bluuebunny/crossref_metadata_2025 huggingface dataset:
MON-627 Number of Antihypertensives Required for Achieving BP Goals in Individuals with Diabetes and Hypertension-A Cross-Sectional Observational Study
Authors: Bhattacharyya Supratik
Published: May 2020

BACKGROUND: The 2019 ADA Standards of Medical Care in Diabetes, recommends blood pressure (BP) target of <130/80 mmHg for individuals with diabetes and hypertension at higher cardiovascular (CV) risk and a BP target of <140/90 mmHg for individuals at lower risk for CV disease.1 Monotherapy can attain goal BP in some patients with diabetes and hypertension. This is most likely to occur in those with BP that are only modestly above goal. However, combination therapy is eventually required in most patients.2

AIM: To assess the number of antihypertensives that are required for optimal control of BP in Indian patients with type 2 diabetes mellitus (T2DM) and hypertension.

METHODS: Data was retrieved from the electronic database of a tertiary super-speciality hospital in Kolkata over a period of four weeks in July to August 2018. The inclusion criteria- T2DM patients with hypertension between 35 to 55 years of age. Patients with recent weight gain, recent use of SGLT 2 inhibitors and those with prior cardiac events were excluded from the study.

The study included 2000 adult patients with T2DM with normal renal function. Of these, 58% were male patients. The mean age was 48 years. The mean HbA1c was 7.4% during the period of observation. Patients were being treated with oral hypoglycaemic agents (OHA) (except SGLT 2 inhibitors which might affect BP) or insulin. All patients were receiving statins. The antihypertensives that were considered were analysis were telmisartan, amlodipine, and hydrochlorothiazide.

RESULTS: The number of T2DM Hypertensive patients requiring 3 or more drugs were 640 (32 %). Out of the 640 patients, 300 patients (15 %) required higher dose of telmisartan 80 mg.

A total 980 patients (49%) required a combination of two drugs (telmisartan and amlodipine) for optimal BP control. Out of these 980 patients, 360 patients (18%) required higher dose of telmisartan i.e. 80 mg. One hundred and eighty patients (9%) required a combination of telmisartan and hydrochlorothiazide. Out of these 180 patients, 80 patients (4%) required higher dose of Telmisartan i.e. 80mg. Two hundred patients (10 %) required only one drug i.e. telmisartan for achieving optimal BP. Out of these 200 patients, 110 patients (5.5 %) required the higher dose of telmisartan i.e. 80 mg

CONCLUSION: The optimal control of BP is mandatory in T2DM patients in order to reduce cardiovascular events as well as microvascular complications. As evident from our study majority of patients required more than one antihypertensive, 32% required triple drug therapy and 49 % required dual therapy for optimal BP control. Regular monitoring of BP and timely up-titration of antihypertensives are of utmost importance to prevent future micro- and macro- vascular complications in young diabetic hypertensives.
MON-475 Discrepant Thyroid Function Tests in Adenocarcinoma-Is This a True Thyroid Disorder?
Authors: Tameemi Mohammed Al , Gilden Janice L
Published: May 2020

Background: Many causes of abnormal thyroid function tests (TFTs) occur that may or may not reflect a true thyroid disorder. The most common include: immune check point inhibitors therapies (ICI) used to treat various types of cancers; biotin supplements, which may interfere with thyroid function test assays; euthyroid sick syndrome; as well as amiodarone therapy for cardiac disorders. Clinical Case: A 67-year old female patient with type 2 diabetes mellitus, taking insulin and oral antihyperglycemic agents, with hyperlipidemia, hypertension and coronary artery disease, who had abnormal TFTs (TSH was 3.7 to 4.9 uIIu/ml; ref range 0.27-4.2 uIU/mL), and Free T4 was 0.92 to 1.06 ng/dL; ref range 0.55-1.6 ng/dl) prior to the diagnosis of metastatic adenocarcinoma of the lungs. She was initially treated with radiation. TFTs were unchanged. Her CEA was noted to be 129.5 (0-3.0 ng/mL). However, following chemotherapy with Tarceva (Erlotinib) 50 mg po daily, the TSH increased to 7.6 uIU/ml with Free T4 of 3.19 ng/dL. She remained clinically euthyroid. A thyroid ultrasound showed 1 -small sub centimeter nodule in each thyroid lobe. The patient later admitted to also taking biotin for an unknown period of time. TSH antibodies and TSI were both negative. Free T4 by dialysis was normal. While still taking Tarceva her TSH was noted to be 2.5 to 3.8 uIU/ml and both Free T4 and Free T3 were elevated and was 6.57 pg/ml;ref range=2.52-4.34 pg/mL). Six months later, the Free T4 decreased to 1.08 ng/dL. Thyroid antibodies and thyroglobulin remain normal. The patient remained clinically euthyroid. Conclusion: It is important to note that several factors can cause abnormal thyroid function tests, such as Immune check point inhibitors therapy, with the exact mechanism for abnormal TFTs unknown, and can also be associated with either Grave’s hyperthyroidism or Hashimoto’s hypothyroidism,as well as other autoimmune endocrine disorders. Biotin, a common supplement, has also been reported to interfere with the thyroid function test assays for free thyroxine (T4), total T4, free triiodothyronine (T3), total T3, TSH, and various cancer markers. However, It is important to clinically evaluate the patient for thyroid disorders, and recognize that therapy may not always be required, when discrepant and fluctuating thyroid function tests are obtained, such as in this patient. References: (1) Holmes EW, Samarasinghe S, Emanuele MA, Meah. Biotin interference in clinical immunoassays: a cause for concern. . Arch Pathol Lab Med. 2017;141:1459-1460. (2) Rossi E, Sgambato, De Chaira G, et al. Thyroid-induced toxicity of check-point inhibitors immunotherapy in the treatment of advance non-small cell lung cancer. J. Endocrinol Diabetes 2016;3:1-10.
SAT-447 Thyroid Function, Cardiovascular Disease, and Mortality: A Mediation Analysis
Authors: Inoue Kosuke , Ritz Beate , Brent Gregory A , Ebrahimi Ramin , Rhee Connie , Leung Angela M
Published: May 2020

Background: Subclinical hypothyroidism is a common clinical entity among the United States (U.S) adults and has been associated with increased risk of cardiovascular disease (CVD) and mortality in some studies. However, the mediation effect of CVD from elevated serum thyroid stimulating hormone (TSH) to mortality has not yet been well established or sufficiently quantified. In this study, we aimed to elucidate the extent to which subclinical hypothyroidism or high-normal thyroid stimulating hormone [TSH] concentrations (i.e. upper normative-range TSH concentrations) contribute to mortality through its effect on CVD among U.S. adults.

Methods: This study relies on the U.S. representative samples of 9,020 adults enrolled in the National Health and Nutrition Examination Surveys (NHANES) 2001-2002, 2007-2012 and their mortality data through 2015. We employed Cox proportional hazards regression models to investigate associations between the TSH concentration categories (subclinical hypothyroidism or tertiles of serum TSH concentrations within the reference range) and all-cause mortality. Utilizing mediation analysis within the counterfactual framework, we estimated the mediation effect of CVD on the association between TSH and all-cause mortality.

Results: The median duration of follow-up for mortality ascertainment was 7.3 (interquartile range, 5.4–8.3) years, during which 435 deaths from all causes were identified. Subjects with TSH in the subclinical hypothyroidism and the high-normal TSH tertile concentrations were associated with increased all-cause mortality (subclinical hypothyroidism: hazard ratio [HR], 1.90; 95% confidence interval [CI], 1.14–3.19; high-normal TSH: HR, 1.36; 95% CI, 1.07–1.73) compared with the middle-normal TSH tertile concentration. CVD mediated 14.3% and 5.9% of the effects of subclinical hypothyroidism and high-normal TSH on all-cause mortality, respectively, with the CVD mediation effect being most pronounced in women and subjects ≥60 years old. No mediation through CVD was found for low-normal TSH levels and all-cause mortality.

Conclusion: CVD mediated the effects of subclinical hypothyroid and high-normal TSH concentrations on all-cause mortality in the U.S. general population. These findings may have potential implications for treatment, and early and more aggressive CVD screening for such at risk populations. Further studies are needed to examine the clinical impact of targeted therapy towards mid-normal TSH concentration.
MON-375 A Sporadic Case of Camurati-Engelmann Disease: A Rare Sclerosing Bone Disorder
Authors: Kosugi Rieko , Usui Takeshi , Matsuyama Midori , Matsuoka Hideaki , Kinoshita Akira , Inoue Tatsuhide
Published: May 2020

Background: Camurati-Engelmann disease (CED)is a rare sclerosing bone disorder. The skull and the diaphyses of the long tubular bones are mainly affected. The symptom developed in childhood and patients suffer from bone pain, easy fatigability, and decreased muscle mass and weakness. CED is caused by mutations in the transforming growth factorβ1 (TGFβ1)gene on chromosome 19q13.113.3. This condition is inherited in an autosomal dominant pattern. Case: A 20- year-old male. He has a so-called marfanoid habitus with long and narrow limbs. At the age of 19,he presented pain in lower limb, then walking became difficult. None of his relatives had similar symptoms. In biochemical tests,calcium, Phosphorus and bone-related hormones levels were all in the normal range. 25(OH)vitamin D levels were low probably due to his eating habits. On radiological evaluation, X-ray showed thickening of the bone cortex of the bilateral tibia. Bone scintigraphy revealed markedly increased tracer uptake in the bilateral temporal bone, femur, and tibia. Based on clinical and radiological features CED was suspected. Sequence analysis of the transforming growth factor β1 (TGFB1)gene revealed a previously reported pathological variant (p.R218H). Discussion: CED is a rare pan-ethnic condition with more than 300 published cases worldwide. Although this case was difficult to diagnose because there was no family history and the onset of adulthood not childhood, this disease was suspected due to the typical localization of affected bone lesions by bone scintigraphy and was diagnosed by genetic testing. The majority of CED are missense variants in exon 4 leading to single amino acid substitutions in the encoded protein. Exon 4 encodes a latency-associated peptide (LAP) that suppresses the activity of TGF-β1 protein. No consensus management guidelines have been developed to date. Treatment with corticosteroids may relieve the pain, improve the muscle weakness and fatigue. Recently, the efficacy of losartan has been reported in some patients. Conclusion: Here we report a de novo case of CED diagnosed by genetic testing. Osteosclerotic diseases are very rare and are often difficult to diagnose. Genetic testing plays an important role in confirming the diagnosis.
MON-661 Association of 25-Hydroxyvitamin D Serum Levels with Markers of Glycemic Control in Diabetic and Nondiabetic Patients on Maintenance Hemodialysis
Authors: Falcetta Pierpaolo , Lucchese Teresa , Garofolo Monia , Penno Giuseppe , Cupisti Adamasco , Del Prato Stefano , Egidi Maria Francesca
Published: May 2020

Introduction: In type 2 diabetic patients (T2DM) with end-stage renal disease (ESRD) on hemodialysis (HD), an inverse relationship between 25(OH)D and glycated hemoglobin (HbA1c) have been reported. However, because of anemia and altered red cells turnover, glycated albumin (GA) has been proposed as a more reliable glycemic marker in these subjects. Therefore, we have examined whether an association exists between 25(OH)D and GA in HD diabetic and nondiabetic (ND) subjects.

Material and methods: A total of 121 HD (M/F: 69/31%; age 69±15), of whom 43 (35.5%) had T2DM, were analyzed. Median Hb level was 10.2 g/dL (IQR, 9.35-10.9) and median albumin was 3.44 g/dL (IQR, 3.09-3.77). The median dialysis vintage was 29.3 months (IQR, 11.6-67.44). In all subjects, 25(OH)D, HbA1c, and GA were determined on the morning of the dialysis.

Results: Median 25(OH)D concentration in the whole study population was 25.5 mcg/mL (IQR, 17.7-33.75), while median HbA1c level was 37 mmol/mol (IQR, 32-43) and GA was 16.5% (IQR, 14.3-20.2). The median serum concentration of 25(OH)D was lower in T2DM group compared to ND (19.0 vs. 27.3 mcg/mL; P=0.002). In the entire cohort, there was an inverse relationship between 25(OH)D and GA (r: -0.255; P=0.005), while there was no significant correlation between HbA1c and 25(OH)D (r:-0.158; p=0.086). The relationship between GA and 25(OH)D levels was confirmed among T2DM patients (r: -0.375; P=0.013) but not in ND (r: -0.036; P=0.751), while HbA1c didn’t significantly correlate with 25(OH)D neither in T2DM (r: -0.255; P=0.099) nor in ND (r: -0.002; P=0.986). Both in the whole cohort as well in T2DM, the independent association of GA and 25(OH)D persisted upon adjustment for age, sex, BMI, dialysis duration, and vitamin D supplementation. By these regression analyses, it was calculated that 10 mcg/mL decline in 25(OH)D was associated with a 2.4% increase in GA. When T2DM individuals were considered, this increase was 75% greater (4.2%).

Conclusions: In HD patients, serum 25(OH)D is more strongly associated with GA than HbA1c in both diabetic and nondiabetic subjects. This might reflect the higher reliability of GA in assessing glucose control in this category of subjects. Furthermore, lower serum 25(OH)D concentration was associated with poorer glycemic control among T2DM subjects, but not in ND. Since 25(OH)D deficiency was more prevalent in T2DM than ND, these findings could emphasize the importance of adequate vitamin D repletion in this category of patients. Whether correction of vitamin D insufficiency might affect GA levels remains to be explored.
MON-349 Left Hip Pseudofracture in a Patient with Refractory Paget Disease of the Bone
Authors: Gastelum Alheli Arce , Pinjala Anusha , Maraqa Sima , Block Megan , Zena Mohsen
Published: May 2020

Background

Paget’s disease of the Bone (PDB) is a benign condition caused by focal abnormal bone remodeling. It is largely asymptomatic and is often discovered incidentally while investigating an elevated alkaline phosphatase (ALP) or imaging studies.

Diagnosis relies on biochemical screening, ALP, as a first line test. X-rays and radionuclide scans can assist in determining the extent of disease. Bisphosphonates are recommended for the treatment of bone pain associated with PDB. Zoledronic acid is recommended as the bisphosphonate most likely to give a favorable pain response. Treatment aimed at improving symptoms is recommended over a treat-to-target strategy aimed at normalizing total ALP in PDB.

Clinical case

A 51-year-old, non-verbal female presented to the Endocrinology office with her legal guardian for a follow-up regarding Paget’s disease of the bone. The patient had a past medical history of mental disability and refractory Paget’s disease that was diagnosed 13 years prior in the setting of elevated alkaline phosphatase. At the time of diagnosis bone scan showed involvement of both tibias, pelvis and right femur stress fracture. She also had a right femoral fracture 7 years before the current presentation that was surgically fixed with an intramedullary rod. The patient had undergone 5 yearly infusions of Zoledronic acid with persistent elevated alkaline phosphatase.

During her clinic visit the patient endorsed left non-traumatic hip pain as well as difficulty walking over the last 2 weeks. Vital signs were within normal limits. On physical exam she appeared well developed, no acute distress was noted, normal heart rate, regular rhythm and normal heart sounds. Pulmonary effort was normal, no respiratory distress or abnormal sounds were appreciated. Musculoskeletal exhibited bilateral lower extremity bowing. No skin warmth, bony growths or tenderness on palpation were noted.

Lab work revealed ALP 277 u/l, bone specific alkaline phosphatase 95.9 (8.1 - 31.6), BUN 12 mg/dl, Creatinine 0.66 mg/dl, GFR 90, Calcium 9.0 mg/dl, Vitamin D 23.3 ng/mL.

She had been treating the hip pain with as needed NSAIDs. An X-ray of the left femur was ordered, and the study showed possible acute subcapital minimally displaced femoral neck fracture with minimal impaction in the setting of known Paget’s disease. The patient was then contacted and asked to present to the ER emergently for further evaluation and treatment.

Upon arrival to the Emergency Department, an MRI of the left hip was performed, demonstrating extensive Paget’s disease with no evidence of acute hip fracture.

Conclusions

It is essential to obtain an urgent x-ray in patients with Paget’s disease who presents with localized pain. However as this case demonstrates x-ray findings can be misleading due to underlying structural deformity of the bone and further imaging like CT or MRI may be necessary.
SAT-376 Secondary Hyperparathyroidism, an Untoward Complication of High Dose Phosphate Supplementation in Hereditary Hypophosphatemic Rickets
Authors: Pinjala Anusha , Gastelum Alheli Arce , Adel Maraqa Sima Abdel Rahman , Samec Joshua , Zena Mohsen
Published: May 2020

Background: Hereditary hypophosphatemic rickets is a debilitating disease with multiple skeletal abnormalities. Children exhibit rickets and growth failure, while adults exhibit bone pain, enthesopathy, HTN, and arthritis. Gene mutations involving renal phosphate reabsorption(PHEX, FGF23, SLC34A3) leads to renal phosphate wasting. Modes of inheritance include X-linked dominant (most common), autosomal dominant, and autosomal recessive. High dose oral phosphate supplements along with calcitriol are the mainstay of treatment. This can lead to complications of secondary hyperparathyroidism. Clinical Case: An 81-year-old Caucasian woman with PMH of X-linked dominant hypophosphatemic rickets (XLH), secondary osteoarthritis of both knees, HTN, and neuropathy was seen in the Endocrinology clinic. She was diagnosed with XLH 47 years ago and was taking calcitriol 0.5 mcg daily along with a phosphate supplement of 250 mg, 2 tablets 5 times a day. She underwent multiple corrective orthopedic procedures and bilateral knee replacements. On exam, she had short stature (height of 149.9 cm), arthritic changes of bilateral hand joints, and dentures. Starting in 2015, there was a rise in PTH to 101 pg/ml (normal 18.4-80 pg/ml). Over the next 4 years her PTH continued to rise to 182.6 pg/ml, 244.4 pg/ml, 350.6 in 2016, 2017, and 2019 respectively. A 24-hour urine collection revealed a calcium level of 175 mg (normal 100-250 mg/24 hours) and a phosphorus level of 2191 mg (normal 900-1300 mg/24 hours). In December of 2018, she developed hypercalcemia with a serum calcium level of 10.9 mg/dl(normal 8.5-10.5 mg/dl). We then tapered off calcitriol and decreased the phosphate supplements to TID. Despite these measures, her PTH continued to rise, but phosphorus remained normal. A Sestamibi scan showed hyperplasia of all four parathyroid glands, and a DXA scan showed normal bone mineral density. Serum alkaline phosphatase was normal. We decreased her phosphate supplements to BID and started cinacalcet at 30 mg BID. Conclusion: This case illustrates the challenges of primary and secondary hyperparathyroidism when treating XLH. It is proposed that an increased oral phosphate load transiently lowers ionized calcium in serum, which then stimulates PTH secretion. Increased mineralization of bone is another possible explanation of this phenomenon. Persistent parathyroid stimulation can cause hyperplasia of parathyroid glands, nephrocalcinosis, hypertension, and renal failure. Early identification, temporary discontinuation of oral phosphate, and an increase of calcitriol will lower PTH. The FDA approved burosumab for the treatment of XLH in 2018. Future studies are needed to see if burosumab therapy prevents the above complications associated with traditional treatment.
MON-602 The Efficacy and Safety of Sodium-Glucose Transport Protein 2 (SGLT-2) Inhibitors for Weight Loss Among Individuals Without Diabetes: A Systematic Review and Meta-Analysis
Authors: Cabrera Carmen Carina , Francisco Miguel Enrico , Dampil Oliver Allan Castillo
Published: May 2020

Background

With the growing prevalence of obesity and its associated metabolic consequences, new strategies for safe and effective weight loss are called for. SGLT2i is a class oral antidiabetic agents that lowers glucose levels through renal glucose loss, with weight reduction as a consequence. Hence, its role in diabetes and obesity is well-recognized. However, its use among individuals without diabetes for safe and durable weight loss has not yet been sufficiently evaluated, although initial studies are promising.

Objective

To determine the efficacy and safety of SGLT2i compared to placebo among subjects without diabetes mellitus in terms of weight loss and adverse effects.

Methods

A meta-analysis was conducted on randomized controlled trials (RCTs) comparing different SGLT2i and placebo among patients without diabetes mellitus using RevMan 5.3 software.

Results

Five trials involving 779 patients met the eligibility criteria. SGLT2i used in these studies include Canagliflozin, Dapagliflozin, Sergliflozin and Remogliflozin with treatment duration ranging from 2 to 26 weeks.

Pooled data of these 5 trials showed a significant difference in weight loss among subjects given SGLT2i (MD -1.34 kg [95% CI -1.51, -1.17]; p < 0.00001, I2 = 0%) as compared to placebo. Four studies reported change in BMI as an outcome measure, likewise showing a significant difference favoring the use of SGLT2i (MD -0.50 [95% CI -0.56, -0.44]; p < 0.0001, I2 = 0%). Two RCTs reported the percentage of weight loss. There was a significantly higher proportion of subjects achieving >5% weight loss among those given SGLT2i (RR 1.61 [95% CI 1.09, 2.38]; p = 0.02, I2 = 0%). There was no significant difference in the proportion of subjects who achieved >10% weight loss (RR 1.42 [95% CI 0.60, 3.33]; p = 0.42, I2 = 12%). Urogenital infections were more common in the SGLT2i group (RR 2.62 [95% CI 1.76, 3.91], p < 0.00001, I2 = 0%) as reported in 4 studies. Only one study reported occurrence of hypoglycemia which did not differ significantly between both groups.

Conclusion

Although this meta-analysis shows a statistically significant decrease in weight (-1.34 kg, [95% CI -1.51, -1.17]) with the use of SGLT2i among subjects without diabetes, this might not be clinically relevant. With the increased risk of urogenital infections with its use, there is insufficient evidence to recommend its routine use as monotherapy for weight loss outside the population of individuals with diabetes.

References

Pereira MJ, Eriksson JW. Emerging role of SGLT-2 inhibitors for the treatment of obesity. Drugs (2019) 79:219-230.
MON-647 Mechanisms of Insulin Resistance in Skeletal Muscle in Women with PCOS
Authors: Moreno-Asso Alba , McIlvenna Luke C , Patten Rhiannon K , McAinch Andrew J , Rodgers Raymond J , Stepto Nigel K
Published: May 2020

Polycystic ovary syndrome (PCOS) is the most common female endocrine disorder affecting metabolic, reproductive and mental health of 8-13% of reproductive-age women. Insulin resistance (IR) appears to underpin the pathophysiology of PCOS and is present in approximately 85% of women with PCOS. This underlying IR has been identified as unique from, but synergistic with, obesity-induced IR (1). Skeletal muscle accounts for up to 85% of whole body insulin-stimulated glucose uptake, however, in PCOS this is reduced about 27% when assessed by hyperinsulinemic euglycemic clamp (2). Interestingly, this reduced insulin-stimulated glucose uptake observed in skeletal muscle tissue is not retained in cultured myotubes (3), suggesting that environmental factors may play a role in this PCOS-specific IR. Yet, the molecular mechanisms regulating IR remain unclear (4). Previous work suggested that Transforming Growth Factor Beta (TGFβ) superfamily ligands may be involved in the metabolic morbidity associated with PCOS (5). In this study, we investigated the effects of TGFβ1 (1, 5ng/ml), and the Anti-Müllerian hormone (AMH; 5, 10, 30ng/ml), a novel TGFβ superfamily ligand elevated in women with PCOS, as causal factors of IR in cultured myotubes from women with PCOS (n=10) and healthy controls (n=10). AMH negatively affected glucose uptake and insulin signalling increasing p-IRS1 (ser312) in a dose-dependent manner in myotubes from both women with and without PCOS. AMH did not appear to activate the canonical TGFβ/BMP signalling pathway. Conversely, TGFβ1 had an opposite effect in both PCOS and control myotubes cultures, decreasing phosphorylation of IRS1 (ser312) and enhancing glucose uptake via Smad2/3 signalling. In conclusion, these results suggest that AMH may play a role in skeletal muscle IR observed in PCOS, however, further research is required to elucidate its mechanisms of action and broader impact in this syndrome. References: (1) Stepto et al. Hum Reprod 2013 Mar;28(3):777-784. (2) Cassar et al. Hum Reprod 2016 Nov;31(11):2619-2631. (3) Corbould et al., Am J Physiol-Endoc 2005 May;88(5):E1047-54. (4) Stepto et al. J Clin Endocrinol Metab, 2019 Nov 1;104(11):5372-5381. (5) Raja-Khan et al. Reprod Sci 2014 Jan;21(1):20-31.
OR01-06 Resistance to Thyroid Hormone Beta Is Associated with an Increase in Hepatic Fat Measured by Transient Elastography (Fibroscan®) with Controlled Attenuation Parameter (CAP)
Authors: Chaves Carolina Marques , Bruinstroop Eveline , Refetoff Samuel , Yen Paul Michael , Anselmo Joao
Published: May 2020

Hepatic regulation of lipid metabolism is dependent on thyroid hormone receptors (TRs) with TRβ as the predominantly expressed TR isoform in the liver. Patients with resistance to thyroid hormone (RTH) harboring mutations in the THRB gene have loss-of-function of TRβ. Thus, we investigated whether these patients can present with alterations in the lipid homeostasis.

We evaluated hepatic fat content and metabolic parameters in patients bearing the R243Q mutation of THRB gene (n=21) and in their non-affected (WT) first degree relatives (n=22). All participants belonged to the same family, lived in the same small island, therefore exposed to similar environmental conditions. Family members with disorders known to affect lipid metabolism as well as a history of drinking habits of more 30 g alcohol/day were excluded. Whenever possible, medications were suspended one month before the tests. Hepatic fat content was estimated by transient elastography (FibroScan®, TE) with controlled attenuation parameter (CAP) as a noninvasive marker of hepatic steatosis. Measurements of CAP and metabolic parameters were carried after an overnight fast. The observers were blinded to the status of the patients.

There were no significant difference between the two groups, RTHβ and WT respectively, in age (mean±SD) 36±11 years (range 18-55) and 34±9 years (19-59) and body mass index, BMI, 21.9 Kg/m2 (14.2-31.7) and 23.8 Kg/m2 (18.9-37.7). CAP values were significantly higher in RTHβ patients when compared to those measured in their WT relatives, 263±21 dB/m and 218.7±43 dB/m, respectively (P<0.001). Measurements of CAP correlated positively with age and BMI in the WT group (r=0.56; P<0.05 and r=0.59; P<0.05 respectively) but not in the group of RTHβ (r=0.19; P>0.05 and r=0.21;P>0.05. The lipid profile was not significant difference between the two group regarding total cholesterol (165±27 and 175±30 mg/dl), LDL cholesterol (103±16 and 113±29 mg/dl) and tryglicerides (115±45 and 108±43mg/dl). However, the HDL cholesterol was significantly lower in RTHβ patients (40±8 and 52±10 mg/dl; P<0.006). Glycemia, insulin levels and HOMA-IR (Homeostatic Model Assessment of Insulin Resistance) were within the normal range and showed no significant differences between the two groups.

In conclusion, RTHβ was associated with hepatic steatosis indicating that the TRβ dependent signaling of thyroid hormone plays an important role in lipid homeostasis. This finding further emphasizes the rational for the development of thyroid hormone analogues selective for TRβ which may offer alternatives for treatment of lipid-associated hepatic disorders without generating cardiac toxicity or accelerated bone loss.
SAT-715 Bisphenol-A Alters Pancreatic B-Cell Proliferation and Mass in an Estrogen Receptor Beta-Dependent Manner
Authors: Nadal Angel , Boronat-Belda Talia , Quesada Ivan , Fuentes Esther , Gustafsson Jan-Ake , Alonso-Magdalena Paloma
Published: May 2020

Bisphenol-A (BPA) is one of the highest volume chemicals produced worldwide. It is used as the base compound in the manufacture of polycarbonate plastics, epoxies and resins. Humans are consistently exposed to BPA and consistently it has been detected in the majority of individuals examined. Experimental research in animals, as well as human epidemiological studies, converge to conclude that BPA is a risk factor for the development of type 2 diabetes. In previous studies we have demonstrated that the exposure to BPA during embryonic development promote an increment of pancreatic β-cell mass. This was correlated with increased β-cell division and altered global gene expression in pancreatic β-cells. The aim of this work was to determinate whether ERβ was involved in the in the β-cell mass and proliferation increment observed in male mice offspring. ERβ+/- pregnant mice were treated with vehicle or BPA (10 μg/kg/day) from day 9 to 16 of gestation. Offspring pancreatic β-cell mass was measured at postnatal day 0 (P0) and 30 (P30). For ex vivo experiments Wild-type (WT) and ERβ-/- neonates as well as adult male and female mice were used. For in vitro, single islets cells were cultured for 48 h in the presence of 10 μmol/L BrdU, and vehicle, BPA (1, 10, 100 nM) or the specific ERβ agonist WAY200070 (1, 10, 100 nM). β-cell proliferation rate was quantified as the percentage of BrdU-positive pancreatic β-cells. In vivo exposure to BPA during pregnancy promoted an increment of pancreatic β-cell mass and proliferation in WT mice at P30 which was absent in ERβ -/- mice. In order to explore if these changes were related to a direct action of BPA on pancreatic β-cell division we performed a series of ex vivo experiments. Augmented β-cell proliferation rate was observed in BPA-exposed β-cells isolated from both adult male and female WT animals in comparison to controls. The increment was significant at all BPA doses tested. The effect was imitated by the selective ERβ agonist, WAY200070, and was abolished in cells from ERβ-/- mice. We also explored the effects of BPA in pancreatic β-cells from neonates and found an increment in BPA-exposed cells compared to controls, although the difference was only significant at the dose of 1 nM. A similar effect was observed in neonate cells treated with WAY200070 (10 nM). The effects on β-cell replication were abolished in cells from ERβ-/- neonate mice treated either with BPA or WAY200070. Our findings suggest that BPA modulate pancreatic β-cell growth and mass in an ERβ-dependent manner. This could have important implications for metabolic programming of T2DM. Ministerio de Economía y Competitividad, Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER) grants BPU2017-86579-R (AN) and BFU2016-77125-R (IQ); Generalitat Valenciana PROMETEO II/2015/016 (AN). CIBERDEM is an initiative of the Instituto de Salud Carlos III.
SUN-740 Low-Dose Dihydrotestosterone Lowers Lipogenic Master Regulator in Liver and Adipose Tissue from Female Mice
Authors: Seidu Tina , Andrisse Stanley
Published: May 2020

Hyperandrogenemia (HA) and insulin resistance (IR) are hallmarks of polycystic ovary syndrome (PCOS), a common endocrine disorder that affects 1 in 10 women. These hallmarks are also integral elements of non-alcoholic liver disease (NALFD), a disorder that is common in women with PCOS. Administering low dose dihydrotestosterone (DHT) induced a lean female mouse model with a PCOS-like phenotype, displaying IR and NAFLD. The molecular mechanism of HA-induced NAFLD has not been determined. We hypothesized that low dose DHT would interrupt hepatic lipid metabolism leading to NAFLD. To investigate the role of androgens on the master regulator of lipogenesis, sterol regulatory element-binding protein 1 (SREBP1), we extracted white adipose tissue (WAT), liver, and skeletal muscle from wild-type, control and low dose DHT female mice; and performed Western blot and real-time quantitative PCR (qRT-PCR) analysis of lipogenic intermediates of the tissue homogenates. Low-dose DHT lowered the active form of cytosolic SREBP1 in the liver and WAT compared to controls. Additionally, low dose DHT lowered inactive SREBP1 in the liver. However, the condition did not alter the levels of the active and inactive forms of SREBP2 in the liver and WAT, though the active form was lowered in skeletal muscle. Further, p-ACC levels were unaltered in liver and WAT. FAS levels were unchanged in WAT and skeletal muscle. Taken together, our findings support the hypothesis that cytosolic SREBP1 decreased due to its translocation to the nucleus, where it regulates lipogenic protein levels. We speculate that low-dose DHT promotes the translocation of SREBP1 from the cytosol to the nucleus to influence lipogenic gene expression leading to increased lipogenesis contributing to NAFLD.
MON-624 Effect of Whole Body Vibration on Glycemic Control in Adults with Type 2 Diabetes
Authors: Michels Manuela de Lucca , d’Acampora Ana Clara , Spivakoski Camila Sartor , Mattje Priscila Nobre Dantas , Réus Bruna da Silva , Alves Débora Monteiro dos Santos , Pilletti Karine , Ronsoni Marcelo Fernando , Hohl Alexandre , van de Sande-Lee Simone
Published: May 2020

Introduction: Physical activity plays an important role in glycemic control in patients with type 2 diabetes, but overall adherence rate is low. For patients not able or willing to engage in regular physical exercise, whole body vibration comes as a potential alternative. Objective: To evaluate the effect of 28Hz whole body mechanical vibration on glycemic control and other metabolic parameters in patients with type 2 diabetes. Methods: 24 adults with type 2 diabetes on oral antidiabetic agents, with a baseline HbA1c between 6.5 and 9.0%, were randomized into two groups. The control group (CG) was advised to adopt lifestyle modifications, and the intervention group (IG) received the same orientations and used a 28 Hz whole body vibrating platform daily for 20-30 minutes during 12 weeks. Results: Data from 22 patients were analyzed (one from each group was excluded). Baseline characteristics of both groups were similar except for triglycerides, which were higher in the CG (111.8±39.9 mg/dL vs. 188.9±68.8 mg/dL, p<0.05). After 12 weeks, there was a significant reduction in glycated hemoglobin in the IG (7.69±0.49 vs. 7.17±0.77%, p<0.05), not observed in the CG (8.05±0.98 vs. 7.92±1.07%, p=0.52). A non-significant trend for weight loss in IG was observed (78.14±10.47 vs. 77.14±11.08Kg, p=0.069). There were no significant differences between the groups regarding fasting blood glucose or any other clinical and biochemical variables analyzed. Conclusion: This study suggests an improvement in glycated hemoglobin at 12 weeks with the use of the 28Hz vibration platform in patients with type 2 diabetes. However, further studies with a larger number of patients and longer follow-up are needed to better define the role of whole body vibration as an adjuvant in glycemic control.
SUN-738 Establishing the Link Between Genetic Variations of Estrogen Receptor 2 and Unexplained Infertility
Authors: Halassy Sophia , Mikhael Sasha , Chorich Lynn Parson , Tam Kerlene Bertwick , Diamond Michael P , Burkholder Adam B , Hall Janet Elizabeth , Korach Kenneth Steven , Layman Lawrence Clarke
Published: May 2020

Background: Unexplained or idiopathic infertility comprises approximately 30% of couples who present with infertility. This has led to investigations seeking to determine the cause(s) of this important diagnosis of exclusion. Estrogen’s role in reproduction has been well- established. Estrogens bind to two hormone receptors (namely estrogen receptor-alpha and estrogen receptor-beta), which are distributed differentially throughout the body. Specifically, the estrogen receptor-beta, coded by the Estrogen Receptor 2 (ESR2) gene, is highly expressed in granulosa cells and growing follicles. The one female patient reported with an ESR2 mutation presented with hypergonadotropic hypogonadism. However, subfertility with inefficient ovulation and resistance to exogenous ovulatory stimulation is seen in an ESR2 knockout mouse model. We therefore hypothesized that less severe ESR2 variants could lead to a normal female phenotype and pubertal development but could be a cause subfertility.

Methods: DNA samples from 200 women with unexplained infertility were obtained from the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) clinical trial, which investigated optimal ovulation induction medications for unexplained infertility. These samples were subjected to targeted next-generation sequencing (NGS) for the ESR2 gene. Likely pathogenic variants that occurred with a minor allele frequency of < 0.01 in the gnomAD database and a Combined Annotation Dependent Depletion (CADD) score of > 20 were selected for confirmation by Sanger sequencing.

Results: From the 200 patient samples, five heterozygous missense variants and one heterozygous in-frame deletion identified by targeted NGS were confirmed by Sanger sequencing. Further studies will need to be performed in vitro to confirm the likely pathogenicity of these variants.

Conclusion: These studies raise the possibility that If these variants in ESR2 that impair estrogen signaling, they could be a potential newly recognized etiology of unexplained infertility in women with unexplained infertility.

Conclusion: These studies raise the possibility that variants in ESR2 that impair estrogen signaling could be a potential newly recognized etiology of unexplained infertility in women.
SAT-462 Coronary Vasospasm-Induced Myocardial Infarction: An Uncommon Presentation of Thyrotoxicosis
Authors: Ataallah Basma , Buttar Barjinder , Kulina Georgia , Kaell Alan
Published: May 2020

Background: Coronary artery vasospasm-induced myocardial infarction is a rare cardiac complication of untreated thyrotoxicosis. Diagnosis is difficult due to the transient and unpredictable occurrence of coronary spasm [1].

Clinical Case: A 47-year-old Hispanic female smoker presented with a one-week history of severe, intermittent substernal chest pain radiating to the left arm. The pain was associated with palpitations and shortness of breath. She was afebrile with a heart rate of 100, a blood pressure of 119/59, a fine tremor, and brisk reflexes. No lid lag or proptosis was appreciated. The thyroid was enlarged, non-tender, without palpable nodules. ECG showed T- Wave Inversions in leads V1-V2 and ST depressions in V4-V5. Chest pain was relieved by SL nitroglycerin.

Lab results showed a peak Troponin of 0.20 (N < 0.06), TSH 0.01 mU/L (N > 0.45mU/L), free T4 5.54 (N < 1.46 ng/dl), total T3 4.50 pg/mL (N < 1.37 ng/mL), free T3 21.0 ng/mL (N < 4.4 pg/ml), TSI 3.61 IU/L (N < 0.55 IU/L), thyrotropin R Ab 7.47 IU/L (N < 1.75 IU/L) and thyroglobulin Ab 1.3 IU/ml (ULN < 0.9 IU/ml). Thyroid US showed a heterogeneous enlarged thyroid gland with increased vascularity.

For her NSTEMI she was treated with a heparin drip, aspirin, clopidogrel, atorvastatin, propranolol, and isosorbide mononitrate. Methimazole was started to treat thyrotoxicosis. Cardiac catheterization revealed coronary vasospasm without evidence of valvular or coronary artery disease. Methimazole restored euthyroidism and she has not had recurrence of angina.

Discussion: Rarely, hyperthyroidism can present with transient myocardial ischemia secondary to coronary artery vasospasm in patients with normal coronary arteries. The etiopathogenesis is unclear and may relate to a direct metabolic effect of excess thyroid hormone on the myocardium. In a Korean study evaluating chest pain in patients who underwent coronary angiography, the incidence of coronary vasospasm was 5%, occurring most frequently in women under 50 years of age with thyrotoxicosis [2].

Conclusion: Patients who present with angina and are thyrotoxic should be evaluated for vasospasm. Females under 50 years old with Graves’ disease are at highest risk. Treatment includes antithyroid medications along with nitroglycerin, and we can consider calcium channel blockers including diltiazem. Treatment of thyrotoxicosis eliminates recurrence of vasospasm [3].

References

1. Chudleigh RA, Davies JS: Grave’s thyrotoxicosis and coronary artery spasm. Postgrad Med J. 2007, 83(985):e1-e2.

2. Zheng W, Zhang YJ, Li SY, et al: Painless thyroiditis-induced acute myocardial infarction with normal coronary arteries. Am J Emerg Med. 2015, 33:5-10.

3. Marah N, Bryant K, Haq S, Khan M: Graves’ disease-induced coronary vasospasm. JACC: Cardiovascular Interventions. 2016, 9(23):2452-2453.
OR09-05 Expression of SLC35F1 in the Plasma Membrane of Cells of Aldosterone Producing Cell Clusters (APCCs) and Its Possible Role in Aldosterone Synthesis
Authors: Goodchild Emily , Stoetaert Jan , Drake William , Linton Kenneth , Brown Morris Jonathan
Published: May 2020

Background Genetic mutations and histological appearances suggest that APCCs are precursors to some aldosterone producing adenomas (APA). They are hypothesised to contribute to post-operative non-cure and recurrence of primary aldosteronism (PA) but are currently undetectable pre-operatively. SLC35F1 is a possible nucleotide sugar transporter. On microarray it is highly expressed in APCCs, but not in the rest of the adrenal cortex (1). Our aim was to investigate the role of SLC35F1 in APCCs, determine its subcellular localisation and establish whether expression is consistent with pathological APCC subtypes (as suggested by recent evidence from in situ metabolomic studies (2)). Methods Comparative bioinformatic analysis of the SLC35F1 amino acid sequence was carried out. Ex vivo 4uM adrenal sections, from 6 PA patients in the MATCH study, were stained on serial sections with anti-CYP11B2 (Gomez-Sanchez) or anti-SLC35F1 (Novus NBP1-86755). In vitro, H295R cells were transfected with SLC35F1 cDNA. Subcellular localisation of SLC35F1-GFP was studied by comparison to organelle markers (golgin 97, RAB11, wheat germ agglutinin, calnexin and Tom20) using confocal microscopy. Overexpression and siRNA knock-down in H295R cells was correlated to aldosterone production. Results SLC35F1 is a decamembrane-spanning transporter molecule predicted to have a negatively charged pocket in the substrate binding site, implying a transport substrate with a positive charge. Strong staining of CYP11B2 in clusters of cells in adrenal cortex, consistent with APCCs, were present in all six adrenal glands (25 APCCs). Serial sections showed specific SLC35F1 staining of APCCs, in cytoplasm and plasma membrane. SLC35F1 staining was absent from normal cortex. 12 APCCs (48%) were SLC35F1-negative. Visualisation of transiently expressed SLC35F1 demonstrated localisation to the endoplasmic reticulum in H295R cells (Pearson’s coefficient r=0.758) with no plasma membrane localisation (r=-0.07). Preliminary transfection data suggest direct involvement in aldosterone production. Conclusions Expression of SLC35F1 in the plasma membrane and cytosol of APCC cells supports a role in pathological aldosterone production by APCCs. The inferred transport substrate of SLC35F1 is the NAD(P)(H) precursor, nicotinamide riboside, a positively-charged nucleotide sugar. If confirmed, the essential requirement for NAD(P)H in steroidogenesis, and heterogeneity of SLC35F1-staining in APCCs, is consistent with a metabolically active, possibly pathological, subtype of APCCs. Detection of SLC35F1 in vivo may therefore facilitate sub-classification of PA patients.

1). Nishimoto et. al. PNAS. 2015 Aug 18;112(33):E4591-9. 2). Murakami et. al. 2019 Hypertension. In press.
OR25-01 Durable CYP21A2 Gene Therapy in Non-Human Primates for Treatment of Congenital Adrenal Hyperplasia
Authors: Eclov Rachel J , Lewis Terra E W , Kapadia Mayank , Scott David W , McCoy Daniel D , Rouse Jeremy L , Romero Kirsten B , Beard Clayton W , Mansfield Gary S
Published: May 2020

Severe Congenital Adrenal Hyperplasia (CAH) is most commonly caused by genetic defects in the CYP21A2 gene, which leads to a deficiency of 21-hydroxylase enzyme and disruption in the biosynthesis of Adrenal corticosteriods. Despite treatment with corticosteroids, patients remain at significant risk for adrenal crisis, experiencing a 3-fold higher mortality rate than age matched controls. They also suffer from significant infertility, bone, metabolic, and cardiovascular disease, and hyperandrogenism in women leading to genital abnormalities, hirsutism, and other complications. We are developing an AAV5- based gene therapy (BBP-631) that will provide a functional copy of the CYP21A2 gene to the adrenal glands of CAH patients. To determine the durability of this therapy we treated cynomolgus monkeys with increasing doses of BBP-631 via intravenous injection. At 4-, 12- and 24-weeks post treatment, expression of hCYP21A2 mRNA and vector genome copies (VGC) in the adrenals and other peripheral tissues was measured. VGC was present in the liver and adrenals at 4 weeks, with durable detection through 24 weeks and total vg levels were dose dependent. hCYP21A2 RNA expression in adrenal and liver tissues was also dose dependent and continued to increase from 4 weeks through 12 weeks. There were no adverse safety signals in any of the treated animals. This data combined with efficacy data of BBP-631 in a Cyp21-/- mouse model supports our continued clinical development of BBP-631 as a treatment for congenital adrenal hyperplasia.
OR04-05 MYOD1 Is Associated with Eosinophil-Mediated Browning of Subcutaneous Adipose Tissue
Authors: Li Ting , Masuda Mia Y , LeSuer William E , Stubblefield Tianna M , Hernandez James D , Jacobsen Elizabeth A , De Filippis Eleanna
Published: May 2020

A novel role for adipose tissue (AT)-resident eosinophils (EOS) in metabolism has been suggested. These data were obtained using genetic animal models with either whole-body overexpression of Interleukin-5 (IL-5Tg) leading to eosinophilia or gene ablation resulting in complete lack of EOS. These models limit the specificity of the findings. We hypothesized that AT-resident EOS play a specific role in whole-body metabolism. To this end, we generated a transgenic mouse model overexpressing human eotaxin-2 (hE2) under the control of a fat-specific aP2 promoter, which would exclusively recruit circulating EOS into AT (hEo2Tg), without any changes in the overall EOS numbers. Compared with wild type (WT) mice, AT-EOS numbers were markedly increased in multiple fat depots from hEo2Tg mice, including subcutaneous white adipose tissue (sWAT). After 12 weeks of high-fat diet (HFD), hEo2Tg mice showed significantly less body weight gain and fat mass compared with WT littermates. These changes were associated with an improvement in glucose tolerance. We also found increased oxygen consumption and heat production in hEo2Tg mice under room temperature conditions. The increased thermogenesis was accompanied with an increased expression of browning genes such as Ucp1, Prdm16, Dio2 in sWAT from hEo2Tg HFD mice. So far, our data suggest that AT-resident EOS promote browning of sWAT. This, in turn, protects our animals against development of HFD-induced obesity and insulin resistance. Next, whole transcriptome mRNA sequencing and bioinformatic analyses were performed and showed a significant increase of myogenic differentiation 1 (Myod1) gene expression in hEo2Tg sWAT mice. This was confirmed by qRT-PCR. Myod1 is a key regulator of skeletal muscle differentiation. Given the shared features between brown fat and skeletal muscle, we speculate that by increasing Myod1 gene expression, (AT)-resident EOS mediate sWAT browning. Additional studies are needed to determine the molecular mechanism(s) underling the regulation of Myod1 gene expression by AT-resident EOS and its effect on sWAT browning.