bluuebunny/crossref_metadata_2025 huggingface dataset:
FRI027 Regulation Of A Novel Sortilin Splice Variant Expression In Human Diabetic Adipocytes By GLP-1 To Maintain Glucose Homeostasis
Authors: Patel Niketa A , Patel Rekha S , Liu Ashley
Published: October 2023

Disclosure: N.A. Patel: None. R.S. Patel: None. A. Liu: None.

Type 2 diabetes mellitus (T2DM) is a chronic and progressive metabolic disease with no cure. 37.3 million Americans have T2DM as of 2021 and 96 million (1 in 3) are prediabetic. Globally 462 million people are estimated to be living with T2DM. T2DM is a complex, polygenic metabolic disease characterized by hyperglycemia and insulin resistance. Adipocytes play a crucial role in glucose homeostasis. In response to insulin, translocation of major glucose transporter-4 (Glut4) from cytoplasm to the plasma membrane facilitates uptake of glucose into the adipocytes. Sortilin, an important constituent of Glut4 storage vesicles, binds to Glut4 with its luminal domain while its C-terminal tail guides intracellular trafficking. In insulin resistant adipocytes, glucose uptake is impaired. In this study, we used human adipose stem cells (hASC) from diabetic (DM) and nondiabetic (NDM) donors and differentiated them in vitro to mature adipocytes. We report that in addition to constitutively spliced full-length sortilin (Sort_FL), we identified an alternatively spliced sortilin variant in human adipocytes. Results show that alternative exon inclusion resulted in inclusion of STOP codon which produced a truncated C-terminal (Sort_T) protein whose expression was significantly increased in DM adipocytes. We elucidated the role and function of Sort_T and our results show that hyperglycemic conditions promoted an increase in Sort_T levels in NDM adipocytes. Overexpression of Sort_T in NDM adipocytes resulted in reduced insulin-stimulated Glut4 translocation and decreased glucose uptake. However, overexpression of Sort_FL does not rescue glucose uptake in DM adipocytes. Computational modeling and molecular dynamics results suggested that Glut4 bound tightly to both Sort_T and Sort_FL. This was validated using co-immunoprecipitation assays which demonstrated robust binding of Sort_T to Glut4. Immunocytochemistry was performed to determine localization of sortilin variants in DM and NDM adipocytes. Results demonstrated that Glut4 co-localized with both Sort_T and Sort_FL and Pearson’s coefficient demonstrated increased Sort_T co-localization with Glut4 in DM adipocytes. Incretin hormone glucagon-like peptide-1 (GLP1) and its analog liraglutide is used to manage T2DM. We evaluated the effect of GLP1 and liraglutide treatment in DM adipocytes on sortilin variant expression and our results demonstrate decreased Sort_T levels at physiological doses (8nM). Using a sortilin splicing minigene, our results demonstrate that GLP1 regulates splicing of Sort_T pre-mRNA and splice factor SRSF10 is involved in GLP1-mediated sortilin alternative splicing in adipocytes. Our study concludes that Sort_T expression in diabetic adipocytes hinders glucose metabolism and Sort_T is a target of GLP1 for maintaining glucose homeostasis.

Presentation: Friday, June 16, 2023
FRI036 Trends In The Racial And Ethnic Disparity Of Metabolic Associated Fatty Liver Disease (MAFLD): Data From NHANES 1988 To 2018
Authors: Shaheen Magda , Schrode Katrina , Pan Deyu , Najjar Sonia Michael , Friedman Theodore C
Published: October 2023

Disclosure: M. Shaheen: None. K. Schrode: None. D. Pan: None. S.M. Najjar: None. T.C. Friedman: None.

Metabolic associated fatty liver disease is a serious and important problem and it affects Hispanics at a higher prevalence compared to Blacks and Whites. This disparity is an important public health concern. The purpose of this study was to examine the trend in the racial/ethnic disparity of MAFLD among a representative sample of the U.S. adult population from 1988 to 2018. Data from the National Health and Nutrition Examination Survey (NHANES) 1988 to 2018 were analyzed. The total sample size was 32,726. Hepatic steatosis was diagnosed using the U.S. fatty liver index (US-FLI). MAFLD was diagnosed among those with both HS and overweight/obesity, diabetes mellitus, and/or metabolic syndrome. We analyzed the data using logistic regression to test for trends over time for the overall sample and for each racial/ethnic group considering the design and sample weights. Prevalence was age-adjusted using the direct method and the census data published by the census bureau. We also estimated the percent change in the prevalence using the formula [(2018 prevalence – 1988 prevalence)/1988 prevalence)*100]. Overall, the age-adjusted prevalence of MAFLD increased over time from 16% in 1988 to 37% in 2018 for 131% percent increase (p<0.05) while the age-adjusted rate of obesity increased from 23% in 1988 to 40% in 2018 for 74% increase (p<0.05). Among Mexican Americans, the age-adjusted prevalence was higher at all times compared to the overall population and there was a significant increase in the age-adjusted prevalence of MAFLD over time (36% in 1988 to 58% in 2018 for a 61% increase) (p<0.05). Among Blacks, a significant increase in the age adjusted prevalence of MAFLD was found (11% in 1988 to 25% in 2018 for a 56% increase) (p<0.05). We also found a significant increase in the age-adjusted prevalence of MAFLD among the White population (15% in 1988 to 35% in 2018 for a 133% increase) (p<0.05). Our study indicated that there is an increase in the age-adjusted prevalence of MAFLD over time that was greater than the increase in obesity. The racial/ethnic disparity in MAFLD persisted over time with Mexican Americans consistently having the highest prevalence that was highest in 2018. Grants: R01MD012579, R24DA017298, U54MD007598, S21MD000103, UL1TR001881

Presentation: Friday, June 16, 2023
SAT165 A Novel Mutation In The HNF4α Gene (C.691C>T, P.arg231trp) Likely To Be Pathogenic For Maturity Onset Diabetes Of The Young Type 1 Presenting With Hyperinsulinemic Hypoglycemia In An Infant
Authors: Rodriguez Adriana , Sastry Shruti , Chemaitilly Wassim , Gurtunca Nursen
Published: October 2023

Disclosure: A. Rodriguez: None. S. Sastry: None. W. Chemaitilly: None. N. Gurtunca: None.

Background: Maturity Onset Diabetes of the Young type 1 (MODY 1) is a monogenic form of diabetes mellitus caused by a defective HNF4α gene, resulting in reduced insulin secretion and diabetes in early adolescence and young adulthood. MODY 1 is also known to be associated with increased insulin secretion during fetal, neonatal and childhood periods with consequences that range from fetal macrosomia to persistent hyperinsulinism. Traditionally, HNF4α gene mutations represents 5% of all cases of diazoxide-responsive hyperinsulinism. Clinical Case: A 1 month old male born full term and large for gestational age (birth weight of 4920g) following an uncomplicated pregnancy and delivery developed hypoglycemia soon after birth and required hospital admission on day of life 2 with a serum glucose of 30 mg/dL and an insulin level of 5 uIU/mL. A fasting challenge showed hypoglycemia at 9 hours with a serum glucose of 47 mg/dL and an insulin level of 10.3 uIU/mL confirming hyperinsulinemic hypoglycemia. He was started on diazoxide to which he responded well and was placed on a continuous glucose monitor (CGM). He was originally started on diazoxide 8mg/kg/day that later was decreased to 6.6mg/kg/day due to blood glucoses in the 200’s. He passed the fasting study 5 days after starting diazoxide and went home with the CGM with subsequent dose titration made with guidance from remote data sharing. A neonatal hypoglycemia panel was sent and showed a novel mutation, c.691C>T, p.ARG231Trp in the HNF4α gene classified as a variant of uncertain significance. Computer modeling software suggested that this gene might disrupts the gene structure and function. This variant is present in population databases at a 0.0009% frequency and this missense change has been observed in individuals with clinical features of maturity onset diabetes of the young. Patient’s father carries the same mutation and paternal grandmother carries a diagnosis of type 2 diabetes mellitus. Conclusion: This is a novel mutation that should be considered pathogenic based on this patient’s neonatal presentation and previous literature. This case also presents possible uses of CGM in infants with diazoxide responsive congenital hyperinsulinism in order to decrease burden from monitoring and streamline communication with the medical team

Presentation: Saturday, June 17, 2023
SAT655 Modifying Effects Of Dash Diet On Food Addiction Two Years After Sleeve Gastrostomy: A Randomized Controlled Clinical Trial
Authors: Ariyanfar Shadi , Tabesh Mastaneh , Noormohammadi Morvarid , Jahromi Soodeh Razeghi , Rashidbeigi Elahe
Published: October 2023

Disclosure: S. Ariyanfar: None. M. Tabesh: None. M. Noormohammadi: None. S. Razeghi Jahromi: None. E. Rashidbeigi: None.

In morbid obese individuals, bariatric surgery is considered an effective intervention due to failure of non-surgical weight management strategies. Sleeve gastrostomy (LSG) accounts for over half of bariatric surgeries. The prevalence of weight regains is 76% over 2-6 years after LSG due to binge eating disorder and food addiction. In our previous study, one-fifth of patients with LSG fulfilled the criteria for food addiction (FA). Various dietary patterns have been studied for their potential benefits in controlling FA in non-surgical weight loss programs. Among them, DASH diet attracted our attention, because, besides its effect on FA, the nature of this diet fully addresses other prevalent complications of patients with morbid obesity who undergoes LSG more than two years ago, i.e., vascular problems and gut microbiota changes. To study the effect of the DASH diet on food addiction after LSG we recruited 100 individuals with LSG two years prior to the study who had mild to moderate FA according to DSM-IV criteria and Yale Food Addiction Scale (YFAS) and weight regain of more than 25% of excess weight loss. Participants were randomly assigned to a calorie-restricted DASH diet (1000-1200 calories, containing 2-3 servings of whole grain, 3-4 servings of vegetables, 3 servings of fruit, 2 servings of skim or low-fat dairy products, 1-2 servings of meat, poultry, and fish, 3 servings of nuts, seeds, and legumes, 2 servings of oil) or a calorie-restricted diet (1000-1200 calories, 3-4 servings of whole grain, 3-4 servings of vegetables, 2 servings of fruit, 2 servings of skim or low-fat dairy products, 2-3 servings of meat, poultry, and fish, 1 serving of nuts, seeds, and legumes, 2 servings of oil, and 1 serving of sugar.) for 16 weeks. Food addiction, serum levels of FBS and insulin were assessed. No significant differences in calorie and macronutrient intake, BMI, amount of excess weight before surgery, physical activity level, depression, anxiety level, and YFAS mean were observed between to studied groups After 16 weeks, individuals in DASH diet group reported a significant reduction in YFAS (from3.64±0.63 to 2.66±0.63, P.Value < 0.001), also Insulin levels and FBS decreased from 12.22±3.13 to 10.12±2.3 mcU/ml (P.Value< 0.001) and from 91.92±8.9 to 86.98±6.8 mg/dl (P.Value< 0.001), respectively. A significant reduction of insulin (13.21±2.97 to11.15±2.18 mcU/ml, P.Vaue< 0.001) and FBS level (92.31±7.5 to 87.63±5.9 mg/dl) was observed among controls. A significantly higher reduction of insulin levels in DASH group was noticed at the endpoint (P.Value: 0.026). It could be concluded that adherence to DASH diet, 2 years after SLG, can combat food addiction by modifying serum insulin levels.

Presentation: Saturday, June 17, 2023
SAT170 Paraneoplastic Hypoglycemia Secondary To Hepatocellular Carcinoma
Authors: Dejhansathit Siroj , Sheung Nicole , Akofu Anota , Uddin Ashraf , Marium Fnu , Akabogu Nwamaka Gloria , Salam Waqar
Published: October 2023

Disclosure: S. Dejhansathit: None. N. Sheung: None. A. Akofu: None. A. Uddin: None. F. marium: None. N.G. Akabogu: None. W. Salam, MD: None.

Introduction: Hypoglycemia is a known but rare Paraneoplastic manifestation of hepatocellular carcinoma and can lead to significant morbidity and mortality. Even though HCC-related hypoglycemia is a known entity, knowledge about prevention and treatment is limited. Case Description: We report a 36-year-old male with no significant past medical history presenting initially to emergency room for abdominal pain and distension for 2 months. He reported associated 10 pounds unintentional weight loss, fatigue, night sweat and loss of appetite in the past 3 months. The patient noted to have hypoglycemia with blood glucose of 20 mg/dl on admission. He was given 2 ampoules of 50% dextrose and started on 5% dextrose solution intravenously. A CT abdomen and pelvis showed enlarged heterogenous liver with numerous hepatic lesions, concerning for multifocal hepatocellular carcinoma. A liver biopsy was done and confirmed hepatocellular carcinoma. Labs showed alpha fetoprotein level over 60500 ng/mL (0-8.3 ng/mL). Hepatitis B surface antigen was reactive with positive hepatitis B DNA, confirming the diagnosis of chronic hepatitis B infection. Gastroenterology, Oncology and Surgical Oncology were consulted. Patient was felt not to be a good surgical or transarterial chemo-embolization. Endocrinology was consulted when patient develops scrotal and legs swelling after receiving high rate of dextrose fluid since admission to maintain blood glucose. Prednisone 20 mg twice a day was initiated and later increased to 30 mg twice day after 2 days without significant improvement. Prednisone was then switched to dexamethasone 4 mg four times a day for longer half-life. 10% dextrose was slowly decreased from 200cc/hr to100cc/hr but resulted in rebound hypoglycemia. Somatropin 4 mg daily was also added with a goal to further decrease fluid rate in order to help with his discomfort from swelling. 10% dextrose was eventually decreased to 75 cc/hr. Patient subsequently opted for hospice care and passed away within 24 hours. Discussion: The paraneoplastic hypoglycemia associated with HCC can be classified into two categories. Type A hypoglycemia is usually found in the late-stage HCC when tumor burden is high. Type B hypoglycemia is caused by an increase in pro-IGF-2 level that is incompletely processed by the tumor cells, stimulating insulin receptors. It is likely our patient had type A hypoglycemia due to the extensive tumor burden. Overall, paraneoplastic hypoglycemia associated with HCC has very poor prognosis and high mortality rate. There is no single effective management and combination of steroids and Somatropin may provide palliative improvement as seen in our patient.

Presentation: Saturday, June 17, 2023
SAT175 Noninsulinoma Pancreatogenous Hypoglycemia Syndrome As A Complication Of Nissen Fundoplication
Authors: Rinn Ryan , Lacount Stephen , Muuse Janelle
Published: October 2023

Disclosure: R. Rinn: None. S. Lacount: None. J. Muuse: None.

Hypoglycemia is a common condition that is typically diagnosed with Whipple’s Triad (hypoglycemic symptoms, low blood glucose, resolution of symptoms with treatment). It is important to recognize and treat early as it has the potential for lethal outcomes. Dumping syndrome is a rare presentation after Nissen’s fundoplication and predominantly reported in children. Here we present a case of an adult with persistent postprandial hypoglycemia after Nissen Fundoplication. A 79-year-old male with a recent Nissen’s fundoplication presented with repeated episodes of extreme fatigue and diaphoresis after eating. Other complaints included weakness and significant weight loss. Finger stick glucose on multiple checks were found to be in 40s. He was hospitalized and underwent extensive workup with Endocrinology and Gastroenterology. Important labs revealed elevated insulin 10.2, C-peptide level at 7.3 and pro-insulin at 27.7, negative insulin antibodies, a normal Insulin like growth factor (IGF-1) at 74, Beta-hydroxybutyrate level 0.1, and a negative screen for sulfonylureas. He was discharged home on a low carbohydrate diet but continued having repeated Whipple’s triad positive hypoglycemic episodes. In terms of imaging, CT of the abdomen did not reveal a mass, other localization studies were deferred since the episodes were mostly post-prandial concerning for NIPHS than insulinoma. For management, he had minimal response to octreotide and verapamil. His symptoms are currently being managed on acarbose and diazoxide with dietary modifications consisting of high protein and limited complex carbohydrates. Postprandial hypoglycemia as a complication of Nissen’s fundoplication is thought to be secondary to dumping syndrome (DS). DS is divided into two stages- early/osmotic stage and late/ hypoglycemic stage. Both types are caused by a large amount of gastric contents emptying into the duodenum, resulting in vasomotor symptoms from changes in blood pressure, pulse and glucose levels, as well as gastrointestinal symptoms. Glucagon like peptide-1 is responsible for the second phase and the levels are directly related to gastric emptying and inversely related to plasma glucose concentration. Accelerated gastric emptying causes increased GLP-1 levels leading to exaggerated insulin response resulting in rebound severe hypoglycemia. It is important to realize that diet plays an important role in symptom management. After Nissen’s fundoplication, a decrease occurs in the storage capacity of the fundus and gastric distensibility, which causes increased gastric motility with rapid emptying. Dietary modifications include reduction of carbohydrate intake and supplementation of dietary fibers with meals greatly help relieve symptoms associated with dumping syndrome in addition to drug therapy.

Presentation: Saturday, June 17, 2023
SAT443 Prevalence Of Immune Checkpoint Inhibitor-related Endocrinopathies In Patients With Cancers
Authors: Pittampalli Shanti , Lubin Sarah R , Acharya Runa
Published: October 2023

Disclosure: S. Pittampalli: None. S.R. Lubin: None. R. Acharya: None.

Background: Immune checkpoint inhibitors (ICIs), emerged as the primary treatment modality for a wide range of cancers improving overall survival. Nevertheless, improved overall survival is complicated by endocrine dysfunctions including thyroid dysfunction, adrenalitis, diabetes mellitus, and hypophysitis. Such adverse events offset the benefits of ICI therapy and are associated with significant morbidity and mortality. Limited data exists concerning the burden of the ICI-related endocrinopathies in cancer treatment.Objective: To identify the prevalence and timing of onset of various endocrinopathies in patients with cancers receiving ICIs. Methods: A retrospective study was conducted at SUNY Upstate Medical University, NY comprising of adult patients. The study population consisted of all patients age 18 and above seen at Upstate Medical University between 1 January 2019 and 31 December 2021. Anonymized aggregate-level data was collected using an EPIC Slicer Dicer to identify all adult patients with cancer who underwent ICI therapy and a total of 199 patients were included. Demographic, clinical, histopathological, laboratory data were examined. The study was reviewed by IRB and deemed exempt.

The following ICI-related endocrinopathies were considered: Hypothyroidism, hyperthyroidism, diabetes mellitus, adrenal insuffiency, and hypophysitis. ICI treatments included: anti-PD-1 (nivolumab, pembrolizumab, cemiplimab), anti-PD-L1 (atezolizumab, avelumab, durvalumab), and combination therapy (ipilimumab and nivolumab, or any other ICI combinations). Statistical analysis including descriptive statistics, ANOVA was conducted using IBM SPSS software.Results: A total of fifty patients (25%) developed ICI-related endocrinopathy (n=28 M, 22 F) with a mean age of onset 63.69 years. Majority of the patients were being treated for lung cancers (51%) and had hypothyroidism (88%) followed by adrenal insufficiency (9%) and diabetes (2%). There were no cases of hyperthyroidism or hypophysitis observed. The average time of onset of endocrinopathies after initiation of ICI therapy was 22 weeks (anti-PD-1=122 days, anti-PD-L1=180 days and combination therapy= 252 days) with a significantly later onset with combined therapy when compared to anti-PD-1 inhibitors (252 vs 122 days, p= 0.004). Conclusion: With the increasing use of immune checkpoint inhibitors in cancer therapy, there is increased prevalence of endocrinopathies. Periodic hormonal assessment along with close monitoring of new symptoms results in early detection of endocrinopathies as the time of onset varies significantly with the type of ICI agent and the use of single vs combination therapy.

Presentation: Saturday, June 17, 2023
THU019 Osilodrostat As An Emergency Alternative For Hypercortisolism In A Patient With An Impaired Liver Function
Authors: Minasyan Mari , Bogusławska Anna , Gamrat Aleksandra , Hubalewska-Dydejczyk Alicja , Gilis-Januszewska Aleksandra
Published: October 2023

Disclosure: M. Minasyan: None. A. Bogusławska: None. A. Gamrat: None. A. Hubalewska-Dydejczyk: None. A. Gilis-Januszewska: None.

Osilodrostat as an emergency alternative for hypercortisolism in a patient with an impaired liver function. A case presents a 34 year old woman with an active Cushing Disease, who underwent non-radical surgery of invasive pituitary adenoma in 2014 and CyberKnife radiotherapy in 2018. Patient demonstrates many complications of long lasting hypercortisolemia- poorly controlled diabetes mellitus, heart failure, hypertension, hypercholesterolemia, mental disturbances and severe hepatic impairment. Challenges in this case are aggravated by very difficult compliance. Due to elevated liver function tests, the patient couldn’t have started ketoconazole and relacorilant treatment. Because of non-controlled DM, pasireotide treatment was contraindicated in her case. She didn’t agree either for metyrapone treatment or for adrenalectomy. Finally osilodrostat has been implemented as the last-chance alternative given at the time of severe hepatic impairment. At the dose of 2x2mg we observe clinical improvement, normalisation of UFC, decrease of Hba1c and spectacular improvement of liver function. However the current data on use of osilodrostat in patients with hepatic impairment are limited, our case shows that osilodrostat can be an emergency alternative for severe hypercortisolism with impaired liver function. The mechanism of improvement of liver function may be indirect through decreasing the level of hypercortisolemia, however potential direct beneficial influence of osilodrostat on liver function seems to be an interesting subject worth further investigation. More studies on the link between hypercortisolemia, liver function and steroidogenesis inhibitors are needed.

Presentation: Thursday, June 15, 2023
THU069 Growth Hormone Secretion And Serum High-sensitivity C-reactive Protein Levels In Adult Patients With Non-functioning Pituitary Tumors
Authors: Seki Yasufumi , Morimoto Satoshi , Bokuda Kanako , Watanabe Daisuke , Watanabe Satoshi , Yamashita Kaoru , Takano Noriyoshi , Ichihara Atsuhiro
Published: October 2023

Disclosure: Y. Seki: None. S. Morimoto: None. K. Bokuda: None. D. Watanabe: None. S. Watanabe: None. K. Yamashita: None. N. Takano: None. A. Ichihara: None.

Background: Growth hormone (GH) deficiency, which causes visceral obesity and non-alcohol fatty liver disease, increases cardiovascular event risks. Serum high-sensitivity C-reactive protein (hs-CRP) levels has been reported to estimate those risks. GH supplementation therapy was reported to decrease the serum hs-CRP levels in GH deficient patients, however, the association between GH secretion and serum hs-CRP levels have been unclear. Patients and Methods: We retrospectively reviewed charts of the patients with non-functioning pituitary adenoma and Rathke’s cysts who underwent preoperative GH-releasing peptide-2 (GHRP-2) tests to assess GH secretion, and investigated the association between GH secretion and background characteristics. Patients who had a history of pituitary surgery, severe renal insufficiency or active inflammatory diseases, or received GH supplementation therapy were excluded. Results: Among 171 patients (100 NFPA and 71 Rathke’s cysts), 55 (32%) presented severe GH deficiency, as diagnosed using GHRP-2 tests. Serum hs-CRP levels were significantly higher in the patients with severe GH deficiency than in those without severe GH deficiency (754 [393—1330] vs 249 [113—537] ng/mL, P < 0.001). Serum hs-CRP levels were significantly correlated with logarithm of peak GH response to GHRP-2 (r = -0.50, P < 0.001), but not with IGF-1 SD score (r = -0.10, P = 0.21). In the multiple regression analysis, peak GH response to GHRP-2 was a significant variable for determining serum hs-CRP levels (β = -0.340, P = 0.001) after adjustment with age, sex, BMI, smoking habit, alcohol consumption, hypertension, diabetes mellitus, dyslipidemia, abnormal liver function, and other pituitary hormone deficiencies. Severe GH deficiency were significantly associated with for serum hs-CRP levels higher than 1000 ng/mL (Odds ratio, 2.58 ;95% Confidence interval 1.15-5.78) when adjusted for obesity and abnormal liver function. Conclusion: GH secretion was significantly and negatively associated with serum hs-CRP levels independent of atherosclerotic risk factors, metabolic complications of GH deficiency, and other anterior pituitary hormone secretions.

Presentation: Thursday, June 15, 2023
SAT670 Is Myostatin A Biomarker Of Skeletal Muscle Mass?
Authors: Orioli Laura , Samaras Sofia , Lause Pascale , de Barsy Marie , Thissen Jean-Paul Mathieu , Loumaye Audrey
Published: October 2023

Disclosure: L. Orioli: None. S. Samaras: None. P. Lause: None. M. de Barsy: None. J.M. Thissen: None. A. Loumaye: None.

Rationale: Our study aims to determine whether myostatin is a biomarker of muscle mass in cancer cachexia and obesity. Methods: The ACTICA study included cancer patients with and without cachexia. The MYDIASECRET study included obese patients evaluated before and 3 months after bariatric surgery. Body composition was assessed using bioelectrical impedance analysis (BIA101 device, Akern). Skeletal muscle mass (SMM) and appendicular SMM (ASMM) were calculated from Janssen’s and Sergi’s equations, respectively. Results were expressed as indexes (kg/m²). Myostatin plasma concentrations were determined using ELISA. Spearman’s coefficient was used to correlate muscle mass indexes and myostatin. Results: The ACTICA study included 143 patients of whom 70 with cachexia. SMM index (SMMI) and ASMM index (ASMMI) were lower in patients with cachexia compared to those without cachexia (SMMI: 8.0 kg/m² [6.7-9.5] vs 9.0 kg/m² [7.8-10.1], p=0.004; ASMMI: 6.2 kg/m² [5.5-7.1] vs 7.2 kg/m² [6.4-7.8], p<0.001). Myostatin was also lower in patients with cachexia (1434 pg/mL [999-2118] vs 2149 pg/mL [1551-2984], p<0.001). Myostatin was positively correlated with SMMI and ASMMI (SMMI: R=0.500, p<0.001; ASMMI: R=0.479, p<0.001). The MYDIASECRET study included 62 patients. SMMI and ASMMI were decreased after surgery (SMMI: -0.8 kg/m², p<0.001; ASMMI: -1.1 kg/m², p<0.001). Myostatin was also decreased after surgery (1773 pg/mL [1440-2309] vs 2582 pg/mL [1708-3522], p<0.001). Myostatin was positively correlated with SMMI before (R=0.388, p=0.002) and after surgery (R=0.435, p<0.001). Change in myostatin after surgery was also positively correlated with change in SSMI (R=0.287, p=0.023). Conclusion: Myostatin is positively correlated with muscle mass indexes in different conditions, suggesting its potential role as a biomarker of muscle mass.

Presentation: Saturday, June 17, 2023
FRI295 Prolactin Exerts Anti- And Pro-inflammatory Actions In Joint Tissues That Are Cytokine-Dependent
Authors: García Rodrigo José Fernando , Ortiz Georgina , Martínez Díaz Oscar Fernando , Herrera Xarubet Ruiz , Ledesma Colunga María Guadalupe , de la Escalera Gonzalo Martínez , Clapp Carmen
Published: October 2023

Disclosure: J.F. García Rodrigo: None. G. Ortiz: None. O. Martínez Díaz: None. X. Ruiz Herrera: None. M. Ledesma Colunga: None. G. Martínez de la Escalera: None. C. Clapp: None.

The close association between rheumatoid arthritis (RA), sex, reproductive state, and stress have long-linked the sexually dimorphic, reproductive, stress-related hormone prolactin (PRL) to disease progression. However, this role is questioned by the fact that PRL has both pro-inflammatory and anti-inflammatory outcomes in RA with mechanisms that are unclear. Here, we show that PRL modifies in an opposite manner the inflammatory action of IL-1β and TNF-α in mouse synovial fibroblasts (SF) in culture and in joints in vivo. SF isolated from the knee joint of male C57BL/6 mice were incubated with or without IL-1β (1 ng/mL) or TNF-α (10 ng/mL) in the presence or absence of PRL (2.3 μg/mL). Both, IL-1β and TNF-α upregulated the metabolic activity (MTT assay) and the RT-qPCR expression of pro-inflammatory mediators (IL-1β, IL-6, iNOS) via the activation of the NF-κB signaling pathway (immunocytofluorescence, Western blot). However, IL-1β increased and TNF-α decreased the levels of the long PRL receptor isoform (RT-qPCR, Western blot) and this opposite action associated with contrasting effects of PRL in these cells. PRL decreased the IL-1β upregulation of metabolic activity and expression of pro-inflammatory mediators by blocking the degradation of NF-κB inhibitors kB-beta (Iκ-Bβ) and alpha (Iκ-Bα) and, thereby, interfering with the nuclear translocation of NF-κB. By contrast, PRL increased TNF-α-induced stimulation of metabolic activity and expression of pro-inflammatory mediators by promoting the nuclear translocation of NF-κB led by the increased degradation of Iκ-Bβ and Iκ-Bα. The double-faceted regulatory role of PRL against the two cytokines also manifested in vivo. IL-1β (80 ng) or TNF-α (300 ng) with or without PRL (2 μg) were injected into the intra-articular space of the knee joint of mice and, after 24 h, joint inflammation was monitored through the expression of pro-inflammatory mediators (IL-1β and iNOS). Both IL-1β and TNF-α upregulated the expression of IL-1β and iNOS in the joint. However, PRL inhibited the joint proinflammatory effect of IL-1β on IL-1β and iNOS, but not that of TNF-α. We conclude that the outcome of PRL actions on joint inflammation is dependent on its interaction with specific inflammatory cytokines, the level of the PRL receptor, and the activation of NF-κB signaling. We speculate that the opposite effects of PRL help balance joint inflammation in RA and that determining the mechanisms underlying dual actions provide insights into the pathophysiology of RA and the development of new treatments. Supported by UNAM (DGAPA-PAPIIT IN202321).

Presentation: Friday, June 16, 2023
FRI305 Impulse Control Disorders In Patients With Prolactinomas And Non-Functioning Pituitary Adenomas Treated With Dopamine Agonists
Authors: Kolitz Tamara , Shemesh Elad , Nathan Alexandra , Eldor Roy , Izkhakov Elena , Greenman Yona
Published: October 2023

Disclosure: T. Kolitz: None. E. Shemesh: None. A. Nathan: None. R. Eldor: None. E. Izkhakov: None. Y. Greenman: None.

Objective Impulse control disorder (ICD) is a well-recognized side effect of dopamine agonist (DA) treatment in patients with Parkinson’s disease and restless leg syndrome. The available data on the incidence of ICD in patients treated with DA for pituitary tumors are sparse. This study aimed to assess the occurrence of ICD among patients with prolactinomas or NFPA treated with DA compared to patients with prolactinomas or NFPA not treated with DA and to patients with non-pituitary endocrine disorders. Methods Patients attending the general endocrine and pituitary clinics at the Institute of Endocrinology in our medical center were invited to fill in an anonymous validated questionnaire on hypersexuality, pathologic gambling, compulsive shopping, and punding. Associated relevant clinical information was also obtained. Results In total, 174 patients consented to participate. Those with pituitary disorders other than prolactinomas and NFPA were excluded. The final study cohort consisted of 67 patients with NFPA (31 DA-treated) and 40 with prolactinomas (35 DA-treated). The control group consisted of 67 non-DA-treated subjects with other endocrine disorders. The entire cohort was comprised of 77 men and 97 women (mean age 56±17 years). ICDs were reported by 19/66 (29%) DA-treated patients with prolactinomas or NFPA, 3/41 (7%) non-DA-treated patients with prolactinomas or NFPA and 8/108 (7.5%) non-DA-treated patients with prolactinomas, NFPA or other endocrine disorders (p<0.001). There were no significant differences in ICD rates between DA-treated patients with prolactinomas compared to those with DA-treated NFPA, or between non-DA-treated patients with either prolactinomas or NFPA and controls. The ICD rate among DA-treated women was significantly higher than that of non-DA-treated women (34.5% and 7.5%, respectively. p<0.001). No comparable differences were observed in DA-treated versus non-DA-treated men or between all participating men and women. Conclusion ICD rates are significantly higher among patients treated with DA for prolactinomas or NFPA compared to non-DA-treated patients with prolactinomas, NFPA or other non-pituitary endocrine disorders. Patients being treated with DA for any pituitary lesion should be informed of the greater risk of associated ICD.

Presentation: Friday, June 16, 2023
SAT679 Telehealth And Metabolic Health: Unraveling The Effects Of A 12-week Low-starch Diet On Homa2B IR In Overweight Women
Authors: Erta Gita , Gersone Gita , Tretjakovs Pēteris
Published: October 2023

Disclosure: G. Erta: None. G. Gersone: None. P. Tretjakovs: None.

Background: Telehealth has emerged as a promising approach for delivering health care interventions remotely, allowing increased access and convenience, especially in the context of lifestyle interventions for metabolic health. In this study, our aim was to investigate the effects of a 12-week low-starch diet on HOMA2B IR (Homeostatic Model As-sessment for Beta Cell Function Insulin Resistance) in overweight women using tele-health consultations. Methods: A prospective single arm intervention study was conducted among 14 overweight women aged 18-48 years with a body mass index (BMI) of 25-29,9 kg/m^2. Participants received weekly telehealth consultations via video conference with an endocrinologist and were prescribed a low-starch diet for 12 weeks. The dietary intervention focused on reducing the intake of high-starch foods, such as refined grains, potatoes, and bread, while promoting the consumption of non-starchy vegetables, lean protein, and healthy fats. HOMA2B IR, a widely used surrogate marker of insulin resistance, was measured at baseline and after 12 weeks. Results: After 12 weeks of the low-starch diet intervention, there was a significant reduction in HOMA2B IR in overweight women (Mean ± SD: Baseline HOMA2B IR data (2.126 ± 1.909) improved to 1.522 ± 1.468 at 12 weeks (p < 0.05)), indicating improved beta cell function and decreased insulin resistance. Participants also showed reductions in bodyweight, waist circumference, and fasting blood glucose levels. The compliance with the low starch diet was generally high. Conclusion: Our findings suggest that a 12-week low-starch diet administered through telehealth consultations may have positive effects on HOMA2B IR, as well as bodyweight and fasting blood glucose levels, in overweight women. These results highlight the potential of telehealth as a convenient and effective mode of delivering lifestyle interventions to improve metabolic health. More research with larger sample sizes and longer follow-up periods is warranted to confirm these findings and explore the long-term effects of telehealth-based interventions on metabolic health outcomes.

Presentation: Saturday, June 17, 2023
SAT599 Molecular Analysis Of Pituitary Transdifferentiation In Response To Physiological Cues
Authors: Lim Juchan
Published: October 2023

Disclosure: J. Lim: None.

In mammals, the control of cell fate is imperative to the development of multicellular organisms as well as tissue homeostasis/regeneration in the adult. The anterior pituitary (AP) controls growth, metabolism, reproduction, and stress responses through the synthesis and secretion of specific hormones by distinct AP cell lineages. Interestingly, the anterior pituitary exhibits a high level of adult cell plasticity that allows committed hormone-producing cells to alter their cell fate and produce different hormones to meet altered organismal demands. The molecular mechanisms underlying this adult cell plasticity have not been fully characterized. To investigate the mechanism(s) of pituitary cell transdifferentiation, our lab has employed a rat GH3 cell culture model that undergoes somatotrope to lactotrope conversion in response to a cocktail of 3 growth factors (EGF, estradiol and insulin). Upon stimulation of lactotrope transdifferentiation, we confirmed a significant reduction of Growth hormone (Gh1) and reciprocal elevation of Prolactin (Prl) protein and transcript levels in the treated group compared to untreated controls. Proteomic and transcriptomic analyses from the same samples detected upregulation of 124 proteins and 553 transcripts and downregulation of 28 proteins and 556 transcripts respectively. Gene ontology analyses identified a number of upregulated proteins involved in autophagy (e.g. autolysosome), MTORC1 signaling, and a number of upregulated transcripts involved in the regulation of cell proliferation and apoptosis. A number of the upregulated proteins and transcripts are involved in Epithelial-to-mesenchymal transition (EMT) and metabolic change (i.e. glycolysis, hypoxia), while downregulated transcripts involved in neurogenesis (i.e. Notch1, Notch2, Sox2, Sox5). Further, differential expression analyses comparing the proteomic and transcriptomic levels of the treated vs. control GH3 cells identified a number of upregulated proteins with no change in their corresponding transcripts related to MTORC1 signaling and glycolysis as well as a number of unchanged proteins with corresponding upregulated transcripts involved in mitochondrial activity suggesting a broad role for post-transcriptional regulation during transdifferentiation. In a complementary in vivo study, we assessed pituitary cell fate changes in response to hypothyroidism, using a similar integrated proteogenomic profiling. Together, we identify a number of altered molecular pathways that underlie distinct pituitary cell plasticity responses to physiological cues.

Presentation: Saturday, June 17, 2023
SAT605 Growth Hormone Action In Somatostatin Neurons Regulates Anxiety And Fear Memory
Authors: dos Santos Willian O , Juliano Vitor A L , Vieira Henrique R , Frazao Renata , Munhoz Carolina Demarchi , Donato Jose
Published: October 2023

Disclosure: W.O. dos Santos: None. V.A. Juliano: None. H.R. Vieira: None. R. Frazao: None. C.D. Munhoz: None. J. Donato: None.

Dysfunctions in growth hormone (GH) secretion increase the prevalence of anxiety and depression. Furthermore, GH receptor (GHR) signaling in the amygdala has been associated with fear memory, a key feature of post-traumatic stress disorder. However, it is currently unknown which neuronal population is targeted by GH action to influence neuropsychiatric diseases. Here we showed that approximately 60% of somatostatin (SST)-expressing neurons in the extended amygdala are directly responsive to GH. GHR ablation in SST-expressing cells (SSTΔGHR mice) led to increased anxiety in the light-dark box and elevated plus maze tests, whereas SSTΔGHR females showed no changes in anxiety, compared to control animals. Using auditory Pavlovian fear conditioning, both male and female SSTΔGHR mice exhibited a significant reduction in fear memory. In contrast, GHR ablation in SST neurons did not affect memory in the novel object recognition test. The gene expression was analyzed in a bilateral micropunch comprising the central nucleus of the amygdala and basolateral complex of male mice. Increased mRNA expression of Gabbr2 (GABAB2 receptor), Syp (synaptophysin), and Bdnf were observed in the amygdala of SSTΔGHR mice. In conclusion, GHR expression in SST neurons is necessary to regulate anxiety in males, but not in female mice. GHR ablation in SST neurons also decreases fear memory and affects the gene expression in the amygdala. Our findings identified for the first time a specific neuronal population responsible for mediating the effects of GH on behavioral aspects associated with neuropsychiatric diseases.

Presentation: Saturday, June 17, 2023
SAT616 Differentiating Resistant Prolactinoma From Macroprolactinemia
Authors: Lacount Steven , Belany Paul
Published: October 2023

Disclosure: S. Lacount: None. P. Belany: None.

Introduction: Prolactinomas are the most common secretory tumor of the pituitary gland. Hyperprolactinemia can present as hypogonadism, infertility, galactorrhea, or it may remain asymptomatic. In asymptomatic hyperprolactinemia, macroprolactinemia and other secondary causes should be considered and ruled out. Prolactinomas treated with dopamine agonists typically respond well, with decreasing tumor size and prolactin level reduction. We present a case of a prolactinoma not responding biochemically or anatomically to maximum doses of dopamine agonists, concerning for resistant prolactinoma versus macroprolactinemia. Clinical Case: A 62 y.o. male with PMH of HTN, HLD and CAD who presented with fatigue and headaches in 2009. Initial work-up showed an elevated prolactin level to 178 ng/mL (reference range 2.0-18.0 ng/mL). MRI pituitary showed a 1.8 x 1.9 x 1.5 cm mass but without optic chiasmal compression. Patient refused medications and opted to pursue endoscopic endonasal approach (EEA), which was completed in March 2009. Pathology and hormonal immunostains confirmed prolactinoma. Due to persistently elevated prolactin levels following EEA, cabergoline was started. Follow-up MRI Pituitary in November 2012 showed stable heterogeneous residual tissue without tumor recurrence. Despite escalating cabergoline doses (up to 8 mg weekly), his prolactin levels remained slightly elevated (50 ng/mL) after surgery with unchanged symptoms from presentation. Due to the association of cabergoline and cardiac valve disease development, his dose was decreased back down to 0.5 mg twice weekly. Given his persistent asymptomatic hyperprolactinemia that was nonresponsive to high-dose cabergoline, there was consideration for macroprolactinemia causing a falsely high level. Screening polyethylene glycol (PEG) precipitation test in November 2022 was normal. MRI pituitary in December 2022 showed a progressive sellar lesion with increased size and cavernous sinus invasion near the carotid artery. Patient was referred to neurosurgery in January 2023 for further evaluation of potential resistant prolactinoma. Due to the MRI findings and persistently elevated prolactin levels, he will undergo repeat EEA in May 2023 for treatment of resistant prolactinoma. Conclusion: Dopamine agonists are very effective in treating prolactinomas. In asymptomatic hyperprolactinemia, PEG precipitation is an inexpensive test to screen for macroprolactinemia. Once macroprolactinemia and other secondary causes are ruled out, resistant prolactinoma can be considered. Resistant prolactinoma is defined by failure to achieve normoprolactinemia and at least 50% reduction in tumor size on maximum-tolerated therapy. Risk factors for resistant prolactinoma include larger tumor volume and male gender. Treatment options include different or increased dopamine agonist doses, radiotherapy and resection.

Presentation: Saturday, June 17, 2023
OR2803 Corticotroph Fate Weighted Cell Differentiation Paradigm For Human Induced Pluripotent Stem Cells
Authors: Elyse Moore M , Chen Kevin G , Park Kyeyoon , Asuzu David , Ramavenkat Nikhil , Walbridge Stuart , Mullaney Dustin , Arhin Martin , Maric Dragan , Mandal Debjani , Chittiboina Prashant
Published: October 2023

Disclosure: M.E. Moore: None. K.G. Chen: None. K. Park: None. D. Asuzu: None. N. Ramavenkat: None. S. Walbridge: None. D. Mullaney: None. M. Arhin: None. D. Maric: None. D. Mandal: None. P. Chittiboina: None.

Introduction: The vertebrate anterior pituitary gland is a highly conserved ‘master’ organ that controls hormonal milieu in real-time. Pituitary adenomas and their treatments (surgery, chemotherapy or radiation) can result in pituitary organ failure, specifically hypocortisolism, a challenging condition to manage. Here, we created an optimized paradigm (anterior pituitary corticotroph or APcor) to preferentially drive human induced pluripotent stem cells (hiPSCs) towards a pituitary corticotroph fate. Methods: We directed U112I hiPSCs towards terminally differentiated cell types using a combination of rho-associated kinase inhibitor (Y-27632), bone morphogenic protein 4 (BMP4), transforming growth factor β inhibitor (SB431542), sonic hedgehog (SHH), fibroblast growth factor 8b (FGF8b), fibroblast growth factor 10 (FGF10) and leukemia inhibitory factor (LIF). Markers for pluripotent stem cells, cranial placode (CP), Rathke’s Pouch (RP), anterior pituitary progenitors and mature cell types were assessed at 10-day intervals using quantitative qRT-PCR and multiplex immunocytochemistry (mICC) or immunohistochemistry (IHC). ACTH activity was measured using ELISA (MD Bio). Results: We tested initial differentiation conditions and found optimal CP initiation in presence of SB431542. We observed decrease in embryonic stem cell markers OCT4 and NANOG by day 10, with concomitant increase in CP/RP markers SIX1, PAX6 and SIX6 using mICC/IHC and qRT-PCR. Continuation of differentiation paradigm with LIF showed strong expression of anterior pituitary progenitor markers PITX1, TBX19 and POU1F1 at day 20. pRT-PCR analysis at this time point confirms differentiation towards pituitary cell types without needing enrichment for SIX1. At day 30, POMC expression was observed by IHC in 10-15% of cells as measured by quantitative analysis (Qupath 0.2.0), indicating mature corticotrophs. Corticotroph cell fate was confirmed with corticotropin releasing hormone (CRH) stimulation which led to up to 40x-fold increase in ACTH expression detected by ELISA (D30 w/CRH vs Pluripotent w/CRH). Conclusions: We found with the APcor paradigm, we can reliably drive towards corticotroph cell fate. We successfully differentiated hiPSCs into mature functioning corticotrophs with ability to recapitulate pituitary organ function. Our method is amenable to 3D organoid formation and pre-clinical implantation in animal models of hypophysectomy as a novel hormone replacement therapy.

Presentation: Sunday, June 18, 2023