IGF-I Levels Research Articles

SAT150 "Sawtooth" Hypoglycemia: Rare Case Of IGF-2 Mediated Hypoglycemia With Elevated Proinsulin Level And "Sawtooth" Pattern On CGMS

Abstract Disclosure: P. Goparaju: None. M. Zena: None. Background: IGF-2 mediated hypoglycemia is usually associated with low Insulin, C-peptide and Proinsulin levels. We present an extremely rare case of IGF-2 mediated hypoglycemia with elevated Proinsulin level and an unusual “saw tooth” pattern on Continuous glucose monitoring system(CGMS). Clinical Case: 53-year-old male with history of metastatic Liposarcoma was admitted to the hospital with severe hypoglycemia. Whipple’s triad was positive on presentation, patient had symptoms of altered sensorium, blood glucose of 24 mg/dl, and symptoms improved upon correction of hypoglycemia. The patient was admitted to the ICU and IV dextrose was initiated.As Liposarcomas are known to be associated with Non-islet cell tumor hypoglycemia (NICTH), treatment with Prednisone was started. Prior to this, initial hypoglycemia workup was sent when blood sample was drawn during a hypoglycemia episode. Patient has no personal or family history of Diabetes. Adrenal insufficiency was ruled out with morning cortisol of 17.8 ug/dl. Serum glucose was low at 40mg/dl, Insulin<1(0-17 pmol/L), C-peptide level low at 0.4 (0.8-3.9 ng/ml), IGF-1 level was low at 68 (74-225 ng/ml), normal IGF-2 at 626 (333-967 ng/ml) and increased IGF-2/IGF-1 ratio of 9.2(Normally around 3:1). All the lab work above is consistent with IGF-2 mediated hypoglycemia with low Insulin, C-peptide and IGF-1 levels and increased IGF-2/IGF-1 ratio. Interestingly, he has an elevated Proinsulin level of 36.9 (0.0-10.0 pmol/L) which is very unusual.Prednisone was started at 20mg daily to which there was reasonable response, dose was eventually increased to 60mg daily before he was safely sent home. He was discharged on a CGMS and the data was downloaded 2 weeks later. He had an interesting “Saw tooth” pattern of glycemia on the daily glucose graphs. As the patient had access to live data, he was trying to correct the falling blood glucose which briefly improved the readings but was quickly followed by another drop and this sequence carried on leading to a unique blood glucose pattern on the CGMS. Conclusion: Proinsulin level is usually suppressed in IGF-2 mediated hypoglycemia. Our case is unusually associated with high Proinsulin level. One hypothesis is the possible structural similarities leading to lab assay interactions between Proinsulin and “Pro-IGF-2”, which is thought to be one of the main molecules responsible for hypoglycemia in this condition. More studies in future will be helpful to study this possible association. Our case also had a remarkable “Saw tooth” pattern on CGMS glucose graphs which is very rarely seen in clinical practice.

OR01-01 Oral, Once-daily, Paltusotine (Non-peptide Selective Somatostatin Receptor Subtype 2 Agonist) Therapy In Patients With Acromegaly Is Associated With Long-term Biochemical And Symptom Control And Is Preferred Over Injectable Somatostatin-Receptor Ligands

Abstract Disclosure: M.R. Gadelha: Advisory Board Member; Self; Crinetics Pharmaceuticals, Ipsen, Novo Nordisk, and Recordati Rare Diseases. Research Investigator; Self; Crinetics Pharmaceuticals and Recordati Rare Diseases. Speaker; Self; Crinetics Pharmaceuticals, Ipsen, Novo Nordisk, and Recordati Rare Diseases. H.S. Randeva: None. M.B. Gordon: Consulting Fee; Self; Crinetics Pharmaceuticals, HRA Pharma, Novo Nordisk, and Recordati Rare Diseases. Grant Recipient; Self; Ascendis, Camurus, Chiasma, Corcept, Crinetics, Ipsen, Novartis, Novo Nordisk, Opko, Pfizer, and Strongbridge. M. Doknic: Advisory Board Member; Self; Pfizer in CEE region. Research Investigator; Self; Crinetics Pharmaceuticals, Pfizer, Camurus, Ascendis, Opko, Ipsen, and Teva. Speaker; Self; Pfizer, Novartis, Novo Nordisk, Sandoz, and Merck. E. Mezosi: Research Investigator; Self; Crinetics Pharmaceuticals. M. Toth: Consulting Fee; Self; Ipsen, Novartis, Pfizer, and Recordati Rare Diseases. Research Investigator; Self; Crinetics Pharmaceuticals. C.L. Boguszewski: Consulting Fee; Self; Novo Nordisk. Research Investigator; Self; Crinetics Pharmaceuticals and Recordati Rare Diseases. Speaker; Self; Ipsen and Recordati Rare Diseases. C.T. Ferrara-Cook: Employee; Self; Crinetics Pharmaceuticals. A. Casagrande: Employee; Self; Crinetics Pharmaceuticals. A. Krasner: Employee; Self; Crinetics Pharmaceuticals. Paltusotine is an investigational oral, once-daily, non-peptide, SST2 agonist in development for the treatment of acromegaly and neuroendocrine tumors. Interim analysis results from patients with acromegaly treated with paltusotine for up to 2 years in ACROBAT Advance (NCT04261712), an ongoing, 4-year, single-arm, open-label extension study, are reported here. Patients who completed ACROBAT Edge (NCT03789656) or Evolve (NCT03792555) phase 2 parent studies were eligible to enroll in Advance. In Edge, patients were either sub-optimally controlled on injectable somatostatin-receptor ligand (iSRL; octreotide or lanreotide) therapy alone or in combination with cabergoline; or required combination therapy or pasireotide to achieve normal IGF-I levels at baseline. Evolve enrolled patients who had normal IGF-I levels on iSRL monotherapy at baseline. In Advance, adjunctive medication with cabergoline or pegvisomant was allowed in patients who had not achieved normal IGF-1 levels on maximum dose of paltusotine (40 mg). Serum IGF-I levels were measured using Immunodiagnostic Systems iSYS immunoassay. Symptoms were assessed using the Acromegaly Symptom Diary (ASD; score range, 0-70; higher numbers indicate greater symptom burden), which was developed based on FDA recommendations for patient-reported outcome tools. Patient treatment preference was also evaluated. Forty-three patients were enrolled in Advance (Edge, n=32; Evolve, n=11; 88% of eligible patients). At baseline on iSRL, mean (SD) age was 53.0 (11.6) years, 56% were females, 86% had previous pituitary surgery, and none had radiotherapy. Median (IQR) IGF-I levels remained stable: baseline on iSRL, 1.15x ULN (0.84, 1.46; n=43); in Advance, Week 51 1.08x ULN (0.87, 1.26; n=37), Week 77 1.01x ULN (0.85, 1.28; n=27), and Week 103 1.10x ULN (0.96, 1.45; n=10). Among patients receiving adjunctive medication in Advance, 94% were from the Edge study. Acromegaly symptoms were stably controlled: median (IQR) ASD scores at baseline on iSRL, 8.57 (3.57, 20.14; n=21) and, in Advance at Week 77, 8.0 (5.0, 18.0; n=14). At Week 52, 32 (88.9%) of the 36 respondents preferred once-daily oral paltusotine, 2 (5.6%) preferred previous injections, and 2 (5.6%) had no preference. The most common treatment-emergent adverse events (TEAEs) reported were headache (30.2%), arthralgia (25.6%), and fatigue (18.6%). No serious drug-related TEAEs were reported. Of the 6 patients who discontinued the study, 1 (2.3%) was due to a TEAE (headache). Glycemic control, as measured by HbA1c, was stable during paltusotine treatment. In conclusion, with up to 2 years of follow-up in patients with acromegaly, once-daily oral paltusotine treatment was well-tolerated, associated with stable IGF-I and symptom control relative to that achieved by iSRLs, and was preferred over injected therapy. Support: Crinetics Pharmaceuticals. Presentation: Thursday, June 15, 2023

THU076 GH, IGF-1 And Inflammatory Marker Interactions With Small Bowel Microbial Diversity Are Age And Sex Dependent

Abstract Disclosure: G. Leite: None. N. Tal: None. G. Barlow: None. W. Morales: None. R. de Souza Santos: None. M. Rashid: None. A. Hosseini: None. M. Pimentel: None. R. Mathur: None. Attenuated somatotroph axis function correlates inversely with age-related comorbidities in both animal and human studies. Mechanisms by which GH and IGF-1 may promote aging include increasing inflammation, DNA damage and cell senescence. Bidirectional interactions between GH, IGF-1 and stool microbial diversity occur with malnutrition, inflammatory bowel disease, colon cancer and acromegaly. Given the importance of the small bowel in sustaining immune system homeostasis, we assessed the relationship of the duodenal microbiome, GH, IGF-1 and inflammatory markers in human subjects of different age groups. Methods: Female (F) and male (M) subjects (18-80 years) undergoing upper endoscopy without colon preparation were recruited. Subjects answered a comprehensive medical history, and whole blood was collected. Duodenal luminal samples were obtained using a double lumen sterile catheter. Microbial DNA was extracted and 16S sequenced. Analyses were performed using CLC Genomics Microbial Module. Circulating GH, IGF-1, IGFBP3 and cytokine (GM-CSF, IFNγ, IL10, IL12P70, IL13, IL1B, IL2, IL4, IL5, IL6, IL8 and TNFα) levels were measured (Luminex FLEXMAP 3D). Results: 177 subjects were grouped by age (sex and BMI, P=NS): 18-35yrs (N=21, F=11), 36-50yrs (N=29, F=15), 51-65yrs (N=69, F=38) and 66-80yrs (N=58, F=28). While IGFBP3 levels were similar (P=0.22), IGF-1 levels gradually decreased in older subjects (18-35yrs: 41.8-173.8 ng/mL; 36-50yrs: 12-160 ng/mL; 51-65yrs: 2-156.8 ng/mL; 66-80yrs: 2-142.6 ng/mL, P<0.0001). Overall GH did not change among groups (P=0.58). In both M and F systemic GH inversely correlated with duodenal microbial diversity [Spearman r (R)=-0.234, P=0.001], and this was most pronounced in older M (66-80yrs, R=-0.517, P=0.003). GH and IGF-1 correlated positively with systemic inflammatory markers: GMCSF (GH: R=0.159, P=0.032; IGF-1: P=NS); IFNγ (GH: R=0.178, P=0.016; IGF-1: R=0.154, P=0.041); IL1B (GH: P=NS; IGF-1: R=0.210, P=0.005); IL6 (GH: R=0.160, P=0.031; IGF-1: P=NS) and IL8 (GH: R=0.219, P=0.003; IGF-1: P=NS). IL8 was negatively linked to duodenal microbial diversity (R=-0.213, P=0.001), and higher in older M and F subjects (P=0.008). All associations seen were stronger in M. In addition, systemic TNFα (P=0.024) and IL5 (P=0.011) levels were also higher in M vs. F.In M only, GH was also associated with TNFα (R=0.226, P=0.034) and IL5 (R=0.279, P=0.008). Conclusion: IGF-1 and GH are associated with circulating inflammatory biomarkers in both a sex-and age- dependent manner. We show that systemic levels of GH and the specific inflammatory marker IL-8 are associated with diminished duodenal microbial diversity. This association is most profound in older males. Considering that IL8 is an important senescence marker, the mutual regulation of the small bowel microbiome and the somatotroph axis suggest a novel mechanism promoting inflammation and aging. Presentation: Thursday, June 15, 2023

THU385 Refractory Hyperglycemia As Main Presenting Symptom In A Patient With Acromegaly

Abstract Disclosure: T. Rave: None. J. Vidovic: None. Y. Gu: None. Acromegaly is a rare disorder caused by the overproduction of growth hormone (GH) from an anterior pituitary adenoma. GH regulates glucose control and about 10% of patients with acromegaly can have complications of hyperglycemia. GH stimulates hepatic release of insulin-like growth hormone-1 (IGF-1), which increases gluconeogenesis and lipolysis and decreases glucose uptake throughout the body. The increase in gluconeogenesis and decrease in glucose uptake results in hyperglycemia. The excess release of fatty acids increases insulin resistance. In this case report we present a case of hyperglycemia resistant to multiple modes of medical management with limited acromegaly features found to have acromegaly induced hyperglycemia. A 58-year-old male with a past medical history of type II diabetes mellitus, hypertension, and obesity presented to the endocrinology clinic with treatment resistant hyperglycemia. The patient also endorsed having progressive carpal tunnel symptoms. He had been using an insulin pump and requiring 3 or more boluses per day for the last 6 months. Trulicity was added in addition to current insulin pump therapy, however, sugars remained elevated with an unimproved A1c level of 9% and a fructosamine level of 538 µmol/L correlating to an A1c of 10.8%. An IGF-1 level was sent to rule out acromegaly in the setting of carpal tunnel symptoms. The IGF-1 resulted in 580 ng/mL with a z-score of +5.1. The patient underwent a GH suppression test with a glucose load which showed a significantly elevated nadir GH level of 26.3 ng/mL. Of note, the patient did not have other acromegaly symptoms such as frontal bossing, ring or shoe enlargement, coarse facial features, headaches or vision changes. An MRI pituitary was obtained which was notable for an enlarged pituitary gland with heterogeneous signal, measuring approximately 2.0cm CC x 1.5cm AP x 1.7cm TV, with the pituitary stalk deviated to the left. At this time the intervention for hyperglycemic therapy shifted. The patient was started on octreotide and referred to neurosurgery for transsphenoidal surgery. The pathophysiology of type II diabetes is complex and multifaceted. Additionally, secondary causes of hyperglycemia must be considered in refractory cases, such as in this patient. This case highlights the importance of considering acromegaly and other hormonal conditions in the treatment of patients with uncontrolled hyperglycemia, even in otherwise asymptomatic patients. Presentation: Thursday, June 15, 2023

FRI319 Diagnostic And Management Challenges In A Patient With A Giant Pituitary Lactosomatotroph Adenoma

Abstract Disclosure: C.R. Peixe: None. D. López-Presa: None. M. Bugalho: None. P. Marques: None. Introduction: Giant prolactinomas are rare, accounting for only 2–3% of all prolactinomas. Although benign, several challenges may emerge at diagnosis and during their management. Case: A 38-yr man was incidentally diagnosed with a large skull base tumor on CT-scan undertaken due to head trauma. MRI showed a 55x33mm skull base mass, involving the clivus and sellar/parasellar regions, with bilateral cavernous sinus invasion. A chordoma was suspected leading to a transnasal biopsy, which revealed a PIT1+-plurihormonal pituitary adenoma. His serum prolactin levels were then assessed, which were markedly elevated at 50,414ng/mL (NR:4-15), with concomitant raised IGF-1 at 323ng/mL (NR:101-221). He was then referred to our Endocrine department. Retrospectively, there was a 3-yr history of erectile dysfunction, decreased libido, and infertility, although his testosterone levels were within reference range (307ng/dL; NR:240-830), and sperm analysis parameters were normal. He commenced on low dose cabergoline (0.5mg/week) and two months later clinical improvement was noted, accompanied by a marked reduction of prolactin (830ng/mL) and tumor shrinkage. He remains on cabergoline for ten months, and his latest prolactin and IGF-1 levels were, respectively, 496 and 224ng/mL. In the light of patient’s normal spermogram and restored sexual function, the couple has been referred to the Fertility clinic. Conclusions: The differential diagnosis of large skull base tumors, particularly those affecting sellar/clival regions, must always include prolactinoma, hence serum prolactin should be measured keeping in mind the possible occurrence of hook effect. Most giant prolactinomas respond to dopamine agonists, which should be considered as a first-line therapy, with marked reductions in both prolactin and tumor size often seen within the first weeks of treatment. GH-cosecretion may also ameliorate/normalize with dopamine agonists. In prolactinoma patients, infertility may or may not be directly related with hyperprolactinemia, hence a careful assessment is required, and its management may imply assisted reproductive techniques. Presentation: Friday, June 16, 2023

THU068 Evaluation Of Nonalcoholic Fatty Liver Disease, Liver Fibrosis And Serum Angiopoietin-like Protein Levels In Patients With Acromegaly

Abstract Disclosure: I. Eroglu: None. B. Gonul Iremli: None. I. Idilman: None. D. Yuce: None. I. Lay: None. D. Akata: None. T. Erbas: None. Background: Due to their impaired glucose and lipid metabolism, acromegaly patients are potentially at risk for NAFLD. However, limited data exist about acromegaly and NAFLD relation. In this study (cross-sectional, case-controlled), we evaluated the risk of NAFLD and hepatic fibrosis in acromegalic patients and its association with noninvasive hepatosteatosis scores (NS) and angiopoietin-like protein-8 (ANGPTL-8) level for the first time in the literature. Methods: Thirty-two (15F/17M - median age=50.15 yrs) acromegalic patients (n=15 active acromegaly - AA and n=17 controlled acromegaly - CA) compared to 19 healthy controls (C) in terms of liver fat ratio (LFR), liver stiffness measurement (LSM), and ANGPTL-8 levels. Subjects had MRI-PDFF to determine LFR and MR elastography to quantify LSM. NAFLD was confirmed in those with LFR of ≥5%, and increased LSM in those with LSM of ≥2.5 kPa. VAI (visceral adipocity index), FLI (fatty liver index), HSI (hepatic steatosis index), and TyG (Triglyceride-glucose index) were calculated as NS. Results: Age, gender and BMI were similiar across groups. The GH and IGF-1 levels in AA group was greater than in CA, and C (p< 0.001). The CA had greater frequency of NAFLD than AA (p<0.001). Increased LSM was detected in three (21.4%) of AA, four (23.5%) of CA, and two (10.5%) of C.The median LFR was 1.75% in the AA group, 6.5% in the CA group, and 3.5% in the control group. LFR was lower in the AA group than in the CA (p=0.026). According to MRI-PDFF results, none of the patients in the AA group were diagnosed with NAFLD, while 58.8% (n=10) in the CA group and 26.3% (n=5) in the control group were diagnosed with NAFLD. The prevalence of NAFLD was found to be higher in the CA group than in the AA group (p<0.001). In acromegaly patients, LFR was positively correlated with TyG (r=0.675, p<0.001), VAI (r=0.508, p=0.004), and FLI (r=0.482, p=0.006). However, no correlation was seen between LFR and traditional risk factors for NAFLD (including BMI, waist circumference, Hba1c, HOMA-IR, and CRP) in acromegalics.ANGPTL-8 was lower in CA group (0.61 ng/mL) than in AA group (0.89 ng/mL) (p=0.006). When all acromegaly patients were evaluated independently, those with NAFLD had lower ANGPTL-8 levels than those without NAFLD (p=0.036). Conclusion: In conclusion, high GH levels seem to be protective against fatty liver in patients with active acromegaly, even if the metabolic profileis impaired. There was no relation observed between LFR and conventional risk factors in acromegaly patients. The strongest connection was found between LFR and TyG index among the noninvasive hepatosteatosis scores. ANGPTL-8 levels were lower in acromegaly patients with NAFLD, suggesting that high levels represent a reaction to insulin resistance rather than a cause of NAFLD. Treatment planning at a level that does not cause GH deficiency while maintaining disease control may be helpful to prevent NAFLD in acromegaly. Presentation: Thursday, June 15, 2023

FRI452 A Rare Case of Klinefelter Syndrome, 48XXYY

Abstract Disclosure: P. Kachhadia: None. S. Khan: None. S. Aldasouqi: None. A. Abu Limon: None. Introduction: Klinefelter Syndrome (KS), 47XXY, is the most commonly seen chromosomal abnormality causing infertility, or primary hypogonadism. Other chromosomal variants are rare. We present a very rare case of nondisjunction of the sex chromosome resulting in a 48XXYY KS variant. Case Presentation: The patient is a 45-year-old male was referred to our clinic for evaluation of early onset osteoporosis. The patient was accompanied by his sister, given his cognitive delay. On initial physical exam, there was a concern about acromegaly with signs of frontal bossing, increased hand size, increased ring size and increased shoe size. More recent pictures of the patient showed significant changes in his facial appearance from few years prior. Other symptoms included night sweats. Physical exam revealed decreased testicular volume (less than 3mL bilaterally). Pituitary labs showed elevated prolactin, elevated LH, FSH and low free and total testosterone. GH, IGF-1 levels were within normal range. Chromosomal analysis showed an unexpected pattern of 48XXYY. In addition, MRI of the pituitary was done which showed increased infundibular stalk and increase in size of the pituitary gland which was thought to be secondary to pituitary microadenoma. DEXA scan confirmed osteoporosis. Patient was treated with testosterone injections and alendronate. The rationale for alendronate therapy was considered as a bridge to prevent fractures while the bone density would expectedly improve with androgen therapy, over time. Discussion: Although KS is commonly seen at a frequency of 1:500-1:1000 males, less common and variable phenotypical presentations can occur and can lead to a delayed diagnosis. The reason for the delay of diagnosis in these rare KS variants is the cognitive impairment which leads to delayed evaluation of fertility or hypogonadism, as contrasted to patients with the common variant, KS 47XXY. Additionally, unlike the classic KS variant, these rare variants are often associated with learning disabilities and gross bony features. Conclusion: Clinicians should be familiar with different clinical presentations of the less common KS genetic variants, in contrast to classical KS variants. Patients with classical KS typically present early in view of recognizable complaints of infertility, while patients with the less common KS variants may not present early on due to cognitive delay. Thus, familiarity with the additional manifestations of the less common KS variants (e.g., gross bony features) can help clinicians to suspect the possibility of these variants, prompting chromosomal analysis for further evaluation in such patients. Presentation Date: Friday, June 16, 2023

SAT595 A Successful Long-time Experience Of A Dose-finding Approach For The Treatment Of Central Adrenal Insufficiency (CAI) With Prednisone

Abstract Disclosure: P.F. Santos-Neto: None. S.R. Correa-Silva: None. B.M. Mascarenhas Nakano: None. J. Abucham: None. Introduction: In patients with CAI, hydrocortisone (HC) is considered the preferred treatment. Recommended daily doses are based on estimates of daily cortisol production which have recently been decreased. Doses in the upper part of the previously suggested range have been associated with higher cardiovascular morbimortality. Currently recommended HC replacement doses have been reduced. In our country, HC has never been commercially available in tablets, but prednisone, an intermediate action glucocorticoid available in 5mg and 20mg tablets (lower doses are available elsewhere) is easily found, at low cost, and doesn't need prescription. Aim: To analyze our experience with prednisone in patients with CAI using the same dose-finding protocol established four decades ago. Patients: Data were extracted from electronic files. After applying inclusion/exclusion criteria, 72 out of 96 patients entered the study. Inclusion criteria: >18y, last consultation <2y, stable and same daily doses of prednisone, stable replacement of thyroid and sex hormone deficits in the last year. Exclusion criteria: Cushing´s disease, alternating prednisone doses, non-controlled acromegaly, intestinal malabsortion, other diseases requiring glucocorticoid, hepatic insufficiency. Dose-finding Protocol: Starting doses of prednisone in outpatients are usually 2.5mg or 5.0mg. Thereafter, dose adjustments are done according to clinical signs and symptoms and a pre-defined minimal dose of 2.5mg is attempted in all patients. Patients requiring >2.5mg are changed to 5.0mg, and then suggested to decrease to 3.75mg (3/4 of a 5.0mg tablet). If 3.75mg doses are judged insufficient, we return to 5.0mg; if unpractical, we suggest to alternate doses or to return to 5.0mg. Statistical Analysis: Patients were divided in two groups according to the prednisone daily dose. Group comparisons: Student´s t-test and Fisher´s exact test. P<0.05 was set as significant. Results: Fifty-four patients were on 2.5mg (75%) and 18 patients were on 5.0mg (25%) of prednisone. None was on GH replacement. The 5mg group tended to be younger (P=0.06). No significant differences (0.10<P<1.0) were found in relation to sex, treatment duration, BMI (both at diagnosis and last visit), other hormone deficiencies, IGF-1 levels, diabetes mellitus, dyslipidemia, and hypertension between the two groups. Conclusions: Adult patients with CAI are successfully treated with a single daily morning dose of prednisone determined by a dose-finding approach. In the absence of GH replacement, most patients stay at 2.5mg and the remaining ones at 5.0mg. The lack of difference between doses in parameters of excessive glucocorticoid exposure indicates that our approach is able to adjust prednisone doses close to individual requirements. A broader range of doses from <2.5mg including intermediate doses <5mg should be tried if low dose tablets are available. Presentation: Saturday, June 17, 2023

FRI663 A Rare Case Of Igf-2 Induced Hypoglycemia Associated With Metastatic Colon Cancer

Abstract Disclosure: A. Alshaakh Mohd Mari: None. A. Varshney: None. A. Sidhu: None. M. Matos: None. M. Kinaan: None. Introduction: The diagnosis of hypoglycemia in patients without diabetes is uncommon and nonislet cell tumor hypoglycemia (NICTH) represent a minority of these cases. The most common mechanism is related to IGF-2 production from tumor cells. Case description: A 66-year-old man with a history of stage IV colon cancer presented to the hospital due to breathlessness while receiving chemotherapy (Bevacizumab plus FOLFOX4). He had partial colectomy and chemotherapy 3 years earlier but was recently found to have metastatic disease to the liver. A CT abdomen during hospitalization showed a 15 cm hepatic mass occupying the entire right hepatic lobe. Endocrinology was consulted due to persistent postprandial and fasting hypoglycemia despite dextrose infusion. He had no history of diabetes and denied taking any diabetes medications. Plasma blood glucose (BG) was noted to be 74 mg/dl (74-106) while on dextrose. An 8AM cortisol was checked to exclude adrenal insufficiency and was 8.08 mcg/dL (4.30-22.40). A 72 hour fast was done but discontinued at 8 hours when plasma BG dropped to 48 and patient became symptomatic. At the time C-peptide and Insulin levels were low <0.05 ng/mL (0.48-5.05) and <1.0 mU/L (3.0-25) respectively, with normal Beta-hydroxybutyrate (BHB) 1.1 mg/dL (0.2-2.8). At the end of the fast 1 mg of glucagon was administered and his BG increased to 112 mg/dl in 2 hrs. IGF-1 levels were undetectable <15 ng/mL and IGF-2 levels were found to be 175 ng/mL. The IGF2:IG1 ratio was at 11 confirming IGF-2 mediated NICTH. Dexamethasone 10 mg daily was started, and BG were maintained > 70mg/dl without dextrose infusion. Discussion: In approximately 50% of NICTH, the tumor is identified prior to the onset of hypoglycemia, but up to 50% of these patients may be asymptomatic despite hypoglycemia. Our patient had a known hepatic lesion and was minimally symptomatic despite very low BG. The mechanism for NICTH can include insulin secretion from the tumor, replacement of hepatic tissue and increased glucose utilization by the tumor, or most commonly, IGF-2 secretion. In the case of IGF-2 mediated hypoglycemia insulin, proinsulin, C-peptide, and β-hydroxybutyrate levels are low. An elevated IGF-2:IGF-1 ratio (>10) confirms the diagnosis. The primary treatment is through surgical removal or debulking of the tumor. Neoadjuvant therapies such as radiation and chemotherapy may reduce occurrences of hypoglycemia, but only temporarily. Glucocorticoids may be used when the underlying malignancy cannot be treated. Presentation: Friday, June 16, 2023

THU065 Evaluation Of Sarcopenia And Bone Health In Patients With Acromegaly

Abstract Disclosure: I. Eroglu: None. B. Gonul İremli: None. A. Erkoc: None. I. Idilman: None. D. Yuce: None. E. C. Kutukcu: None. D. Akata: None. T. Erbas: None. Background: Although many complications related to high GH exposure develop in patients with acromegaly, musculoskeletal complications are among the most important complications that reduce the quality of life of patients. However, the effects of acromegaly on muscle and bone have not been adequately researched and are still not entirely understood. We aimed to investigate muscle and bone quality in acromegalic patients in this cross-sectional, case-controlled study. Methods: The study consisted of thirty-two (15F/17M) acromegalic patients (n=15 active acromegaly - AA and n=17 controlled acromegaly - CA) and 19 healthy controls (C). Dual energy X-ray absorptiometry (DXA) was used to determine body composition, appendicular skeletal muscle mass (ASM), relative skeletal muscle index (RSMI), and bone mineral density (BMD). The handgrip strength (HGS) and quadriceps muscle strength were measured by hand dynamometer. Magnetic resonans imaging at the L3 level was used to measure total abdominal muscle area (TAMA, cm2) and vertebral fat ratio (VFR). HGS adjusted by ASM (HGS/ASM) was used to define skeletal muscle quality (SMQ). SMQ was regarded “normal” when the HGS/ASM ratio was >1.53, and “weak” when the ratio was ≤1.36 in males and ≤1.35 in women. The SMQ of those with HGS/ASM levels between these ranges was considered “low”. Results: Age, gender, and BMI were similar between groups. The GH and IGF-1 levels in AA was greater than in CA, and C (p<0.001 for all). While lean tissue was higher in AA than CA and C (p=0.038 and p=0.041, resp.), body fat ratio was lower in AA than CA and C (p=0.04 and p=0.042 resp.). ASM, RSMI, TAMA, HGS and quadriceps strength were similar between groups. Median (IQR) HGS/ASM were 1.67 (1.15-1.9) in AA, 1.57 (1.36-1.79) in CA and 1.77 (1.67-1.93) in C. This difference was found to be significant between CA and C (p=0.008). According to skelatal muscle quality, 94.7% of the individuals in the C group were of normal SMQ, while this rate was 60% in the AA and 52.9% in CA. The ratio of those with low/weak SMQ was higher in the AA and CA compared to C (p=0.012 and p=0.013, resp.). Total and vertebra BMD were similar across groups. Pelvic BMD in CA was lower than C (p=0.02). VFR was higher in CA (56.5%) than in AA (43.75%) and C (42.6%) (p=0.04 and p=0.001 resp.). Conclusion: We showed for the first time that patients with acromegaly had lower muscle quality and pelvic BMD, while patients with controlled acromegaly had higher vertebral fat ratio. Even though lean tissue increased in AA patients, regional muscle distributions (ASM and TAMA) were shown to be similar. The increased muscle mass in acromegaly patients is not expressed as muscular strength, and muscle quality is low in these patients. The high vertebral fat ratio seen in patients with CA may be a result of ectopic adiposity with disease control, as well as the reason for the increased frequency of vertebral fractures seen in patients with acromegaly. Presentation: Thursday, June 15, 2023

THU057 Predictors Of Response To Oral Octreotide Capsules In Patients With Acromegaly In A Large Prospective International Trial

Abstract Disclosure: M. Fleseriu: Consulting Fee; Self; Amryt (fka Chiasma), Ipsen, Ionis Pharmaceuticals Inc., Recordati, Pfizer, Inc. Research Investigator; Self; Amryt(fka Chiasma), Crinetics, Ionis Pharmaceuticals Inc., Recordati. Other; Self; Deputy Editor at EJE. A. Dreval: Research Investigator; Self; Research Investigator: Amryt(fka Chiasma). Y. Pokramovich: Research Investigator; Self; Research Investigator: Amryt(fka Chiasma). I. Bondar: Research Investigator; Self; Amryt(fka Chiasma). E. Isaeva: Research Investigator; Self; Chiasma. D.P. Macut: Research Investigator; Self; Principle Investigator: Amryt(fka Chiasma). Speaker; Self; Novartis Pharmaceuticals, Novo Nordisk, Sanofi, Pfizer, Inc., (spouse) Novo Nordisk. Other; Self; member of the Executive Committee of the European Society of Endocrinology (ESE). M.E. Molitch: Consulting Fee; Self; Corcept, Janssen Research & Development Company, Merck, Novo Nordisk, Pfizer, Inc., Novartis Pharmaceuticals. Grant Recipient; Self; Amryt(fka Chiasma), Crinetics, Ionis Pharmaceuticals Inc. Research Investigator; Self; Bayer, Inc. N.V. Leonova: Research Investigator; Self; Chiasma. G. Raverot: Consulting Fee; Self; Pfizer, Inc., Recordati Rare Diseases, Ipsen. Research Investigator; Self; Chiasma, Pfizer, Inc., Novartis Pharmaceuticals. Speaker; Self; Ipsen, Pfizer, Inc., Recordati Rare Diseases. A. Haviv: Employee; Self; Amryt(fka Chiasma). N. Biermasz: Advisory Board Member; Self; Recordati, Pfizer, Inc., Macro Registry. Grant Recipient; Self; Amryt(fka Chiasma). C.J. Strasburger: Advisory Board Member; Self; Sandoz, Ipsen, Recordati. Consulting Fee; Self; Ascendis, Amryt(fka Chiasma), Novo Nordisk, Merck, Sandoz, Recordati. Speaker; Self; Ipsen, Novo Nordisk, HRA Pharmaceuticals. S. Melmed: Advisory Board Member; Self; Ionis Pharmaceuticals Inc., Crinetics. Consulting Fee; Self; Ipsen. Grant Recipient; Self; Pfizer, Inc. Background: Oral octreotide capsules (OOC) are a treatment option for patients with acromegaly in several countries. Global MPOWERED trial (NCT02685709; Fleseriu et al, Lancet Diabetes Endocrinol. 2022; 10: 102-111)1 showed that OOC were noninferior to injectable somatostatin receptor ligands (iSRLs; octreotide or lanreotide) in maintenance of biochemical response in those previously responding to both OOC and iSRLs. Clinical characteristics predictive of response are useful to devise and implement personalized acromegaly treatment. Objective To identify patient and disease characteristics to predict the likelihood of OOC responsiveness. Methods Eligibility criteria included adults aged 18-75 years, acromegaly diagnosis at screening, and ≥6 months iSRL treatment (≥4 months responding to stable dose). All patients received OOC during the 26-week run-in phase. Responders at week 24 (IGF-I <1.3 × ULN and mean integrated GH <2.5 ng/mL) were randomized to receive OOC or iSRLs during the subsequent randomized controlled treatment (RCT) phase.1 Multivariate logistic regression analyses were performed to assess the relationship of baseline characteristics with OOC response during the run-in phase by comparing the group randomized to the RCT phase (those responding at end of run-in who opted to continue, n=92) to the group not randomized (n=54). Results One hundred forty-six patients enrolled in the run-in phase; 116 patients completed, 94 OOC responders, 92 randomized to RCT phase. IGF-I level prior to initiating OOC was the only predictor of response in the run-in phase for randomization into the RCT phase; randomized mean (SD) 0.8 × ULN (0.25), not randomized 1.0 × ULN (0.25), adjusted P<.0001. Other acromegaly characteristics, including duration of acromegaly, history of surgery and/or radiation, baseline pituitary adenoma size, residual postoperative pituitary adenoma size, GH level (randomized mean [SD] 0.78 ng/mL [0.644]; not randomized 1.06 ng/mL [1.010]), and signs/symptoms of GH excess (eg, joint pain, fatigue, sweating, swelling of extremities, snoring, sleep apnea, carpal tunnel syndrome, headache, and others) were not associated with subsequent OOC response (adjusted P=.11-P=1.0). Prior iSRL dose received was not a predictor of OOC response (adjusted P=1.0); randomized n (%): low dose 19 (20.7), middle 33 (35.9), high 40 (43.5); not randomized: low 11 (20.4), middle 22 (40.7), high 21 (38.9). Conclusions Baseline IGF-I level on iSRLs, but not other acromegaly baseline characteristics, were the sole predictor of subsequent OOC response. This IGF-I-value association may be expected, as response at end of run-in was determined by a strictly defined IGF-I cutoff. These results may guide clinicians considering transitioning patients with acromegaly from iSRLs to OOC. Presentation: Thursday, June 15, 2023

THU171 Reference Intervals For Bioavailable IGF-I Values In Dutch Healthy Children, Adolescents And Young Adults

Abstract Disclosure: K. Pellikaan: None. M. Elizabeth: None. A.C. Hokken-Koelega: None. S.A. van den Berg: None. L. de Graaff-Herder: None. Background: Immunoreactive ‘total’ IGF-I is the main biochemical marker for titration of growth hormone (GH) treatment. However, in several endocrine disorders like Prader-Willi syndrome (PWS) and Silver-Russell syndrome, total IGF-I levels are often higher than expected based on GH dose and clinical effects. When patients reach total IGF-I concentrations above +2SDS, fear of negative long-term effects makes clinicians reduce GH dose. This dose reduction often leads to a deterioration in body composition, growth (in children) and quality of life, which suggests that bioavailability of IGF-I is reduced in patients with these disorders. Measurement of bioavailable IGF-I could improve GH dose titration. However, use of bioavailable IGF-I assays has been hindered by the lack of proper reference intervals. We report reference intervals of bioavailable IGF-I in a large group of healthy children, adolescents and adults. Methods: Serum was collected of 260 Dutch healthy controls aged 1-21 years. Total IGF-I and unbound, bioavailable IGF-I were measured manually using Ansh Labs total and free IGF-I assays. We calculated male and female age-related reference intervals for total and bioavailable IGF-I. Results: We present male and female age-related reference intervals. Both total and bioavailable IGF-I increased with age and were significantly higher in females than in males (p < 0.001). Conclusions: the reported reference intervals for bioavailable IGF-I concentrations will facilitate the use of bioavailable IGF-I levels as an alternative marker for GH dose titration in patients with disorders in which total IGF-I levels are unreliable. Presentation: Thursday, June 15, 2023

THU077 Differences In Clinicopathological Features Of Acidophil Stem Cell Adenomas Compared To Other Subtypes Of Acromegaly: A Retrospective Study

Abstract Disclosure: K.C. Yuen: Advisory Board Member; Self; Novo Nordisk, Ascendis, Corcept Therapeutics, Ipsen, Amryt, Strongbridge, Crinetics, Recordati, Xeris. Grant Recipient; Self; Corcept Therapeutics, Crinetics, Ascendis, Amryt. Speaker; Self; Corcept Therapeutics, Novo Nordisk, Recordati. E. Smith: None. F. Bernabe: None. J.M. Eschbacher: None. M. Rodriguez: None. A.S. Little: None. Background: Acidophil stem cell adenomas (ASCAs) are tumors derived from a precursor of somatotrophs and lactotrophs. Often presenting clinically like prolactinomas that respond to dopamine agonist therapy, some may also present with subtle clinical symptoms and biochemical features of acromegaly. Because ASCAs are so rare, their clinicopathological features have not been well-studied. Aims: Clinicopathological features of ASCAs were analyzed and compared with mixed somatotroph-lactotroph adenomas (MSLAs), mammosomatotroph adenomas (MSAs) and pure somatotroph adenomas (PSAs). Methods: We retrospectively reviewed the medical records of acromegaly patients from a single institution presenting from 2001 to 2022. All growth hormone-secreting adenomas were categorized into ASCAs, MSLAs, MSAs and PSAs based on their histopathological findings in surgically treated patients, and their pre- (preop) and post-operative (postop) clinical data were analyzed. Results: Among 135 patients within this cohort, ASCAs, MLSAs, MSAs and PSAs accounted for 21 (15.5%), 11 (8.1%), 59 (43.7%) and 44 (32.6%) cases, respectively. ASCA patients were younger (mean age ASCA: 48.6 vs MLSA 56.5, MSA 59.0, PSA 63.4 years; P < 0.05), had higher preop prolactin levels (ASCA: 1190 ± 639.0 vs MSLA: 44.9 ± 23.2, MSA: 39.7 ± 6.8, PSA: 23.8 ± 5.5 µg/L; P < 0.01), had higher rates of MIB-1 labeling indices (ASCA 76.2% vs MSLA 39.0%, MSA 45.5%, PSA 43.2%; P < 0.05) and preop visual field defect (VFD) (ASCA 32.3% vs MSLA 13.6%, MSA 27.3%, PSA 29.6%; P < 0.05), and had lower rates of preop hypertension (HTN) (ASCA 14.3% vs MSLA 52.5%, MSA 36.4%, PSA 31.8%; P < 0.05) and diabetes mellitus (DM) (ASCA 14.3% vs MSLA 27.2%, MSA 54.5%, PSA 20.5%; P < 0.05). ASCA tumors were larger than MSAs (2.3 ± 1.0 vs 1.6 ± 0.7 cm; P < 0.01), but comparable to MSLAs and PSAs. Rates of cavernous sinus invasion and preop GH levels were similar between groups. Postop GH levels were higher in ASCA (8.6 ± 5.3 µg/L) compared to MSLAs (2.4 ± 0.5 µg/L) and MSAs (1.1 ± 0.7 µg/L) (P < 0.05). ASCA preop IGF-I levels were lower than PSA (ASCA: 466.7 ± 118.5 vs PSA: 803.7 ± 56.5 µg/L; P < 0.05), while postop IGF-I levels were comparable to MLSAs, MSAs and PSAs. ASCAs also had lower postop remission rates compared to MLSAs, MSAs and PSAs (ASCA 19.0% vs MLSA 45.5%, MSA 38.6% and PSA 54.2%; P < 0.05). Most ASCA (85.7%), MLSA (81.4%), MSA (100%) and PSA (77.2%) patients underwent one surgery and more ASCA (23.8%), MLSA (25.4%) and PSA (22.7%) patients underwent radiation therapy than MSA (9.1%) patients. Conclusions: Our data demonstrated important insights into the differences of clinicopathological features of ASCAs compared to other acromegaly subtypes. Notably, ASCAs occurred in younger patients, had larger and more aggressive tumors, had lower postop remission rates and had higher VFD rates. In addition, ASCAs had higher rates of preop hyperprolactinemia and lower rates of preop HTN and DM. Presentation: Thursday, June 15, 2023

SAT140 A Rare Case Of Asymptomatic Severe Refractory Hypoglycemia Due To Hyper-Warburgism In A Young Patient With T-cell Acute Lymphoblastic Leukemia (ALL)

Abstract Disclosure: S. Choe: None. Background: Hyper-Warburgism, exaggerated Warburg effect, is a rare but serious paraneoplastic syndrome caused by excess glucose consumption by cancer cells through glycolytic pathway leading to lactic acidosis and treatment refractory hypoglycemia. Neuroglycopenic symptoms are absent in these patients hence patients do not meet Whipple triad. Clinical Case: A 33yo African American male with past medical history of recently diagnosed cardiomyopathy and atrial fibrillation was initially admitted to outside institution for cardiac ablation then subsequently transferred to our institution for escalation of care in the setting of post-procedural persistent hypoglycemia. He reported symptoms of fatigue and poor appetite. He noted an unintentional weight loss of 30lb over the past 2 weeks. However, he denied fever, night sweats, classic signs and symptoms of hypoglycemia. Vital signs and physical examination were unremarkable. Clinical manifestation of neuroglycopenia was absent despite serum glucose as low as 46 while serum lactate of 23.8 mmol/L (0.5-2 mmol/L). Initial laboratory test notable for lactic acid of 24.2 mmol/L, glucose of 57 mg/dL, bicarbonate of 12 mEq/L, anionic gap of 39 mEq/L, beta hydroxybutyrate of 5.3 mmol/L, IGF-1 of 192 ng/mL (75–212 ng/ml), IGF-II of 570 ng/mL (288–736 ng/ml), AM cortisol of 14.3 μg/dl, ACTH of 41.6 pg/ml, hemoglobin A1c of 4.8 %, fasting insulin of 1 IU/liter, C-peptide of 0.4 ng/ml, and pro-insulin of 2.9 pg/ml. Given suppression of insulin and proinsulin levels and IGF-II level >275 ng/ml, noninsulin-mediated hypoglycemia was suspected. A CT of chest/abdomen/pelvis revealed a subpleural soft tissue mass involving the posterior mediastinum measuring 4.4 x 3.6 x 3.7 cm, diffuse bilateral renal involvement suspicious for renal lymphoma, adenopathy in the bilateral inguinal, axillary, and external iliac chains. Bone marrow biopsy was performed and result was consistent with T-cell ALL. 20% dextrose infusion was titrated up to keep his BG above 70 mg/dl and high dose steroids was initiated to bridge to chemotherapy. Chemotherapy was initiated soon after confirmation of diagnosis by bone marrow biopsy. The lactic acidosis and hypoglycemia dramatically improved shortly after. PET/CT done 4 weeks after first cycle of chemotherapy failed to identify active disease proving the patient’s good response to chemotherapy. Conclusion: The patient presented with noninsulin-mediated hypoglycemia due to rapid glucose use by cancer cell leading to hyper-Warburgism, evident by severe lactic acidosis, spontaneous hypoglycemia, and large tumor burden on CT scan. Absence of neuroglycopenia presumable due to brain using lactate as fuel and, for this reason, Whipple triad cannot be applied to diagnose hypoglycemia in this case. Chemotherapy must be initiated timely manner as it would resolve metabolic abnormalities dramatically as it was seen in our patient. Presentation: Saturday, June 17, 2023

THU022 A Case Of Delayed Diagnosis Of Acromegaly

Abstract Disclosure: K. Blanchard: None. C. Musurakis: None. A. Havrylyan: None. A 57-year-old hispanic female with hypertension, prediabetes, hyperlipidemia, and uterine leiomyomata with hysterectomy one year ago presented to our emergency department with sensations of numbness, tingling, and pressure on the top of her head for 12 days’ duration and left eye blurred vision with photosensitivity for 3 days’ duration. Physical exam was significant for evident enlarged facial features including macroglossia, macrognathia, separation of teeth, enlarged lips, enlarged ears and increased size of hands and feet with thickening of the skin on the fingers and toes. Many skin tags were noted on the neck and chest. She reported noticing these changes gradually over the past five years, as well as noticing an increase in shoe size and ring size. Admission labs were significant for IGF-1 965 ng/mL (47-236), Glucagon 172 ng/mL (0.05-8.00), AM cortisol 24 ug/dL (6.7-22.6), ACTH 29.6 pg/mL (7.2-63.3), FSH 13.22 mIU/mL (16.74-113.59), LH 3.79 mIU/mL (10.87-58.64), and Prolactin 24.3 ng/mL (2.74-19.64). Hemoglobin A1c was 5.8% (<5.7) and lipid profile was significant for triglycerides of 202 mg/dL (<150). TSH was within normal limits. A chest x-ray showed no cardiomegaly. An echocardiogram showed no cardiomyopathy. A CT scan of the brain showed a hyperdense sellar/suprasellar mass measuring 2.1 x 0.7 x 2.4 cm with mass effect on the optic chiasm and intracranial optic nerve not excluded. An MRI brain confirmed a large pituitary macroadenoma measuring 2.7 x 2.5 x 2.2 cm with mass effect on the optic chiasm and pituitary stalk. In addition to the above workup, we recommended Neurosurgery evaluation for symptomatic macroadenoma with optic chiasm mass effect, Ophthalmology evaluation for visual fields testing, and referral to a tertiary care center for evaluation and treatment of acromegaly. The patient was discharged with Neurosurgery and Endocrinology outpatient follow-up, but unfortunately did not attend her appointments. Acromegaly is a rare condition with a prevalence of 60 cases per million. While the mean age of occurrence is 32 years, the mean age of diagnosis is 40 to 45 years, highlighting a persisting delay in the diagnosis. The changes associated with acromegaly occur slowly and therefore can be overlooked by the patient, their family members, and even physicians. Left untreated, continued exposure to increased levels of growth hormone and IGF-1 leads to development of comorbidities including Cushing’s disease, cardiovascular disease, diabetes, arthralgias, decreased bone mineral density, sleep apnea, and uterine leiomyomata, as well as increased mortality and decreased quality of life. This case highlights the importance of physicians in all specialties being familiarized with the symptoms and physical features of acromegaly to aid in timely diagnosis. Presentation: Thursday, June 15, 2023

SAT029 Goldfish Phoenixin: Role In Feeding Control And Its Regulation At The Hepatic Level

Abstract Disclosure: X. Qin: None. C. Ye: None. M. He: None. W.K. Ko: None. A.O. Wong: None. Phoenixin (PNX), a novel peptide first identified by bioinformatics, is known to have pleiotropic functions and its biological actions are mediated via the orphan receptor GPR173. At present, the study of PNX in non-mammalian species, especially in lower vertebrates, is limited and hormone regulation of PNX as well as the post-receptor signalling involved are still unclear. Using goldfish as a model for bony fish, two forms of PNX, PNXa & b, and one form of GPR173 were cloned. Phylogenetic analysis confirmed that goldfish PNXa, PNXb & GPR173 could be clustered in respective clades of target genes in fish species. Alignment of a.a. sequences and 3D protein modelling also revealed that goldfish PNXa & b were highly comparable to PNX reported in other vertebrates. Using RT-PCR, PNXa/b & GPR173 were found to be ubiquitously expressed at tissue level. For functional testing, PNXa & b were synthesized and tested for their effects on feeding control by IP injection in goldfish. In this case, parallel rises in foraging behaviours and food intake were noted after PNX treatment. Similar results were also obtained with ICV injection of PNXa & PNXb, respectively. In goldfish, food intake could elevate plasma levels of glucose, insulin, growth hormone (GH) and IGF-I with parallel rises in transcript expression of GH in the pituitary and PNXa, PNXb, insulin & IGF-I mRNA in the liver. In goldfish hepatocytes, insulin and IGF-I were both effective in up-regulating PNXa & b mRNA expression via activation of IGF-I receptor (IGF1R) but not insulin receptor. Using a pharmacological approach, IGF-I induced PNXa & b gene expression could be blocked by the inhibitors for PI3K, Akt and mTor but not by the inhibitors for MEK1/2, ERK1/2 and P38MAPK. Our results, as a whole, indicate that (i) PNX & GPR173 are co-expressed in goldfish at tissue level & involved in feeding induction, presumably via central action in the brain, (ii) food intake can up-regulate hepatic expression of PNXa & b via insulin signal caused by glucose uptake and parallel activation of the GH/IGF-I axis after feeding, and (iii) hepatic expression of PNXa & b induced by insulin/IGF-I signal is mediated via IGF1R functionally coupled with the PI3K/Akt/ mTOR but not MEK/ERK & P38MAPK pathways. Presentation: Saturday, June 17, 2023

FRI312 Diplopia And Headache After Treatment With GnRH Agonist

Abstract Disclosure: A.A. Zakkar: None. M. Al Mushref: None. M. Fadanelli: None. Case Report: The Patient is a 46-year-old male with past medical history of hypertension and prostate cancer, currently undergoing treatment with leuprolide acetate injections, who presented to the emergency department with a complaint of worsening headache. He received his second injection 3 days prior to admission and within hours he developed a headache in the frontal area that was continuous and worsening over time, increasing with positional changes of his head. One day after the treatment he developed persistent double vision. The patient reported that he has had worsening vision over the last year and was to see an ophthalmologist but was diagnosed with prostate cancer at the same time so he became more focused on the oncologic care. He also reported poor balance, excessive thirst and increased urination of large volumes of urine every hour with nocturia several times. On exam the vital signs were normal, he was A&Ox4 and in no distress. He had left abducens and oculomotor nerve palsy but an otherwise benign exam. MRI of the brain revealed a sellar mass measuring 2.2 x 1.7 x 2.3 cm consistent with pituitary macroadenoma extending into the suprasellar cistern, compressing the pituitary stalk and the optic chiasm. Patient was evaluated by ophthalmology who noted +2 optic nerve edema of the left eye. Laboratory evaluation revealed low ACTH of 6 pg/mL at 5:30AM along with corresponding cortisol level of only 1.6 mcg/dL. FSH was low and LH undetectable as expected with GnRH agonist therapy. Growth hormone level, IGF-1, l and prolactin levels were all normal. The TSH was 0.50 microunits/mL with a freeT4 of 1.0. Urinalysis revealed dilute urine with specific gravity <1.006. Serum sodium on admission was 137 mmol/L and after overnight fasting was 140 mmol/L. The patient was started on desmopressin 0.1 mg po at bedtime and on intravenous dexamethasone 4 mg q6hrs. He was evaluated by neurosurgery and ENT who recommended trans-sphenoidal resection of the mass. Pathology report of the specimen was consistent with a pituitary adenoma with infarction without hemorrhage. The patient reported an improvement in his left eye vision and lateral rectus palsy. He was transitioned to oral hydrocortisone 20 mg daily and 10 mg every afternoon prior to discharge. On follow up with endocrinology several months later he was found to have persistent adrenal insufficiency and developed central hypothyroidism that required treatment. Conclusion: Patients with an undiagnosed pituitary adenoma are at risk of tumor expansion and mass effect as well as pituitary apoplexy during treatment with GnRH agonists. In our case clinical presentation was consistent with pituitary apoplexy without evidence of pituitary hemorrhage soon after GnRH agonist. A full ophthalmologic exam may be an appropriate screening prior to initiation of such therapy. Presentation: Friday, June 16, 2023

THU182 Widening The Spectrum Of ABCC8-related Disease: Insulin-mediated Pseudoacromegaly

Abstract Disclosure: I.F. Machado: None. B.B. Mendonca: None. A. Latronico: None. M.Y. Nishi: None. L.G. Gomes: None. Introduction: Insulin-mediated pseudoacromegaly is a rare condition characterized by acromegaloid phenotype without excessive GH secretion in the context of severe hyperinsulinemia. Case report: A 10.5 years old girl with tall stature, obesity, acanthosis nigricans, neurosensorial hearing deficiency and acromegaloid features was referred for clinical investigation. She was born of non-consanguineous parents, full-term, with normal birth weight and stature. She had no history of neonatal hypoglycemia or in infancy. At six years of age, she presented marked accelerated growth velocity and weight gain resulting in bilateral slipped femoral epiphysis. She developed thelarche at 7 years old, and was treated with gonadotropin releasing hormone agonist (GnRHa) from 8-10.5 years. Hearing deficiency was diagnosed at 7 years of age. Her family history was remarkable for paternal sudden cardiac death at age 35. At physical examination, she had an acromegaloid facial appearance with a prominent forehead and jaw, large hands and feet, and severe acanthosis nigricans in neck and axillae. Her weight and height were 99.5 kgs (Z 8.8) and 170 cm (Z 4.6), respectively; target height was 1.66 m (Z 0,72) and BMI was 34.4 (Z 3.5). Her breast and pubic hair development were Tanner stage IV. Laboratory exams showed normal IGF-1 and random GH levels. There was an abnormal response of GH (2.63 ng/mL) following an oral glucose tolerance test (OGTT), considered as false positive in the context of obesity and puberty. Her brain magnetic resonance was normal. She had a hemoglobin glycated of 6.1% and very high basal insulin levels of 98 µUI/mL with a normal glucose value of 81 mg/dL and OGTT-120 minutes insulin levels > 1000 µUI/mL with glucose of 113 mg/dL. Exome sequencing analysis showed a heterozygous missense ABCC8 variant c.622G>A p.(Glu208Lys), located in an exonic hotspot, and allele frequency absent from gnomAD databases. The ACMG classified this variant as pathogenic. Pseudoacromegaly, a heterogeneous condition, is caused by multiple genetic and pathophysiological backgrounds. In insulin-mediated pseudoacromegaly, the defects are mainly associated with postreceptor insulin signaling and action. We described a new type of hyperinsulinemic pseudoacromegaly caused by a mutation in the ABCC8 gene, which encodes the sulfonylurea receptor, a member of the K(ATP) channel superfamily. This gene is associated with congenital hyperinsulinemia causing hypoglycemia, generally when in homozygous state. This clinical report illustrates a new phenotype associated with ABCC8 mutation, and identifies a new genetic cause of hyperinsulinemic pseudoacromegaly. Conclusion: We described a patient with insulin-mediated pseudoacromegaly associated with neurosensorial hearing deficiency caused by a dominant variant in the ABCC8 gene, defining a new genetic cause of this intriguing disorder. Presentation: Thursday, June 15, 2023

THU047 Growth Hormone (GH) Signaling In Hepatocytes Controls Hepatic Insulin Sensitivity And Nutrient Disposition

Abstract Disclosure: M. del Rio-Moreno: None. M. Vazquez-Borrego: None. J. Cordoba-Chacon: None. O.P. McGuinness: None. R.D. Kineman: None. It is commonly accepted that GH reduces the actions of insulin. However, we reported plasma GH levels within a physiological range are negatively associated with insulin-mediated glucose uptake, but positively associated with insulin-mediated suppression of hepatic glucose production (HGP) [Cordoba-Chacon J. et al. 2014. AJP Endocrinol Metab]. These findings suggest that GH may promote insulin’s actions on the liver. To determine the direct contribution of GH signaling on hepatic insulin sensitivity, hyperinsulinemic-euglycemic clamps were performed with stable isotope tracers in chow-fed adult-onset, hepatocyte-specific GHR knockdown (aHepGHRkd) mice. aHepGHRkd mice show reduced IGF1 and increased GH levels [Cordoba-Chacon J. et al 2015, Diabetes] which indirectly impacts systemic insulin sensitivity and substrate flux to the liver. To normalize plasma IGF1 and GH levels, aHepGHRkd mice were co-treated with adeno-associated virus (AAV) that express IGF1 or a constitutively active form of STAT5b (STAT5bCA). These AAVs have a thyroxin binding globulin promoter, leading to hepatocyte-specific expression. Under both basal and clamped conditions, aHepGHRkd mice exhibited hyperinsulinemia, that was normalized by AAV-mediated IGF1 and STAT5bCA expression. Interestingly, glucose disappearance (Rd), tissue-specific glucose uptake, or HGP (gluconeogenesis and glycogenolysis) did not differ across all groups. However, higher insulin tone in aHepGHRkd mice was required to achieve the same level of Rd and suppression of HGP in the steady-state, which was indicative of systemic and hepatic insulin resistance. These observations are consistent with our previous findings that GH reduces tissue-specific glucose uptake but promotes insulin-mediated control of HGP. In contrast, aHepGHRkd mice exhibited an increased rate of hepatic de novo lipogenesis, and an increase in plasma levels of newly formed triglyceride and triglyceride-bound palmitate, that was normalized by IGF1 and STAT5bCA expression. Taken together, these results indicate loss of hepatocyte GH signaling leads to pathway selective hepatic insulin resistance. This pathway selective hepatic insulin resistance has also been reported in mouse models due to altered substrate delivery to the liver as consequence of excess dietary intake and/or increased adipose tissue lipolysis. However, chow-fed aHepGHRkd mice show hyperinsulinemia that was sufficient to normalize systemic glucose uptake and suppress WAT lipolysis, as noted by normal plasma NEFA levels under both basal and clamped conditions. Therefore, changes in substrate delivery to the liver cannot readily explain the changes observed, suggesting hepatocyte GHR-signaling plays a direct role in partitioning of hepatic nutrients in response to insulin. Presentation: Thursday, June 15, 2023

Colostrum supplement, IGF-1, and diarrhea in mechanically-ventilated patients: A double-blind, randomized, placebo-controlled study

BackgroundDiarrhea is relatively common in critically-ill mechanically-ventilated patients. This study investigated the effect of bovine colostrum supplement in the prevention of diarrhea. MethodsMechanically-ventilated patients expected to require enteral nutrition for at least five days were randomly assigned to the intervention or placebo groups. The intervention group received enteral diet providing 30g of bovine colostrum daily, and the control group received a similar diet except for whey protein as a placebo. The duration of the intervention was ten days. Serum levels of IGF-1 were measured at baseline and the end of the intervention. Patients were followed up for the occurrence of diarrhea. ResultsOut of 136 participants, 45 patients in the colostrum group and 45 patients in the control group were included in the final analysis of the outcomes. Plasma IGF-1 concentration increased significantly in the colostrum group after the intervention (P=0.02). In the between-group comparison, the increase in IGF-1 was significantly higher in the colostrum group compared with the placebo group (P=0.04). Furthermore, the incidence of diarrhea was significantly lower in the colostrum group compared to the control group. ConclusionBovine colostrum supplementation increased serum levels of IGF-1 and may reduce the incidence of diarrhea in critically-ill mechanically-ventilated patients.