bluuebunny/crossref_metadata_2025_split huggingface dataset:
6617 A Case of Doege-Potter Syndrome With Normal IGF-II
Authors: Yip A T , Donangelo I 
Published: October 2024

Abstract
Disclosure: A.T. Yip: None. I. Donangelo: None.
Background: Doege-Potter syndrome is a rare presentation of non-islet cell tumor hypoglycemia that results from ectopic secretion of IGF-II prohormone from a solitary fibrous tumor (SFT). Case: A 57-year-old woman came to medical attention after a syncopal episode requiring hospitalization for severe hypoglycemia. She had an unremarkable brain MRI but chest CT showed a 18cm pleural based mass in the right thorax with biopsy consistent with SFT. The patient left the hospital against medical advice but had recurring events of severe hypoglycemia occurring overnight. She had resorted to taking glucose tabs nightly and had her spouse routinely wake her up at 2AM to take more glucose tabs. She required direct hospital re-admission for refractory hypoglycemia and expedited investigation and surgical intervention. Blood work revealed serum glucose 31 mg/dL (65-99 mg/dL), C-peptide &lt;0.5 ng/mL (1.1-4.3 ng/mL), insulin&lt;1 uU/mL (3-25 uU/mL), beta-hydroxybutarate &lt;1.0 mg/dL (≤3.0 mg/dL), negative serum and urine sulfonylurea screen, negative insulin antibody, IGF-II 130 ng/mL (180-580 ng/mL), and IGF-I 31 ng/mL(50-317 ng/mL) which confirmed suspicion for a non-insulin mediated process although her IGF-II levels were not elevated with a IGF-II to IGF-I ratio of 4. She was placed on a continuous dextrose infusion with the rate titrated to target euglycemia. She underwent right pleural mass resection and post-operatively was liberated from the dextrose infusion without subsequent episodes of hypoglycemia. Pathology sections demonstrated a well-circumscribed tumor composed of bland spindle cells arranged in a pattern-less architecture. The tumor cells stained positively for CD34 (cytoplasmic) and STAT6 (nuclear) which were consistent with SFT. During her 3-month post-op follow up she denied any further episodes of hypoglycemia. Her follow up labs showed serum glucose 81 mg/dL (65-99 mg/dL), C-peptide 1.3 ng/mL (1.1-4.3 ng/mL), insulin 3 uU/mL (3-25 uU/mL), IGF-II 467 ng/mL (180-580 ng/mL), and IGF-I 128 ng/mL (50-317 ng/mL). Oncology recommended routine surveillance with PET CT scans. Clinical Lessons: Although rare, Doege-Potter syndrome should be on the differential diagnosis for non-insulin mediated hypoglycemia. Despite being an IGF-II mediated process, SFTs most commonly produce a high molecular weight “big” IGF-II molecule that is usually not detected by commercial laboratory assays thus leading to non-elevated levels of IGF-II, normal IGF-II:IGF-I ratios, and potential a delay in diagnosis of cases where a tumor has yet to be identified. Additionally, when IGF-II tumor immunostaining is unavailable, STAT6 serves as a highly sensitive and specific marker for SFT. This tumor generally does not have malignant potential and the associated hypoglycemia typically resolves after surgical resection of the SFT.
Presentation: 6/1/2024
8299 A Case of Hypoglycemia in a Patient with Cirrhosis and Previous Bariatric Surgery
Authors: Risbud A , Bao G , Kirkeby K M 
Published: October 2024

Abstract
Disclosure: A. Risbud: None. G. Bao: None. K.M. Kirkeby: None.
Background: Hypoglycemia is a known complication of both chronic liver and kidney disease as well as gastric bypass surgery. It can be challenging to treat in the setting of multiple medical conditions without definitive treatment, such as organ transplantation. Clinical case: A 47-year-old woman presented with symptomatic hypoglycemia. Her past medical history included obesity, for which she had undergone Roux-en-Y gastric bypass surgery 9 years prior; alcohol and metabolic dysfunction-associated cirrhosis complicated by hepatic encephalopathy and ascites, for which she was actively listed for liver transplantation; and stage 3 chronic kidney disease. Continuous glucose monitoring elucidated that hypoglycemic episodes (as low as 30 mg/dl) often followed periods of significant postprandial hyperglycemia (up to 300 mg/dl) without the use of exogenous insulin or insulin secretagogues. Hypoglycemia persisted despite smaller, more frequent meals with more complex and fewer simple carbohydrates, but was better managed with subcutaneous octreotide injections before meals for the next 11 months. Hypoglycemia eventually resolved after she underwent liver transplantation approximately 16 months after her initial presentation. Conclusion: Postprandial hyperinsulinemic hypoglycemia has been reported following gastric bypass surgery, sometimes occurring years after surgery. While nutrition intervention and somatostatin analogs such as octreotide may be helpful, hypoglycemia may be worsened by concurrent liver and/or kidney disease, wherein gluconeogenesis is impaired. Liver transplantation may be an effective strategy. References: Mala, T. (2014). Postprandial hyperinsulinemic hypoglycemia after gastric bypass surgical treatment. Surgery for Obesity and Related Diseases, 10(6), 1220-1225.Pfortmueller, C.A., Wiemann, C., Funk, G.C., Leichtle, A.B., Fiedler, G.M., Exadaktylos, A.K., & Lindner, G. (2014). Hypoglycemia is associated with increased mortality in patients with acute decompensated liver cirrhosis. Journal of critical care, 29(2), 316-e7.Singh, E., & Vella, A. (2012). Hypoglycemia after gastric bypass surgery. Diabetes Spectrum, 25(4), 217-221.
Presentation: 6/3/2024
7449 A Genome-wide CRISPR Screen Identifies Drivers of Impaired Glucose Uptake in Human Insulin Resistance
Authors: Haider N , Lee Y C , Yi P , Kahn C R 
Published: October 2024

Abstract
Disclosure: N. Haider: None. Y. Lee: None. P. Yi: None. C.R. Kahn: None.
Insulin resistance is a major risk factor in the development of type 2 diabetes (T2D), and metabolic syndrome. Although 25% of people within the general non-diabetic population are insulin resistant, the primary underlying cause of insulin resistance remains elusive. In this study, we have used induced pluripotent stem cells (iPSC) derived from non-diabetic humans at both ends of the insulin sensitivity spectrum, i.e., the top 20% of insulin resistance vs. the top 20% of insulin sensitive, as well as individuals with T2D to model human insulin resistance. We find that iPSCs differentiated into myoblasts (iMyos) from T2D and non-diabetic individuals in the highest quintile of insulin resistance (I-Res) show impaired insulin signaling and defective insulin-stimulated glucose uptake, as compared to iMyos from the insulin sensitive individuals (I-Sen), indicating that these cells in vitro mirror the alterations seen in vivo in a cell autonomous manner. To uncover the primary upstream drivers that contribute to the impaired glucose uptake associated with insulin resistance, we conducted a genome-wide loss-of-function screen using a CRISPR-based approach to identify genes that positively or negatively regulated glucose uptake in I-Res and T2D iMyos. Knockdown of ∼525 genes show effect to rescue the impaired glucose uptake in both I-Res and T2D iMyos, i.e., were negative regulators of glucose uptake. We hypothesized that important negative regulators of glucose uptake might be over-expressed at the protein level in I-Res and T2D iMyos and crossing the iMyos proteomics data with the CRISPR screen revealed 8 top candidates that are increased at the protein level and whose knockdown rescued glucose uptake in I-Res and T2D iMyos. These included candidates associated with cytoskeleton changes, protein kinases, transmembrane transport, mitochondrial and nuclear proteins. In summary, iPSC derived myoblasts from patients with insulin resistance and T2D mirror defects in glucose uptake observed in vivo. Combining CRISPR screening and global proteomics, we have identified important upstream regulators of insulin resistance in humans.
Presentation: 6/2/2024
8090 A Gut Commensal, Parabacteroides distasonis, and Molecular Mimicry in Type 1 Diabetes
Authors: Randall Audrey , Girdhar Khyati , Altindis Emrah 
Published: October 2024

Abstract
Disclosure: A. Randall: None.
Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the destruction of pancreatic, insulin-producing beta cells by autoreactive T-cells. The trigger(s) of T1D are unclear and genetics alone cannot explain the recent increase in T1D incidence. The gut microbiome composition in T1D patients is altered and thought to play a key role in T1D pathogenesis. Most longitudinal studies have been descriptive. However, a direct cause-and-effect relationship hasn't been established yet. Insulin is a key autoantigen in T1D autoimmunity, and insulin B-chain amino acids 9-23 (insB:9-23) is an important, commonly recognized T-cell epitope. Molecular mimicry is an autoimmunity mechanism where host-like microbial proteins trigger autoimmune responses. We previously identified a peptide mimic of insB:9-23, amino acids 4-18 of hypoxanthine phosphoribosyl transferase (HPRT:4-18) of Parabacteroides distasonis (Girdhar et al., 2022). HPRT:4-18 stimulated insB:9-23-specific human and non-obese diabetic (NOD) mice T-cells. We hypothesize that P. distasonis HPRT:4-18 is required to accelerate diabetes via molecular mimicry of insB:9-23. By orally gavaging NOD mice (n=40 mice/group), we showed that P. distasonis accelerated diabetes onset. Next, we colonized NOD mice with another common gut commensal, Bacteroides fragilis, as a control, and did not observe any effect on islet infiltration. In addition, P. distasonis colonization increased infiltration of immune cells into the islets of germ-free NOD mice (n=6-8 mice/group), while the diabetes incidence experiment in mice is ongoing. P. distasonis-colonized mice had significantly more splenic CD8 and naïve T-cells, dendritic cells and macrophages but fewer FOXP3 cells (n=3-6 mice/group). To determine whether P. distasonis’s effect is specific to the pancreas, we checked intestinal barrier function and intestinal immune cell composition. Disruption of intestinal barrier function has been associated with diabetes. P. distasonis colonization did not alter gut permeability. Furthermore, P. distasonis did not increase intestinal inflammation. Among the intestinal intraepithelial lymphocytes (IELs), there were fewer naïve, central and effector T-cells and B-cells. The findings indicate that P. distasonis does not stimulate an unspecific immune response and its inflammatory effect is specific to the pancreas, supporting our initial hypothesis. Taken together, our results indicate that exposure to P. distasonis in the first years of life has the potential to stimulate molecular mimicry mechanism and cause T1D onset. Reference: Girdhar, K., Huang, Q., Chow, I. T., Vatanen, T., Brady, C., Raisingani, A., . . . Altindis, E. (2022). A gut microbial peptide and molecular mimicry in the pathogenesis of type 1 diabetes. Proc Natl Acad Sci U S A, 119(31), e2120028119. doi:10.1073/pnas.2120028119
Presentation: 6/2/2024
12374 A Prospective Study Of Plasma Levels Of Asprosin And Incident Type 2 Diabetes Among Postmenopausal Women In The Women’s Health Initiative
Authors: Yang B , Li J , Silva E S , Phillips L S , Manson J E , Reiner A P , Chopra A R , Liu S 
Published: October 2024

Abstract
Disclosure: B. Yang: None. J. Li: None. E.S. Silva: None. L.S. Phillips: None. J.E. Manson: None. A.P. Reiner: None. A.R. Chopra: None. S. Liu: None.
Background: Asprosin, a 30-kDa hormone identified from white adipose tissue, has been shown to play key roles in regulating hepatic glucose release and appetite stimulation. Despite an increasing body of experimental studies demonstrating asprosin as a promising therapeutic target, little is known about its distribution in the general population particularly concerning its association with incident type 2 diabetes (T2D). Objectives: To evaluate whether higher plasma levels of asprosin are associated with incident T2D among postmenopausal women independently of known risk factors for T2D. Methods: We conducted a case-control study nested in the Women’s Health Initiative (WHI), including 5,198 participants free of diabetes, cardiovascular diseases, and cancer at baseline (2,602 incident T2D cases and 2,596 controls). Plasma levels of asprosin were measured using a sandwich enzyme-linked immunosorbent (ELISA) assay. We used conditional logistic regression models to estimate the association between asprosin and T2D risk with adjustment for matching variables (age, race, sampling batch), education, body mass index (BMI), physical activity, tobacco smoking, alcohol drinking, family history of diabetes, age at menopause, total energy intake, the Alternate Healthy Eating Index (AHEI), and multivitamin use. Results: Approximately 43% of participants were white and the mean age at baseline was 63 years. The median plasma levels of asprosin were 38 (IQR: 30, 50) pmoL/L in the controls and 39 (IQR: 31, 50) pmoL/L among those who developed T2D during follow-up. Compared with the participants in the lowest quintile of plasma levels of asprosin at baseline, those in the highest quintile had a 26% increased risk of T2D (adjusted odds ratio: OR: 1.26 [95% CIs, 1.01, 1.57], p for trend=0.03) in the fully adjusted model. The OR estimates exhibited a large variation across race and BMI, although there was a linear dose-response relation between levels of asprosin and T2D risk (p for nonlinear=0.44). Genetic analysis revealed that women with the heterozygous allele (CG) at single nucleotide polymorphisms (SNP) rs56407701 had higher levels of asprosin compared to women with the homozygous reference allele (CC). Further, Mendelian Randomization analysis revealed that genetically predicted asprosin levels were associated with higher T2D risk. Conclusion: Among postmenopausal women, higher plasma levels of asprosin were prospectively associated with elevated T2D risk independent of known T2D risk factors. Further work is needed to confirm the potential causal role of this peptide hormone in the clinical risk stratification and potential prevention of T2D.
Presentation: 6/2/2024
6663 Amputation Rate in Hospitalized Patients With Diabetic Foot Ulcer at Montefiore Medical Center, Bronx, NY
Authors: Lopez Fanas Raul , Herrera Chancay Azucena , Tabassum Humera , Milosavljevic Jovan , Xu Shiming , Daily Johanna , Myers Alyson K 
Published: October 2024

Abstract
Disclosure: R. Lopez Fanas: None. A. Herrera Chancay: None. H. Tabassum: None. J. Milosavljevic: None. S. Xu: None. J. Daily: None. A.K. Myers: None.
Introduction: Diabetic foot ulcers (DFU) are associated with poor outcomes including lower extremity amputations and death in individuals with diabetes. Our study aims to define health outcomes and explore the association of sociodemographic and clinical factors on amputation rates in patients hospitalized with DFU addressing an existing knowledge gap in our population. Methods: This was a retrospective review of the electronic health record of adult patients hospitalized with DFU at one of the three major Montefiore Medical Center hospitals in the Bronx, New York between 06/01/2016 and 05/30/2021. Patient data extracted from the index admission included demographics, comorbidities, and laboratory values. Survival and amputation rates were calculated for each patient over the five-year study period. Results: In our analysis of 650 patients, 88% self-identified as non-white, and only 23% had commercial insurance. The amputation rate during the initial DFU admission was 44%, with 76% experiencing at least one amputation over five years. Male sex, low BMI, and smoking were associated with amputation during the study period, with an OR of 0.62 (p=0.01), 0.98 (p=0.05), and 1.45 (p=0.05) respectively. Patients with history of osteomyelitis had a higher risk of any amputation during the index admission (OR 2.05, p&lt;0.0001), and the 5-year study period (OR 3.03, p&lt;0.0001). PAD or prior history of amputation increased the risk of any amputation during the study period, OR 2.11 (p=0.0002) and OR 7.92 (p&lt;0.001) ESRD was associated with a higher risk of AKA and BKA during the index admission (OR 2.31, p=0.05). Elevated ESR, CRP, WBC, and low albumin were associated with amputation during admission, with ORs of 1.01 (p=0.0006), 1.05 (p&lt;0.0001), 1.11 (p&lt;0.0001), and 0.41 (p&lt;0.0001), respectively. Discussion: This study revealed a 44% amputation rate during the initial DFU admission, with 76% experiencing at least one amputation within five years. Bivariate analyses identified male sex, lower BMI, and smoking as correlated with a heightened amputation risk, consistent with previous studies. Prior amputation, PAD, ESRD, and osteomyelitis were also associated with an increased risk. Multiple regression analysis found significant associations between elevated ESR, CRP, WBC, and low albumin with amputations. As a result, interventions need to be devised for patients with these characteristics to prevent this high rate of amputation.
Presentation: 6/2/2024
7360 An Overlooked Cause of Hypoglycemia and Weight Loss: Phosphodiesterase-4 Inhibitors
Authors: Aurora John , Cappetta Kate , Lechan Ronald M 
Published: October 2024

Abstract
Disclosure: J. Aurora: None. K. Cappetta: None. R.M. Lechan: None.
Background: Phosphodiesterase-4 (PDE-4) inhibitors, apremilast and roflumilast, are anti-inflammatory agents used to treat psoriasis, psoriatic arthritis, and COPD. These agents are commonly associated with gastrointestinal intolerance. However, patients may also experience profound weight loss (&gt;10%). We present a case of a patient with T2DM who developed significant hypoglycemia and weight loss on apremilast. Clinical Case: A 57-year-old female with T2DM, obesity, psoriasis, and postsurgical hypothyroidism due to papillary thyroid cancer developed symptoms of hypoglycemia and weight loss over 1 month. Prior to this, her A1c was 7.8% and weight 104 kg on stable doses of metformin, repaglinide, and insulin glargine. Insulin glargine and repaglinide were both discontinued given her symptoms, yet hypoglycemia persisted, and she continued to lose weight. Further investigations into the cause of this sudden change were carried out. Initial fasting labs: BG 53 mg/dL, C-peptide 4.48 ng/mL (RR 0.8-3.85 ng/mL), insulin 12.8 uIU/mL (RR &lt;18.4 uIU/mL), proinsulin 29.8 pmol/L (RR &lt;18.8 pmol/L), A1c 6.8%, cortisol 24.9 mcg/dL (RR 4-22 mcg/dL), IGF-1 95 ng/mL (Z-score -0.7), and IGF-2 434 ng/mL (RR 267-616 ng/mL). 1 month later, hypoglycemia symptoms improved but she continued to lose weight. Fasting labs were repeated: BG 84 mg/dL, C-peptide 5.62 ng/mL, insulin 24.3 uIU/mL, proinsulin 35 pmol/L, and beta-hydroxybutyrate (BHB) 0.17 mmol/L (RR &lt;0.28 mmol/L); metformin was subsequently stopped. A MR abdomen revealed a 2 cm cystic pancreatic lesion that showed atypical mucinous epithelium by biopsy under endoscopic ultrasound guidance. Gallium-68 DOTATATE-PET scan was unremarkable for an insulin-producing tumor. Two months off metformin, she had no further episodes of hypoglycemia, but her weight loss continued. Fasting labs were repeated: BG 129 mg/dL, C-peptide 5.15 ng/mL, insulin 18.2 uIU/mL, proinsulin 40.5 pmol/L, and BHB 0.27 mmol/L. Review of her medications identified apremilast as a potential culprit contributing to both her hypoglycemia and weight loss, as her symptoms started 1 month after starting apremilast. Over 9 months using apremilast, her A1c decreased by 1% and weight decreased by 27%. Hypoglycemia resolved off all glucose-lowering agents. Conclusion: Significant weight loss with apremilast may be explained by PDE-4 inhibition increasing cyclic AMP, which triggers the release of GLP-1 with subsequent effects on pancreatic beta cells. Apremilast has also been shown to significantly increase fasting insulin levels in patients without insulin resistance, as seen in our patient (1). Given these effects, patients may be at higher risk of hypoglycemia with concurrent glucose-lowering agents, particularly secretagogues. BG and weight need careful monitoring for patients with T2DM using PDE-4 inhibitors. Reference: 1. Ikumi K, et al. J Dermatol. 2022;49(4):e125-e126.
Presentation: 6/3/2024
7753 Anoctamin 4 in the Area Postrema Regulates Glucose and Energy Homeostasis
Authors: Tu L , Xu Y 
Published: October 2024

Abstract
Disclosure: L. Tu: None. Y. Xu: None.
Located on the floor of the 4th ventricle within the dorsal surface of the medulla oblongata, the area postrema (AP) is a circumventricular organ where a proper blood-brain barrier is missing. Numerous studies reveal that neurons in the AP are implicated into suppression of food intake (e.g., glucagon-like peptide 1 (GLP-1)-mediated anorexia), but the role of AP neurons in whole-body glucose homeostasis is less investigated. Here we identified and fully characterized the physiological functions of anoctamin-4 (Ano4, a calcium activated chloride channel)1 in the AP. CRISPR-mediated deletion of Ano4 in the AP caused a lower body weight and reduced blood glucose, concurrent with an improved glucose tolerance and increased insulin sensitivity. Chemogenetic activation of Ano4-expressing neurons in the AP (APAno4) increased food intake and blood glucose, and did not induce conditioned flavor avoidance. Both Ano4 neurons and non-Ano4 neurons (i.e., neurons do not express Ano4) sent projections to the lateral parabrachial nucleus (LPBN). Optogenetic stimulation of APAno4 ◊ LPBN circuit promoted feeding behavior and increased blood glucose, whereas stimulation of APnon-Ano4 ◊ LPBN circuit inhibited food intake and did not influence glucose homeostasis. Finally, RNAscope studies reveal that 45.7% of APAno4 neurons are glutamatergic neurons, and 41.8% of them are GABAergic neurons. Furthermore, APAno4 neurons showed only a 2.6% overlap with Glp-1r-expressing neurons in the AP, but had a 60.8% co-localization with protein tyrosine phosphatase receptor δ2, which serves as orexigenic asprosin receptor. Together, our results indicate that Ano4 neurons in the AP are the first reported orexigenic neurons, and represent potential therapeutic targets for human diseases with glucose imbalance and abnormal feeding behavior. Reference: (1) Tu, L. et al. Anoctamin 4 channel currents activate glucose-inhibited neurons in the mouse ventromedial hypothalamus during hypoglycemia. J Clin Invest 133,14. (2023). (2) Mishra, I. et al. Protein tyrosine phosphatase receptor δ serves as the orexigenic asprosin receptor. Cell Metab 34, 549-563. (2022).
Presentation: 6/2/2024