Journal of the Endocrine Society最新文献

{"title":"Hepatic Glucose Uptake During Euglycemic Hyperinsulinemia Associates With Glycemia During Oral Glucose Tolerance Test.","authors":"Miikka-Juhani Honka, Eleni Rebelos, Laura Pekkarinen, Nelli Tuomola, Aino Latva-Rasku, Leena Koukkari, Heidi Immonen, Andrea Mari, Kari K Kalliokoski, Jarna C Hannukainen, Pirjo Nuutila","doi":"10.1210/jendso/bvaf054","DOIUrl":"10.1210/jendso/bvaf054","url":null,"abstract":"<p><strong>Context: </strong>Postprandial hepatic glycogen synthesis and glycolysis are reduced in hepatic insulin resistance. However, the physiologic interpretation of the reduction in hepatic glucose uptake (GU) during the gold-standard measurement of insulin sensitivity, hyperinsulinemic euglycemic clamp, in insulin resistance is unclear. This is because the peripheral route of glucose and insulin delivery during a clamp study differs greatly from the physiological route.</p><p><strong>Objective: </strong>We hypothesized that hepatic GU during hyperinsulinemic euglycemic clamp would predict glycemia during oral glucose tolerance test (OGTT).</p><p><strong>Design: </strong>We analyzed cross-sectional data of 120 individuals (70 men and 50 women) who did not have diabetes from the CMgene study cohort. Hepatic GU was measured with [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) and positron emission tomography.</p><p><strong>Results: </strong>In a multiple regression analysis, hepatic GU, endogenous glucose production, insulin secretion capacity, and serum triglycerides predicted OGTT glucose area under the curve (<i>P</i> for all <.05), whereas skeletal muscle GU, the antilipolytic insulin index, and insulin clearance were not statistically significant predictors (<i>P</i> > .05).</p><p><strong>Conclusions: </strong>Hepatic GU measured during hyperinsulinemic euglycemic clamp is an independent predictor of OGTT glucose area under the curves even when accounting for well-known other factors affecting glycemic control. This finding supports the idea that insulin-mediated hepatic GU, and more broadly, first-pass glucose extraction, have a meaningful contribution to glycemic control. Thus, this measurement provides useful information about hepatic insulin sensitivity in the more physiologic conditions of the OGTT which may be useful when studying the pathophysiology of impaired glucose tolerance and when evaluating potential treatments for impaired glycemic control.</p>","PeriodicalId":17334,"journal":{"name":"Journal of the Endocrine Society","volume":"9 5","pages":"bvaf054"},"PeriodicalIF":3.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12086998/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144102047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>SLC25A11</i>, a Novel Gene Associated With Carney-Stratakis Syndrome.","authors":"Felipe Freitas-Castro, Lucas S Santana, Gustavo F C Fagundes, Eduardo C Lobato, Ana Caroline F Afonso, Izabel T Nakamura, Felipe L Ledesma, Ibere C Soares, Berenice B Mendonca, Ana Claudia Latronico, Constantine A Stratakis, Madson Q Almeida","doi":"10.1210/jendso/bvaf052","DOIUrl":"https://doi.org/10.1210/jendso/bvaf052","url":null,"abstract":"<p><strong>Background: </strong>Carney-Stratakis syndrome (CSS), a rare condition characterized by paragangliomas and/or pheochromocytomas and gastrointestinal stromal tumors (GIST), is caused by germline heterozygous pathogenic variants in the succinate dehydrogenase subunit genes (<i>SDHB, SDHC, SDHD</i>).</p><p><strong>Methods: </strong>Histological, genetic, and functional analyses were conducted in a 59-year-old female with CSS (9 cm left pheochromocytoma, 4.8 cm paraganglioma, and 9.3 cm GIST). Whole-exome sequencing (WES) of germline DNA paired with tumor DNA was performed.</p><p><strong>Results: </strong>WES identified a rare heterozygous germline variant (c.293G>A/p.Arg98His) in the mitochondrial 2-oxoglutarate/malate carrier gene (<i>SLC25A11</i>). This variant, located in a highly conserved residue of the <i>SLC25A11</i> mitochondrial carrier domain, is predicted to be deleterious in silico (REVEL score = 0.81). WES of pheochromocytoma, paraganglioma, and GIST did not reveal somatic pathogenic variants in genes previously associated with these tumors. A significant reduction in <i>SLC25A11</i> expression was observed in the tumors of this patient with the <i>SLC25A11</i> c.293G>A variant (0.69 ± 0.003) compared to tumors from cluster 1 (1.39 ± 0.45; <i>P</i> = 0.0229) and cluster 2 (1.79 ± 0.71; <i>P</i> = .0154). Consistent with the mRNA findings, <i>SLC25A11</i> protein levels were markedly reduced in the pheochromocytoma and paraganglioma compared to other tumors. Negative staining for 5-hydroxymethylcytosine in all 3 tumors suggests a DNA hypermethylation profile characteristic of cluster 1A, despite normal SDHB expression levels. However, genome-wide copy number variation analysis did not reveal any loss of heterozygosity at the <i>SLC25A11</i> locus.</p><p><strong>Conclusion: </strong>The loss of SLC25A11 expression in tumors, the absence of somatic drivers, and the hypermethylation status strongly support the role of <i>SLC25A11</i> in CSS pathogenesis.</p>","PeriodicalId":17334,"journal":{"name":"Journal of the Endocrine Society","volume":"9 5","pages":"bvaf052"},"PeriodicalIF":3.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12000648/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143978667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adrenal Tumors in Children and Adolescents in Sweden: A Register-Based Study Covering 15 Years.","authors":"Eleni Terezaki, Jan Calissendorff, Buster Mannheimer, Jonatan D Lindh, Henrik Falhammar","doi":"10.1210/jendso/bvaf058","DOIUrl":"https://doi.org/10.1210/jendso/bvaf058","url":null,"abstract":"<p><strong>Context: </strong>Adrenal tumors (ATs) are highly uncommon in children and adolescents, and more information on these tumors is needed.</p><p><strong>Objective: </strong>The aim of this study was to describe the tumor incidence, patient and tumor characteristics, treatment, and mortality in pediatric patients with ATs.</p><p><strong>Methods: </strong>This is a Swedish nationwide, register-based, retrospective study. All patients up to 21 years old diagnosed between 2005 and 2019 with an AT were identified through national registers and then manually reviewed. Age-, sex-, and municipality-matched controls in a ratio 4:1 were selected from the total population register.</p><p><strong>Results: </strong>In total, 230 patients were included (and 920 controls), with an annual incidence of 6.20 new ATs per million for individuals up to 21 years old. The median age was 6.0 years (interquartile range, 1.0-17.70), with 120 (52.2%) being boys. Regarding tumor biology, 132 (57.4%) were malignant, 77 (33.5%) benign, and 21 (9.1%) were undetermined. There were at least 39 (16.9%) hormonally active ATs recognized as either pheochromocytomas, adrenocortical carcinomas, or benign functional adenomas. Patients with malignant tumors were younger than patients with benign tumors (mean age 2 vs 18, <i>P</i> < .001). Among patients with malignant ATs, the mortality reached 33.3% during a follow-up period of up to 15 years. Patients who were younger and received less aggressive treatments had better overall survival. Mortality was increased in all patients with malignant ATs compared to controls (<i>P</i> < .0001). Mortality was similar between patients with benign ATs and controls (<i>P</i> > .05).</p><p><strong>Conclusion: </strong>Although rare, most identified tumors were malignant and associated with high mortality.</p>","PeriodicalId":17334,"journal":{"name":"Journal of the Endocrine Society","volume":"9 5","pages":"bvaf058"},"PeriodicalIF":3.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11986419/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143998916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacodynamic Modeling of Cinacalcet in Secondary Hyperparathyroidism: Efficacy and Influencing Factors Analysis.","authors":"Zhizhou Wang, Yexuan Wang, Shun Han, Peixian Chen, Ruo Wu, Chuyao Fang, Junjie Cheng, Yujiao Wu, Tingting Guo, Xin Wen, Lujin Li","doi":"10.1210/jendso/bvaf021","DOIUrl":"10.1210/jendso/bvaf021","url":null,"abstract":"<p><strong>Context: </strong>Cinacalcet, the first FDA-approved calcimimetic agent for treating secondary hyperparathyroidism (SHPT), has unclear factors influencing its therapeutic efficacy in clinical practice.</p><p><strong>Objective: </strong>To establish a pharmacodynamic model for cinacalcet use in SHPT, analyze drug effect distribution and influencing factors, and determine optimal treatment strategy.</p><p><strong>Methods: </strong>We searched public databases for randomized trials on cinacalcet for SHPT, modeling changes in serum parathyroid hormone (PTH), calcium, and phosphorus postintervention. Key pharmacodynamic parameters and influencing factors were identified, with subgroup analysis for factors not in the covariate model. We also compared cinacalcet efficacy between United States/European Union (30-180 mg) and Asia (25-100 mg) dosage ranges.</p><p><strong>Results: </strong>Twenty-six studies (4242 subjects) were analyzed. Covariate analysis showed increasing PTH baseline and vitamin D use proportionally affected PTH and calcium decrease. Postintervention, maximum effects were observed with onset times of 0.46, 0.15, and 0.29 months. Subgroup analysis showed factors such as dialysis time, baseline calcium and phosphorus, phosphate binder use, gender proportion, patient ethnicity, blinding, and age influenced PTH, calcium, and phosphorus decrease. The efficacy of cinacalcet at a dosage of 25 to 100 mg in Asian populations was comparable to that observed at a dose range of 30 to 180 mg in Western populations, suggesting that reducing the therapeutic dose of cinacalcet may potentially yield a better benefit-risk ratio.</p><p><strong>Conclusion: </strong>We established a pharmacokinetic model for cinacalcet in SHPT treatment, providing crucial data for identifying effective patient populations and optimizing treatment strategies.</p>","PeriodicalId":17334,"journal":{"name":"Journal of the Endocrine Society","volume":"9 5","pages":"bvaf021"},"PeriodicalIF":3.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11949687/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Etomidate in Severe Cushing Syndrome: A Systematic Review.","authors":"Dimuthu Tharanga Muthukuda, Kamani Dhanushka Liyanaarachchi, Kushalee Poornima Jayawickreme, Pasyodun Koralage Buddhika Mahesh, Vidana Gamage Dinithi Ruwanga, Sinduja Kumar, Chandrika Subasinghe, John Newell-Price","doi":"10.1210/jendso/bvaf039","DOIUrl":"10.1210/jendso/bvaf039","url":null,"abstract":"<p><strong>Background: </strong>Severe Cushing syndrome is a medical emergency. Etomidate is the only IV option available for treating hypercortisolism, especially in critically ill patients obviating oral medications.</p><p><strong>Methods: </strong>A systematic review and meta-analysis were conducted on the use of etomidate in the treatment of severe Cushing syndrome. This was registered in PROSPERO, and data reporting was done as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Thirty-six published articles comprising 76 clinical cases of 78 clinical episodes of etomidate use were included in the analysis for this review.</p><p><strong>Results: </strong>Etomidate was administered safely to patients with ages ranging from 2 months to 82 years. It served as the first-line treatment in 53.2% of the cases, with 84.3% of patients treated in intensive care unit (ICU) settings. Infusion durations varied from 3 hours to 5.5 months, but 84.8% of treatments were completed in under 2 weeks. Faster cortisol reduction rates were observed in patients with higher baseline cortisol levels (<i>P</i> = .02), those receiving a prior bolus dose (<i>P</i> = .015), and those given higher initial infusion rates (<i>P</i> = .004). Etomidate as first-line therapy (<i>P</i> = .01) and in ICU settings (<i>P</i> < .01) were associated with more rapid cortisol reduction compared to its use as subsequent therapy or in non-ICU settings. Overall, 80.9% of patients survived to receive definitive treatment.</p><p><strong>Conclusion: </strong>Etomidate is effective and safe for reducing cortisol levels in Cushing syndrome. There is a need for standardized guidelines on etomidate use, including detailed recommendations for different clinical settings and patient conditions to ensure safety and effectiveness.</p>","PeriodicalId":17334,"journal":{"name":"Journal of the Endocrine Society","volume":"9 4","pages":"bvaf039"},"PeriodicalIF":3.0,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11920866/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association Between Bone Ultrasonometry and Cardiovascular Morbimortality: A Systematic Review and Meta-analysis.","authors":"Clément Vachey, Aurélie Dufour, Pier-Alexandre Tardif, Aboubacar Sidibé, Lynne Moore, Fabrice Mac-Way","doi":"10.1210/jendso/bvaf049","DOIUrl":"10.1210/jendso/bvaf049","url":null,"abstract":"<p><strong>Context: </strong>Quantitative ultrasound (QUS) can estimate bone mineral density and predict fracture risk, but its association with cardiovascular outcomes remains unclear.</p><p><strong>Objective: </strong>We aimed to assess the associations between bone QUS parameters and cardiovascular event risk, cardiovascular mortality (CVM) and all-cause mortality (ACM).</p><p><strong>Data sources: </strong>Pubmed, Embase, Cochrane Library databases, and grey literature were searched.</p><p><strong>Study selection: </strong>We considered studies including people aged >40 years who reported associations between bone QUS parameters (any bone site) and our outcomes.</p><p><strong>Data extraction: </strong>Two reviewers selected eligible studies, extracted and analyzed data, and assessed risk of bias with the Risk of Bias in Non-randomized Studies of Exposure tool. Adjusted hazard ratios (HR) with 95% confidence intervals (CIs), estimated for 1 SD reduction of QUS parameters, were pooled using random effects meta-analyses.</p><p><strong>Data synthesis: </strong>We included 9 studies with 275 to 477 683 (median = 3244) participants (follow-up duration range 2.8-12.8 years). All studies presented associations based on calcaneal QUS parameters; only 2 reported associations with cardiovascular events with discordant results. Seven studies reported associations with CVM and 7 with ACM. Meta-analyses based on 3 studies showed that broadband ultrasound attenuation (BUA) was inversely associated with CVM (HR = 1.22, 95% CI: 1.11-1.34, <i>I</i> ² = 0%) and ACM (HR = 1.16, 95% CI: 1.10-1.23, <i>I</i> ² = 0%). Meta-analyses, based on 4 and 3 studies, respectively, showed that speed of sound (SOS) was also inversely associated with CVM (HR = 1.19, 95% CI: 1.11-1.27, <i>I</i> ² = 29%) and ACM (HR = 1.15, 95% CI: 1.07-1.23, <i>I</i> ² = 0%).</p><p><strong>Conclusion: </strong>In a cohort of middle-aged individuals, a decrease in calcaneal BUA and SOS were both independently associated with higher cardiovascular and ACM.</p>","PeriodicalId":17334,"journal":{"name":"Journal of the Endocrine Society","volume":"9 5","pages":"bvaf049"},"PeriodicalIF":3.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11949689/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recombinant TSH Performs as Well as Thyroid Hormone Withdrawal for Iodine-131 Therapy With Dosimetry for Thyroid Cancer.","authors":"Anupam Kotwal, Abbey Fingeret, Jarod Hamsa, Dana Awad, Craig Johnson, Frank Rutar, Carrie Carson, Anery Patel, Whitney Goldner","doi":"10.1210/jendso/bvaf050","DOIUrl":"10.1210/jendso/bvaf050","url":null,"abstract":"<p><strong>Introduction: </strong>Dosimetry helps calculate the optimal iodine-131 (I-131) dose for treating metastatic differentiated thyroid cancer (DTC). We aimed to evaluate if recombinant human TSH (rhTSH) and thyroid hormone withdrawal (THW) are equivalent methods of preparation for dosimetry-guided I-131 therapy in metastatic DTC.</p><p><strong>Methods: </strong>We performed a retrospective cohort study of 51 adults with metastatic DTC who received I-131 with dosimetry from 2010 through 2022. Gamma camera and blood activity measurements were taken following the pretherapeutic I-131 dose. Statistical analysis compared rhTSH and THW groups; <i>P</i> < .05 was considered significant.</p><p><strong>Results: </strong>Fifty-one adults undergoing 55 I-131 dosimetry-guided treatments were included: 22 by rhTSH and 33 by THW. The median age was lower (<i>P</i> = .0008), and the proportion of stage IV (<i>P</i> = .009) was higher in rhTSH compared to the THW group. The terminal effective half-life at 24 to 48 hours in the whole body was longer in rhTSH compared to THW group (21.9 vs 17.1 hours; <i>P</i> = .014), but this difference was less significant when limited to the n = 37 metastatic cases (<i>P</i> = .046) and not different for red marrow effective half-life. The calculated allowed I-131 dose was lower in rhTSH compared to THW group (187.5 mCi vs 259.9 mCi; <i>P</i> = .0000). Thyroglobulin was higher during treatment in the rhTSH group (<i>P</i> = .031), whereas its reduction at 3 months was not different after adjusting for age and stage.</p><p><strong>Conclusion: </strong>rhTSH is noninferior to THW in preparation for I-131 dosimetry. Compared to THW, rhTSH results in lower calculated allowed I-131 dose after dosimetry, which could translate to fewer side effects or impact on quality of life.</p>","PeriodicalId":17334,"journal":{"name":"Journal of the Endocrine Society","volume":"9 5","pages":"bvaf050"},"PeriodicalIF":3.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11965782/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicting Glycemic Control in Patients With Impaired Fasting Glucose With Fasting Respiratory Exchange Ratio.","authors":"Andrea Foppiani, Federica Sileo, Francesca Menichetti, Giorgia Pozzi, Silvia Gallosti, Ramona De Amicis, Alessandro Leone, Simona Bertoli, Alberto Battezzati","doi":"10.1210/jendso/bvaf047","DOIUrl":"10.1210/jendso/bvaf047","url":null,"abstract":"<p><strong>Context: </strong>Impaired metabolic flexibility is associated with prediabetes. However, its assessment with reference methods is impractical in routine clinical practice.</p><p><strong>Objective: </strong>This study investigates the relationship between fasting respiratory exchange ratio (RER), measured through indirect calorimetry, and glucose metabolism in individuals with prediabetes.</p><p><strong>Methods: </strong>The study involved 2 cohorts: (1) a cross-sectional cohort of 10 176 individuals to assess the association between fasting RER and glucose metabolism parameters, and (2) a matched longitudinal cohort of 86 patients with impaired fasting glucose, categorized into fat oxidation (RER < 0.775) and glucose oxidation (RER > 0.925) groups, to evaluate the impact of fasting RER on impaired fasting glucose resolution and fasting glucose after a 1-year lifestyle intervention.</p><p><strong>Results: </strong>In the cross-sectional cohort, a higher fasting RER was associated with higher fasting glucose, insulin, and Homeostatic Model Assessment for Insulin Resistance. In the longitudinal cohort, the fat oxidation group showed a greater reduction in fasting glucose (+5.9; 95% CI 1.4, 10; <i>P</i> = .011) and a higher probability of achieving normal fasting glycemia (log(odds ratio) -0.89; 95% CI -1.8, -0.03; <i>P</i> = .046) after the intervention, despite similar weight loss between groups.</p><p><strong>Conclusion: </strong>Our findings suggest that fasting RER, a readily accessible clinical measure, can provide valuable insights into glucose metabolism and impaired fasting glucose resolution. A lower fasting RER, indicative of a greater capacity for fat oxidation, is associated with improved glycemic control after a lifestyle intervention.</p>","PeriodicalId":17334,"journal":{"name":"Journal of the Endocrine Society","volume":"9 5","pages":"bvaf047"},"PeriodicalIF":3.0,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11965783/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Role of Estrogen and ER Stress in Glycemic Regulation in the Sexually Dimorphic TALLYHO/JngJ Mouse Model of Diabetes.","authors":"Monica De Paoli, Zinal Patel, Susanna Fang, Geoff H Werstuck","doi":"10.1210/jendso/bvaf048","DOIUrl":"10.1210/jendso/bvaf048","url":null,"abstract":"<p><p>The global incidence of diabetes mellitus is increasing, causing a heavy burden on health care management and costs. Sex differences in the incidence and prevalence of diabetes mellitus do exist, with premenopausal women being protected from developing this disease, compared to men or postmenopausal women. The mechanisms underlying these differences are not yet known and experimental animal models can significantly advance our understanding of these processes. In this study we characterized a mouse model of polygenic type 2 diabetes, the TALLYHO/JngJ mouse, which shows sexual dimorphism in blood glucose regulation. Male TALLYHO/JngJ mice develop chronic hyperglycemia by 5 weeks of age, while females remain normoglycemic. We analyzed the role of endoplasmic reticulum (ER) stress and the activation of the unfolded protein response (UPR) in the development of hyperglycemia in this mouse model. Additionally, we evaluated the effect of estrogen depletion in female TALLYHO/JngJ mice through ovariectomies. Ovariectomized female mice and males become chronically hyperglycemic (fasting blood glucose threshold >15 mM) and show significantly increased expression of GRP78/GRP94, markers of the adaptive unfolded protein response (UPR). GADD153/CHOP, a marker of the apoptotic UPR, is significantly increased in ovariectomized female mice. Treatment with a chemical chaperone 4-PBA, an ER stress alleviator, improves but does not normalize blood glucose levels in male and ovariectomized female TALLYHO/JngJ mice. Together, these findings support a protective role for estrogen and identify the UPR as a pathway through which estrogen may maintain pancreatic beta cell health.</p>","PeriodicalId":17334,"journal":{"name":"Journal of the Endocrine Society","volume":"9 5","pages":"bvaf048"},"PeriodicalIF":3.0,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11968335/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Osilodrostat Treatment of Cushing Syndrome in Real-World Clinical Practice: Findings From the ILLUSTRATE study.","authors":"Maria Fleseriu, Richard J Auchus, Wenyu Huang, Joanna L Spencer-Segal, Kevin C J Yuen, Kelley C Dacus, Julianne Padgett, Elizabeth K Babler, Ashis K Das, Cynthia Campos, Michael S Broder, Adriana G Ioachimescu","doi":"10.1210/jendso/bvaf046","DOIUrl":"https://doi.org/10.1210/jendso/bvaf046","url":null,"abstract":"<p><strong>Context: </strong>In clinical trials, osilodrostat (11β-hydroxylase inhibitor) effectively reduced cortisol levels in patients with endogenous Cushing syndrome (CS).</p><p><strong>Objectives: </strong>A real-world study (ILLUSTRATE) was conducted evaluating osilodrostat use in patients with various etiologies of CS in the United States.</p><p><strong>Methods: </strong>A retrospective chart-review study was conducted of adults with CS treated with osilodrostat between May 1, 2020, and October 29, 2021.</p><p><strong>Results: </strong>A total of 42 patients (Cushing disease, n = 34; CS due to adrenal adenoma, n = 5; ectopic adrenocorticotropin syndrome [EAS], n = 3) were included. Starting doses were 2 mg twice daily in 27/42 patients (64.3%), maintenance doses were 2 mg twice daily in 6 of 9 patients (66.7%) attaining them. During osilodrostat treatment, urinary free cortisol (UFC) decreased below the upper limit of normal (ULN) in 14 of 20 patients (70.0%) with pretreatment UFC greater than the ULN. Osilodrostat response was observed across a range of doses (2-20 mg/day). In Cushing disease, median UFC and late-night salivary cortisol decreased from 3.03 and 2.39 × ULN, respectively, to 0.71 and 1.13 × ULN at last assessment in those with available data (n = 17 and 8, respectively). UFC decreased in all patients with adrenal CS or EAS with available data (n = 2 each). There were no unexpected safety signals; the most common adverse events (incidence ≥20%) were fatigue, nausea, and lower-extremity edema. Glucocorticoid withdrawal syndrome and/or adrenal insufficiency were reported in 12 of 42 patients (28.6%) after osilodrostat initiation, resulting in treatment discontinuation in 4.</p><p><strong>Conclusion: </strong>In routine practice with dosing individualized according to clinical condition, response, and tolerability, osilodrostat was effective and well tolerated regardless of CS etiology and severity.</p>","PeriodicalId":17334,"journal":{"name":"Journal of the Endocrine Society","volume":"9 5","pages":"bvaf046"},"PeriodicalIF":3.0,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11986586/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144031939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}