bluuebunny/crossref_metadata_2025_split huggingface dataset:
PSUN329 Non-islet Cell Tumor Hypoglycemia Secondary to Advanced Hepatocellular Carcinoma in a 29-Year-Old Male
Authors: Bao Ginny , Chang Christine , Price Austin , Yin Anthony 
Published: November 2022

Abstract
Summary: Non-islet cell tumor hypoglycemia (NICTH) is a rare, but serious complication that can be seen in most all tumors. It is typically mediated by high levels of an incompletely processed form of insulin-growth factor 2 ("big IGF-2") that is produced by the tumor. We describe a case of a 29-year-old male with history of chronic hepatitis B and advanced stage hepatocellular carcinoma (HCC) who had failed prior chemotherapies. The patient was admitted to the hospital for a liver biopsy, following which he developed severe hypoglycemia, refractory to high dose, continuous dextrose infusion. Evaluation was remarkable for low levels of insulin, proinsulin, C-peptide, and IGF-1, normal cortisol, and an IGF-2: IGF-1 ratio of 8, suggestive of NICTH due to IGF-2, although the patient's hypoglycemia may additionally have been due to worsening, and strikingly extensive tumor invasion of the liver. This patient was unfortunately not considered a surgical candidate; hypoglycemia was ultimately controlled with initiation of high dose corticosteroids and total parenteral nutrition with high amounts of dextrose.
Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSUN337 Evaluation of Intensive Behavioral Therapy as a Tool to Combat Obesity in a Rural Outpatient Endocrinology Clinic
Authors: Kabir Purnima , Lewis Chantal , Peñaherrera Carlos A 
Published: November 2022

Abstract

Introduction
The prevalence of obesity in the United States has risen from 30.5% in 2000 to 42.4% in 2018. Given this steep increase and the association of obesity with multiple comorbidities, the focus has now turned to behavioral modifications. In 2011, Medicare began to reimburse providers for intensive behavior therapy (IBT) for obesity.

Background
Medicare beneficiaries with a BMI ≥ 30 kg/ m2 are eligible for IBT. The program at Hamilton Diabetes and Endocrinology Center (HDEC), followed a structure similar to that of the nationwide IBT program. It begins with a nutritional assessment and a personalized lifestyle intervention plan. The program includes 20 visits over a 12-month period. At the six-month point mark, we aim to achieve a target weight loss of 6.6 lbs. A thorough literature review revealed limited data on the outcomes of the program. The purpose of our study is to present data which has shown effectiveness of this program in the rural setting.

Methods
A retrospective cohort study was conducted with data obtained between September 2020 to October 2021. The sample being studied included 96 participants after exclusion of those that were unable to complete the program. The participants were matched based on their baseline demographic characteristics. The outcomes studied were weight in pounds, BMI and HbA1C. Using paired t-tests we compared the change in weight before and after implementation of the program, with BMI and HbA1C as secondary outcomes.

Results
The participants began the IBT program with an initial mean weight of 249.4 lbs. and ended the program with a final mean weight of 244.7 lbs. Comparison of the data using paired t-tests revealed that the change in weight was about 4.7 lbs. (95% confidence interval of 2.9 - 6.6, P &lt;0.001). The change in BMI was 0.8 kg/m2 (95% CI: 0.5–1.1, P &lt;0.001). About 31.25% of our study participants were able to lose more than 6.6 lbs. However, it is pertinent to note that our study was conducted during the time of the pandemic, leading to missed appointments and effects on lifestyle. Despite our limitations, the data revealed a statistically significant difference in weight and BMI at the final visit compared to the initial visit. The HbA1C values were reduced by 0.25%, however this change was not statistically significant (P = 0.185).

Conclusion
Analysis of the IBT program at the HDEC has shown a favorable response. In an ideal world, free of limitations by the pandemic, this program is likely to, achieve an even greater degree of weight loss. This brings about a need for raising awareness within the community. Implementation of IBT programs and promoting lifestyle interventions result in reduction of obesity and therefore lead to an improved quality of life.
Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSUN339 Persistent Hypoglycemia and Hyperinsulinism in a Patient With Kabuki Syndrome Type 1.
Authors: Gomez Patricia , Stosic Mariana Nunez 
Published: November 2022

Abstract

Background
Transient neonatal hypoglycemia typically resolves within the first few days of life. Persistence of neonatal hypoglycemia is a more significant finding that warrants further investigation.

Clinical case
A 2-year-old female born at 37 weeks of gestation via C-section due to a history of maternal preeclampsia. Delivery was complicated by meconium aspiration syndrome for which the patient was admitted to the NICU where she had a prolonged course. Patient was initially depressed at birth with APGARs of 3/6/8 at 1, 5 and 10 minutes of life, respectively. During the neonatal period, she had multiple complications including GERD, FTT (G-tube was placed), recurrent UTIs, congenital heart disease (mild RVH and ASD) and hypoglycemia.
Regarding her hypoglycemia, the initial work up was suggestive of hyperinsulinism with a critical sample remarkable for a BG: 57 mg/dl (60-100mg/dl), Insulin level: 8.3 uUm/mL Subsequent glucagon challenge test confirmed hyperinsulinism. She initially required a continuous glucose infusion and Diazoxide was started. She was discharged home on Diazoxide and Diuril. Subsequently, Diazoxide was successfully discontinued at the age of 2 months. A Congenital Hyperinsulinism genetic panel was negative for the most frequent mutations.
At 11 months old, she presented to our clinic due to persistent hypoglycemia when enteral feeds were attempted to be spaced. Patient was started on cornstarch which was discontinued secondary to frequent diarrhea. SolCarb was started with enteral feeds with good tolerance and response, maintaining target blood glucose levels.
On physical examination, she had some dysmorphic features that were suggestive of a syndromic condition: prominent ear lobes, broad and flat nasal bridge, a single prominent tooth at the center of the bottom gum line, long palpebral fissures with upward curvature at the lateral edges, prominent finger pads and neurodevelopmental delay.
Since she had features suggestive of Kabuki syndrome, WES was ordered which was remarkable for a pathogenic mutation in KMT2D (Autosomal dominant, Heterozygous, variant c.5269C&gt;T and p.R1757X).

Conclusion
Persistent hypoglycemia beyond the neonatal period is a rare finding in Kabuki syndrome. In addition, it is a more common finding in Kabuki Syndrome type 2 (Mutations in the KDM6A gene).
Our patient presents a rare case of a 2-year-old female with persistent hypoglycemia and hyperinsulinism secondary to KS1.
Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
RF04 | PSUN133 Assessment of the Rnf20 Histone Modifier in Regulating Pancreatic Beta-Cell Identity and Function
Authors: Pierre Tanya , Liu Yanping , Bethea Maigen , Hunter Chad 
Published: November 2022

Abstract
Type 1 and Type 2 Diabetes are characterized by a loss of functional pancreatic islet β-cells. With the prevalence of diabetes increasing worldwide, a complete understanding of the gene regulatory mechanisms governing the development and function of insulin-producing β-cells is requisite for improving diabetes therapies. Islet 1 (Isl1) is a LIM-homeodomain class transcription factor (TF) required for the maturation, proliferation, function, and survival of islet cells. In our previous study, we identified Isl1 interactions with the ring finger ubiquitin ligases Ring Finger 20 (Rnf20) and Rnf40 in mouse β-cell extracts, mouse islets, and human islets. Rnf20 and Rnf40, exist as homodimeric or heterodimeric complexes to deposit a mono-ubiquitin epigenetic mark on histone (H)2B (i.e., H2Bub1) and regulate gene transcription as a precursor to active H3K4 trimethylation (H3K4me3) and H3K79 methylation (H3K79me) marks. We demonstrated that Rnf20 and Rnf40 are required for the expression of several important β-cell genes and glucose-stimulated insulin secretion in vitro. Specifically, loss of Rnf20and Rnf40 in MIN6 β-cells resulted in a significant dysregulation of β-cell Slc2a2/Glut2 and MafA expression, target genes which were occupied by Rnf20 and H2Bub1. Additionally, using proximity ligation assay (PLA) in MIN6 β-cells, we demonstrated a robust increase in interactions between Isl1 and Rnf20 under high glucose conditions. Based on this, we hypothesize that Rnf20 and/or Rnf40 are required to establish and maintain β-cell identity in adult islets. To begin addressing this, we disrupted Rnf20/Rnf20 and/or Rnf20/Rnf40 complexes in β-cells via generation of adult inducible Rnf20 β-cell-specific knockout mice. In the adult inducible model, 2 weeks following tamoxifen induction (i.e., by 8 weeks of age) both male and female mice became hyperglycemic and severely glucose intolerant. These 8-week-old Rnf20-deficient mice also had reduced plasma insulin following a glucose challenge yet normal insulin sensitivity. Islet RNA exhibited dysregulated mRNAs encoding islet hormones, glucose-stimulated insulin secretion markers, and β-cell identity markers, including Slc2a2/Glut2, Ucn3, and Hb9 . Our findings of similar phenotypes between Isl1 and Rnf20 adult knockout models, a glucose sensitive interaction between Isl1 and Rnf20, and their occupancy of the Slc2a2/Glut2 locus support mechanisms of Isl1-Rnf driven β-cell regulation.
Presentation: Saturday, June 11, 2022 1:12 p.m. - 1:17 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
RF04 | PSUN163 In High Glucose Exposed Endothelial Cells BTK is a Novel Component of the Nuclear Factor-Kappa B Pathway
Authors: Singh Madhu , Badr Heba , Moorjani Sonia , Wong Thomas , Dokun Ayotunde 
Published: November 2022

Abstract
Peripheral artery disease (PAD) is atherosclerotic occlusion of vessels outside the heart and most commonly affects the lower extremities. Diabetes worsens PAD outcomes, but the mechanisms involved are poorly understood. A key component of perfusion recovery in experimental PAD is induction of NFkB signaling in ischemic endothelial cells (EC). We have shown that prolonged exposure of ECs to high glucose before simulated ischemic exposure resulted in impairment of the canonical NFkB pathway through activation of protein kinase C β (PKC β). However, the signaling pathways upstream of PKC β involved in this high glucose induced desensitization of NFkB signaling are not known. We used arrays of antibodies to approximately 100 proteins known to participate in the NFkB pathway to identify the changes in their phosphorylation states in human umbilical vein endothelial cells (HUVEC). Cells grown for three days either in culture medium with normal glucose (NG) or high glucose (HG) were subjected to ischemia for 24 hours (NGI and HGI, respectively). Cell lysates were then incubated with the array of antibodies printed on glass slides and fluorescent signals were digitally recorded and normalized. The change in protein phosphorylation was calculated by dividing the intensity of the phosphorylated spot by the signal intensity of the corresponding non-phosphorylated spot for each protein. Differential expression between samples, were calculated by dividing the phosphorylation ratio of the NGI and HGI with that of the NG and HG controls, respectively. A combination of pathway analyses using bioinformatics tools on 65 modulated phosphorylation sites in HGI (represented by 35 genes) and analysis of differential phosphorylation between NGI and HGI samples suggested involvement of B cell linker/adapter protein (BLNK)/Bruton's tyrosine kinase (BTK). BTK plays a key role in B cell antigen receptor (BCR)-coupled signaling but not known to be expressed in ECs or play a role in EC function. Here we confirmed BTK expression in ECs by immunoblotting. Inhibition of BTK by a specific inhibitor terreic acid or by shRNA mediated knockdown decreased PKCβ-S661 phosphorylation and restored NFkB activation in ECs suggesting a critical role of BLNK/BTK in the EC. Thus, we have identified BLNK/BTK as a potentially new component of the NFkB pathway in ECs that may be a therapeutic target to improve PAD outcomes in diabetes.
Presentation: Saturday, June 11, 2022 1:06 p.m. - 1:11 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
RF04 | PSUN333 Divergent Pathways in Liver Triglyceride Storage and Secretion in Partial Lipodystrophy vs. Obesity Associated NAFLD
Authors: Klein Rachael , Viana Gracia , Koh Christopher , Brown Rebecca , Rotman Yaron 
Published: November 2022

Abstract

Background
Partial lipodystrophy (PL) syndromes are characterized by deficiency of subcutaneous fat, increased liver fat and insulin resistance (IR). Nonalcoholic fatty liver disease (NAFLD) is an important cause of morbidity and mortality in both PL and obesity. Hepatic lipid derives from re-esterification of free fatty acids (FFA) from adipose tissue lipolysis and dietary sources, as well as de novo lipogenesis. Hepatic TG can be used for energy by β-oxidation, stored in hepatocytes as lipid droplets or secreted as VLDL. Hepatosteatosis develops when the rate of intrahepatic TG production is greater than the rate of TG disposal (oxidation and secretion). Here we investigate the contributions of insulin resistance and adipose tissue to hepatic steatosis in patients with PL vs non-syndromic, obesity associated NAFLD (NAFLD).

Methods
Single-center retrospective analysis of subjects with NAFLD (N=73) and PL (N=28). Fibroscan Controlled Attenuated Parameter (CAP) was used to estimate liver fat. A1c, β-hydroxybutyrate, and circulating lipids by NMR were measured simultaneously and within 6 months of CAP measurement. Insulin resistance was estimated by HOMA-IR (fasting glucose x insulin ÷ 405) and LP-IR (a lipoprotein-based measure of IR derived from circulating lipid particles).

Results
The PL group was 86% female vs 48% in NAFLD (P&lt;0.001) and younger (43±8 vs. 50±14 years, P&lt;0.03). BMI was lower PL vs NAFLD (27±6 vs 33±6 kg/m2, P&lt;0.0001). Fasting insulin was not statistically different between PL and NAFLD (median 26.4 [interquartile range 21.3,51.2]) vs 31.6 mcU/L [15.1-33.4], P=0.052); however, IR was more severe in PL vs NAFLD based on both HOMA-IR (15.5±16.2 vs 7.6±5.2, P=0.003) and LP-IR (65.1±19.3 vs 58.5±16.7, P=0.03). A1c was higher in PL (7.5±2.1 vs 5.9±0.8%, &lt;0.001). CAP was similar in PL and NAFLD (301±57 vs 320±49 dB/m, P=0.1). CAP correlated with HOMA-IR in both PL (r=0.51, p=0.01) and NAFLD (r=0.44, p=0.003), but for any given HOMA-IR liver fat was lower in PL vs NAFLD. FFA levels were comparable between groups (0.52± 0.28 vs 0.50±0.27 mEq/L, P=0.058). TRLP concentration by NMR was higher in PL compared to NAFLD (240±123 vs165±86 nmol/L, p=0.001) as was β-hydroxybutyrate (162±67 vs 115±58 mmol/L, P=0.004).

Conclusions
Patients with PL have comparable liver fat vs. non-syndromic NAFLD despite worse insulin resistance. To understand the lower liver fat relative to insulin resistance in PL, we examined input, oxidation, and export of lipid from the liver. Surprisingly, despite lower adipose mass in PL vs NAFLD, FFA input to the liver was similar. Hepatic fat oxidation and export, estimated by β-hydroxybutyrate and large VLDL respectively, were both higher in PL. This suggests a shift of fat storage out of the liver into the circulation in PL.
Presentation: Saturday, June 11, 2022 1:18 p.m. - 1:23 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
RF04 | PSUN334 Mineralocorticoid receptors mediate diet - induced lipid infiltration of skeletal muscle and insulin resistance
Authors: Habibi Javad , Hulse Jack L , Jia George , Jia Prof Guanghong , Sowers James R , Whaley-Connell Adam 
Published: November 2022

Abstract
Excess blood lipids increase the total intramyocellular (IMC) lipid content and ectopic fat storage resulting in lipotoxicity and insulin resistance in skeletal muscle, which is one of the main targets of insulin whose action is central for the maintenance of glucose homeostasis. Consumption of a diet high in fat and refined sugars, a Western Diet (WD), has been shown to activate mineralocorticoid receptors (MRs) to promote insulin resistance. However, our understanding of the precise mechanisms by which enhanced MR activation promotes skeletal muscle insulin resistance remains unclear. In this study we investigated the roles and mechanisms by which enhanced MR signaling in soleus muscle promotes ectopic lipid accumulation and related insulin resistance in diet-induced obesity. Six week-old C57BL6J mice were fed either a mouse chow diet or WD with or without spironolactone (1 mg/kg/day) for 16 weeks. Spironolactone attenuated 16 weeks of WD - induced in vivo glucose intolerance and improved soleus insulin metabolic signaling (protein kinase B and AMP kinase α pathways). Improved insulin sensitivity was accompanied by increased Glut-4 expression in conjunction with decreased IMC lipid content and reduced free fatty acid (FFA) levels and CD36 expression in soleus skeletal muscle tissue. Related to this, miR-99a was identified to negatively target CD36(www.targetscan.org/vert_72/) and elevated CD36 induced excessive FFA uptake, ectopic lipid accumulation, as well as systemic and tissue insulin resistance. Furthermore, in skeletal muscle cells spironolactone prevented enhanced MR signaling mediated reduction of miR-99a and related increased CD36. These data indicate that inhibition of MR activation with spironolactone reversed diet - induced reduction of miR-99a, thereby reducing CD36 expression, leading to reduced IMC lipid content and improved soleus insulin sensitivity.
Presentation: Saturday, June 11, 2022 1:48 p.m. - 1:53 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
RF05 | PSUN376 Incidence of Diabetes Mellitus Following Pancreatic Surgery in Individuals with Multiple Endocrine Neoplasia Type 1
Authors: Else Tobias , Henry Marie-Louise , Koeppe Erika , Osborne Jenae , Wolf Katherine 
Published: November 2022

Abstract
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant hereditary disorder characterized by hyperparathyroidism, pituitary adenomas, and well-differentiated neuroendocrine tumors of the foregut. Pancreatoduodenal neuroendocrine tumors are often managed via surgical intervention, which increases the risk for new onset, post-operative diabetes mellitus (DM). Current estimates of post-operative DM in MEN1 range between 10-86%. Here, we present a retrospective review of the incidence of DM following pancreatic surgery in individuals with MEN1at a single tertiary care center between 2005-2021.
Patients with a clinical or molecular diagnosis of MEN1 with and without pancreatic surgery were identified via the electronic medical record system. A retrospective chart review collected baseline demographic and clinical data. Individuals with an insulinoma diagnosis were excluded. A diagnosis of DM was defined as a hemoglobin A1c greater than 6.5%, fasting plasma glucose level greater than 126 mg/dl, or a random plasma glucose greater than 200 mg/dl.
One-hundred and eighteens adult patients (66F, 52M) with MEN1 were identified. Radiographic evidence of a pancreatic tumor was demonstrated in 84 (71.2%) patients, of which 49 (41.5%) underwent surgical resection (40 (81.6%) distal pancreatectomy with or without enucleation, 6 (12.2%) Whipple procedure, 2 (4.1%) enucleation, and 1 (2.0%) total pancreatectomy) of a pancreatic neuroendocrine tumor (pNET). All but one individual were included in the post-surgical study cohort as it was unknown if onset of DM preceded operation. Fourteen (28.5%) underwent another subsequent pancreatic surgery. Of the above 48 surgical patients, 3 (6.1%) had a pre-operative diagnosis of diabetes. Within the remaining 45 patients, 31 (68.9%) developed a diagnosis of DM following surgery (mean post-operative onset 4.2 years [range 0.1–16.3]). Of the 69 individuals who did not undergo surgery but did have a diagnosis of MEN1, just 15 (21.7%) developed DM and at an older average age 53.4 [range 14–70] when compared to their surgical cohorts 47.5 [range 27–75].
With 61.2% of patients with resected pNET developing DM compared to their non-operative counterparts (21.7%) (p = 0.25), there is a strong suggestion of morbidity associated with pancreatic surgery secondary to the development of DM. Endocrinologists and surgical teams should be aware of the associated risks and screen accordingly with yearly hemoglobin A1c compared to the standard three-year interval begun at age 45 as suggested by the American Diabetes Association. Additionally, patients should be appropriately educated on the signs/symptoms of DM.
Presentation: Saturday, June 11, 2022 1:30 p.m. - 1:35 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
RF27 | LBSUN361 Understanding The Genetics Of Multiple Endocrine Neoplasia Type 1: The Road Ahead
Authors: Worthy Charlita 
Published: November 2022

Abstract

Background
About 10-30% patients have genotype-negative (GN)-MEN1. Here, we compare our cohort of comprehensively phenotyped GN-MEN1 and genotype-positive (GP)-MEN1 patients. We also investigate somatic mosaicism as a cause of GN-MEN1.

Methods
GN-MEN1 patients showed no mutations in MEN1 or other primary hyperparathyroidism (PHPT) genes (CASR, RET, CDKN1B, CDC73, AIP, GNA11, AP2S1, GCM2) performed per clinical indication. Index patients (first patient in kindred to be diagnosed with MEN1) or probands (first patient in kindred to be evaluated at our center) from kindreds with GP-MEN1 were identified. All patients underwent testing for tumor biomarkers, imaging and evaluation for Zollinger-Ellison syndrome (ZES). Whole exome sequencing was performed on multiple tumors from 13 GN-MEN1 patients. GP-MEN1 patients were also categorized into high-impact (nonsense, frameshift, splice site, whole or partial gene deletion) or low-impact (missense or in-frame indels) mutation-bearing groups.

Results
We identified 43 (31 females, 12 males) patients with GN-MEN1 and 160 (102 index, 58 probands) patients with GP-MEN1 (98 females, 62 males). Among GP-MEN1, 97 had high impact and 34 had low-impact mutations. Mean age at last follow-up was 56 (±14) years for GN-MEN1 and 52 (±16) years for GP-MEN1 patients. Among the GN-MEN1 patients, 38/42 developed PHPT - 3/38 (8%) had recurrent disease. In GP-MEN1, 144/149 developed PHPT - 83/144 (58%) with recurrent disease. Median age of index presentation with PHPT significantly differed between the groups (27.5 years in GP-MEN1 vs 53 years in GN-MEN1 (χ2 (1)=5.5: p &lt;0.05)). 33/42 GN-MEN1 patients had a pituitary adenoma (22/33 functioning - 9/22 prolactinomas; 8/22 GH-secreting). In comparison, 94/145 GP-MEN1 patients developed a pituitary adenoma (51 functioning - 37/51 prolactinomas, no GH-secreting tumors). In the GN-MEN1 group, 12/42 (29%) patients developed a gastro-entero-pancreatic (GEP)-NET. In comparison, 86/130 (66%) patients with GP-MEN1 had a GEP-NET. Somatic variants in MEN1, CDC73 or CDKI were observed in six tumors. However, these mutations were not seen in another tumor/s or germline DNA from the patient. All patients with high-impact mutations had PHPT (63% had recurrent disease), 70% had pituitary tumors (35% with macro-adenomas) and 61% developed GEP-NETs (29% with distant metastases). In comparison, 91% patients with low-impact mutations developed PHPT (41% with recurrent disease), 69% developed pituitary tumors (23% with macro-adenomas) and 65% developed GEP-NETs (35% with distant metastases).

Conclusion
Patients with GP-MEN1 generally experience younger age of onset, greater likelihood of recurrent PHPT and co-occurrence of GEP-NETs in comparison to GN-MEN1. Our findings do not support somatic mosaicism as a cause of GN-MEN1. No apparent correlation in phenotype between high-impact vs. low-impact mutations is noted.
Presentation: Monday, June 13, 2022 12:51 p.m. - 12:56 p.m.