR6 Chemokine-Receptor Interactions As A Strategy To Prevent Immune Checkpoint Inhibitor Autoimmune Diabetes
Authors: Wang S , Huang N , Ortega J G , Lee J , Kimbrell K , Nguyen J , Olay J , McCarthy E , Peluso E , Chen H C , Lechner M G
Published: October 2024

Disclosure: S. Wang: None. N. Huang: None. J.G. Ortega: None. J. Lee: None. K. Kimbrell: None. J. Nguyen: None. J. Olay: None. E. McCarthy: None. E. Peluso: None. H. Chen: None. M.G. Lechner: None.

Autoimmune diabetes mellitus is a rare but life-threatening side effect of immune checkpoint inhibitor (ICI) cancer therapy. Checkpoint inhibitors increase immune activation by blocking regulatory molecules on T cells, including programmed death protein (PD1). As a result of this heightened immune activation, patients can develop autoimmunity in healthy tissues, known as immune related adverse events (IRAEs). ICI-associated diabetes mellitus (ICI-T1DM) is an IRAE that results in autoimmune destruction of insulin-producing pancreatic beta-cells. Patients with ICI-T1DM require life-long insulin therapy and more than half present initially with diabetic ketoacidosis. Unfortunately, the mechanism of this IRAE is not fully understood. Anti-PD1 antibody treatment (10mg/kg/dose, twice weekly, i.p.) of male and female non-obese diabetic (NOD) mice leads to autoimmune infiltrates in multiple tissues, including accelerated insulitis and DM. Single cell RNA sequencing of islet infiltrating immune cells from ICI-treated mice previously showed a role for CD8+ T cells and cytokine interferon gamma (IFNγ) in the development of ICI-T1DM. Using CellChat to perform receptor-ligand interaction analysis of these data, we identified both CD8+ and CD4+ T cells as the primary source of IFNγ in immune infiltrates and islet myeloid cells as the primary target. Furthermore, CellChat analysis showed increased receptor-ligand interactions between T cell receptor CXCR6 and its chemokine CXCL16, as well as CXCR3 and chemokines CXCL9 and CXCL10. In vitro IFNγ stimulation of myeloid cells induced strong expression of CXCL16, 9, and 10, suggesting a potential mechanism by which effector T cells are recruited to islets during ICI therapy. Immunophenotyping of islet-infiltrating immune cells indeed showed increased IFNγ+CXCR6+ effector CD8+ cells in anti-PD1 treated mice compared to isotype-treated controls. Moreover, these IFNγ+CXCR6+CD8+ T cells stained positively for the NRP-V7 mimotope tetramer, a known antigen for CD8+ T cells in spontaneous autoimmune diabetes in NOD mice, suggesting this as an antigen-specific population contributing to the immunopathogenesis of ICI-T1DM. Finally, genetic deletion of CXCR6 in NOD mice delayed the onset of autoimmune diabetes during anti-PD1 treatment in female (p=0.0162) but not male mice (p=0.3656). In summary, these data further elucidate the cellular mechanisms by which IFNγ and chemokine signaling pathways drive the development of ICI-T1DM and identify the CXCR6-CXCL16 axis as a potential therapeutic target to prevent this IRAE in checkpoint inhibitor-treated cancer patients.

Presentation: 6/2/2024
6905 The Necessity For New Criteria To Evaluate Overbasalization In East Asian Patients With Type 2 Diabetes Using Basal Insulin
Authors: Jang Han Na
Published: October 2024

Disclosure: H. Jang: None.

Background: Overbasalization, which refers to adjusting the dose of basal insulin beyond an appropriate dose, should be avoided when using basal insulin in patients with type 2 diabetes. It is recommended to evaluate overbasalization when the basal insulin dose exceeds 0.5 units/kg/day or when post-meal glucose levels are > 180 mg/dL. However, this is an expert opinion, and specific criteria for East Asians have not been presented. Methods: Patients with type 2 diabetes using basal insulin (insulin glargine U-100, insulin glargine U-300, insulin degludec, NPH) at Seoul National University Bundang hospital from December 2020 to November 2023, with fasting plasma glucose (FPG) levels between 80 mg/dL and 130 mg/dL, were retrospectively analyzed. Patients with CKD ≤ grade 3b (estimated glomerular filtration rate < 45 mL/min/1.73m2), those taking medications such as steroids that may affect blood glucose levels, and patients undergoing cancer treatment were excluded. Results: A total of 548 patients were analyzed. The mean age of the subjects was 64.7 ± 12.4 years, with 299 (54.6%) being male, and the mean body mass index was 25.1 ± 6.6 kg/m2. The mean duration of diabetes was 18.1 ± 9.6 years. The mean HbA1c level was 7.7 ± 1.1%, while the mean fasting plasma glucose and median fasting C-peptide levels were 105.4 ± 13.9 mg/dL and 1.4 [0.8, 2.1] ng/mL, respectively. Insulin degludec being the most commonly administered (279 [50.9%]). The mean 2-hr postprandial glucose was 206.3 ± 64.8 mg/dL, with 350 (63.9%) having 2-hr postprandial glucose > 180 mg/dL. The administered insulin dose was 0.35 ± 0.17 units/kg/day, and 101 (18.4%) had an insulin dose > 0.5 units/kg/day. Conclusion: In East Asian patients with type 2 diabetes receiving basal insulin, although high 2-hr postprandial glucose levels suggest the possibility of overbasalization, the administered dosage of basal insulin was relatively low. Considering the lower insulin secretion capacity in East Asians, it is thought that new, specific criteria for overbasalization in East Asians are necessary.

Presentation: 6/3/2024
7064 The Newest LLMs: Can They Help Patients With Diabetic Macular Edema?
Authors: Wu Gloria , Cheng Emily , Rosen Kyler , Zhao Weichen , Wong Adrial , Toram Viki V
Published: October 2024

Disclosure: G. Wu: None. E. Cheng: None. K. Rosen: None. W. Zhao: None. A. Wong: None. V.V. Toram: None.

Background: Cohere and Claude, the newest LLMs, use retrieval augmented generation (RAG) architecture versus ChatGPT and Bard, which use Transformer architecture and can supplement knowledge gaps from the internet. RAG supplements knowledge gaps with vector databases to answer user prompts. Diabetic macular edema is a common visual complication of diabetes. According to the CDC, 38.4 million people have diabetes, and approximately 750,000 Americans have diabetic macular edema and may have vision loss. Due to their prevalence, AI could be applied to address these conditions. Purpose: To evaluate four different LLMs to see which one provides the most accurate information for diabetic macular edema treatment. Methods: We queried Cohere (Coral) + Claude and ChatGPT + Bard. 1) I have diabetic macular edema and I am 40 y/o white male, with 15 years of diabetes and I cannot pass the driving test in California. What will it cost me per year for treatment? I have no health insurance. 2) I am 40 years old, white male, and have had diabetes for 15 years. I was told that I cannot pass the driving test in California. How much will I pay for one year of treatment? I have no health insurance. We use a custom scoring system that has the following metrics. We then take a weighted average: Readability: 20% Accuracy: 40% Helpfulness: 30% Specificity: 10% Results: Cohere Coral: Q1=Read 16/20 | Acc 36/40 | Help 28/30 | Spec 9/10 | Total 89/100 | Q2=Read 14/20 | Acc 34/40 | Help 26/30 | Spec 8/10 | Total 82/100 Claude: Q1=Read 18/20 | Acc 32/40 | Help 26/30 | Spec 7/10 | Total 83/100| Q2= Read 18/20 | Acc 30/40 | Help 25/30 | Spec 6/10 | Total 79/100 ChatGPT: Q1=Read 18/20 | Acc 28/40 | Help 25/30 | Spec 6/10 | Total 77/100| Q2= Readability 18/20 | Acc 28/40 | Help 24/30 | Spec 6/10 | Total 76/100 Bard: Q1=Total 80/100| Q2=Read 16/20 | Acc 30/40 | Help 27/30 | Spec 7/10 | Total 80/100 Cohere Coral consistently provided the most detailed and accurate information, leading with average scores of 85.5/100. Claude, ChatGPT, and Bard followed with scores of 81, 76.5, and 80, respectively. Conclusions: In our small study, RAG-based LLMs can provide accurate and instantaneous health education. Physicians should follow the new, evolving LLMs as it may affect patient education.

Presentation: 6/1/2024
7796 The Profile And Associated Risk Factors Of Diabetic Foot Disease Among Patients With Type 2 Diabetes Mellitus Seen At Outpatient Clinics In A Tertiary Private Hospital In Quezon City, Philippines
Authors: Lopez D C , Lim K T , S. B C , Dampil O C
Published: October 2024

Disclosure: D.C. Lopez: None. K.T. Lim: None. B.C. S.: None. O.C. Dampil: None.

The Profile and Associated Risk Factors of Diabetic Foot Disease Among Patients with Type 2 Diabetes Mellitus Seen at Outpatient Clinics in a Tertiary Private Hospital in Manila, Philippines. Background: Diabetic foot disease is a debilitating complication of diabetes mellitus and is a major source of morbidity, mortality, and reduced quality of life. Determining the risk factors of diabetic foot ulcer is important to prevent the devastating consequences among patients with diabetes. This study aims to determine the profile and associated risk factors of diabetic foot disease among patients diagnosed with type 2 diabetes mellitus being seen in private specialty clinics. Methodology: A single center, analytical cross-sectional study was conducted among patients with type 2 diabetes mellitus at outpatient clinics in a tertiary private hospital in the Philippines. Clinical information and laboratory results were obtained during the time of consult; and patients were classified as either low risk, moderate risk, high risk for diabetic foot disease or in active foot disease. Interaction between various risk factors was explored by multivariate analysis. Results: A total of 129 adult patients with diabetes mellitus were evaluated using the Diabetes Foot Screening and Risk Stratification Tool from January to May 2021. The demographic and clinical profile of the study showed that proportion of patients with neuropathy (χ2=60.66, p=0.001), long duration of diabetes (F=5.92, p=0.004), and low estimated glomerular filtration rate (eGFR) (F=3.70, p=0.023) was significantly higher in patients with moderate to high risk for diabetic foot disease. Univariate polynomial logistic regression analyses showed that neuropathy greatly increased the odds of having moderate (OR=115.63, p=0.001) and high risk stratification (OR=166.50, p=0.001). Other factors were also noted to affect the risk stratification for diabetic foot disease such as duration of diabetes (OR=1.09, p=0.004) and hypertension (OR=2.45, p=0.027). On the other hand, normal eGFR (OR=–1.02, p=0.011), left normal ankle brachial pressure index (OR=–4.32, p=0.042), and good glycemic control (OR=–5.41, p=0.050) significantly decrease the likelihood of having high risk stratification for diabetic patients. Conclusion: Those most susceptible to developing high risk for diabetic foot disease were patients with neuropathy, hypertension, and long duration of diabetes. High-risk patients with the given profile should be followed closely in order to prevent complications brought by diabetes. Keywords:Diabetes mellitus, Diabetic foot disease, Foot ulcer

Presentation: 6/3/2024
8343 The Role Of Pancreatic Nerve Activity On The Development Of Beta Cell Dysfunction With The Macrophage-Beta Cell Interaction
Authors: Yu J , Wang Y , Sha L
Published: October 2024

Disclosure: J. Yu: None. Y. Wang: None. L. Sha: None.

Islet inflammation is a vital factor to the beta cell dysfunction which is driven by inflammatory cytokines TNF-α and IL-1β released by resident macrophages. Pancreatic nerve innervates islet function and our previous study suggested that pancreatic nerve activity might involved in the development of pancreatic beta cell dysfunction. However, it is not known whether pancreatic nerve activity modulates macrophage activity and contributes to the macrophage - beta cell interaction. The aim of our study was to investigate the role of nerve activity on it and the possible mechanism. Methods: Sprague Dawley Rats and high fat diet-induced obese rates were used. An intrapancreatic nerve truck with its intact innervated pancreatic islets were used for the study. The nerve activity was evoked with electric nerve stimulation and insulin and ATP released by beta cells, TNF-α released by macrophages, and IL-1β released mainly by macrophages were measured with nerve activation. Results: Insulin secretion was induced significantly with the nerve activation (8 Hz). With nerve activation, ATP level was significantly increased by 25.5 ± 11.7%. The increased releases of insulin and ATP were abolished with cholinergic M receptor blocker atropine. With nerve activation, TNF-α and IL-1β levels were increased by 25.3±7.6% and 51.8±11.7%, respectively (p<0.05). Interestingly, the increases of TNF-α and IL-1β with nerve activation were also blocked by atropine. Since it is known that acetylcholine does not induce pro-inflammatory cytokine release in macrophages, we suspected that the nerve activity induced TNF-α and IL-1β releases were indirect. ATP is likely a candidate for the indirect effect as receptors. With applying Suramin, a ATP receptor blocker, nerve activation increased TNF-α release was inhibited significantly and IL-1β release was trended to inhibited. atropine, an M receptor blocker, compared with the Control group, decreased by 88.0±3.7% and 63.1±19.6%, respectively (p< 0.01). In obese rats, nerve activation increased TNF-α and IL-1β content by 68.1 ± 22.6% and 39.7 ± 7.4%, respectively, and suramin significantly inhibited the nerve activation induced increase of TNF-α release and trended to inhibit IL-1β release. Conclusion: Our results suggested that the pancreatic nerve activity contribute to the macrophage-beta cell interaction in the development of beta cells dysfunction by enhancing ATP release from islet beta cells.

Presentation: 6/3/2024
8668 Total And Trunk Body Fat Are Associated With Chronic Kidney Disease Progression In Type 2 Diabetes Patients: A Prospective Study
Authors: Zelmanovitz T , Weber D , Pavinatto C , Bello G , de Souza M R , Junior R B , Azevedo M , Dama B L , Silveiro S
Published: October 2024

Disclosure: T. Zelmanovitz: None. D. Weber: None. C. Pavinatto: None. G. Bello: None. M.R. de Souza: None. R.B. Junior: None. M. Azevedo: None. B.L. Dama: None. S. Silveiro: None.

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease and obesity is considered an independent risk factor for the development and progression of this complication. However, BMI alone, the most commonly used measure to assess adiposity, may not be enough to identification of high risk patients. The ideal markers of adiposity in these patients still need to be better determined. The aim of this study was to evaluate the association between the progression of DKD in type 2 diabetes patients and the following body adiposity markers: BMI, waist circumference (WC) and estimated total and trunk body fat. Research design and methods: In this prospective cohort study, at baseline, type 2 diabetes outpatients were submitted to percentage body fat (PBF) evaluation estimated by bioelectrical impedance (BIA; InBody 230, Biospace, Korea) as well as Dual Energy X-Ray Absorptiometry (DXA; Lunar - iDXA), as a reference standard. Clinical evaluation consisted of glycemic and lipid profile, blood pressure control and the search for diabetic chronic complications. Urinary albumin was measured twice and estimated glomerular filtration rate (eGFR) was estimated by using the CKD-EPI equation. The progression of DKD was defined by the presence of at least one of the following: worsening of albuminuria, a decline of eGFR ≥ 5 ml/min/1.73m2 per year, a decline in eGFR of ≥ 40% from baseline or kidney failure defined by sustained eGFR < 15 ml/min/1.73m2. Results: A total of 201 patients with type 2 diabetes (aged 63 ± 9 years; 42% male), were followed during 6 years. In a multivariate Cox regression analysis, the PBF was associated with progression of DKD (HR=1.04, 95% CI: 1.008 - 1.08; P= 0.015), adjusted for age, gender, using ACE inhibitors or angiotensin receptor blockers, and systolic blood pressure values. In a different model, percentage of trunk fat was also associated with progression of DKD (HR=1.05, 95% CI: 1.02 - 1.09; P= 0.003), adjusted for the same covariates. No association was observed with BMI and WC. Conclusion: In patients with type 2 diabetes, percentage total and trunk body fat, as markers of body adiposity, seem to be associated with progression of DKD. Confirming these findings with further studies, it could provide one more tool in the evaluation and management of a modifiable risk factor of this complication.

Presentation: 6/1/2024
8158 Transient Blindness In Metformin-Associated Lactic Acidosis
Authors: Abouelkheer Y , Nasir A , Ibrahem M
Published: October 2024

Disclosure: Y. Abouelkheer: None. A. Nasir: None. M. Ibrahem: None.

Transient Blindness in Metformin-associated Lactic Acidosis Background: Metformin-associated lactic acidosis (MALA) is a rare side effect of metformin use. MALA can result in acute transient blindness in patients with severe metabolic derangements. Clinical Case: A 62-year-old woman presented with severe diarrhea, poor oral intake, malaise, and vomiting on a background of metformin-treated type 2 diabetes mellitus. Laboratory investigations showed bicarbonate <2 mmol/L, anion gap 48 mmol/L, lactic acid 20.5 mmol/L, serum osmolality 352 mOsm/kg, negative urine toxicology screen, and positive SARS-CoV-2. In the emergency department, the patient developed sudden onset bilateral vision loss. The examination was remarkable for complete vision loss bilaterally in all fields, associated with minimally reactive pupils and spontaneous ocular movements with an otherwise unrevealing neurological examination. Computed Tomography (CT) of the brain with stroke protocol showed no evidence of acute intracranial process. CT angiogram of the brain and neck showed patent intracranial and cervical vasculature without high-grade stenosis, large vessel occlusion, or aneurysm. While receiving medical management with intravenous fluid resuscitation and sodium bicarbonate supplementation, the patient had a spontaneous return of vision with no additional neurological complications or deficits. The severe metabolic derangements were associated with distributive shock, requiring admission to the intensive care unit for urgent hemodialysis, pressor support, empiric antibiotics, and stress-dose steroids. Shortly after the patient’s only hemodialysis session, we noted the resolution of her critical metabolic disturbances, renal failure, and shock state. Laboratory investigations post-dialysis showed bicarbonate 12 mmol/L, anion gap 36 mmol/L, and lactic acid 10.5 mmol/L. Follow-up MRI showed chronic lacunar infarct of the left basal ganglia, and she was discharged home six days later. Conclusion: Transient blindness in MALA can mimic acute neurovascular events. Prompt correction of metabolic derangements can aid in reversing systemic symptoms and blindness. Reference: DeFronzo R, Fleming GA, Chen K, Bicsak TA. Metformin-associated lactic acidosis: Current perspectives on causes and risk. Metabolism. 2016;65(2):20-29. doi:10.1016/j.metabol.2015.10.014

Presentation: 6/2/2024