bluuebunny/crossref_metadata_2025 huggingface dataset:
MON-069 Uncontrolled Central Precocious Puberty Patient Against GnRH Agonist, After Showing Granuloma Formation and Sterile Abscess to Both Leuprorelin Acetate and Triptorelin Actate
Authors: Kim Dae Hyun , Choi Ju-hee
Published: May 2020

For more than 30 years, Gonadotropin-releasing hormone (GnRH) agonist has been the treatment of choice for central precocious puberty (CPP) to expect regression of secondary sexual characteristics, delayed menarche, and maximization of linear growth. There are several kinds of GnRH agonists such as leuprorelin, triptorelin, goserelin and histrelin, etc. In Korea, leuprolide acetate and triptorelin acetate are most common used drugs, and a monthly depot preparation is typically used for suppression of the HPG axis. Local complications related to GnRH agonists, including erythematous macules, granulomas, subcutaneous nodules, and sterile abscesses, occur in 10~15% of patients, and sterile abscesses have been known to occur in less than 2~3% of patients. In present case, we would like to introduce a case of CPP patient who was treated with GnRH agonist, but not suppressed and experienced recurrent vaginal bleeding, after showing granuloma formation and sterile abscess to both leuprorelin acetate and triptoreline actate. A 8.9 year-old girl visited our clinic with breast development and vaginal bleeding. On physical examination, she had enlarged breasts (Tanner stage 4) with pigmentation of the areola. Her height and weight was measured as 144.4cm (98th percentile) and 44.2kg (98th percentile) respectively. Her bone age was advanced as 12~12.6 years of age by TW3 method. Therefore, Leuprolide acetate (Lorelin depot®, Dongkook pharm) 3.75mg was administered to the patient every 4 weeks, and until the 6th injection, she exhibited no other complications. However, after 7th injection, the patient presented with granuloma and subcutaneous nodule at the left injection site and elevated hormone levels. Although that we switched to triptorelin acetate from 8th injection, the patient also showed a sterile abscess at the injection site. We switched from triptorelin acetate to leuprolide acetate again, however, after 2 months of the switch, the patient showed abrupt vaginal bleeding and elevated hormone levels. Therefore, after assumption of unsuppression of HPG axis, leuprolide acetate 3.75mg was administered every 2 weeks for 2 months. However, her vaginal bleeding occurred monthly and hormonal level was still unsuppressed, and also, the granuloma appeared again at the injection site. So, we discussed with her parents about her uncontrolled symptoms, and we discontinued the treatment. There are many theories about the cause of local complications of GnRH agonist, but the mechanism has still not been revealed. Further studies are required to identify the mechanism and the relationship between treatment effect and local complications, which could induce uncontrolled CPP.
SUN-054 Genetic Studies of Height-Associated Protein Expression Levels in Childhood
Authors: Fujimoto Masanobu , Bartell Eric , Khoury Jane C , Khoury Philip R , Vedantam Sailaja , Dauber Andrew Nahum , Hirschhorn Joel N
Published: May 2020

Background: Genome-wide association studies (GWAS) have identified thousands of common genetic variants associated with human height, implicating hundreds of genes and loci. However, the mechanisms by which many of these genetic variants contribute to human adult height are still unknown. Integrating knowledge of the interaction between genetic background and protein levels in childhood can provide insights into the biology of human growth. Objective: To investigate biological associations at height-associated loci in the GH-IGF signaling pathway. Methods: We used data from the Cincinnati Genomic Control Cohort, a community-based cohort comprised of 1,020 children. The study was approved by the institutional review board at Cincinnati Children’s Hospital Medical Center. Protein levels for free and total IGF-I, intact and total IGFBP-3, PAPP-A2, IGF-II, and IGFBP-5 were measured by ELISA in 839 children (ages 3-18 years) and corrected for age- and sex-effects. We associated protein-level phenotypes using plink qassoc and stratified by sex and population, in ~870 European- and African-descent individuals. Meta-analyses were performed using the METAL fixed-effects model. GWAS of anthropometric traits were performed in the UK Biobank of ~400,000 individuals using Bolt-LMM, or curated from publicly available summary statistics. Results: We identified 17 independent genome-wide significant protein-level-associated loci (p<5x10-8). The most robust associations were previously identified expression quantitative trait loci (eQTLs). The IGFBP3 locus was associated with serum total IGFBP3 and IGF-II levels. Despite falling within a height locus, conditional analyses showed that the effect on IGFBP-3 protein levels was independent of the height signal (p=2.8e-31, post conditioning). However, conditional analyses showed that the protein level signal colocalizes with a known GWAS signal for sitting height ratio (SHR). The IGFBP5 locus was associated with IGFBP-5 protein levels and was also independent of height signals identified in the region (p=3.3e-32, post conditioning). Conclusions: We have identified novel pQTLs for IGF2, IGFBP3, and IGFBP5 that act independently from genetic signals in the same regions associated with adult height but may interact with related anthropometric traits including SHR. Additionally, this suggests that SNPs affecting adult height in these loci do not work via increasing serum levels of these proteins but rather through a different and undetermined mechanism.
SAT-101 The Booster Effect of Aromatase Inhibitor to Overcome Waning Effect of Recombinant Human Growth Hormone
Authors: Kim Dae Hyun , Choi Ju-hee
Published: May 2020

Aromatase inhibitor (AI) is a drug that blocks the conversion of androgens to estrogens, originally approved by FDA as a treatment of breast cancer in postmenopausal women. In several studies, it has been proposed that AI appears effective to improve the final adult height especially combined with rhGH therapy, by delaying growth plate closure. Patients treated with rhGH showed highest growth rate during the first year of treatment, with an average increase of 8–10 cm per year (often called “catch-up” growth), however, followed by a progressive decrease in growth rate over the next several years, which is called “waning effect” of rhGH. In this report, we would like to introduce 2 cases of short pubertal boys showing booster effect of AI when co-treated with rhGH, to overcome waning effect of rhGH and improve the final adult height. Case 1. A boy at the age of 8 years and 1 month visited out clinic with short stature. His height was 118cm (4%), weight was 19.2kg (0%). His MPH was calculated as 173cm. Bone age was 6.9 years by the TW3 method. Initial laboratory finding showed no other abnormal findings including normal IGF-1 levels, so we diagnosed the patient as idiopathic short stature (ISS), and started rhGH treatment. During the rhGH treatment of 4 years and 9 months, the patient obtained additional 30.7cm growth to 148.7cm (23%). However, the patient showed decreased growth velocity of 2.2 cm in the last 6 months, which was thought to be “waning effect” of rhGH. The patient and his parents wanted to improve his height using AI, and after taking agreement about the drug, we added AI. During the combined treatment of 1 year and 10 months, his height was improved to 164.9cm (32%) with a gain of 16.2cm, and no adverse reaction was observed. Case 2. A 8 years and 2 months-old boy visited out clinic with short stature. His height was 116.3cm (0%) and weight was 22.6kg (14%). There have been no unusual findings in past history and family history. His MPH was calculated as 165.9cm. Bone age was 8.2 years by the TW3 method. He was also diagnosed as ISS, and started rhGH treatment. During 5 years and 1 month of rhGH treatment, the patient obtained additional 33.3cm growth to 149.6cm (17%). However, the patient showed progressive decreased growth velocity of 3.3 cm in the last 6 months, so we added AI treatment, and after the combined treatment of 1 year and 5 months, his height was 161.6cm (23%). After that, his parents wanted to quit AI, so we maintained only rhGH treatment for 7 months, and his final height was checked as 167cm. In our cases, we suggest that the additional use of AI to patients with progressive decreased growth rate during previous years of GH treatment can improve growth velocity again, and increase the final adult height with successful bone age suppression, which has not been reported before. Therefore, AI could be expected as effective booster drug to overcome waning effect of rhGH.
SAT-054 Gigantism and Hypothalamic Obesity: Rare Endocrine Manifestations of Neurofibromatosis Type 1
Authors: Roberts Richard Ogden , Chambers Christina
Published: May 2020

Background: Neurofibromatosis type 1 (NF-1) is a heritable, autosomal dominant, multisystem disorder caused by mutations or deletions in NF1, with approximately 30-50% of cases arising from de novo mutations. In the pediatric population, growth hormone deficiency is among one of the most commonly described endocrine sequelae, although aberrations of pubertal development are also commonly seen.

Clinical Case: A 3-year-old female, who was clinically diagnosed with NF-1 at the age of 4 months based on the presence of multiple café-au-lait macules, underwent screening MRI, which noted a left optic glioma and a hypothalamic mass favored to represent a hypothalamic glioma. Review of her growth chart showed a height much greater than the 99th percentile, with an increase in height velocity beginning 1 year prior. Weight was also noted to be much greater than the 99th percentile, with an increase in weight gain coinciding with the timing of alterations in linear growth. Mid-parental height is at the 95th percentile, and the patient’s height had tracked between the 86th and the 99th percentiles until age 2 years. Weight had tracked between the 68th and the 95th percentiles during that period. Initial laboratory evaluation showed an IGF-1 of 644 ng/mL (26-164 ng/mL). Gonadotropins were prepubertal; prolactin and thyroid studies were normal. ACTH stimulation demonstrated a rise in serum cortisol from 6.8 mcg/dL to 30.2 mcg/dL at 60 minutes. Growth hormone failed to suppress following an oral glucose load with a baseline GH of 4.4 ng/mL and values of 3.7, 6.5, 6.8, and 9.0 ng/mL at time +30, +60, +90, and +120 minutes respectively. Leuprolide stimulation did not show significant rises in gonadotropins. Bone age was advanced by more than 1 year. The patient was started on subcutaneous octreotide with a decrease in IGF-1 to 258 ng/mL after 1 month of therapy. On treatment, linear growth velocity slowed with no interval height gain over the initial 1-month period; however, the patient’s weight continued to increase with a gain of 1.8 kg. Parents additionally reported hyperphagia, which prompted concern for hypothalamic obesity in the setting of her known hypothalamic mass. Thyroid function remained normal on somatostatin therapy. To date, there has been no concern for diabetes insipidus.

Conclusion: Growth hormone excess may rarely complicate a diagnosis of NF-1 in the setting of intracranial gliomas. Increased height velocity and/or tall stature for family should raise clinical suspicion and prompt evaluation. Hyperphagia and significant increases in weight in the setting of hypothalamic gliomas in patients with NF-1 should raise suspicion for hypothalamic obesity and prompt lifestyle modifications to curb ongoing weight gain.
SUN-234 Brain-Selective Estrogen Therapy to Prevent Androgen Deprivation Therapy-Related Hot Flushes
Authors: Merchenthaler Istvan , Lane Malcolm , Stennett Christina , Zhan Min , Prokai Laszlo
Published: May 2020

Synthetic estrogens are used in the clinic to alleviate debilitating neurological symptoms associated with androgen deprivation therapy (ADT), an effective treatment improving survival in prostate cancer patients when administered timely in the course of the cancer. However, this therapy to relieve the symptoms, most commonly hot flushes, causes feminizations that significantly diminishes patients’ compliance because of physical and psychological discomfort. Because only estrogens can provide adequate therapy of hot flushes based on current clinical practices, there is an unmet medical need for an effective, side effect-free and, consequently, compliance-gaining intervention to alleviate these vasomotor symptoms distressing prostate cancer patients on ADT. The goal with our experiments was to show that treatment with 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED, a brain-selective bioprecursor prodrug of 17β-estradiol (E2) will ease ADT-associated hot flushes without feminizing side-effects.

To evaluate the effect of DHED on hot flushes the pharmacological rat hot flush model was used. Orchiectomized (ORDX) rats were treated orally with three different doses (10, 30, and 100 µg/kg) of DHED or ethynyl estradiol (EE, 200 µg/kg) for ten days. They were addicted to morphine and the tail skin temperature (TST) of saline-treated rats raised by 4.4±0.5 °C when morphine effect was withdrawn with naloxone injection. DHED and EE treatments significantly lowered such TST rise from 4.4 °C to 2.9 ±0.5°C and 1.8 ±0.5°C, respectively.

The conversion of DHED to E2 in the brain was confirmed by measuring the effect of DHED-derived E2 on the expression of progesterone receptors (PR) in the preoptic area of the hypothalamus with in situ hybridization histochemistry. Both DHED and EE treatment stimulated PR expression compared to saline-treatment in ORDX rats.

In our previous studies, we have shown the lack of conversion of DHED to E2 in the periphery in ovariectomized female rats; i.e., DHED treatment did not have uterotrophic, mammotrophic activities and did not stimulate galanin expression in the anterior pituitary. In these studies, the lack of conversion of DHED to E2 was also confirmed in male rats by measuring the expression of galanin, a highly estrogen-regulated gene, in the pituitary with quantitative RT-PCR. Contrary to EE, DHED treatment did not stimulate galanin expression in this estrogen target.

These observations support subsequent translational research focusing on DHED’s therapeutic use to remedy hot flushes and potentially other neurological symptoms in prostate cancer patients undergoing ADT to manage their malignancy. An estrogen therapy with the brain-selective DHED would provide a safe approach to prevent these neurological symptoms without causing peripheral estrogenic side effects such as gynecomastia or deep vein thrombosis.
OR14-01 FSTL3 Neutralizing Antibodies Restore Function to Diabetic Mouse and Human Islets: A New Approach for Treating Diabetes
Authors: Schneyer Alan , Brown Melissa L , Meyer Nolan , Lopez Alexa , Richter Alden
Published: May 2020

Activin, GDF11 and myostatin are structurally related members of the TGFbeta superfamily of growth factors with many biological roles in animal models and humans. Their actions are neutralized by extracellular proteins such as follistatin and follistatin like-3 (FSTL3). We have previously demonstrated that genetic inactivation of Fstl3 results in enlarged pancreatic islets containing increased numbers of beta cells that produce more insulin in response to glucose compared to wild type litter mates. We further discovered that at least some of these new beta cells arise via transdifferentiation from alpha cells. We also demonstrated that functional human islets from normal donors produce very high levels of activin. In contrast, activin biosynthesis is vastly reduced and FSTL3 synthesis is significantly increased in human islets from diabetic donors suggesting that activin is critical for normal insulin production. This was substantiated by direct treatment of human diabetic islets with activin which restored their response to glucose. These observations support the hypothesis that an FSTL3 neutralizing antibody would constitute a novel therapeutic approach to curing diabetes through restoring beta cell function as well as accelerating generation of new beta cells through transdifferentiation. To test this hypothesis, we produced a mouse monoclonal antibody that neutralized hFSTL3 (FP-101), thereby releasing bioactive activin, GDF11, and myostatin. We have now tested this antibody for biological activity in vitro on mouse and human islets. We used islets from high fat diet (HFD) treated mice to model diabetes-inducing effects of obesity as well as 24-hour incubation in hyperglycemic (33 mM glucose) medium to create human islets that lose responsiveness to high glucose as a model for human diabetes. In mouse islets we found that stimulation of normal (chow diet) islets by high glucose produced a stimulation index (SI) of 3.5 that was reduced to 2 in HFD islets. Treatment with activin, FP-101, or a commercial polyclonal antibody to mFSTL3 all increased response of HFD islets to elevated glucose and partially restored SI to normal levels. In human islets, hyperglycemia eliminated the normal (2.5 SI) response to high glucose while activin or FP-101 treatments dose-responsively restored this response. These results demonstrate that anti-FSTL3 therapy can restore function to compromised beta cells from mouse and human diabetes models. The observation that activin has the same action as anti-FSTL3 antibody indicates that FP-101 works through enhancing the activin signaling pathway. Finally, these results demonstrate that the FSTL3-activin pathway is an important regulator of beta cell function in humans as well as mice, supporting further development of this therapy as a diabetes treatment.
SUN-653 Bypassing Skeletal Muscle Lipid Handling Deficiencies as a Therapy for Metabolic Disease
Authors: Fan Liyan , Sweet David R , Prosdocimo Domenick A , Keerthy Komal S , Jain Mukesh K
Published: May 2020

Metabolic diseases and their serious sequelae such as non-alcoholic fatty liver disease (NAFLD) pose a substantial clinical burden. It is now well recognized that skeletal muscle is a major site for the metabolism of all major macronutrients, and derangements in these muscle processes significantly contribute to metabolic disease. Studies over the last 15 years have identified the transcription factor Krüppel-like factor 15 (KLF15) as an important regulator and effector of metabolic processes across various tissues, and furthermore, genome-wide studies have identified human KLF15 variants with increased body mass index and diabetes. Given the importance of skeletal muscle in maintaining metabolic homeostasis, we generated a skeletal muscle specific KLF15 knockout (K15-SKO) mouse to study the role of skeletal muscle KLF15 in regulating systemic metabolism. We found that this animal is prone to developing obesity and insulin resistance at baseline, a phenotype that is greatly exacerbated in response to high fat diet (HFD). Strikingly, K15-SKO mice show a propensity toward developing NAFLD, as demonstrated by increased micro- and macrovesicular steatosis, hepatocellular ballooning, increased hepatic fatty acid and triglyceride deposition, and elevated Cd36 expression. A potential cause of NAFLD is the accumulation of excess lipids and lipid intermediates due to defects in the lipid flux pathway in extrahepatic tissues. Indeed, we see defects in the expression of genes involved in the carnitine shuttle and a paucity of long-chain acylcarnitines in K15-SKO skeletal muscle. Furthermore, RNA sequencing of skeletal muscle from K15-SKO mice shows downregulation in a number of pathways involved in lipid handling. This indicates that KLF15 serves as a novel extrahepatic molecular regulator of hepatic health. It has been previously shown that a diet rich in short-chain fatty acids (SCFA) can bypass defects in lipid handling and ultimately improve metabolic health. To explore this therapeutic avenue, we gave K15-SKO mice either normal chow (NC) or a SCFA-rich diet for 7 weeks. We observed decreased weight gain and improved glucose homeostasis in SCFA-rich diet fed mice. In addition to being a preventative strategy, SCFA-rich diets may also serve as a potential therapy to rescue from metabolic disease. To this end, we gave K15-SKO mice HFD for 5 weeks followed by 7 weeks of either NC or SCFA-rich diet. We observed that providing SCFAs can improve metabolic health and ameliorate the phenotype seen due to defects in skeletal muscle lipid handling: mice given SCFA-rich diet following HFD had significantly decreased weight gain and improved insulin sensitivity. These studies demonstrate that skeletal muscle KLF15 serves as an important regulator of lipid flux and hepatic health, and that SCFA-rich diets are a promising candidate for metabolic disease resultant of impaired lipid handling.
SAT-641 Self-Reported Psychological Stress and Glucose Variability in Type 1 Diabetes on Sensor Augmented Pump over 5 Weeks
Authors: Kaur Ravinder Jeet , Pinsker Jordan E , Dadlani Vikash , Thapa Prabin , Batthula Sreedhar , Church Mei Mei , Reid Corey , Spitzer Shelly McCrady , Kremers Walter K , Dassau Eyal , Kudva Yogish C
Published: May 2020

Introduction: Patients and their families and medical providers have assumed that psychologic stress impacts glucose control in T1D (Type 1 Diabetes) though studies providing confirmatory evidence in real world settings are, to our knowledge, lacking. We hypothesized that self-reported psychologic stress worsens glucose control in T1D.

Method: We studied 20 adults with T1D on continuous glucose monitor (CGM), sensor augmented insulin pump (SAP) prospectively at 2 clinical research centers. Patients reported psychological stress through stress diaries for 5 weeks on a severity scale of 1-7 using hard copy logs including time of onset and offset of stress and severity. For analytic purpose, grades 1-4 are classified as mild and grades 5-7 as severe.

Results: Baseline characteristics were age 44.9±15.0 years, F/M 12/8, HbA1c 6.8 ± 0.7%, and diabetes duration of 22.9±15.9 years. We analyzed glucose variability during days of stress versus days without stress. During a 24 hour period, patients experienced less hypoglycemia during days with stress versus days without stress (p value 0.03). During the 5 week period, patients reported 23 ± 19.5 events. We analyzed the impact of self-reported stress on CGM data streams after excluding stress events associated with missing CGM data, nocturnal events (from 12 MN to 6 AM, too few events) and events for which subjects did not provide duration of stress. Thus, we analyzed 19.5 ± 17 events per patient from 6AM to 12MN. From 6 AM to 12 MN, the episodes lasted 179 ± 255 minutes with 83 % episodes being mild/moderate and 17% moderate/ severe. Number of CGM readings during daytime stress episodes were 717± 1120 compared to 8768± 1238 during non-stress periods. Impact of stress from 6 AM to 12 MN (Mid-Night) on CGM glucose was analyzed using matched paired t test. Mean glucose (160.6±41.9 vs 148.3± 28.6) and SD (53.2 ±17.7 vs 56.1±14.6) did not show a difference; however % of time spent below 70 mg/dl was less (4 ± 5) in patients during stressful periods compared to times without stress (6.3± 5.5, P value 0.02).

Conclusions: To our knowledge, this is the first study attempting to analyze the impact of self-reported stress using daily stress diaries on CGM data streams in T1D patients on SAP. The study revealed significant challenges experienced by patients in reporting adequate data. Self-reported stress was not associated with hyperglycemia. However, days of self-reported stress and periods during patients reported stress were characterized by less hypoglycemia on CGM data streams.
OR05-02 The IGFBP-3/IGFBP-3 Receptor Axis Is a New Therapeutic Target for Triple Negative Breast Cancer
Authors: Cai Qing , Harrell J Chuck , Koblinski Jennifer , Oh Youngman
Published: May 2020

Insulin-like growth factor binding proteins (IGFBPs) are components of the IGF signaling system, which is comprised of ligands IGF-I and IGF-II as well as a family of transmembrane receptors including the IGF-IR and IGF-IIR. IGFBPs bind to both IGF-I and IGF-II with high affinity and are essential for transporting IGFs. This prolongs their half-lives and regulates the availability of free IGFs for interaction with IGF receptors, thereby modulating the effects of IGFs on growth and differentiation. Amongst the six IGFBPs, IGFBP-3, the only IGFBP species regulated by the p53 tumor suppressor, is a well-documented potent tumor suppressor in a variety of human cancer. IGFBP-3 has been further suggested as a potent anti-metastatic factor. Recently, more direct evidence for antitumor effect of IGFBP-3 has been reported in various cancer cells including triple negative breast cancer (TNBC) cells in vitro and in vivo, but the underlying mechanisms of antitumor action of IGFBP-3 are largely unknown.

We have identified a new class of cell death receptor called IGFBP-3R, which constitutes a novel cell-death receptor that mediates the anticancer effects of IGFBP-3 in human cancer. IGFBP-3 is significantly reduced whereas IGFBP-3R is broadly expressed in many human cancer types such as breast, prostate, lung and colon cancer. In order to discover novel IGFBP-3/IGFBP-3R antitumor signaling as a therapeutic target, a panel of IGFBP-3R specific monoclonal antibodies (mAbs) have been generated and further identified IGFBP-3R agonistic mAbs acting like IGFBP-3 showing anticancer effects in human cancer cells. Further in vivo studies using a bioluminescent orthotopic TNBC mouse model and Patient Derived Xenograft (PDX) TNBC mouse models demonstrated that administration of IGFBP-3R agonistic mAbs results in significant shrinkage of primary and metastatic tumors up to 75%, accompanying induction of caspase-dependent apoptosis and suppression of tumor-activated NF-κB signaling. More importantly, IGFBP-3R agonistic mAbs have synergistic anticancer effects with therapeutic agents such as carboplatin and Bcl-2 family inhibitors in a variety of human cancer including TNBC, and it was further identified molecular mechanisms involved in its synergy in vitro.

These findings clearly demonstrate the IGFBP-3/IGFBP-3R system as a new target and the IGFBP-3R agonists such as IGFBP-3R agonistic mAbs as a new monotherapy and a combination therapy with therapeutic agents for TNBC.
SAT-354 Isolated Hypoparathyroidism: A Rare Initial Manifestation of Hereditary Hemochromatosis (HH)
Authors: Shaheen Zainab , McCann Kevin , Khthir Rodhan Abass
Published: May 2020

Background:

We present a case of hypoparathyroidism diagnosed in a patient as initial manifestation of hereditary hemochromatosis. As per our literature search, it is very rarely reported as an isolated abnormality in HH.

Case:

A 27 year old male with history of seizure disorder, well controlled on Oxcarbazepine, referred for evaluation of chronic hypocalcemia. His PMH includes cerebral palsy, with good functional capacity and mild cognitive impairment. He denied muscle spasm, perioral numbness, bone pain, muscle weakness or fracture. He was taking calcium carbonate 600mg bid and vitamin D 50,000 IU q2monthly.

There was no family history of any Ca disorders. Physical exam was unremarkable.

Laboratory evaluation revealed Ca levels ranging from 7.6 to 8.5mg/dl with intact PTH values ranging from 11 to 22pg/ml. His ionized calcium was also low. Patient’s 24 hr urinary Ca was 122mg/24hrs. In this case, he did initially have hypomagnesemia and vitamin d deficiency, which could potentially explain low calcium. But even after supplementing Vitamin D and Mg, patient’s Ca remained low. His kidney function was normal. Hemoglobin was in range of 14-15g/dl. To further evaluate the cause of hypoparathyroidism, iron saturation and iron levels were also sent. His iron saturation % was high at 89% with iron level of 286 ug/dl. His ferritin was 224 ng/ml and TIBC was 265 ug/dl. A sample was sent for genetic analysis to rule out hemochromatosis. Homozygous mutations in C282Y gene were found. A diagnosis of hereditary hemochromatosis was made. His other entire hormonal axis was intact. In this case, patient’s hypoparathyroidism is likely an initial manifestation of his HH.

Discussion:

Hereditary Hemochromatosis (HH) is a genetic disease characterized by an excessive (unregulated) entry of iron into the bloodstream with increased iron deposition in the parenchymal cells of a variety of organs leading to their failure. A defect in the hemochromatosis gene (HFE) is the most common form of HH, also known as the classic form or type 1 HH, where the principal mutation is represented by a substitution of tyrosine for cysteine at position 282 of the HFE gene (C282Y) as seen in our case. According to the genetic forms, the clinical manifestation usually ranges from simple biochemical abnormalities to severe organ damage and disease such as liver cirrhosis, arthritis, DM, cardiomyopathy and hypogonadism.

There are reports of hypoparathyroidism from iron overload seen in thalassemia patients and patients who receive long term blood transfusions. In our literature review, this is the first documented case of HH initially manifesting as hypoparathyroidism. As HH is not uncommon in Caucasians, the work up for hemochromatosis as a possible cause of endocrinopathies should be kept in the differential diagnosis. It will help in early diagnosis & treatment which can reverse the effects of the disease leading to better outcomes.
SAT-659 Micro/Nanoparticles from Antidiabetic Chinese Herbal Medicine Soup Increase Bioavailability of Phytochemicals and Regulate Glucose and Lipid Metabolism
Authors: Ke Lijing , Rao Pingfan
Published: May 2020

Herbal soups have always been a popular option for treating oxidative stress-related chronic diseases including diabetes. Various components of these soups have been studied in the hope to identify the active principles, mainly focusing on the individual phytochemicals. As we have revealed previously, the micro/nanoparticles (MNPs) formed incidentally during the boiling water extraction of herbal soups may be bioactive and functional. This study aims to elucidate the underlying mechanism of the biological functions of these MNPs. A Chinese herbal medicine soup prepared by Radix Puerariae lobatae, ginger and other three herbs, namely Ge-Gen-Qin-Lian-Tang, was employed here, as it was proven to be effective in treating type 2 diabetes clinically.

The soup was separated with high-speed centrifuge (15600×g) to obtain the supernatant (solutes and nanoparticles) and sediments (MNPs), and determined for the content of three bioactive phytochemicals, e.g. puerarin, berberine and baicalin. Their hypoglycemic, hypolipidemic and antioxidant effects were determined on streptozotocin (STZ)-induced Type 2 diabetic Wistar male rats fed on high fat-high sugar diet. The animals were divided into six groups (normal control, diabetic model, whole soup, supernatant, MNPs and metformin, 8 rats each), recording weight, diet, excretion, mental status, etc. The fasting blood glucose and oral glucose tolerance test were conducted regularly. Eight weeks after the administration, the rats were sacrificed after anesthesia. Abdominal aorta blood and tissue samples of pancreas, heart, skeletal muscle, liver, kidney, spleen were collected. The glycated hemoglobin, glucose, lipid, insulin, glucagon, AMPK, SOD, puerarin, berberine, baicalin in blood plasma, insulin in pancreas, SOD in tissues, AMPK in skeletal muscle were measured. Liver tissue sections were observed with HE staining. Statistical analysis (t-test) were performed.

The MNPs reduced blood glucose, ameliorated glucose tolerance, elevated insulin secretion and significantly improve glucose and lipid metabolism (P <0.05), showing stronger effects than the supernatant components. Notably, MNPs elevated the AMPK level in skeletal muscle, even more potently than the whole soup. The therapeutic effects of MNPs on the liver damage were even stronger than metformin. Meanwhile, MNPs promoted absorption of puerarin, berberine and baicalin and increase their concentration in blood (P <0.05). Therefore, the MNPs from the herbal soup exhibited more potent effects than the soluble components on ameliorating glucose and lipid metabolism and pancreatic functions of diabetic rats. The actions of these MNPs provide a new perspective for understanding the antidiabetic effects of herbal soups and serve as a vehicle for the multiple phytochemicals to synergistically possess therapeutic effects.
SUN-049 Male Pattern Baldness and Waist-Hip Ratio as Markers of Arterial Stiffness in Transgender Men Undergoing Long-Term Testosterone Therapy
Authors: Alvares Leonardo Azevedo Mobilia , Cunha Flávia Siqueira , Oliveira Tainã Aci Amaral , Mendonca Berenice Bilharinho , Costa Elaine Maria Frade , Costa-Hong Valéria Aparecida , Bortolloto Luiz Aparecida , Domenice Sorahia
Published: May 2020

Introduction: Association between male pattern baldness, also called androgenetic alopecia (AGA) and risk of coronary artery disease has been suggested by several epidemiological studies. Exogenous testosterone (T) therapy in transgender men (TM) promotes the development of alopecia in genetically susceptible individuals, and increases facial and body hair, muscle mass (MM) and visceral fat. The outcome of a long-term androgenic therapy over the functional properties of large arteries and the cardiovascular system of TM are not well stablished. Objective: To investigate the possible association between AGA and arterial stiffness assessed by measurement of carotid-femoral pulse wave velocity (VOPcf) and intima-media thickness carotid artery (cIMT) in TM receiving long-term T therapy. Methods: Forty-six TM (mean age: 43 ± 10 yo) undergoing T therapy (mean time of treatment duration: 13 ± 10 y; mean serum T levels: 611 ± 439 ng/dL) were evaluated in a cross-sectional study. Hair pattern (Ferriman & Gallway scale), grades of male pattern baldness (Hamilton-Norwood scale) and waist-hip ratio (WHR) were analyzed. Subjects were considered to have AGA if they have vertex alopecia (grade ≥ 3). Arterial Hypertension was defined as systolic blood pressure > 140 and/or diastolic blood pressure > 90mmHg or under pharmacological treatment, and dyslipidemia as total cholesterol ≥ 240 mg/dL and/or LDL-c≥ 160 mg/dL and/or HDL-c < 40 mg/dL and/or triglycerides > 200 mg/dL, or under pharmacological treatment. Current smoking has been investigated. The aortic stiffness, assessed by VOPcf and cIMT, was measured using the Complior® device and carotid ultrasound, respectively. Results: TM’s Ferriman degree was 21 ± 6 and AGA was identified in 70% of them. The WHR was 0.9 ± 0.1. TM with AGA showed higher cIMT than TM without AGA (0.66 ± 0.1mm vs. 0.54 ± 0.07mm, p = 0.001), as well as higher WHR (0.93 ± 0.08 vs.0.87 ± 0.04, p = 0.02), higher score in terminal body hair (Ferriman 23 ± 6 vs. 18 ± 6, p = 0.007) and higher frequency of hypertension (94% vs. 6%, p = 0.01). The cIMT positively correlated with age (p = 0.01) and WHR (p = 0.002). The VOPcf was positively correlated with the age (p = 0.0001), androgen treatment duration (p = 0.01) and WHR (p = 0.04). There was a positive correlation between androgen treatment duration and WHR (p = 0.01). There was no difference in the VOPcf values, age, T treatment duration, serum T levels, frequency of dyslipidemia and smoking between the groups. Conclusion: The severe vertex AGA pattern may be considered a possible marker of arterial stiffness in TM undergoing long-term testosterone therapy.
MON-200 Clinical Characterizations of Aldosterone- and Cortisol-Producing Adrenal Tumors in Primary Aldosteronism
Authors: Guo Jingcui , Chen Xiaoyu , Zhang Junqing , Guo Xiaohui , Gao Ying
Published: May 2020

Objective: Aldosterone- and cortisol-producing adrenal tumors (A/CPTs) are considered to be a subtype of primary aldosteronism (PA). The clinical characterizations of these tumors are still unclear, and they are often neglected by clinicians. The aim of this study was to summarize the clinical characterizations of these tumors to reduce the missed diagnosis.

Methods: The clinical, imaging and pathological data of patients with PA admitted to our hospital from January 1, 2013 to December 31, 2016 was reviewed. All the PA patients with a combination of a positive aldosterone-to-renin ratio (ARR) and a positive captopril challenge test (CCT), in whom the dexamethasone inhibition test was performed as well, were included in our study. These patients were divided into two groups, A/CPTs group and simple PA group, according to the function of cortisol secretion. The data of the two groups were compared and analyzed with SPSS 23.0. P<0.05 was statistically significant.

Results: There were 87 patients with PA included in our study, 32 of whom (36.8%) were diagnosed with A/CPTs. In these 32 A/CPTs patients, 31 patients (96.9%) were combined with subclinical Cushing syndrome. Compared to these in simple PA group (n=55), the patients in A/CPTs group (n=32) were elder (53.81±10.70 ys vs 48.42±10.17 ys, P=0.022), with larger diameter of adrenal tumors (1.50cm vs 1.15cm, P=0.001), higher fasting plasma glucose (5.33mmo/L vs 4.99mmol/L, P=0.047), higher serum cortisol levels and lower serum ACTH levels (all P<0.05). 24 patients in A/CPTs group and 23 patients in simple PA group underwent adrenalectomy. 6 patients (25.0%) in A/CPTs group and 3 patients (13.0%) in simple PA group received glucocorticoid replacement therapy after adrenalectomy.

Conclusions:The prevalence of A/CPTs in PA is high. The patients with A/CPTs are mainly combined with subclinical Cushing syndrome, and prone to need glucocorticoid replacement therapy. Therefore, we recommend that all patients with PA should evaluate the function of cortisol secretion, and all patients with A/CPTs should be followed up closely after adrenalectomy to reduce the morbidity of adrenal insufficiency.
SAT-671 Glycogenic Hepatopathy. A Rare and Dramatic Manifestation of Poorly Controlled Type 1 Diabetes
Authors: Maciel Cassie , Salvo Rebecca , Wilson Mark D
Published: May 2020

Background: Glycogenic hepatopathy (GH) is a well described, yet underdiagnosed disorder in type 1 diabetes. Erratic blood glucose values and high insulin levels promote the excessive deposition of glucose storage in the liver as glycogen, resulting in hepatomegaly, right upper quadrant pain and abnormal liver function. GH was first described with the introduction of insulin as a therapy to treat type 1 diabetes in the early 20th century. As our ability to effectively treat type 1 diabetes mellitus has improved, GH is seen much less commonly. Today, GH generally effects adolescent or young adult patients with poorly controlled type 1 diabetes mellitus and DKA. It is reversible with successful treatment of hyperglycemia.

Clinical Case: An 18 year old woman with a history of poorly controlled type 1 diabetes mellitus and frequent admissions for DKA was admitted for DKA and pyelonephritis. On admission, the patient complained of significant right upper quadrant pain and was found to have elevated transaminase values of: AST 1199 U/L (<37 U/L), ALT 371 U/L (56 U/L), an elevated alkaline-phosphatase of 319 IU/L (<135 IL/L) and normal indices of biosynthetic function (INR/PT). After inpatient treatment of DKA and pyelonephritis, the right upper quadrant pain persisted and required pharmacologic analgesia. Radiographic evaluation demonstrated severe hepatomegaly (24 cm in maximum length) without focal lesions. Laboratory evaluation for viral hepatitis, autoimmune hepatitis, Celiac Disease, Wilson’s Disease and hemochromatosis were unremarkable. Given the patient’s persistent symptoms and severity of hepatomegaly, hepatic biopsy was performed.Biopsy findings were consistent with glycogenic hepatopathy demonstrating steatosis and glycogen deposition with nucleic glycogenation and mega mitochondria.Our patient had higher than usual insulin requirements for type 1 diabetes (~1 unit/kg/day). Abdominal pain, hepatomegaly and elevated LFTs resolved over a 2 month duration with improvement in her blood glucose control. Conclusions: GH is an established yet rare complication of poorly controlled type 1 diabetes. Glycogen deposition in the liver leads to painful hepatomegaly due to stretching of the liver capsule. GH has a female predominance (77%) and is characterized by elevated AST >>ALT with preserved liver biosynthetic function.It is postulated that GH is a result of elevated blood glucose levels and elevated insulin levels. The patient we describe has long standing poorly controlled type 1 diabetes mellitus, frequent admissions for DKA and high insulin requirements. To our knowledge, insulin requirements have not been investigated or previously reported as a potential risk factor for this condition.
MON-468 Hypoechoic Nodule Is Not Always the Bad Guy: Lessons Learned from a Patient with Subacute Painful Thyroiditis
Authors: Vorasart Pakaworn , Sriphrapradang Chutintorn
Published: May 2020

Introduction: The diagnosis of subacute painful thyroiditis (SAT) is primarily based on clinical manifestations (thyroid tenderness and diffuse goiter). Suppressed TSH, elevated erythrocyte sedimentation rate (ESR) and low thyroid uptake help confirm the diagnosis. Thyroid ultrasonography and fine-needle aspiration biopsy (FNAB) are rarely necessitated. SAT produces a typical sonographic findings of ill-defined heterogeneously hypoechoic areas, which is difficult to differentiate from thyroid carcinoma. We herein report a patient with SAT who was initially diagnosed as malignancy. Case Presentation: A 36-year-old female had pain and swelling at the left thyroid gland for 3 weeks. A left thyroid nodule was diagnosed by her primary care physician. Ultrasonography revealed a poorly defined hypoechoic nodule measuring 2.5x1.1x1.5 cm at the mid pole of the left thyroid gland, for which biopsy was recommended. The nodule showed peripheral vascularity and no calcification. No suspicious cervical lymphadenopathy was detected. Histologic analysis from core biopsy found findings consistency with follicular neoplasm. Thyroid function tests were within normal range. She was treated with ibuprofen as management of thyroid pain and referred for surgery. However, the repeated ultrasonography was performed by endocrinologist in the next 2 weeks and found an interval reduction in size of hypoechoic lesion. FNAB was performed due to the risk of infiltrative malignancies. Cytologic analysis was compatible with SAT. ESR was slightly elevated. Surgery was cancelled and she was treated with ibuprofen. Two weeks later, she reported that the left thyroid pain and swelling had subsided. However, she developed thyroid pain associated with glandular tenderness and swelling of the right thyroid. On sonographic examination, the right lobe, which was previously normal was now similarly affected. Thyroid function showed thyrotoxicosis. The patient was given a further course of beta-blocker, ibuprofen and prednisolone for 2 weeks and recovered well. On follow-up at 2 months, the patient developed biochemical hypothyroidism and received levothyroxine replacement. The lesions in the thyroid gland were not visualized in the 6-month follow-up sonography. Conclusion: The ultrasonographic features of the thyroid during the acute stage of SAT may mimic thyroid carcinoma. Awareness of the sonographic findings and interval changes of SAT lesions may helpful for proper diagnosis and treatment of SAT.
MON-666 Glucokinase Within the Hypothalamic Paraventricular Nucleus Is Important in GLP-1 Release
Authors: Ratnasabapathy Risheka
Published: May 2020

When glucose is taken orally more insulin is secreted than when glucose is injected directly into the bloodstream. This is known as the incretin effect. Glucagon like peptide 1 (GLP-1) is one of the hormones responsible for this effect. GLP-1 is released from enteroendocrine L-cells in the gut in response to oral glucose intake. GLP-1 increases insulin synthesis and secretion. Release of GLP-1 is thought to be solely dependent upon gastrointestinal tract mechanisms. Here we identify a brain mechanism via the hypothalamic paraventricular nucleus (PVN) which is important in the release of GLP-1 in response to oral glucose. The role of the paraventricular nucleus in glucose homeostasis was previously unknown. We found that a glucokinase dependent glucose sensing mechanism in the PVN works in conjunction with the gut to regulate GLP-1 release. We show that increasing expression of GK (sense GK, sGK) into the PVN improves glucose tolerance (15 minutes glucose: GFP: 8.93±0.27mmol/L, n=11; sGK: 7.72±0.22mmol/L, n=12; p<0.01 and 15 minutes insulin GFP: 2.84±0.14mmol/L, n=11; sGK: 3.73±0.27mmol/L, n=12; p<0.01) and increases GLP-1 release in response to oral glucose (GFP: 6.16±0.18mmol/L, n=11; sGK: 6.90±0.26mmol/L, n=12; p<0.01). On the contrary decreasing expression of GK (antisense GK, asGK) in the PVN worsens glucose tolerance (30 minutes glucose: GFP: 8.22±0.28mmol/L; asGK: 9.46±0.24mmol/L, n=8; p<0.01 and 15 minutes insulin: GFP: 4.07±0.37mmol/L; asGK: 2.25±0.17mmol/L, n=8; p<0.001) and blunts (GLP-1 release 30 minutes GLP-1: GFP: 6.93±0.25pMol/L, n=8; p<0.01 asGK: 5.47±0.13pMol/L, n=8; p<0.001). Our results demonstrate that glucosensitive GK neurones in the PVN, are important to the response to oral glucose and the subsequent release of GLP-1.
SUN-640 Sex-Specific Difference in REG3G Expression Directs the Maintenance of Islet Function in Offspring of Obese Mice
Authors: Casasnovas Jose , Jarrell James C , Kua Kok Lim
Published: May 2020

Offspring exposed to maternal obesity are more likely to develop pancreatic islet dysfunction, but the underlying mechanistic pathway is unclear. We previously reported that fetal rats exposed to in-utero hyperglycemia had decreased fetal β-cell REG3G, and then developed lower β-cell mass and insulin secretion at adulthood. REG3G is reported to bind EXTL3 which initiates heparan sulfate (HS) synthesize important for pancreatic islet integrity. In this study, we sought the delineate the impact of maternal obesity exposure in altering offspring islet Reg3g and HS, and determine how changes in Reg3g and HS alters offspring islet insulin secretion. We hypothesize that exposure to maternal obesity (MatOb) suppresses offspring β-cell REG3G leading to decreased HS affecting β-cell health/function. We induced maternal obesity by feeding female mice western style diet for 4 weeks, while control mice were fed with regular chow. Offspring were evaluated for fat body mass, glucose intolerance, insulin secretion at postnatal day 21 and at 2-month-old. MatOb mouse offspring had increased fat-to-lean ratio and glucose intolerance but no insulin resistance at postnatal day 21, indicating decreased islet function. We performed islet perifusion to measure insulin induced secretion in postnatal day 21 offsprings. We found that male offspring but not female had impaired insulin secretion. In 2-month old offspring fat-to-lean ratio persisted but only males presented glucose intolerance. We found that pancreatic islet Reg3g expression was higher in MatOb females than males. This was accompanied increased HS in pancreatic islets of MatOb females compared to males. All together our data indicates a sex-specific protective role of Reg3g/HS in pancreatic islet function.