bluuebunny/crossref_metadata_2025 huggingface dataset:
PSUN63 Approach to hyperlipidemia management in Carnitine Palmitoyltransferase II deficiency
Authors: Anbari Raghda A , Ghayee Hans , Xhikola Majlinda , Kadiyala Sushma
Published: November 2022

Background

Carnitine Palmitoyltransferase II deficiency (CPT II) is a disorder of long-chain fatty-acid oxidation. Clinical presentations include a lethal neonatal form, severe infantile hepatocardiomuscular form, and myopathic form. The myopathic form is the most common disorder of lipid metabolism affecting skeletal muscle. Individuals with CPT II deficiency are unable to metabolize long-chain fatty acids and can have myalgia. The incidence of statin-induced muscle symptoms is 1.5% to 5%. Individuals with CPT II deficiency have been reported to have an increased incidence of statin-associated myopathy. Yet, it remains crucial to place patients with high ASCVD risk on the appropriate statin therapy.

Case Presentation

We present a 70-year-old male with medical history of CPT II deficiency (myopathic form), hyperlipidemia with significant hypertriglyceridemia, hypertension, type 2 diabetes mellitus, carotid artery stenosis, atrial fibrillation, and recurrent pancreatitis. Family history was positive for hyperlipidemia and premature coronary artery disease. After history of recurrent pancreatitis and severe myalgias, patient was diagnosed with CPT II deficiency at the age of 30 years. The myalgias were managed by increased carbohydrates intake for many years. Multiple low potency statins, and fenofibrate were attempted but he developed severe myalgia with elevated CPK levels. Eventually he was started on ezetimibe 10 mg daily with fish oil 2000 mg twice daily but his LDL-C continued to rise. CMP and TSH were within normal limits. Nuclear stress test was normal but his ASCVD risk score was 39%. Given the patient's CPT II deficiency and high risk for ASCVD score, statin was recommended for primary prevention. After a thorough discussion of risks and benefits of lipid-lowering therapy, the patient was started on pitavastatin 2 mg twice-weekly regimen and ezetimibe 10mg was continued. Eight weeks later, his LDL-C reduced from 132 mg/dl to 94 mg/dl (n <129mg/dl), TG from 449 mg/dl to 307 mg/dl (n 0-149 mg/dl). As he experienced no myalgias, an extra tablet of pitavastatin a week was added until he reached a daily regimen. He continued to tolerate this treatment and his LDL-C improved to 66 mg/dl with normal CPK levels. Clinical Lesson: We present a case of CPT II deficiency and significant hyperlipidemia successfully managed with pitavastatin and ezetimibe, which helped to achieve a desirable LDL-C. Pitavastatin is not metabolized by hepatic CYP3A4 isoenzyme as other statins and is minimally metabolized by CYP2C9. In addition, patients with CPT II deficiency may benefit from avoiding extended episodes of exertion and high-fat diet. When treating patients with CPT II deficiency and hyperlipidemia, close follow-up and laboratory monitoring will be needed.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSUN250 Empagliflozin Induced Bladder Cancer in an Adult Patient With Latent Autoimmune Diabetes
Authors: Alzenaidi Ahlam , Alkhalidi Hisham
Published: November 2022

Sodium glucose cotransporter type 2 (SGLT2) inhibitor is a novel class of antidiabetic agent. The association of SGLT2 inhibitors and incidence of bladder cancer has not been well established due to few numbers of cases and not enough length of exposure. Here we describe a case of bladder cancer developed one year after empagliflozin exposure in a patient with latent autoimmune diabetes.

Case description

A 51-year-old man presented to our endocrine clinic with a one-year diagnosis of type 2 diabetes mellitus. His glycosylated hemoglobin (HbA1c) was 8% on maximum dose metformin and well adherence to diet. The patient had no significant past medical history and his body mass index was 23.6 kg/m2. Empagliflozin 25 mg daily was added to his regimen, in addition to sulfonylurea and dipeptidyl peptidase-4 (DPP-4) inhibitor drugs. The patient continued to have persistent hyperglycemia despite medical therapy with HbA1c ranged between 7.5-7.9%. After one year, he presented with fatigue, unintentional 7-kg weight loss and perianal pain. A transrectal ultrasound of the pelvis showed a 10-mm solid lesion in the urinary bladder. He underwent transurethral resection of bladder tumor; pathology showed a low grade papillary urothelial carcinoma with focal areas of high grade. Empagliflozin was discontinued and due to persistent hyperglycemia, further labs were requested. Fasting blood glucose of 265 mg/dl, HA1c of 7.9%, anti-GAD antibody was positive 37.52 u/ml (<10.0), C-peptide of 0.51 ng/ml (0.37-1.47), insulin of 2.0 mu/ml (2.6-24.9). These findings suggested latent autoimmune diabetes with mild pancreatic reserve. Patient was then started on insulin therapy of Glargine and Aspart.

Conclusion

The use of SGLT2 inhibitors in patients with autoimmune diabetes may have a higher risk of bladder cancer as compared to patients with type 2 diabetes. An individualized selection of antidiabetic agent with consideration of proper diagnosis is recommended to prevent a serious consequence.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSUN251 Euglycemic DKA In A Patient Undergoing Major Surgery
Authors: Dapas Natalie , Baral Neelam , Sterrett Yamini , Sharma Meeta
Published: November 2022

Background

Euglycemic DKA represents a diagnostic challenge as a lack of hyperglycemia can lead to a delay in recognition and administration of appropriate treatment. We present a case of euglycemic DKA in the setting of starvation and surgical stress in a patient with type 2 diabetes without SGLT2 inhibitor use.

Clinical Case

A 61-year-old type 2 diabetic woman presented with a two-day history of vomiting associated with abdominal pain. She was previously treated with glipizide, metformin, and sitagliptin, which had been discontinued months ago due to poor oral intake. CT imaging demonstrated a 12.4×11.2×10.5 cm pelvic mass with ascites and omental nodularity in the setting of a history of prior right granulosa cell tumor and mature cystic teratoma status post total abdominal hysterectomy with bilateral salpingo-oophorectomy. The patient subsequently developed hematemesis on hospital day 7, for which she was made NPO. She underwent EGD which demonstrated severe esophagitis and duodenitis. She was given an oral diet for one day, prior to resuming NPO status on hospital day 10 for exploratory laparotomy and tumor debulking. On hospital day 11, the patient's labs were notable for an anion gap metabolic acidosis (pH 7.26, n 7.4; CO2 16 mmol/L, n 20-31 mmol/L; anion gap 15 mmol/L, n 5-15 mmol/L), elevated beta-hydroxybutyrate (5.5 mmol/L, n 0.02-0.27 mmol/L), and a blood glucose range of 141-233 mg/dL (n 65-140 mg/dL). The patient was not on any scheduled insulin other than a low dose correctional scale with Lispro subcutaneously pre-meals and had not used SGLT2 inhibitors. There was no suspicion for alcohol toxicity or other poisoning given that the patient had been hospitalized. The lactate level was normal. Thus, the patient met criteria for euglycemic DKA likely secondary to prolonged fasting, exacerbated by the stress of major surgery. The patient was started on an insulin drip with dextrose infusion until the metabolic parameters improved, and she was transitioned to subcutaneous insulin. In diabetic patients unable to tolerate enteral nutrition or with enteral nutrition delays due to surgery, initiation of parenteral nutrition may prevent progression to euglycemic DKA. Ultimately, her pathology was consistent with metastatic granulosa cell tumor, and she was discharged to subacute rehabilitation.

Conclusion

Euglycemic DKA may be overlooked due to normoglycemia leading to a delay in the diagnosis and appropriate management. It is a medical emergency and should be treated with an intravenous insulin infusion and dextrose. It can be prevented in diabetic patients undergoing major surgical stress by ensuring adequate nutritional support.Reference: Modi, A., Agrawal, A. and Morgan, F., 2017. Euglycemic diabetic ketoacidosis: a review. Current diabetes reviews, 13(3), pp.315-321.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSUN262 A Case of Hypoglycemia and Diabetic Ketoacidosis in an Adult with Down Syndrome
Authors: Lung John , Graves Brad
Published: November 2022

Introduction

Down syndrome is associated with a higher risk of autoimmune endocrinopathies including diabetes mellitus. Due to intellectual disabilities characteristic of Down syndrome, good glycemic control of insulin-dependent diabetes can be challenging with several reports of complications in the literature. We present an adult female with several admissions for hypoglycemia and DKA.

Case Presentation

A 52-year-old female with a notable past medical history of insulin-dependent diabetes mellitus, hypothyroidism, and Down syndrome with intellectual disability equivalent to a 12-year-old presented to the emergency department unresponsive with a point of care blood glucose of 21 mg/dL. Dextrose 10% was given by EMS en route to the ER with improvement in the blood sugars to 118 on arrival. Her hemoglobin A1c was 7.1%. Of note the patient was taking insulin detemir 24 units in the morning and 30 units in the evening and metformin 1g BID. She was not checking her blood sugars before self-injecting and was skipping meals while injecting insulin. Caregiver fatigue was also reported. She was admitted one month ago for similar hypoglycemia. She was taken off insulin and continued her metformin. Her blood glucose was at inpatient goals by discharge. One month later, the patient presented with altered mentation and a point of care blood glucose greater than 600 mg/dL. Her glucose on chemistry panel was 732 mg/dL, anion gap was 21 mEq/L, bicarbonate was 21 mmol/L, and her beta-hydroxybutyrate was 1.67 mmol/L. Calculated serum osmolality was 316 mOsm/kg. The patient was admitted for DKA with a possible component of hyperosmolar hyperglycemic nonketotic coma. She was placed on a DKA protocol with an insulin drip and isotonic fluids then switched to subcutaneous insulin once her anion gap closed. She was then placed on 20 units insulin detemir daily and discharged. The patient then presented 2 weeks later with 2 days of no oral intake complicated by septic shock of unclear origin. After discussion with the mother, the patient was transitioned to comfort care and died 4 days later.

Conclusion

Our case illustrates the difficulty of glycemic control in patients with Down syndrome and diabetes complicated by caregiver fatigue, intellectual disability, and a complex insulin regimen. Clinicians should aim for a balance between glycemic control and treatment regimen simplicity while avoiding hypoglycemia and ketoacidosis.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSUN266 A Case of Ipilimumab Induced New-Onset type1 Diabetes Mellitus in a Patient With Renal Cell Carcinoma.
Authors: Thota Geethika , Luo Hongxiu
Published: November 2022

A 50-year-old female with a recent diagnosis of Renal cell cancer (RCC) with hepatic metastasis and hypothyroidism was referred to the clinic for management of Diabetes Mellitus (DM). The patient was diagnosed with RCC in 2017 and was treated with immunotherapy Ipilimumab for two years. No family history of Diabetes Mellitus and denies history of corticosteroid usage. No previous episodes of Diabetic Ketoacidosis. She was diagnosed with GAD65 negative type 1 Diabetes Mellitus one year after starting Ipilimumab and was managed on a basal-bolus insulin regimen. She was on levothyroxine for the last two years for hypothyroidism and remained clinically and biochemically euthyroid. She attained menopause 10years ago. Physical examination is unremarkable with normal monofilament tests. Initial labs showed a Complete blood count within normal. The comprehensive metabolic panel showed Glucose 104mg/dl (74-106 mg/dl), Potassium 4.2 mmol/L (3.5 -5.0 mmol/L), Bicarb 25mmol/L (21-33 mmol/L).Hb A1C 6.5%, C-peptide 0.3ng/ml(0.8-3.85ng/ml), GAD 65, ia2 and insulin antibodies negative,TSH 3.420uIU/L (0.5-4.5 uIU/L), Free T4 1.16ng/dl (0.79-2.35 ng/dL), Total T3 78 (71-180ng/dl),Thyroid Peroxidase Antibodies(TPO) negative.Pituitary hormone analysis ruled out possible central, which showed FSH >200 IU/L, LH 78.6 IU/L, ACTH 31pg/mL(10-60pg/mL), Serum AM cortisol within normal. Her DM1 was well controlled with an insulin pump with DEXCOM for continuous glucose monitoring, requiring a total daily dose of around 15-20 units/day. The patient currently remains asymptomatic and will be followed in the clinic with labs.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSUN273 Endocrine Management of Renal Transplant Patients: A Role in Successful Graft Survival? Updated Data
Authors: Mumtaz Mirrah , Joseph Jalaja , Abdelgyed Ehab , Mohamed Hadir , Conti David , Leinung Matthew
Published: November 2022

Introduction

Graft survival after renal transplantation is dependent upon multiple factors. Many patients undergoing renal transplantation have endocrine disorders, such as pre-existing diabetes and metabolic bone disease, and can develop post-transplant diabetes (PTDM) and hyperlipidemia. Diabetes, lipid abnormalities, and hypovitaminosis D have been associated negatively with patient and graft survival1, 2. Our kidney transplant program ranks among the top 3 programs in the country for its kidney transplant outcomes according to the data by the Scientific Registry of Transplant Recipients. We hypothesized that our multidisciplinary team management of these patients was one factor in this success. We reported our findings in 2017. Here we present follow up data through 2021 on this same cohort.

Methods

Over 20 years ago members of the Endocrine division began attending the transplant clinic in the Department of Surgery to facilitate patient care. In 2016 we identified all patients followed over the previous 3 years. Charts were reviewed after IRB approval and data collected retrospectively. Data for this cohort has been updated through 2021.

Results

A total of 241 patients were seen (of 626 total transplant recipients). There were 154 males, 87 females, and the average age at transplant was 47 years. Diabetes was present prior to transplant in 118 (46.6%) and an additional 51 (21%) developed PTDM. For patients with diabetes, the pre transplant A1c fell from 7.5 ± 1.6% to 7 ± 1.2% at 6 months (p = 0.13). At 6 months, the A1c was 6.45% for those who had developed PTDM. Pre-transplant, 79 (31%) were on some form of lipid lowering therapy. Post-transplant, 216 (90%) had hyperlipidemia: 186 (77%) were on a statin, in addition to 51(21%) on fish oil, 28 (12%) on gemfibrozil, and 4 (1.5%) on niacin. The average Vitamin D level within 1 year post-transplant was 19.9 ± 8, but increased to 33± 14 at most recent visits (P < .01). Of 217 patients over the age of 40, 93 (43%) have had a DEXA: Osteoporosis was diagnosed in 43 patients and osteopenia in an additional 31. Of these patients, 34 are or have been on treatment (bisphosphonate).

Conclusions

We believe that multidisciplinary team management of post renal transplant patients can improve graft survival. While our improvement in A1c values at 6 months post-transplant was not statistically significant, the trend was clearly there even considering potential artefactual lowering of the A1c in renal failure patients. We did demonstrate improvement in Vitamin D levels and frequency of statin use. We also found that there remain some barriers for care (evidence, for example, by many patients not having Vitamin D levels or DEXA).

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSUN286 A Rare Case of Non-Islet Cell Tumor Hypoglycemia in Young Female With Metastatic Neuroendocrine Tumor
Authors: Zweibach Eugenia , Izkhakov Neriy , Zweibach Eugenia , Vernetti Nicholas , Nakhle Samer
Published: November 2022

Background

Non-islet cell tumor hypoglycemia (NICTH) is a rare paraneoplastic syndrome caused by a benign or cancerous tumor that over-secretes various hormones that lead to hypoglycemia. Multiple etiologies were described in literature, the most common of them is abnormal secretion of insulin-like growth factor-2 (IGF-2) known as Doege-Potter syndrome (first described in 1929). Other etiologies include oversecretion of proinsulin, IGF-1, and somatostatin. Estimated incidence of NICTH is one per one million person-years. Tumors of mesenchymal origin are most often described in association with NICTH. Laboratory diagnosis of fasting hypoglycemia associated with serum insulin levels below 3 μU/ml confirm the diagnosis of NICTH. In the case of Doege-Potter syndrome, lab findings show low levels of insulin, c-peptide, IGF-1 and a high IGF-2: IGF-1 ratio, which indicate non-insulin-mediated hypoglycemia due to IGF-2 oversecretion. Neuroendocrine tumors presented with NICTH are rare and only described in several case reports.

Clinical Case

We report a case of a 34 year old female with metastatic neuroendocrine high grade tumor (WHO grade 3, non small cell, diagnosed 3 years prior to presentation) with metastasis to the bone (status post debulking and radiation) and brain (status post radiation therapy). Patient was admitted due to left ankle cellulitis. Endocrinology was consulted due to incidental finding of hypoglycemia serum glucose of 44 mg/dL. Repeat serum levels showed c-peptide 1 ng/dL (normal 1.1 - 4.4) and glucose of 54 mg/dL. She denied a history of diabetes mellitus, alcohol intake, insulin or sulfonylurea use. She had normal renal and liver function. Continuous infusion of D10 started and after 24 hours the patient's hypoglycemia improved. However, hypoglycemia recurred every morning. Following morning hypoglycemia repeat serum labs showed insulin 1.3 (Normal 2.6-24.9), c-peptide 0.9 ng/dL, and serum glucose of 114 mg/dL confirming that her hypoglycemia was not insulin induced. She was not on any medications known to cause hypoglycemia. CT abdomen without contrast showed left upper quadrant heterogeneous hypoattenuating mass with calcifications, measuring approximately 8.5 cm×10.1 cm×2.6 cm.

Conclusion

This is a case of a patient with a high grade non small cell metastatic neuroendocrine tumor who presented with NICTH. This is the first case of a neuroendocrine tumor with non-small cell pathology causing NICTH that has been described to-date. Based on the patient's clinical presentation and available laboratory findings with recurrent fasting hypoglycemia, low insulin and c-peptide levels we confirmed diagnosis of NICTH. This patient`s hypoglycemia was most likely induced by IGF-2 overexpression (Doege-Potter syndrome) which is the most common cause of NICTH.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSUN316 Racial Disparities in Diabetes Control and Use of Technology in a High Risk Cohort of Youth with Diabetes
Authors: Carrillo-Iregui Adriana , Bishop Meredith , Granados Andrea , Pagan Pedro , Arteaga Yadmara , Verme Jacquelyn , Alvarez-Salvat Rose , Carrillo-Iregui Adriana
Published: November 2022

Background

Racial and ethnic minority children experience significant disparities in achieving the American Diabetes Association-recommended hemoglobin A1c (HbA1c) levels when compared to non-Hispanic Whites (NHW). Continuous glucose monitoring (CGM) and insulin pump (IP) use are associated with improved glycemic control. Racial and ethnic disparities exist in the use of these technologies in youth with Type 1 diabetes (T1D), which may contribute to the observed poor glycemic outcomes in this population. However, racial and ethnic differences in CGM and IP use have not been examined in children and adolescents with diabetes.

Objective

We describe the differences in glycemic control, CGM and IP use in an ethnically diverse cohort of children and adolescents seen in a multidisciplinary diabetes clinic designed to provide support (i.e., diabetes education, psychology, social work, nutrition) to youth with poorly controlled diabetes.

Methods

Demographic data, HbA1c levels, CGM and IP use were collected from a cohort of high-risk youth with T1D and T2D attending a multidisciplinary diabetes clinic from January to December of 2021.

Results

A total of 125 children and adolescents (age: 4-20 years) diagnosed with diabetes were included. Twenty (16%) were African Americans (AA), 81 (65%) Hispanic (H), 23 (15%) non-Hispanic White (NHW), and 1 (0.8%) Asian (A). The mean HbA1c in the cohort was 9.07%. HbA1c in AA patients was 12.9% (SD + 3.11), in Hispanics 8.64% (SD + 2.28), and 9.00% (SD + 1.84) in NHW. Seventy percent of AA patients had an A1c> 9%, compared to 36% of Hispanics and 48% of NHW. Use of CGM and IP was 40% and 10% in AA, 79% and 36% in Hispanics, and 82% and 57% in NHW, respectively.

Conclusions

Our study describes recent data on glycemic control and use of diabetes technology among a racially diverse cohort of children and adolescents seen in a multidisciplinary diabetes clinic. Consistent with literature on adults, HbA1c was highest and CGM and IP use were lowest in AA as compared to H and NHW youth. Data was collected during the COVID-19 pandemic, which may have disproportionately impacted AA patients’ economic, social, and personal behaviors that may contribute to diabetes care. These data support the need for multidisciplinary interventions using systems-based and culturally tailored approaches to improve access and use of technology for diabetes management. The current multidisciplinary diabetes clinic is designed to identify high-risk factors and reduce barriers to optimal management of diabetes. Future research will focus on the impact of multidisciplinary intervention on diabetes control through the use of technology, especially for African Americans.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
LBSUN310 Developmental Programming: Gestational Bpa Treatment Leads To Pancreatic Beta Cell Compromise
Authors: Ciarelli Joseph , Sun Haijing , Domke Stephanie , Gregg Brigid , Padmanabhan Vasantha
Published: November 2022

Developmental exposure to endocrine disrupting chemicals (EDC) such as bisphenol A (BPA) have been shown to be associated with many metabolic defects in humans. Studies in animals have documented detrimental effects of fetal exposure to BPA on metabolic variables such as insulin resistance, adiposity, and cardiac function. For instance, developmental exposure of sheep to bisphenol A (BPA), a ubiquitously present EDC, causes insulin resistance and compensatory hyperinsulinemia but the underlying mechanism of it is not fully understood. To determine if pancreatic hyperplasia or hypertrophy contributes to the hyperinsulinemic status and the ontogeny of these effects, pregnant Suffolk sheep were administered daily subcutaneous injections of BPA (0. 05, 0 .5 or 5 mg/Kg BW) in corn oil from days (D) 30-90 of gestation (term 147 days). Controls received corn oil during the same period. Pancreas were taken at Day 65 and 90 of gestation from control and 0.5mg/kg BPA (environmental exposure level)-treated female fetuses, and control and prenatal BPA-treated female offspring at 2 years of age (all 3 doses) during synchronized follicular phase of the cycle. Immunohistochemistry was used to determine beta cell number, size, and islet insulin content. In addition, to determine if the pancreas was fibrotic, islet collagen content was determined by Picro Sirius red staining and whole pancreas collagen content was measured with scroll collagen assay. Data were analyzed by ANOVA (Y2) and Students's t-test (D65 and D90), and magnitude of response by Cohen's Effect Size analysis. Findings showed large magnitude reduction of islet insulin content at day 65, significant decrease in islet insulin and beta cell count at D90 along with large magnitude decrease in pancreas/fetal weight. In contrast, in the Y2 sheep prenatal BPA treatment induced a large magnitude decrease in beta cell count (0. 05mg/kg dose group), a large magnitude increase in islet insulin content (5mg/kg dose group) and large magnitude increase in islet collagen content (all 3 BPA doses). The decrease in insulin in the D65 and D90 sheep along with the decrease in beta cells and pancreas/fetal weight at D90 indicates adverse developmental impact of BPA exposure on pancreatic beta cell differentiation. Increase in collagen accumulation in Y2 sheep likely contributes to the beta cell loss reflected as decrease in beta cell number seen in 0. 05 mg/kg dose of BPA. Absence of beta cell loss in 0.5 and 5mg/kg dose in the face of increased collagen is consistent with the nonmonotonic responses these EDCs manifest. Taken together, these results highlight the risks posed by developmental exposure to BPA on beta cell function and the corresponding risk for beta cell loss as animals age. Supported by NIH R01 grants ES016541 and ES030374

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
ODP263 A Nonbiased Single-Cell Transcriptomic Analysis of Mouse Mammary Gland after Low Dose/Long Term vs. High Dose/Short Term Exposure to PBDEs
Authors: Saeki Kohei , Chang Gregory , Mori Hitomi , Ha Desiree , Yoshitake Ryohei , Wang Xiaoqiang , Tzeng Tony , Shim Hyunjeong , Neuhausen Susan , Chen Shiuan
Published: November 2022

Introduction

Polybrominated diphenyl ethers (PBDEs) are persistent environmental contaminants and associated with breast carcinogenesis. In this study, we examined the effects of PBDEs during the menopausal transition in a 4-vinylcyclohexene diepoxide (VCD)-induced mouse menopause model, which presents a follicle-depleted and ovary-intact animal that closely approximate the gradual menopause transition in humans. The aim of this study was to compare the impacts of PBDE exposures on the mammary gland at the macroscopic gland structures and the single-cell resolution under three treatment schedules.

Materials and Methods

We treated nine-week-old female C57BL/6 mice with VCD (160 mg/kg) for 15 days. Then, the animals had high dose PBDE exposure for 1 week during peri- (Perimenopause/High group) or post-menopausal periods (Menopause/High group). The third group was exposed to low dose PBDE (the 1/20th of the high dose) for 20 weeks during the postmenopausal period (Menopause/Low group). In each group, the mice received various combinations of 17B-estradiol and progesterone treatments simultaneously. Our experimental design allowed us to directly compare the effects of PBDE under three potential exposure conditions.

Results

The mammary glands significantly regressed by the VCD treatment, more evident at the postmenopausal period. All PBDE exposures did not augment or compromise the macroscopic ductal reorganization resulting from the VCD and/or hormonal treatments. Single-cell sequencing revealed that the PBDE exposure in the Menopause/High group caused specific transcriptomic changes in the non-epithelial compartment such as Errfi1 upregulation in fibroblasts and AY036118 downregulation in multiple cell types. The PBDE exposure in the Menopause/Low group resulted in similar transcriptomic changes to a lesser extent.

Conclusion

PBDEs may affect the postmenopausal gland through impacts on the non-epithelial compartments. Low dose PBDE exposure, which is presumably equivalent to the maximum environmental exposure in humans, can exert the influences.

Presentation: No date and time listed
ODP265 Bph, Androgenic Alopecia, and Acne - Markers of Progesterone Deficiency
Authors: Kalinchenko Svetlana , Nikiforov Igor , Samburskaya Olga
Published: November 2022

Materials and methods

The study at this stage involves 6 male patients from 21 to 50 years with the diagnosis: BPH. Androgenic alopecia. Acne disease. All patients were examined for vitamin D in the blood by calcidiol 25(OH)D using mass spectrometry and steroid hormone levelsusing a steroid profile in saliva by mass spectrometry. Findings. Vitamin D level in three patients was below 30 ng/ml, in three patients - below 20 ng/ml. The steroid profile in the saliva of all six patients revealed progesterone deficiency, with normal testosterone levels. Patients were prescribed vitamin D in a dose of 20,000 IU daily and progesterone in a dose of 100 mg daily; patients with acne were additionally prescribed topical treatment - progesterone in gel form. As a result, after 6 months of using this therapy, patients have a cessation of hair loss, growth of downy hair and transition of downy hair to terminal hair,improvement in all patients was 80-90%. Two patients with the papulopustular form of moderate acne improved by 90%, a patient with the conglobate form improved by 50% (transition to the papulopustular form of moderate severity). Improvement of clinical picture of symptoms of BPH is also noted: decrease of IPSS questionnaire score to 7-9. Vitamin D level from 70 to 100 ng/ml. On the steroid profile of saliva, the levels of testosterone and progesterone are within normal limits. Interpretation. The main cause of androgenetic alopecia, acne, BPH is thought to be: an excess of DHT (dihydrotestosterone), increased activity of 5-α-reductase enzyme. These three diseases accompany each other. The main drug which is used 5-α-reductase blockers. The side effects of which greatly exceed the benefitsof treating. Vitamin D is involved in regulation of proliferation, differentiation and apoptosis of keratinocytes, regulation of skin immunity, regulation of pro-inflammatory cytokines, stimulation of the expression of antimicrobial peptides, regulation of the integrity and permeability of the lipid barrier, reducing the severity of systemic inflammation, regulation of cellular, humoral, congenital and acquired immunity. Also, in an in vitro study it was found that progesterone can inhibit the activity of 5-α-reductase, so in the skin the activity of this enzyme is reduced by 97±5.3%. And the positive effect was also established in the treatment of prostate diseases, inhibiting 5-α-reductase, progesterone reduces the growth of the prostate gland and the growth of prostate cancer cells.

Conclusion

Laboratory studies have shown vitamin D and progesterone deficiencies in patients with these diseases. Correction of these deficiencies resulted in improvement both in BPH (reduction of clinical manifestations) and in androgenic alopecia (cessation of hair loss and restoration of terminal hair growth) and acne (significant reduction of inflammation).

Presentation: No date and time listed
ODP274 Shift work is associated with normal weight obesity in community-dwelling adults
Authors: Ahn Chul Woo , Hong Namki , Lee Seunghyun , Park Hye-Sun , Rhee Yumie , Shin Sungjae
Published: November 2022

Objective

Shift working is known to be associated with metabolic syndrome and increased cardiovascular risk. In this study, we aimed to investigate whether shift work is associated with normal weight obesity (NWO), defined as normal weight with high body fat percentage. Method: From the national representative Korea National Health and Nutrition Examination Survey dataset (KNHANES 2008-2011), data of 3800 full-time workers with age≥ 19 years and body mass index (BMI)≤ 25 kg/m 2 were analyzed. In this study, we defined NWO was defined as BMI≤25 kg/m 2 and body fat (BF)percentage≥25% in men and≥37% in women according to the most strict threshold from literature review. Working patterns were classified into 'daytime', 'other than daytime', and 'shift time' based on the self-reported survey data. Multivariable logistic regression was performed to evaluate the relationship between shift time workers and NWO. Prespecified subgroup analysis were analyzed to determine the consistency of the result. Result: Shift work was associated with elevated odds of NWO than daytime work (adjusted odds ratio [aOR] 1.47, 95% CI 1. 04-2. 09) and night/evening work (aOR 1.87, 95% CI 1.11-3.14), after adjustment for working form, working hours, age, sex, BMI, vitamin D, homeostatic model assessment for insulin resistance, and other sociodemographic factors. In the subgroup analysis, association between shift work and NWO were consistent, and, those age ≥ 60 years (aOR 2.23, p=0. 043; p for interaction=0. 097) or working hours ≥ 56 hours per week (aOR 2. 00, p=0. 013; p for interaction=0. 057) showed a tendency to increase the risk.

Conclusion

Shift working was associated with NWO in Korean community-dwelling adults, independent of age, sex, BMI, and other covariates. Keywords: Shift work, Obesity, Normal weight obesity, Body fat percentage, KNHANES

Presentation: No date and time listed
PMON12 Effects of Endocrine Disruptors on Autophagy Markers Gene Expression in Immortalized GnRH Neurons and Hypothalami of Adult Male Mice
Authors: Fernandez Marina , Gomez Juan Manuel Riaño , Sorianello Eleonora , Lux-Lantos Victoria
Published: November 2022

Benzophenones (BP) and Bisphenol A (BPA) are endocrine disrupting chemicals (EDC). Previously, we showed that the in-vitro exposure to EDC inhibited Kiss-induced gene expression in GT1-7 and GN11 cells (donated by Pamela Mellon, UCSD), and altered expression of inflammatory markers in GT1-7 cells and hypothalami of adult male mice.In the present study, we evaluated the effects of the in-vivo exposure to BP2 and BP3 (250 µg/kg/day, orally, for 5 days) on the expression of autophagy markers in hypothalamic nuclei in C57Bl/6 adult male mice, and the in-vitro exposure to BPA, BP2 or BP3 in immortalized GnRH neurons. Animals were sacrificed, brains rapidly dissected and conserved -80°C until processed. Micropunches containing Anteroventral Periventricular (AVPV) or Arcuate (ARC) nucleus were obtained. Effects of the in-vitro exposure for 12 or 24 hours to BPA, BP2 or BP3 (1×10-9M, Sigma), or DMSO as control, were evaluated in GT1-7 and GN11 cell lines, mature and immature GnRH neurons. ARN was obtained using Tri-Reagent (Molecular Research Center, Inc), reverse-transcribed and gene expression analyzed by qPCR, using Ppib as control gene. Results were presented as Media±SE and analyzed by ANOVA (Statistica, StatSoft Inc, USA).In-vivo, five-day exposure to BP2 or BP3 did not alter Lamp2 or p62 gene expression in the AVPV or ARC in adult male mice (ANOVA: ns). In GT1-7 cells, Ulk1 was not significantly altered by any of the stimuli (ANOVA: ns; n=5), whereas in GN11 cells, BP3 significantly increased Ulk1 gene expression after 12 and 24 h exposure [DMSO-24h: 0.93±0.21, DMSO-12h: 0.73± 0.19, BPA-24h: 1.78±0.31, BPA-12h: 1.47±0.33, BP2-24h: 1.51±0.49, BP2-12h: 1.06±0.23, BP3-24h: 2.41±0.89, BP3-12h: 2.45±0.82, Repeated Measures ANOVA: Main effect "TREATMENT" p<0.05, BP3 different from DMSO, p<0.05, n=4]. Our results reinforce the notion that the exposure to EDC have different effects depending on the experimental model and time of exposure, with developing cells being more susceptible to disruption that mature cells. We need more experiments to fully understand if exposure to EDC alters other markers of the autophagy process in mouse hypothalamus and GnRH neurons.Funding: CONICET, ANPCYT, International Society for Neurochemistry, Fund. Williams, Fund. R. Barón.

Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
PSAT161 Effect of Hyperlipidemia and Statin Use on the Risk of Dementia and Functional Dependence in the Vietnamese Immigrants
Authors: Na Kim Yu , Arif Saleena
Published: November 2022

The role of cholesterol in the etiology of dementia is still controversial. Some studies aiming to explore the association between lipids and/or lipid-lowering treatment and dementia indicated a harmful effect of dyslipidemia and a beneficial effect of statin therapy on the risk for dementia. Still, it is not well studied in the Vietnamese population. We sought to evaluate the impact of hyperlipidemia and statin use on the risk of dementia and functional frailty in Vietnamese immigrants.We identified 38(female(F) 26, male(M) 12) community-dwelling Vietnamese patients aged ≥ 55 seen at the cognitive assessment clinic in a community health center 1/2021-8/2021 through chart review. This cohort's mean age(±SD) was 72.3(±9.35). Because lipid panel results were unavailable, 1 patient (F 1) was excluded. We assigned the patients with normal cognitive tests results or a diagnosis of mild cognitive impairment to the control group and those diagnosed with dementia to the study group. To assess function, we obtained ADLs (activities of daily living) and IADLs (instrumental activities of daily living). This study defined hyperlipidemia (HLD) as LDL >100 and functional dependence as dependence in ADLs and/or IADLs.Among 37 patients (F25, M12), 21 patients were diagnosed with dementia (F15, M 6), and 16 patients (F10, M6) were assigned to the control group. In the study group, 19 patients (F13, M 6) were diagnosed with HLD, and 13 patients (F 8, M 5) were taking statins. Fifteen patients (F 10, M 5) were diagnosed with HLD, and 14 patients (F9, M5) were taking statins in the control group. Thirty-three patients (F 23, M 10) were functional dependent. Among them, 31 patients (F 21, M 10) were diagnosed with HLD, and 24 patients (F 15, M 9) were taking statins. Four patients (F 2, M2) were functionally independent, and 3 patients (F 2, M1) were diagnosed with HLD, and all of them were taking statins.The persons with HLD had an about 12% reduction in risk of dementia (RR 0.8382, P=0.6855), but they were about 37% likely to develop functional dependence (RR 1.3676, P=0.4470). Statin users had a nearly 40% reduction in risk of dementia (RR 0.6019, P=0.0462) but the risk for developing functional dependence was not significantly different from non-users (RR 0.9877, P=0.9211). These findings suggested statin treatment has a beneficial effect on decreasing the risk for dementia in patients with HLD, and HLD has a harmful impact on developing functional frailty. This study showed a risk reduction of dementia in patients with HLD, which was different from other study results. More studies with a larger number of patients in this cohort are needed to investigate this further.

Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
ODP281 JDP2 Interacts with MDM2 and Decreases MDM2-Mediated p53 Repression
Authors: Yang William , Wang Chiung-Min , Yang Richard , Yang Wei-Hsiung
Published: November 2022

JDP2 and ATF3 belong to the family of AP-1 protein. JDP2, a transcription factor, can bind to AP-1 site as well as cAMP responsive element (CRE) site in numerous cis-elements of the target genes. JDP2 has been shown to be involved in cancer development and cell-cycle regulation. Previously, we had shown that JDP2 activates Mc2r transcriptional activity. Since ATF3 and JDP2 share high similarity in C-terminal domains with identities of 65% and ATF3 can bind to p53 and regulate p53 transcriptional activity and stability, we hypothesized that JDP2 may have ability to regulate p53 and MDM2 (the main regulator of p53). Herein, we demonstrate for the first time the relationship between JDP2 and MDM2. First, we found that JDP2 can directly bind to MDM2. Secondly, though ATF3 dose-dependently increases MDM2 level, JDP2 dose-dependently decreases MDM2 level. Moreover, the C-terminus of JDP2 is required for regulation of MDM2 level. Finally, using p53RE-Luc (14X) for p53 transactivation study, while MDM2 decreases p53 transactivation, JDP2 dose-dependently abolishes MDM2-mediated p53 repression. Taken together, our results demonstrate that JDP2 directly binds to MDM2 and reduces MDM2-mediated p53 repression, suggesting that JDP2 is a novel regulator of MDM2. Since p53-MDM2 pathway is an important regulator in endocrinology and reproduction, our finding provides a new layer of regulatory mechanism for fertility, tumor suppression, and longevity.

Presentation: No date and time listed
OR22-3 Uterine TGFβ Signaling Controls Endometrial Cell Homeostasis And Regeneration
Authors: Monsivais Diana
Published: November 2022

The transforming growth factor beta (TGFβ) signaling pathway has critical roles in the transduction of paracrine and autocrine signals that control development, reproduction, and cancer. To study the tissue-specific contribution of TGFβ signaling in the endometrium, we developed mice with conditional deletion SMAD2 and SMAD3 in the endometrial epithelium (using Lactoferrin-cre, "Ltf-cre"). We identified that double conditional deletion of SMAD2 and SMAD3 in the endometrial epithelium resulted in endometrial hyperplasia by 12-weeks of age, with myometrial invasion, metastasis, and death by 6-9-months of age. Smad2/3-Ltf-cre mice also lost epithelial progesterone receptor expression in the endometrium by 12 weeks of age. To study the signaling mechanism that controlled the malignant transformation of the glandular epithelium in Smad2/3-Ltf-cre mice, we developed 3-dimensional (3D) endometrial organoid cultures from the uterine epithelial tissues of control and mutant mice. To test how suppression of TGFβ signaling affected endometrial regeneration, 3D endometrial organoids from WT or Smad2/3-Ltf-cre mice were grown in the presence or absence of the TGFβ receptor inhibitor, A83-01. Using these conditions, we identified that WT endometrial organoids cultured with the SB505124 inhibitor or from Smad2/3-Ltf-cre mice, developed abnormal morphology. Histological analysis of the endometrial organoids showed that organoids cultured with A83-01 or from Smad2/3-Ltf-cre mice, developed increased secretory-like cells with increased mucin-1 expression. RNA-sequencing of the endometrial organoids revealed that a large number of differentially expressed genes were conserved between the WT organoids cultured with A83-01 and those from Smad2/3-Ltf-cre mice. Gene ontology analysis of the differentially expressed genes indicated that pharmacological or genetic inhibition of TGFβ signaling, resulted in over-representation of gene families related to BMP/SMAD1/5 signaling and retinoic acid signaling, with decreased enrichment of WNT/β-catenin signaling. These studies indicate that TGFβ-mediated signals are critical to endometrial function and that perturbation of this balance results in endometrial cancer. Funding support NICHD grants R00-HD096057 (to DM) and R01-HD032067 (to MMM), and grants NGP10125 and 1016187 from the Burroughs Wellcome Fund (to DM).

Presentation: Monday, June 13, 2022 11:30 a.m. - 11:45 a.m.
OR22-5 Effect of Melatonin Receptor 1 on Glucose and Lipid Metabolism in Melatonin-proficient (c3hf+ ∕+) Female Mice
Authors: Goyal Varunika
Published: November 2022

Various functions of the pineal gland hormone melatonin are mediated via receptors, MT1 and MT2. Both receptors are known to regulate glucose metabolism in mice and humans. In addition, the MT1 receptor also controls lipid metabolism in mice. Light exposure, jet lag and shift work often cause the inhibition of melatonin production and hence the action of its receptors. So far, the loss of melatonin signaling was studied in male mice only. Here, we analyze the effect of removal of MT1 receptor in female mice under a control diet (CD)/high fat diet (HFD) regimen. Female C3H-f+∕+ (WT) and C3H-f+∕+ MT1 KO (MT1KO) mice (n=9-12/group) at six weeks of age were housed singly and exposed to CD (D12450H, 10% kcal/fat) or HFD (D12451, 45% kcal/fat) for 14 weeks. Weight, food intake and fasting blood glucose level (FBG) of each mouse was measured weekly. Insulin (ITT) and glucose tolerance tests (GTT) were performed after 14 weeks. At the end of experiment, mice were euthanized and liver and blood samples were collected to assess the lipid profile in these samples. RNA-seq was performed on the liver tissue. No difference was seen in weight gain by WT and MT1KO female mice on a CD while MT1KOs tend to gain more weight on HFD than WT mice (16.94g vs 17.26g). WT and MT1KOs consumed same amount of food on CD, but MT1 KOs on HFD ate significantly more food than WT (283.16g vs 323.06g, P<0.05). Under HFD, FBG in MT1KOs was significantly increased with respect to WTs (107.71mg/dL vs 158.50 mg/dL, P<0.05). While no difference in CD mice was seen with IIT and GTT, HFD negatively affected GTT and ITT in MT1 KOs. No difference was observed in the lipid profile (e.g., total cholesterol, triglycerides, phospholipids and free fatty acids) of WT and MT1KO mice under CD, while HFD significantly increased the cholesterol (149.5 vs 225.2 mg/dL, P<0.05) and phospholipids (287.8 vs. 358.6 mg/dL P<0.05) levels in MT1KOs. Finally, HFD leads to a significant increase in lipid deposition in the liver of MT1KOs when compared to other groups (34.46 vs 54.88 mg/g tissue, P<0.05). RNA-seq revealed a higher number (644) of differentially regulated genes and increase in lipid and glucose-related pathways in MT1KO mice with HFD. Our data show that C3H-f+∕+ female mice are protected from diet-induced obesity and its detrimental effects on glucose and lipid metabolism. However, under HFD conditions, removal of MT1 receptor abolishes such a protection. Lack of MT1 also leaded to an increase in lipid deposition in the liver. In conclusion, our data indicate that that melatonin (MT1) signaling is crucial for protection of females from diet induced obesity and its consequences.

Presentation: Monday, June 13, 2022 12:00 p.m. - 12:15 p.m.
PMON29 A Comparative Analysis of Musashi-Dependent Control of Mouse and Human Pituitary mRNA Translation
Authors: Banik Jewel , Childs Gwen , Hardy Linda , MacNicol Angus , MacNicol Melanie , Tomlinson Sophia
Published: November 2022

Specialized cell lineages within the anterior pituitary produce specific hormones which, in turn, regulate diverse biological processes ranging from growth, metabolism, and reproduction to stress. Interestingly, these specialized cell lineages exhibit a high degree of cellular plasticity, readily altering their differentiation state to produce different hormones in response to organismal demand. Underlying molecular mechanisms controlling cellular plasticity in the pituitary are not fully defined but appear to involve post-transcriptional regulation exerted by the Musashi family of sequence-specific RNA binding proteins. Musashi is a bifunctional regulator of target mRNAs and can exert either repression or activation of translation in a context-dependent manner. Our recent work has implicated a role for Musashi-dependent repression of key pituitary mRNAs in the mouse, including a lineage-specific transcription factor (Pou1f1), the gonadotropin releasing hormone receptor (Gnrhr), and two anterior pituitary hormones (Prl and Tshb). In this study, we look to determine the potential relevance of Musashi-dependent mRNA translational control to the human pituitary. Reflecting our findings in the adult mouse, a re-analysis of published human fetal pituitary single cell RNA sequencing data revealed Musashi1 (MSI1) and Musashi2 (MSI2) expression in both stem/progenitor cell populations as well as in all hormone-producing cell lineages of the anterior pituitary. We further report that the human homologs of identified Musashi-target mRNAs in the mouse pituitary also possess Musashi binding elements (MBEs) in their 3' untranslated regions (UTRs). In the case of the human Pou1f1 3' UTR, we were able to verify Musashi-dependent mRNA translational repression in reporter assays as seen with the murine Pou1f1 3' UTR. Interestingly, a germline Pou1f1 mutation identified in human patients, disrupts a consensus MBE in the human Pou1f1 3' UTR and abolishes Musashi-dependent repression. We developed a bioinformatic pipeline to characterize pathogenic human mutations catalogued in the Geno2MP database for disruption or creation of consensus MBEs in pituitary-specific mRNA 3' UTRs. Our findings suggest an evolutionarily conserved role for Musashi in the post-transcriptional regulation of pituitary mRNAs in both mice and humans and identify several human mutations which may perturb Musashi regulation of human pituitary function.

Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.