Obese Patients Research Articles

12376 Comparison Of 1 Mg Versus 2 Mg Dexamethasone Suppression In Obesity

Abstract Disclosure: H. Babu: None. A. Nawaz: None. A.J. Spiro: None. T.D. Hoang: None. M.K. Shakir: None. The overnight 1 mg dexamethasone suppression test (DST) is widely used to screen for Cushing’s Syndrome (CS), especially due to its low incidence of false negative results. Serum cortisol concentrations <1.8 µg/dL suggests adequate HPA axis suppression and usually excludes CS. Concentrations >1.8 µg/dL should be verified with a second test. However, the lack of suppression on DST has been documented previously in 1.46% to 15% of obese patients without CS. Previous studies have suggested simultaneous measurements of serum cortisol, ACTH, and dexamethasone levels after DST to ensure adequate suppression. In this retrospective analysis, we compared the plasma levels of ACTH, dexamethasone, and cortisol levels after 1 mg and 2 mg DST in healthy obese (class III) subjects. The study involved 6 subjects (2 males, 4 females, age 37.5 ± 8.79 years, BMI 43.65 ± 3.12 (kg/m2) who were referred for evaluation of abnormal weight gain. Exclusion criteria for these subjects included diabetes mellitus, pregnancy, history of CS, psychiatric disorders, chronic liver disease, chronic renal failure, malabsorption disorders and nephrotic syndrome. The exclusion of CS was done by history and physical examination showing the lack of specific clinical features of CS. Additionally, none of the subjects were taking drugs that interfered with CYP3A4 or oral contraceptives within 3 months preceding the study. None of the participants reported alcohol consumption of more than 30 g per day. Screening tests for CS involved 1 mg, 2 mg DST, LNSC and 24-hour urine cortisol levels. Results: Following 1 mg DST in 5 subjects, the mean serum cortisol levels were 1.35 ± 0.13 mcg/dL and the mean serum dexamethasone levels, and ACTH levels were 282 ± 44 ng/dL and 5.92 ± 1.56 pg/mL, respectively. However, in one subject (BMI 43.5) the post-DST cortisol level was 2.96 mcg/dL with corresponding dexamethasone level of 138 ng/dL and ACTH level of 21 pg/mL. However, following 2 mg DST in all 6 subjects the serum cortisol levels were less than 1.8 mcg/dL (1.21± 0.22 mcg/dL) with ACTH levels (3.87 ± 0.70 pg/mL) and dexamethasone levels of 482 ± 80 ng/dL. The LNSC levels were normal in 4 subjects (0.010 ± 0.005 mcg/dL), whereas in 2 subjects these were minimally elevated. 24-hour urine cortisol levels were normal in 5 subjects (29.4 ± 3.74 mcg) and in one subject this was mildly elevated (67 mcg). Long term follow-up of all subjects confirmed normal cortisol status. Previous studies have demonstrated that routine CS screening of patients affected by severe obesity is not indicated. However, other investigations have shown CS may occur in a small percentage of severe obese patients. In conclusion, 2 mg DST is a preferred test in obese patients suspected to have CS although 1 mg DST generally can be used as an initial screening test. Additionally, serum dexamethasone and ACTH measurements may still be useful in patients who are suspected to have a false-positive DST. Presentation: 6/1/2024

8000 Intestinimonas Butyriciproducens As A New Preventive Therapy For Type 2 Diabetes: a Proof Of Concept Randomized Controlled Trial

Abstract Disclosure: V. Antoniotti: None. M. Caputo: None. E. Mollero: None. A. Antonioli: None. S. Tini: None. M. Manfredi: None. S. Gul: None. N. Bui: None. J. Seegers: None. W. De Vos: None. G. Aimaretti: None. F. Prodam: None. Background. The incidence of type 2 Diabetes Mellitus (T2D) is increasing worldwide. Prevention is possible by changing lifestyle but it’s not effective alone in real life, due to poor compliance over time. New strategies are necessary, mostly for high-risk individuals. Therapeutic microbiology is a further proposed target, and butyrate-producing bacteria can improve metabolic parameters in obese patients. Our study aims to evaluate the effect of Intestinimonas butyriciproducens as a preventive therapy for T2D in prediabetes thanks to its effects in decreasing Advanced Glycation End Products (AGEs), converting sugars and proteins in butyrate, and increasing insulin sensitivity.Methods. The trial is a double-blind, randomized, placebo-controlled (phase 1) and open-label pilot study with two different doses (phase 2) of 26 weeks. I. butyriciproducens (105 CFU/day) or placebo were given for 12 weeks, then subjects in placebo will start the treatment (105 CFU/day), and the other group will increase the dose (108 CFU/day) for 14 weeks. Overweight or obese patients with impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) were included. Patients were assessed for clinical, biochemical, and microbiota parameters at the time of recruitment (V1), after phase 1 (V7) and phase 2 (V10), during which the eating and lifestyle habits were also evaluated. No dietary advice was given. Results. Nineteen have completed the study. Treated patients during the first phase had a significant improvement in glucose-insulin metabolism demonstrated through the HOMA Disposition Index (p= 0.0075). Lipid profile also ameliorates in patients treated at a low dose and then at a high dose, particularly decreasing triglycerides (phase 1: p= 0.0212; phase 2: p= 0.0261). The weight and BMI of patients were stable throughout the period of study. Data from Flash glucose Monitoring (FGM) show a more stable glucose, mainly at the end of the study. Serum AGE concentrations showed a trend towards a decrease in treated patients, whereas IL-10 slowly increased without changes in IL-6 and IL-17.Lastly, 10 out of 19 patients after 26 weeks of treatment had a remission in IFG or IGT (52.6%). Conclusions. Intestinimonas butyriciproducens seems to improve insulin sensitivity and triglycerides in treated patients. Intestinimonas butyriciproducens could be a new strategy in the work-up of T2D prevention. Presentation: 6/1/2024

8688 Pseudopheochromocytoma Due To Severe Obstructive Sleep Apnea

Abstract Disclosure: L.M. José: None. M. Ataide: None. F. Aratani: None. S. Beeby: None. G.F. Fagundes: None. F. Coelho: None. F. Ledesma: None. A. Latronico: None. B.B. Mendonca: None. M.C. Fragoso: None. M.Q. Almeida: None. Background: Obstructive sleep apnea (OSA) represents an independent risk factor for cardiovascular disease, and it is associated with a wide range of conditions, such as resistant hypertension and primary aldosteronism (PA). Patients with sleep apnea have a higher sympathetic activity during wakefulness due to chronic hypoxia. We present the case of pseudopheochromocytoma caused by severe OSA in an obese patient with RH and PA.Clinical Case: A 58-year-old female Brazilian patient was referred to an endocrinologist to investigate a 1.8 cm right adrenal nodule at computed tomography (CT) performed to investigate abdominal pain. Her medical history includes resistant hypertension diagnosed at 27 years of age, type 2 diabetes, dyslipidemia, Class II obesity, a previous acute myocardial infarction, and severe OSA (apnea-hypopnea index 61.6/hour). She has used irregularly the continuous positive airway pressure (CPAP) therapy at night. She is currently using carvedilol 50 mg bid, chlorthalidone 25 mg, olmesartan 40 mg, amlodipine 10 mg, spironolactone 50 mg, clonidine 0.2 mg tid, hydralazine 50 mg every 6 hours, acetylsalicylic acid 100 mg, atorvastatin 80 mg, and metformin XR 1000 mg. At physical examination, she had BMI 37 kg/m2, BP 150 x 90 mmHg, HR 64 bpm, and no signs of Cushing syndrome. Abdominal CT revealed a right adrenal nodule measuring 1.8 cm with 18 Hounsfield unit (HU) in the pre-contrast phase, reaching a density of 117 HU at the arterial phase and showing an absolute washout of 65% and a relative washout of 56%. A nodular thickening of 1.4 cm (-4 HU) at the left adrenal gland was also displayed at CT scan. Hormone evaluation showed basal cortisol 7 µg/dL, ACTH 15.7 pg/mL, DHEAS 1152 ng/mL (189-2050 ng/mL), 1 mg overnight dexamethasone suppression test 2.3 ug/dL, aldosterone 9.9 ng/dL, direct renin concentration 36.8 uIU/mL, plasma metanephrines 0.3 nmol/L (<0.5 nmol/L) and plasma normetanephrines 1.3 nmol/L (<0.9 nmol/L). It was not possible to change anti-hypertensive medications to investigate PA. A 0.3 mg clonidine suppression test did not suppress normetanephrine levels, confirming the biochemical diagnosis of pheochromocytoma. Then, alpha-blockade with doxazosin 4 mg was started and the patient underwent right adrenalectomy. Pathological examination revealed an adenoma with immunohistochemistry positive for CYP11B2. BP control was achieved with only two medications and aldosterone decreased to 3 ng/dL confirming PA. Plasma normetanephrine levels remained elevated post-surgery and only normalized after the CPAP regular use.Clinical lessons: Chronic activation of sympathetic autonomic drive in OSA can increase norepinephrine and normetanephrine levels. OSA is a very prevalent disease and it is frequently associated with RH. Therefore, OSA should be considered a possible cause of pseudopheochromocytoma in hypertensive patients. Presentation: 6/3/2024

8517 Low Peak GH in Stimulation Tests Among Obese Children; Is it Clinically Meaningful?

Abstract Disclosure: D. Strich: None. C. Meirman: None. S. Edri: None. D.J. Gillis: None. Background: Peak growth hormone (GH) levels in stimulation tests are lower in obese subjects. The clinical significance of this finding is unclear. It has been suggested that results of tests should be adjusted for body mass index (BMI). Aims: A. To evaluate the association between GH peak levels and body mass index (BMI ) in a single center. B. To discuss the biological and clinical significance of the findings and make recommendations based on this study and other data from the medical literature. Methods: Peak GH levels and BMI standard deviation scores (BMI-SDS) for a total of 988 tests (Clonidine - 694, Glucagon - 198, Arginine - 96) performed in one center were analyzed. Studies referring to the biology of growth hormone and to the evaluation of GH deficiency were reviewed. Results: In the testing center studied, mean peak GH levels were significantly lower in arginine (p=0.015) and clonidine tests (p=0.018) starting at BMI standard deviation score over 1 compared to below 1 BMI-SDS. The differences still remained significant for a subgroup with peaks below 7.5 ng/dl (p=0.003 and p=0.042 respectively). The proportion of overweight and obese children in our cohort and in similar cohorts of children undergoing stimulation tests was about tenfold lower than in the corresponding general population. In other studies, short obese patients responded better than non-obese to GH treatment and had greater increases both in height and IGF-1. Obese adult patients with low GH peaks had high carotid intima-media thickness compared with non GH deficient obese. Conclusion: Obese children are generally tall and therefore are not referred for testing. Those who are short, tend to have lower peaks than their lean peers in GH stimulation tests and respond better to GH therapy. These patients have biologically significant GH deficiency. We do not recommend "correcting" GH test results for BMI in the decision algorithm for GH therapy. Presentation: 6/3/2024

7943 In Obese C57Bl6 Male Mice, Weight Loss due to Caloric Restriction Reduced Bone Morphology but Improved Components of Systemic Metabolism

Abstract Disclosure: C. Chlebek: None. C. McAndrews: None. S.N. Costa: None. C.J. Rosen: None. Obesity and calorie restriction individually alter systemic cellular metabolism and affect musculoskeletal tissue health. Obesity reduces trabecular and cortical bone quality. Clinically, obese patients are advised to lose weight, despite the negative effects of calorie restriction on bone in nonobese preclinical models. Little is known about bone quality following weight loss in obese preclinical models. We hypothesized that in obese models, caloric restriction would further worsen bone quality. To induce obesity, male C57Bl6 mice (8 weeks old) received 60% high fat diet for 12 weeks (high fat feeding phase). Following obesity induction, the HFD-CR group was acclimated to control low fat diet for 2 wks and then underwent 30% caloric restriction for 8 wks (caloric restriction feeding phase). The HFD group received 60% kcal high fat diet from ages 8 to 30 wks. LFD mice received control low fat 10% kcal diet for the study duration. Mice were euthanized at 30 wks of age. Body weight, body composition, and bone mineral density were recorded at baseline and at the end of each diet. Glucose and insulin tolerance were recorded at the end of the high fat and caloric restriction feeding phases. At euthanasia, cortical and trabecular bone morphology (µCT) were assessed.Adverse metabolic parameters worsened with high fat feeding but improved by caloric restriction. Compared to LFD animals, HFD and HFD-CR mice gained body weight, fat mass, and lean mass during the high fat feeding phase. After the caloric restriction feeding phase, body weight, fat mass, and lean mass were reduced in HFD-CR compared to both HFD and LFD controls (p < 0.0001). After 12 weeks of high fat feeding, glucose and insulin tolerance were reduced in HFD and HFD-CR mice compared to LFD (p < 0.0001). Caloric restriction improved both glucose and insulin tolerance in HFD-CR mice compared to both HFD and LFD animals (p < 0.0001). Caloric restriction improved areal bone mineral density, but at euthanasia, HFD-CR mice had worse bone morphology compared to LFD or HFD animals. Although areal bone mineral density (aBMD) was reduced by the high fat feeding phase, HFD-CR and LFD aBMD was not different at the end of the study (p < 0.0001). At euthanasia, HFD-CR mice had reduced cortical area and cortical thickness (p < 0.05). Marrow area and moment of inertia were not different between diets. Compared to LFD, both HFD and HFD-CR mice had reduced tibial bone volume fraction (p < 0.05). HFD-CR animals had smaller trabecular thickness (p < 0.05) and greater trabecular number (p < 0.01) compared to HFD mice. Despite improvements in components of systemic metabolism, caloric restriction in obese preclinical models reduced bone morphology in both trabecular and cortical compartments. This work will improve our understanding of the musculoskeletal system following caloric restriction in obese models and will aid in nutritional counseling for obese patients. Presentation: 6/1/2024

8660 Bodipy Labeled Vitamin D3 Associates With Lipid Droplets In Adipocytes

Abstract Disclosure: N. Ucar: None. J.T. Deeney: None. R. Pickering, PhD: None. M.T. Kirber: None. T. Fan: None. R. Loo, PhD: Research Investigator; Self; Carbogen Amcis BV. M.F. Holick: Grant Recipient; Self; Carbogen Amcis BV. Research Investigator; Self; Carbogen Amcis BV. Obese patients are often found to be deficient in vitamin D, requiring higher levels of supplementation than normal weight subjects. While this has been attributed to vitamin D3‘s lipid solubility and accumulation in fat tissue, little is known about how vitamin D3 enters adipocytes and associates with the intracellular lipid droplet. The goal of this study was to investigate this association using a novel fluorescently labelled vitamin D3. Bodipy, 4,4-difluoro-1,3,5, 7,8-pentamethyl-4-bora-3a,4a-diaza-s-indacene (BODIPY 493/503), was covalently linked to vitamin D3 and its structure was confirmed by NMR and mass spectroscopy. Murine 3T3L1 and primary adipocytes were used for our study. Mouse 3T3L1 preadipocytes were cultured in multiwell plates or glass bottom dishes in high glucose DMEM media and differentiated for 7-14 days. Primary adipocytes were obtained by collagenase digestion after surgical extraction of adipose tissue from male/female C57BL/6J mice and attached to glass bottom dishes. The cultured adipocytes were exposed to 10 microM BODIPY labelled Vitamin D3 (vitD-B). BODIPY was added to cultured cells and served as the control. Cells were imaged at various times on a wide-field epifluorescence microscope and analysed with NIH ImageJ software. VitD-B adipocyte uptake and accumulation in lipid droplets was observed over 24 hrs. Isolated lipid droplets were also incubated with vitD-B and BODIPY. VitD-B in mature 3T3L1 cells was observed in lipid droplets after 1h incubation and increased fluorescent intensity was observed over the next 24 hrs. BODIPY was observed in the lipid droplets after 15-20 mins. As a negative control, non-differentiated 3T3L1 cells did not exhibit staining by BODIPY even after 24-hrs. When vitD-B was added to primary cultured adipocytes, it appeared in the adipocytes within 1-hr. Fluorescence intensity of primary adipocytes was increased 1.2-fold at 8 hrs and 5.7-fold at 24 hrs compared to 1 hr. For comparison the positive control treated with BODIPY exhibited rapid fluorescence uptake into primary adipocytes that was increased 29-fold higher than that of vitD-B at 1 hr. VitD-B and BODIPY both demonstrated rapid uptake into isolated lipid droplets (less than 2 min) based on fluorescence microscopy.These results hold promising implications for understanding of the interaction between vitamin D and intracellular lipid droplets. Keywords: Adipocyte, Vitamin D3, BODIPY, adipocytes, lipid droplet, fluorescent labelled vitamin D3 Presentation: 6/2/2024

7316 A Unique Presentation of Diabetes Mellitus in an 8-Year-Old Male Positive For 3 Different Mutations Related to MODY

Abstract Disclosure: R. Senguttuvan: None. A. Pamfil: None. Background: Maturity-Onset Diabetes of the Young (MODY) is the most common form of inherited non-autoimmune diabetes mellitus, characterized by autosomal dominant inheritance, young age at onset and beta cell dysfunction. There are at least 14 MODY mutations and we present a pediatric case not meeting criteria for type 1[T1DM] or type 2 diabetes mellitus[T2DM], who tested positive for mutations in 3 different genes known to cause MODY. Case: An 8-year-old male, born full term, 2776 grams and 48.3 cm, without history of neonatal hypoglycemia or hyperglycemia, was referred for new onset diabetes mellitus management. While undergoing evaluation for abdominal pain and constipation, he was found to have a fasting glucose of 126 mg/dL (7 mmol/L) and hemoglobin A1C of 6.5%. He endorsed polyuria, but no polydipsia. He had no clinical signs of insulin resistance (e.g., acanthosis nigricans) and a BMI of 23.65 kg/m2, at the 97th percentile. Family history is positive for diabetes mellitus requiring insulin, in father (diagnosed at 11 years) and paternal grandmother and T2DM in paternal aunt. Laboratory evaluation was negative for all 5 antibodies (GAD, IA-2, Anti-islet cell antibody, Zinc Transporter 8 and Insulin antibodies) and revealed an insulin level of 15.9 uIU/mL (RR: <2.0-13.0) and C peptide: 2.3 ng/mL (RR: 1.1-4.4). Lacking diagnostic criteria for T1DM or T2DM, genetic testing was performed. Patient tested heterozygous for mutations in 3 genes known to cause MODY: GCK [(c.350 G>T p. (G117V)], ABCC8 [(c.2270 C>G p.(T757R)], and HNF1B [(c.68A>G p.(K23R)], all variant of uncertain significance. Over an 8-month period, patient's weight decreased from 98 lbs. (44.9 kg) to 90 lbs. (41.1 kg) after meeting with our dietician and implementing healthy dietary changes, and his beta cell function markers improved from diagnosis: Fasting insulin (4.5 uIU/mL), C peptide (1.3 ng/mL), and glucose 119 mg/dL; Hemoglobin A1C remained relatively stable at 6.1%. A kidney ultrasound was normal. No medical intervention were started yet, and patient is being monitored clinically and biochemically every 3-4 months. Discussion: Clinical monitoring over time, genetic testing in the parents, are critical in this patient’s long-term treatment plan and prognosis. To our knowledge, this may be the first case of diabetes mellitus in a pediatric patient, positive for mutations in 3 different genes known to cause MODY. South Texas has one of the highest incidences of T2DM in the USA. In addition to screening for genetic forms of diabetes, in patients with negative T1DM antibodies and atypical phenotype for T2DM, we should consider genetic screening in mildly obese pediatric and young adult patients without significant acanthosis nigricans, who were already diagnosed as T2DM. Presentation: 6/1/2024

6893 The Interaction Effect Between BMI, Diabetes, and Age at Diabetes Onset on the Risk of Thyroid Cancer: A Population-Based Cohort Study

Abstract Disclosure: T. Hou: None. Y. Li: None. J. Tian: None. Z. Bloomgarden: None. Y. Shi: None. ObjectiveThe relationship between type 2 diabetes mellitus (T2DM) and thyroid cancer was confounded by some characteristics of diabetes. We aimed to determine the association of the presence of diabetes and, among persons with diabetes, the age at T2DM onset, BMI, and the interactive effect with the subsequent thyroid cancer risk. MethodsWe conducted a population-based longitudinal cohort study including 428,568 persons with new-onset T2DM matched with the general population (100,649,346 person-years). Risk of thyroid cancer by subgroups were calculated based on standardized incidence ratio (SIR), hazard ratio (HR), and Cox proportional hazards models. ResultsIn T2DM patients, 1142 thyroid cancer cases were identified during eight years of follow-up, with an incidence rate of 59.01/100,000 person-years and a higher SIR: 1.21 (95% CI: 1.14-1.28) compared to the general population. New-onset T2DM had an overall 21% higher risk of thyroid cancer. Both the earlier age at T2DM onset and higher BMI were associated with a significant increasing risk of thyroid cancer independently (T2DM onset age <50: SIR 1.46 (1.27-1.69); BMI ≥30.0 Kg/m2 SIR: 1.93 (1.57-2.38)). The highest risk of cancer appeared in the patients with both BMI ≥30.0 Kg/m2 and T2DM onset age <50 years (SIR=3.91, HR=3.04). Among patients with T2DM onset age <60 years, SIR shows an increasing trend of cancer risk with higher BMI levels, while no significant increasing trends with higher BMI in T2DM onset age ≥60 years. For patients with BMI ≥25.0 Kg/m2, SIR of cancer risk decreases with an later T2DM onset age, whereas no significant decreasing trends of cancer risk in BMI <24.9 Kg/m2 group. Obese (BMI ≥30.0 Kg/m2) patients had a significant higher HR of thyroid cancer only when T2DM onset age <60 years. ConclusionsBoth earlier age of T2DM onset (<50 years) and higher BMI (≥30 Kg/m2) contributed to higher risk of thyroid cancer. These results suggest that earlier screening of thyroid cancer might be appropriate in patients diagnosed with T2DM, especially in individuals with young-onset T2DM and obesity. Presentation: 6/3/2024

8687 The Efficacy of GLP1 Receptor Agonists in Obese Women with PCOS in Promoting Weight Loss and Hormonal Regulation: A Systematic Review and Meta-Analysis

Abstract Disclosure: B. Austregesilo Athayde H Morais: None. V.M. Prizão: None. B. Ximenes Mendes: None. M.L. Defante: None. O.C. Martins: None. T.L. Correa: None. M.D. De Moura de Souza: None. Background: GLP1 receptor antagonists (GLP1a) are known for their efficacy in promoting weight loss among obese and diabetic patients. However, their impact on weight reduction and hormonal regulation in obese females with polycystic ovarian syndrome (PCOS) remains understudied. Therefore, we aimed to perform a meta-analysis exploring the efficacy of GLP1a against placebo for ameliorating symptoms of PCOS. Hypothesis: The use of GLP1 receptor agonists in obese women with PCOS reduces body mass index and waist circumference as well as normalizes hormone levels such as total testosterone, total cholesterol, and HOMA-IR. Methods: We conducted a comprehensive search of PubMed, Cochrane, and Scopus databases to identify trials comparing GLP1a against placebo among women diagnosed with PCOS based on the Rotterdam Criteria. Our primary outcomes of interest included body mass index (BMI), triglycerides, waist circumference, total testosterone, total cholesterol, and HOMA-IR. We performed data extraction and quality assessment for studies that met the inclusion criteria. Subsequently, we conducted a statistical analysis using Review Manager 5.1.7 (Cochrane Collaboration). We evaluated heterogeneity using I² statistics. Results: We included 176 participants from 4 studies, which all were RCTs. GLP1a was used to treat 111 (63.06%) patients. Analyzed outcomes included waist circumference (MD: −5.16 cm; 95% CI: −6.11 to −4.21; p < 0.00001), total testosterone (MD: −1.33; 95% CI: −2.55 to −0.12; p =0.03), BMI (MD: -2.42; 95% CI: -3.10 to -1.74; p < 0.00001), total cholesterol (MD: −0.04; 95% CI: −0.10 to 0.01; p =0.15), HOMA-IR (MD: −0.30; 95% CI: −0.92 to 0.32; p =0.35), Triglycerides (MD: −0.20; 95% CI: −0.30 to −0.11; p < 0.00001) were lower in patients treated with GLP1a compared with placebo. Most patients who discontinued the trials did so because of a nausea side effect. Conclusion: The utilization of GLP1a demonstrates efficacy in reducing body mass index (BMI), triglycerides, waist circumference, total testosterone, total cholesterol, and HOMA-IR. These results signify its viability as a favorable treatment option for managing PCOS in obese females. Presentation: 6/3/2024

8421 The Effect of Dietary Glycotoxins on Insulin Resistance in Polycystic Ovary Syndrome

Abstract Disclosure: A. Weidner: None. K. Vann: None. J. Zhang: None. A. Roy: None. O. Astapova: None. Polycystic ovary syndrome (PCOS) is a chronic systemic disorder that affects both metabolism and reproduction. PCOS is characterized by hyperandrogenism and insulin resistance, which are closely intertwined in this disease pathophysiology. PCOS affects an estimated 10% of people with ovaries and increases risk of endometrial cancer, type 2 diabetes, and major cardiovascular events. Furthermore, treatment options are generally poorly tolerated. Despite its prevalence, severity, and enormous public health burden, the etiology of PCOS is not well-understood. Insulin resistance likely plays a central role in PCOS pathogenesis, and often leads to hyperinsulinemia as the pancreas attempts to compensate for insulin’s decreased efficacy in the body. Moreover, the Western diet is becoming increasingly rich in advanced glycation end products (AGEs): non-enzymatically modified biomolecules that have recently been found to have a harmful effect on insulin sensitivity and are associated with diabetes, aging, and oxidative stress. Serum AGE levels have been reported to be higher in both lean and obese PCOS patients, regardless of PCOS subtype. We have also found higher levels of AGE precursors in the serum of our chronic dihydrotestosterone-induced mouse model of PCOS. Using this mouse model, we have shown that ovarian granulosa cells (GCs) remain insulin-sensitive despite systemic insulin resistance and hyperinsulinemia, manifested by impaired glucose tolerance and increased HOMA-IR. To assess whether GCs respond to insulin through alternative receptor pathways, we knocked down insulin receptor in human granulosa-derived KGN cells and found that insulin-stimulated AKT phosphorylation was only minimally reduced, suggesting that insulin may signal in large part through the insulin-like growth factor 1 receptor (IGF1R) in these cells. Therefore, we believe that compensatory hyperinsulinemia plays a key role in chronic GC hyperstimulation, possibly by rerouting the insulin signal through IGF1R to overcome the resistance to insulin receptor activation, suggesting a mechanism for AGE toxicity in PCOS. We hypothesize that in PCOS, this results in impaired GC function and exacerbation of ovarian dysfunction. We will use our PCOS mouse model to study the effects of a reduced-AGE diet in ameliorating the reproductive and metabolic phenotype of an androgenized PCOS mouse. In preliminary experiments, we have found that a low-AGE diet results in lower fasting glucose in C57BL/6J mice after only 4 weeks. We expect that reproductive symptoms, such as estrous cyclicity, and metabolic symptoms, such as GTT and circulating insulin, will improve in our PCOS mouse model when mice are fed a low-AGE diet throughout development and adulthood. This project has significant clinical implications, as reducing dietary AGEs could provide an effective, tolerable, non-drug therapy option for patients with PCOS. Presentation: 6/3/2024

8040 Precision-Engineered Activin and GDF Ligand Trap HS235: A Novel Lean Mass-Preserving Treatment for Obesity

Abstract Disclosure: G. Schang: Employee; Self; 35Pharma. M. De Molliens: Employee; Self; 35Pharma. E. Brule: Employee; Self; 35Pharma. C. Chauvet: Employee; Self; 35Pharma. J. Denis: Employee; Self; 35Pharma. A. Sours: Employee; Self; 35Pharma. V. Ganesh: Employee; Self; 35Pharma. G. Tremblay: Employee; Self; 35Pharma. J. Schoelermann: Employee; Self; 35Pharma. M. O'Connor: Employee; Self; 35Pharma. Introduction: Novel anti-obesity medications including incretin mimetics have revolutionized the pharmacotherapy of obesity and type 2 diabetes, leading to unprecedented weight loss and clinically meaningful improvement of glucose metabolism and cardiometabolic health. However, incretins reduce body mass in a non-selective manner; both fat mass and lean mass are lost with incretin treatment. In obese patients treated with incretins, undesirable loss of lean body mass (LBM) can account for up to 40% of overall weight loss. Loss of LBM negatively impacts resting metabolic rate, leading to a weight loss plateau and often unsustainable results. Furthermore, individuals with sarcopenia, characterized by low muscle mass and strength, are at greater risk for heart failure. The preservation, or even increase, of LBM is therefore a desirable treatment goal for obesity pharmacotherapy and overall cardiometabolic health. Activins and growth differentiation factors (GDFs), which are members of the TGF-beta superfamily, are validated targets controlling body composition and metabolism. Specifically, blockade of activins and GDFs has anabolic effects in metabolically active tissues such as skeletal muscle and brown adipose tissue, while reducing white adipose tissue mass. Therefore, specific and selective blockade of activins and GDFs represents a novel anti-obesity treatment strategy which can act orthogonally to current anti-obesity medications. HS235 is an activin receptor ectodomain-based (ActR) Fc-fusion protein that has been rationally designed to attain optimal inhibition of ligands controlling body composition in obesity. Methods: A structure-assisted rational molecular engineering approach coupled with cell-based potency screening was employed to design HS235. To validate the anti-obesogenic potential of HS235, diet-induced obese (DIO) mice were injected with HS235, an incretin mimetic, or a combination of both. Fat mass, LBM, muscle weights, and biomarker readouts were assessed at the end of study. Results: In cell-based assays, HS235 potently and selectively neutralized activins and GDFs implicated in body composition. This translated to complete in vivo target engagement and pharmacodynamic response. In a DIO mouse model, both HS235 and the incretin mimetic significantly improved metabolic parameters and decreased fat mass, but only HS235 increased LBM, while incretin-based treatment led to LBM loss. Importantly, the addition of HS235 to the incretin mimetic lead to a synergistic fat mass loss and prevented loss of LBM. Conclusion: Potent and selective inhibition of activins and GDFs by HS235 represents a novel LBM preserving weight loss strategy orthogonal to incretin mimetics. Collectively, these data support the development of HS235 as a novel anti-obesity agent to complement currently approved incretin-based medications to improve quality of weight loss. Presentation: 6/3/2024

Evaluation of Inflammation and Platelet Apoptosis Parameters in Obese Patients in Various Types of Anticoagulant Prophylaxis of Venous Thromboembolic Complications in Context of COVID-19

INTRODUCTION: The physical inactivity, hypoventilation, as well as chronic inflammation in obese patients aggravates their condition in various diseases. These features have become important with the advent of the COVID-19 pandemic, in which inflammation and platelet-activated coagulopathy are closely linked. AIM: To study laboratory parameters of inflammation and platelet apoptosis in obese patients using various types of anticoagulant prophylaxis of venous thromboembolic complications with the underlying COVID-19. MATERIALS AND METHODS: The study included 370 patients with COVID-19. Depending on the presence or absence of obesity and the type of parenteral anticoagulant, patients in our study were divided into groups: group 1 — non-obese + low molecular weight heparin (LMWH) (n = 114), group 2 — non-obese + unfractionated heparin (UFH) (n = 58), group 3 — obesity + LMWH (n = 76), group 4 — obesity + UFH (n = 66). The incidence of venous thromboembolic complications (VTEC), bleeding, general markers of the acute phase of inflammation, and specific markers of platelet apoptosis (phosphatidylserine and calreticulin) have been analyzed. RESULTS: At the end of hospital treatment, a decrease in ferritin levels was noted in patients both with and without obesity receiving LMWH. The concentration of calreticulin was higher in patients taking LMWH (groups 1 and 3). Phosphatidylserine levels were high in patients receiving LMWH only if they were obese. In patients taking UFH compared to LMWH, a high incidence of pulmonary embolism (PE) without a source (13.6% of cases versus 2.6%, respectively, p = 0.029) and PE with a source in the lower extremities (9.1% of cases versus 0%, respectively, p = 0.018) was found. When using LMWH, a lower incidence of bleeding was observed compared to using UFH (5.3% of cases versus 16.7%, respectively, p = 0.056). CONCLUSION: The levels of phosphatidylserine and calreticulin are higher in obese patients receiving LMWH. At the same time, patients in this group have a low incidence of VTEC and hemorrhagic complications compared to the group of patients taking UFH.

Effect of the Composition of the Mediterranean Diet on Body Mass Index, Waist Circumference, Fat Level, and Visceral Fat in Patients with Obesity

Excessive and unhealthy fat storage is known as obesity. Both monounsaturated and polyunsaturated fatty acids are highly encouraged in the Mediterranean diet. Obese patients at a Bandung clinic were studied to examine how the Mediterranean diet affects their BMI, waist size, fat percentage, and visceral fat. Analytical observational methods utilizing prospective cohort observations were employed. A systematic random sample technique was used to carry out the sampling. Participants were 34 overweight individuals who had twelve monthly food pattern assessments and two monthly examinations for body mass index (BMI), waist size, fat percentage, and visceral fat. To compare proportions between the rMED adherence groups and to look for differences in the composition of the Mediterranean diet on BMI, waist circumference, fat content, and visceral fat, we used the ANOVA test and Tuckey’s post-hoc test. In addition, the eight tenets of the Mediterranean diet were assessed using linear regression. The average age of the obese patients who followed the Mediterranean diet was 57.54 years, and 79.41% of them were female. It was found that the components of vegetables, fruits, nuts, seafood, and dairy products had a substantial impact on the body mass index of the participants, while the components of vegetables, fruits, nuts, legumes, seeds, meat, fish, olive oil, and dairy products did not have a significant impact on the waist circumference, fat content, or visceral fat. Keywords: body mass index, fat content Mediterranean diet composition, obesity, visceral fat, waist circumference

Redefining Surgical Boundaries for Obese Patients? Full Endoscopic Lumbar Discectomy Proves Equally Effective With Shorter Hospital Stay in Obese Patients.

This cohort study aims to evaluate the impact of obesity on the outcomes of full endoscopic lumbar discectomy (FELD) in patients with lumbar disc herniation. We conducted a retrospective analysis of 156 adult patients who underwent FELD for lumbar disc herniation from January 2015 to February 2023. Patients were divided into 3 groups: obese endoscopic (n = 71), obese open surgery (n = 31), and nonobese endoscopic (n = 54). Clinical outcomes were assessed using the visual analog scale for leg and back pain, the Oswestry Disability Index, and patient satisfaction rates. Operative time, hospital stay duration, and complication rates were also analyzed. No significant differences were observed in patient-reported outcome measures, operative time, or complication rates between obese and nonobese patients undergoing FELD. The mean operative time was longer in the endoscopic group compared with the open surgery group (70.2 vs 59.8 minutes), but the hospital stay was significantly shorter for endoscopic patients (1.7 vs 2.4 nights, P = 0.0006). Both obese and nonobese groups showed significant improvements in visual analog scale and Oswestry Disability Index scores at the final follow-up, with satisfaction rates of 85.7% in the endoscopic group reporting good to excellent outcomes. FELD is a viable and effective alternative to traditional open surgery for obese patients, offering comparable clinical outcomes and the added benefit of a shorter hospital stay. These findings suggest that obesity does not inherently affect surgical outcomes, underscoring the need for further research with larger sample sizes and longer follow-up periods. FELD offers a viable and effective surgical option for obese patients, with outcomes comparable to traditional surgery but with the added benefit of shorter hospital stays.

The relationship between iron metabolism markers and parameters of carbohydrate and lipid metabolism in patients with overweight and obesity

Background: Hyperferritinemia associated with obesity and insulin resistance is a link between the components of the metabolic syndrome and a possible triggering factor in the pathogenesis of carbohydrate metabolism disorders and dyslipidemia.Aim: To establish possible relationships between ferrokinetic parameters, parameters of lipid and carbohydrate metabolism in overweight and obese patients, and to analyze the possibility of using iron metabolism parameters (ferritin and serum iron) as predictors of carbohydrate metabolism disorders in this cohort of patients.Material and Methods. The study included 52 overweight or obese patients. In the course of the study, patients were stratified into groups depending on the presence of carbohydrate metabolism disorders (CMD), and depending on the state of iron metabolism. Among all patients included in the study, an assessment of anthropometric data, a study of glycated hemoglobin, a standard glucose tolerance test with 75 g of glucose, a study of hematological parameters, as well as biochemical parameters of iron metabolism – the concentration of serum iron, transferrin and ferritin, was carried out.Results. Patients with CMD – impaired glucose tolerance or impaired fasting glycaemia – had significantly higher serum ferritin levels than obese patients without CMD (p = 0.019). In persons with a high level of ferritin, CMD developed significantly more often than in patients with a ferritin content in the range below the 75th percentile (χ2 = 5.278, p = 0.022). According to the ROC analysis, ferritin showed a rather high sensitivity – 75%, and specificity – 84.4% at a diagnostic threshold of 126.65 ng/ml (area under the curve = 0.738; p = 0.016) in the diagnosis of prediabetes (IGT/IFG) in overweight and obese individuals.Conclusion. High concentrations of iron and ferritin are positively associated with CMD, with ferritin being a promising predictor of prediabetes and type 2 diabetes mellitus.

In Patients Presenting with an ST-Elevation Myocardial Infarction, Overweight and Obese Patients Have the Lowest Inpatient Mortality whereas Cachexia Patients Have the Highest Inpatient Mortality Followed by Patients with Morbid Obesity

Introduction: The obesity paradox has been observed in patients with cardiovascular disease. The goal of this study was to evaluate whether obesity has a protective effect in patients presenting with an ST elevation myocardial infarction (STEMI). Method: Using the large Nationwide Inpatient (NIS) sample database, we evaluated the mortality in patients with a STEMI based on weight categories. Results: A total of 2,161,640 STEMI patients were found in the database over age 18. We found that overweight and obesity had the lowest mortality using univariate (overweight mortality of 5% vs. obesity mortality of 6.5% vs. 10.9% for normal weights) and multivariate analyses (overweight OR: 0.52, CI: 0.43–063; p < 0.001 and obesity OR: 0.7, CI: 0.67–0.74; p < 0.001), whereas cachexia was associated with the highest mortality in the univariate (cachexia 24.5%) and multivariate (OR: 2.28, CI: 2.13–2.44; p < 0.001) analyses, followed by morbid obesity in the multivariate analysis (OR: 1.07, CI: 1.02–1.12; p = 0.004). Conclusions: We observed a partial obesity paradox in patients with a STEMI showing that overweight have the best survival rates followed by obesity. Cachexia followed by morbid obesity had the lowest survival rates.

PDOC-01 THERAPEUTIC DIFFICULTY IN THE MANAGEMENT OF A RECURRENT CRANIOPHARYNGIOMA IN A CHILD: REVIEW OF THE LITERATURE AND CASE REPORT

Abstract BACKGROUND Craniopharyngiomas are rare, benign epithelial tumors of embryonic origin in children that develop along the craniopharyngeal duct from Rathke’s pouch. The optimal treatment algorithm remains challenging. We report a child case of recurrent craniopharyngioma with therapeutic challenges. CASE PRESENTATION 12-year-old patient, followed for a multi-operated type 2 craniopharyngioma (December 2017, November 2018, and April 2022), stroke on left sylvian stenosis with right hemiplegia in 2020 during proton therapy (52 Gray), thrombolysed with good recovery after rehabilitation, sequellar panhypopituitarism. He was seen in consultation for visual field deterioration. Clinical examination showed a conscious, coherent, obese patient with a deteriorating visual field. Ophthalmological examination showed visual acuity 10/10 with slight temporal visual field amputation on the left and monocular blindness on the right due to probable optic atrophy sequelae of the craniopharyngioma. Magnetic resonance imaging revealed progression of the residual multicystic lesion in the sellar and left temporal regions, entering the sylvian valley and severely compressing the optic pathways. The tumor was removed under general anesthetic in a supine position, with release of the optic nerve, the carotid artery, and its division, and the left 3rd cranial nerve. The postoperative course is straightforward. CONCLUSION Morbidity and the assessment of sequelae are now at the forefront of the management of craniopharyngiomas. The current therapeutic approach should be reconsidered, in terms of the indications for surgery and the surgical protocol. This patient’s case is a typical example of the therapeutic difficulties involved in the management of craniopharyngiomas.

A-018 Diagnostic Performance of the Novel Beckman-Coulter NT-proBNP-assay in the Early Diagnosis of Acute Heart Failure

Abstract Background The diagnostic performance of the novel Beckman Coulter N-terminal pro-B-type natriuretic peptide (NT-proBNP) assay in the early diagnosis of acute heart failure (AHF) is unknown. Methods This major unmet clinical need was addressed in a secondary analysis using frozen plasma samples obtained in a prospective diagnostic study, enrolling patients presenting with acute dyspnea to the emergency department (ED). Two independent cardiologists/internists centrally adjudicated the final diagnosis using all individual patient's information. NT-proBNP-Beckman Coulter plasma concentrations were measured blinded and directly compared to NT-proBNP-Elecsys concentrations. Agreement analysis was performed by Bland Altman plot. The primary endpoints were the diagnostic accuracy of both assays using the Area-under-the-Receiver-Operating-Curve and the comparison of the performance for diagnosing AHF using the validated NT-proBNP-Elecsys clinical decision values (<300ng/L for rule-out, age-adjusted >450/900/1800ng/L for rule-in). The secondary endpoint included the application of the recently suggested NT-proBNP-Elecsys clinical decision values for obese patients. Results 1400 patients (46% 3women, median age 76 years, BMI 25.9m2/kg, LVEF 53%) had both NT-proBNP measurements on presentation to the ED. Of those 744 (53%) had an adjudicated diagnosis of AHF. The agreement analysis showed overall higher concentrations for the NT-proBNP-Beckman assay. The diagnostic accuracy of both assays was excellent (AUC: 0.915 vs 0.922; P = 0.006, respectively). In the clinical application less patients were ruled-out using the Beckman assay compared to the Elecsys assay (18.7% vs 26.3%) with comparable sensitivities (98.9% vs 98.5%). Regarding rule-in NT-proBNP-Elecsys had a significantly higher specificity (78.8% vs 70.9%) and positive predictive value (83.1% vs 78.7%; both P<0.001; Figure 1). Similar findings were obtained in recently suggested cutoffs for obese patients. Conclusions In comparison to established NT-proBNP-Elecsys cutoffs, a derivation of Beckman-specific cutoffs is needed to implement NT-proBNP-Beckman Coulter clinical decision values providing a higher rule-out proportion and an optimal specificity for diagnosing AHF.

Clinical evidence of low-calorie and ketogenic nutrological therapy before, during and after bariatric surgery: a systematic review

Introduction: Obesity is a multifactorial disease that causes serious comorbidities. There are more than 2.2 billion overweight and obese people in the world. Obese patients tend to be predisposed to micronutrient deficiency even before bariatric surgery, therefore, it is imperative to supplement nutrients orally, enterally, or parenterally, according to the indications of each patient. Objective: It was highlighted the importance of low-calorie and ketogenic nutritional therapy before, during, and after bariatric surgery through the systematic analysis of clinical studies. Methods: The systematic review rules of the PRISMA Platform were followed. The search was conducted from June to July 2024 in the Scopus, PubMed, Science Direct, Scielo, and Google Scholar databases. The quality of the studies was based on the GRADE instrument and the risk of bias was analyzed according to the Cochrane instrument. Results and Conclusion: 119 articles were found. A total of 40 articles were fully evaluated and 34 were included and developed in the present systematic review study. Considering the Cochrane tool for risk of bias, the overall assessment resulted in 23 studies with a high risk of bias and 27 that did not meet GRADE and AMSTAR-2. Most studies presented homogeneity in their results, with X2=76.5%>50%. It was concluded that nutrological therapy strategies could represent a possible alternative to other methodologies, especially when it is recommended to improve patient adherence to following the prescribed diet before bariatric surgery. Weight loss induced by the ketogenic diet before bariatric surgery has beneficial effects on reducing liver volume, metabolic profile, and intra- and postoperative complications. Knowledge of the type of bariatric surgery performed and an understanding of its anatomy and physiology are useful to provide optimal care to patients, especially in nutritional complications. Nutritional deficiencies and metabolic disorders result from “malabsorption” procedures such as RYGB. Immediate administration of thiamine is essential. Dextrose should be avoided in intravenous hydration until thiamine is adequately replaced. For all bariatric patients, a protein intake of 60-70 g/d and a multivitamin with iron and vitamin B12 supplementation is recommended. Daily calcium and vitamin D supplementation is also encouraged. In addition, serum micronutrient levels should be monitored regularly and additional supplementation should be prescribed as indicated.

Impact of Obesity on Outcome for Inflammatory Bowel Disease Patients From 2008 Through 2020.

The incidence and prevalence of obesity have been rising in the U.S. It is known to affect the course and treatment of a variety of gastrointestinal disorders. It has been proposed to particularly worsen the symptoms of inflammatory bowel disease (IBD) and put patients at risk of treatment failure. Our study seeks to understand better the impact of obesity on morbidity, mortality, hospital length of stay (LOS), and charges in patients with IBD. The National Inpatient Sample (NIS) from 2008 to 2020 was used to identify patients over 18 diagnosed with IBD using the International Classification of Disease (ICD) 9 and 10 codes. Records were weighted per the NIS algorithm to produce accurate population estimates. Patients were classified by obesity status and then analyzed for baseline characteristics such as age, gender, race, insurance status, and various comorbidities. Various primary outcomes were analyzed. Outcomes were compared between groups, and odds ratios (ORs) were calculated using weighted logistic regression. ORswere adjusted for common co-founders. A weighted total of 2,105,418 patients admitted for IBD were included in this study. Of these, 170,475 were obese, and 1,934,943 were not obese. Obese patients were older, more complex (Charlson comorbidity index [CCI] 2.03 vs. 1.53), and more likely to be female (p<0.01) than non-obese patients. Compared to non-obese patients, IBD patients with obesity had a higher prevalence of coronary artery disease (11.35% vs. 7.87%), hyperlipidemia (29.27% vs. 15.09%), hypertension (45.38% vs. 25.60%), diabetes mellitus type 2 (27.15% vs. 9.38%), congestive heart failure (4.58% vs. 2.35%), gastroesophageal reflux disease (30.73% vs. 17.98%), and CCI (2.03% vs. 1.53%). Obese IBD patients had slightly higher odds of shock (OR 1.228, p<0.05), acute myocardial infarction (AMI, OR 1.692, p<0.01), acute kidney injury (AKI, OR 1.187, p<0.01), and chronic steroid treatment (OR 1.149, p<0.01). Conversely, obese IBD patients had lower odds of intestinal fistula (OR 0.837, CI 0.77-0.91, p<0.001). Obesity poses a diverse set of complications in IBD patients. Our study found that obese patients admitted with IBD had significantly higher odds of shock, AKI, and chronic steroid treatment. Interestingly, these patients were less likely to develop intestinal fistulas. These findings suggest further research into how obesity affects the disease course.