Merisa Abusdal,Kjersti R Normann,Tuula A Nyman,Kristin A B Øystese,Arvind Y M Sundaram,Daniel Dahlberg,Tove Lekva,Jens Bollerslev,Jens P Berg,Nicoleta C Olarescu
PURPOSESilent corticotroph adenoma (SCA) exhibits more tumor aggressiveness features than functioning adenomas (FCA). We aimed to investigate PCSK1N expression in CA and examine if ER stress-induced responses affect cell survival in a corticotroph tumor cell model.METHODSClinical and imaging characteristics were recorded in 33 patients with FCA (20 women, 11 macroadenomas) and 18 SCA (8 women, all macroadenomas). Gene expression of proopiomelanocortin (POMC), T-box transcription factor 19(TBX19)/TPIT, proprotein convertase subtilisin/kexin type 1(PCSK1)/PC1/3, and its inhibitor PCSK1N, was measured by RT-qPCR in adenoma tissue.Mouse pituitary corticotroph tumor (AtT-20) cells were treated with tanespimycin (17-AAG), a HSP90 chaperone inhibitor, to induce ER stress, followed by gene and protein analyses.RESULTSPOMC, TPIT, and PCSK1 expression were higher, whereas PCSK1N was lower in FCA compared to SCA. PCSK1N correlated with POMC (rs= -0.514, p <0.001), TPIT (rs= -0.386, p = 0.005), PCSK1 (rs= -0.3691, p = 0.008), and tumor largest diameter (rs= 0.645, p <0.001), in all CA. Induction of ER stress by 17-AAG in AtT-20 cells led to a decrease of POMC and an increase of PCSK1N gene expression at 24h. Moreover, a downregulation of cell cycle, apoptosis, and senescence pathways, and alterations in cell adhesion and cytoskeleton were observed at the protein level.CONCLUSIONSPCSK1N is higher in SCA compared with FCA, and associated with corticotroph cell markers and tumor size. PCSK1N is likely to be part of the adaptive response to ER stress, potentially conferring a survival advantage to the corticotroph tumor cell in conjunction with other proteins.
{"title":"PCSK1N as a tumor size marker and an ER stress response protein in corticotroph pituitary adenomas.","authors":"Merisa Abusdal,Kjersti R Normann,Tuula A Nyman,Kristin A B Øystese,Arvind Y M Sundaram,Daniel Dahlberg,Tove Lekva,Jens Bollerslev,Jens P Berg,Nicoleta C Olarescu","doi":"10.1210/clinem/dgae643","DOIUrl":"https://doi.org/10.1210/clinem/dgae643","url":null,"abstract":"PURPOSESilent corticotroph adenoma (SCA) exhibits more tumor aggressiveness features than functioning adenomas (FCA). We aimed to investigate PCSK1N expression in CA and examine if ER stress-induced responses affect cell survival in a corticotroph tumor cell model.METHODSClinical and imaging characteristics were recorded in 33 patients with FCA (20 women, 11 macroadenomas) and 18 SCA (8 women, all macroadenomas). Gene expression of proopiomelanocortin (POMC), T-box transcription factor 19(TBX19)/TPIT, proprotein convertase subtilisin/kexin type 1(PCSK1)/PC1/3, and its inhibitor PCSK1N, was measured by RT-qPCR in adenoma tissue.Mouse pituitary corticotroph tumor (AtT-20) cells were treated with tanespimycin (17-AAG), a HSP90 chaperone inhibitor, to induce ER stress, followed by gene and protein analyses.RESULTSPOMC, TPIT, and PCSK1 expression were higher, whereas PCSK1N was lower in FCA compared to SCA. PCSK1N correlated with POMC (rs= -0.514, p <0.001), TPIT (rs= -0.386, p = 0.005), PCSK1 (rs= -0.3691, p = 0.008), and tumor largest diameter (rs= 0.645, p <0.001), in all CA. Induction of ER stress by 17-AAG in AtT-20 cells led to a decrease of POMC and an increase of PCSK1N gene expression at 24h. Moreover, a downregulation of cell cycle, apoptosis, and senescence pathways, and alterations in cell adhesion and cytoskeleton were observed at the protein level.CONCLUSIONSPCSK1N is higher in SCA compared with FCA, and associated with corticotroph cell markers and tumor size. PCSK1N is likely to be part of the adaptive response to ER stress, potentially conferring a survival advantage to the corticotroph tumor cell in conjunction with other proteins.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"208 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Precision medicine in Acromegaly: The Potential of Multimodal Therapy.","authors":"Jens Bollerslev,Ansgar Heck","doi":"10.1210/clinem/dgae636","DOIUrl":"https://doi.org/10.1210/clinem/dgae636","url":null,"abstract":"","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"77 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CONTEXTCardiometabolic multimorbidity (CM) is an increasing public health concern. Previous observational studies have suggested inverse associations between coffee, tea, and caffeine intake and risks of individual cardiometabolic diseases; however, their associations with CM and related biological markers are unknown.METHODSThis prospective study involved 172 315 (for caffeine analysis) and 188 091 (tea and coffee analysis) participants free of any cardiometabolic diseases at baseline from the UK Biobank; 168 metabolites were measured among 88 204 and 96 393 participants. CM was defined as the coexistence of at least 2 of the following conditions: type 2 diabetes, coronary heart disease, and stroke.RESULTSNonlinear inverse associations of coffee, tea, and caffeine intake with the risk of new-onset CM were observed. Compared with nonconsumers or consumers of less than 100 mg caffeine per day, consumers of moderate amount of coffee (3 drinks/d) or caffeine (200-300 mg/d) had the lowest risk for new-onset CM, with respective hazard ratios (95% CIs) of 0.519 (0.417-0.647) and 0.593 (0.499-0.704). Multistate models revealed that moderate coffee or caffeine intake was inversely associated with risks of almost all developmental stages of CM, including transitions from a disease-free state to single cardiometabolic diseases and subsequently to CM. A total of 80 to 97 metabolites, such as lipid components within very low-density lipoprotein, histidine, and glycoprotein acetyls, were identified to be associated with both coffee, tea, or caffeine intake and incident CM.CONCLUSIONHabitual coffee or caffeine intake, especially at a moderate level, was associated with a lower risk of new-onset CM and could play important roles in almost all transition phases of CM development. Future studies are warranted to validate the implicated metabolic biomarkers underlying the relation between coffee, tea, and caffeine intake and CM.
{"title":"Habitual Coffee, Tea, and Caffeine Consumption, Circulating Metabolites, and the Risk of Cardiometabolic Multimorbidity.","authors":"Xujia Lu,Xiaohong Zhu,Guochen Li,Luying Wu,Liping Shao,Yulong Fan,Chen-Wei Pan,Ying Wu,Yan Borné,Chaofu Ke","doi":"10.1210/clinem/dgae552","DOIUrl":"https://doi.org/10.1210/clinem/dgae552","url":null,"abstract":"CONTEXTCardiometabolic multimorbidity (CM) is an increasing public health concern. Previous observational studies have suggested inverse associations between coffee, tea, and caffeine intake and risks of individual cardiometabolic diseases; however, their associations with CM and related biological markers are unknown.METHODSThis prospective study involved 172 315 (for caffeine analysis) and 188 091 (tea and coffee analysis) participants free of any cardiometabolic diseases at baseline from the UK Biobank; 168 metabolites were measured among 88 204 and 96 393 participants. CM was defined as the coexistence of at least 2 of the following conditions: type 2 diabetes, coronary heart disease, and stroke.RESULTSNonlinear inverse associations of coffee, tea, and caffeine intake with the risk of new-onset CM were observed. Compared with nonconsumers or consumers of less than 100 mg caffeine per day, consumers of moderate amount of coffee (3 drinks/d) or caffeine (200-300 mg/d) had the lowest risk for new-onset CM, with respective hazard ratios (95% CIs) of 0.519 (0.417-0.647) and 0.593 (0.499-0.704). Multistate models revealed that moderate coffee or caffeine intake was inversely associated with risks of almost all developmental stages of CM, including transitions from a disease-free state to single cardiometabolic diseases and subsequently to CM. A total of 80 to 97 metabolites, such as lipid components within very low-density lipoprotein, histidine, and glycoprotein acetyls, were identified to be associated with both coffee, tea, or caffeine intake and incident CM.CONCLUSIONHabitual coffee or caffeine intake, especially at a moderate level, was associated with a lower risk of new-onset CM and could play important roles in almost all transition phases of CM development. Future studies are warranted to validate the implicated metabolic biomarkers underlying the relation between coffee, tea, and caffeine intake and CM.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"216 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Min Jin Lee,Ji Hyun Bae,Ah Reum Khang,Dongwon Yi,Joo Yeon Kim,Su Hyun Kim,Dong Hee Kim,Dasol Kang,Sujin Park,Yun Kyung Jeon,Sang Soo Kim,Bo Hyun Kim,Mi Sook Yun,Yang Ho Kang
CONTEXTWith rising the prevalence of type 2 diabetes mellitus (T2DM) and prediabetes, the importance of 1-hour post-load plasma glucose (1-h PG) for early hyperglycemia screening is emphasized.OBJECTIVEThis study investigates the utility of 1-h PG in predicting T2DM in adults with normal fasting plasma glucose (FPG) levels.METHODS7,504 participants were categorized into three groups: normal glucose tolerance (NGT) with 1-h PG < 155 mg/dL, NGT with 1-h PG ≥ 155 mg/dL, and impaired glucose tolerance (IGT). Insulin sensitivity and secretion indices were compared between groups at baseline, and T2DM incidence was analyzed using Cox proportional hazards models. The predictive abilities of 1-h PG and 2-hour post-load plasma glucose (2-h PG) were assessed with receiver operating characteristic analysis.RESULTSAt baseline, the composite insulin sensitivity index in the NGT & 1-h PG ≥ 155 mg/dL group was similarly reduced as in the IGT group (P = .076). Over a mean follow-up of 7.4 years, T2DM developed in 960 patients (12.8%). The highest risk was in the IGT group (hazard ratio [HR] 5.47), followed by the NGT & 1-h PG ≥ 155 mg/dL group (HR 2.74), compared to the NGT & 1-h PG < 155 mg/dL group. The 1-h PG level had a higher area under the curve (0.772) than other glycemic parameters, including 2-h PG.CONCLUSIONEven with normal FPG, a 1-h PG ≥ 155 mg/dL indicates lower insulin sensitivity similar to IGT and increased T2DM risk, making it a more effective early screening tool than 2-h PG.
{"title":"1-Hour Post-Load Glucose: Early Screening for High Risk of Type 2 Diabetes in Koreans with Normal Fasting Glucose.","authors":"Min Jin Lee,Ji Hyun Bae,Ah Reum Khang,Dongwon Yi,Joo Yeon Kim,Su Hyun Kim,Dong Hee Kim,Dasol Kang,Sujin Park,Yun Kyung Jeon,Sang Soo Kim,Bo Hyun Kim,Mi Sook Yun,Yang Ho Kang","doi":"10.1210/clinem/dgae632","DOIUrl":"https://doi.org/10.1210/clinem/dgae632","url":null,"abstract":"CONTEXTWith rising the prevalence of type 2 diabetes mellitus (T2DM) and prediabetes, the importance of 1-hour post-load plasma glucose (1-h PG) for early hyperglycemia screening is emphasized.OBJECTIVEThis study investigates the utility of 1-h PG in predicting T2DM in adults with normal fasting plasma glucose (FPG) levels.METHODS7,504 participants were categorized into three groups: normal glucose tolerance (NGT) with 1-h PG < 155 mg/dL, NGT with 1-h PG ≥ 155 mg/dL, and impaired glucose tolerance (IGT). Insulin sensitivity and secretion indices were compared between groups at baseline, and T2DM incidence was analyzed using Cox proportional hazards models. The predictive abilities of 1-h PG and 2-hour post-load plasma glucose (2-h PG) were assessed with receiver operating characteristic analysis.RESULTSAt baseline, the composite insulin sensitivity index in the NGT & 1-h PG ≥ 155 mg/dL group was similarly reduced as in the IGT group (P = .076). Over a mean follow-up of 7.4 years, T2DM developed in 960 patients (12.8%). The highest risk was in the IGT group (hazard ratio [HR] 5.47), followed by the NGT & 1-h PG ≥ 155 mg/dL group (HR 2.74), compared to the NGT & 1-h PG < 155 mg/dL group. The 1-h PG level had a higher area under the curve (0.772) than other glycemic parameters, including 2-h PG.CONCLUSIONEven with normal FPG, a 1-h PG ≥ 155 mg/dL indicates lower insulin sensitivity similar to IGT and increased T2DM risk, making it a more effective early screening tool than 2-h PG.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"49 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lucas Bandeira Marchesan,Thais Rasia da Silva,Poli Mara Spritzer
CONTEXTPolycystic ovary syndrome (PCOS) is often linked with obesity, and weight management can improve endocrine and cardiometabolic features.OBJECTIVETo evaluate the effects of adding topiramate (TPM) to metformin (MTF) on weight control, hormonal and metabolic outcomes in women with PCOS.METHODSIn a randomized, double-blind, placebo-controlled trial, participants with PCOS and body mass index ≥30 kg/m² or ≥27 kg/m² associated with hypertension, type 2 diabetes, or dyslipidemia followed a 20 kcal/kg diet in addition to 850 mg of MTF or a previous MTF regimen. They were randomized to receive either TPM or placebo (P) alongside MTF. Anthropometric measurements, blood pressure, modified Ferriman-Gallwey score (mFGS), and adverse events were assessed every 4 weeks for 6 months.MAIN OUTCOME MEASURESThe primary endpoint was the percent change in body weight from baseline in both groups. Secondary endpoints included changes in clinical, cardiometabolic, and hormonal parameters and psychosocial features.RESULTSThirty-one participants were in the MTF+P group and 30 in the MTF+TPM group. The MTF+TPM group showed greater mean weight loss at 3 months (-3.4% vs. -1.6%, p=0.03) and 6 months (-4.5% vs. -1.4%, p=0.03). Both groups improved androgens, lipids, and psychosocial scores. Participants with ≥3% weight loss at 6 months improved mFGS (8.4 to 6.5, p=0.026). Paresthesia was more common in the MTF+TPM group (23.3% vs. 3.2%, p=0.026).CONCLUSIONSCombining TPM with MTF and a low-calorie diet may be an effective, low-cost, easy-to-use, and safe strategy for weight management in women with PCOS, with mild adverse effects.
{"title":"Topiramate added to metformin for obesity control in women with polycystic ovary syndrome: a randomized clinical trial.","authors":"Lucas Bandeira Marchesan,Thais Rasia da Silva,Poli Mara Spritzer","doi":"10.1210/clinem/dgae637","DOIUrl":"https://doi.org/10.1210/clinem/dgae637","url":null,"abstract":"CONTEXTPolycystic ovary syndrome (PCOS) is often linked with obesity, and weight management can improve endocrine and cardiometabolic features.OBJECTIVETo evaluate the effects of adding topiramate (TPM) to metformin (MTF) on weight control, hormonal and metabolic outcomes in women with PCOS.METHODSIn a randomized, double-blind, placebo-controlled trial, participants with PCOS and body mass index ≥30 kg/m² or ≥27 kg/m² associated with hypertension, type 2 diabetes, or dyslipidemia followed a 20 kcal/kg diet in addition to 850 mg of MTF or a previous MTF regimen. They were randomized to receive either TPM or placebo (P) alongside MTF. Anthropometric measurements, blood pressure, modified Ferriman-Gallwey score (mFGS), and adverse events were assessed every 4 weeks for 6 months.MAIN OUTCOME MEASURESThe primary endpoint was the percent change in body weight from baseline in both groups. Secondary endpoints included changes in clinical, cardiometabolic, and hormonal parameters and psychosocial features.RESULTSThirty-one participants were in the MTF+P group and 30 in the MTF+TPM group. The MTF+TPM group showed greater mean weight loss at 3 months (-3.4% vs. -1.6%, p=0.03) and 6 months (-4.5% vs. -1.4%, p=0.03). Both groups improved androgens, lipids, and psychosocial scores. Participants with ≥3% weight loss at 6 months improved mFGS (8.4 to 6.5, p=0.026). Paresthesia was more common in the MTF+TPM group (23.3% vs. 3.2%, p=0.026).CONCLUSIONSCombining TPM with MTF and a low-calorie diet may be an effective, low-cost, easy-to-use, and safe strategy for weight management in women with PCOS, with mild adverse effects.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BACKGROUNDUniversity Hospitals Dorset (UHD) has over 1,000 thyroid patient contacts annually. These are primarily patients with autoimmune hyperthyroidism treated with Carbimazole titration. Dose adjustments are made by a healthcare professional (HCP) based on the results of thyroid function tests, who then prescribes a dose and communicates this to the patient via letter. This is time-consuming and introduces treatment delays. This study aimed to replace some time-intensive manual dose adjustments with a machine learning model to determine Carbimazole dosing. This can in the future serve patients with rapid and safe dose determination and ease the pressures on HCPs.METHODSData from 421 hyperthyroidism patients at UHD were extracted and anonymised. A total of 353 patients (83.85%) were included in the study. Different machine-learning classification algorithms were tested under several data processing regimes. Using an iterative approach, consisting of an initial model selection followed by a feature selection method the performance was improved. Models were evaluated using weighted F1 scores and Brier scores to select the best model with the highest confidence.RESULTSThe best performance is achieved using a random forest (RF) approach, resulting in good average F1 scores of 0.731. A model was selected based on a balanced assessment considering the accuracy of the prediction (F1 = 0.751) and the confidence of the model (Brier score = 0.38).CONCLUSIONTo simulate a use-case, the accumulation of the prediction error over time was assessed. It was determined that an improvement in accuracy is expected if this model was to be deployed in practice.
背景多塞特郡大学医院（UHD）每年接触的甲状腺患者超过 1000 人。这些患者主要是接受卡比马唑滴定治疗的自身免疫性甲状腺功能亢进症患者。专业医护人员（HCP）根据甲状腺功能检测结果调整剂量，然后开出剂量处方，并通过信件告知患者。这种做法既耗时又会延误治疗。这项研究旨在用机器学习模型来确定卡比马唑的剂量，从而取代一些耗时的人工剂量调整。方法提取并匿名化了日内瓦大学附属医院421名甲状腺功能亢进症患者的数据。研究共纳入 353 名患者（83.85%）。在几种数据处理机制下对不同的机器学习分类算法进行了测试。采用迭代方法，包括初始模型选择和特征选择方法，提高了性能。使用加权 F1 分数和布赖尔分数对模型进行评估，以选出置信度最高的最佳模型。结果使用随机森林（RF）方法取得了最佳性能，平均 F1 分数达到 0.731。在平衡评估预测准确性（F1 = 0.751）和模型置信度（布赖尔得分 = 0.38）的基础上选出了一个模型。结果表明，如果在实践中使用该模型，准确度有望得到提高。
{"title":"Data-Driven Strategies for Carbimazole Titration: Exploring Machine Learning Solutions in Hyperthyroidism Control.","authors":"Thilo Reich,Rashid Bakirov,Dominika Budka,Derek Kelly,James Smith,Tristan Richardson,Marcin Budka","doi":"10.1210/clinem/dgae642","DOIUrl":"https://doi.org/10.1210/clinem/dgae642","url":null,"abstract":"BACKGROUNDUniversity Hospitals Dorset (UHD) has over 1,000 thyroid patient contacts annually. These are primarily patients with autoimmune hyperthyroidism treated with Carbimazole titration. Dose adjustments are made by a healthcare professional (HCP) based on the results of thyroid function tests, who then prescribes a dose and communicates this to the patient via letter. This is time-consuming and introduces treatment delays. This study aimed to replace some time-intensive manual dose adjustments with a machine learning model to determine Carbimazole dosing. This can in the future serve patients with rapid and safe dose determination and ease the pressures on HCPs.METHODSData from 421 hyperthyroidism patients at UHD were extracted and anonymised. A total of 353 patients (83.85%) were included in the study. Different machine-learning classification algorithms were tested under several data processing regimes. Using an iterative approach, consisting of an initial model selection followed by a feature selection method the performance was improved. Models were evaluated using weighted F1 scores and Brier scores to select the best model with the highest confidence.RESULTSThe best performance is achieved using a random forest (RF) approach, resulting in good average F1 scores of 0.731. A model was selected based on a balanced assessment considering the accuracy of the prediction (F1 = 0.751) and the confidence of the model (Brier score = 0.38).CONCLUSIONTo simulate a use-case, the accumulation of the prediction error over time was assessed. It was determined that an improvement in accuracy is expected if this model was to be deployed in practice.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"11-oxygenated androgens originate from the adrenals. Period! And now?","authors":"Martin Bidlingmaier,Nicole Reisch","doi":"10.1210/clinem/dgae638","DOIUrl":"https://doi.org/10.1210/clinem/dgae638","url":null,"abstract":"","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"189 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
INTRODUCTIONObservational study suggested SGLT2 inhibitors might promote healthy aging. However, whether brain-related phenotypes mediate this association. We applied Mendelian randomization (MR) to investigate the effect of SGLT2 inhibition on chronological, biological age and cognition and explore the mediation effects of brain imaging-derived phenotypes (IDPs).METHODSWe selected genetic variants associated with both expression levels of SLC5A2 (GTEx and eQTLGen data; N=129 to 31,684) and HbA1c levels (UK Biobank; N=344,182) and used them to proxy the effect of SGLT2 inhibition. Aging related outcomes, including parental longevity (N=389,166) and epigenetic clocks (N=34,710), and cognitive phenotypes, including cognitive function (N=300,486) and intelligence (N= 269,867) were derived from genome-wide association studies. Two-step MR were conducted to explore the associations between SGLT2 inhibition, IDPs, and aging outcomes, cognition.RESULTSSGLT2 inhibition was associated with longer father's attained age (years of life increase per SD (6.75 mmol/mol) reduction in HbA1c levels = 6.21, 95%CI 1.95 to 11.15), better cognitive function (beta = 0.17, 95%CI 0.03 to 0.31) and higher intelligence (beta = 0.47, 95%CI 0.19 to 0.75). Two-step MR identified two IDPs as mediators linking SGLT2 inhibition with chronological age (total proportion of mediation = 22.6%), where four and five IDPs were mediators for SGLT2 inhibition on cognitive function and intelligence respectively (total proportion of mediation = 61.6% and 68.6% respectively).CONCLUSIONSOur study supported that SGLT2 inhibition increases father's attained age, cognitive function and intelligence, which was mediated through brain images of different brain regions. Future studies are needed to investigate whether similar effect could be observed for users of SGLT2 inhibitors.
{"title":"The effect of SGLT2 inhibition on brain-related phenotypes and aging: a drug target Mendelian randomization study.","authors":"Zhihe Chen,Xueyan Wu,Qianqian Yang,Huiling Zhao,Hui Ying,Haoyu Liu,Chaoyue Wang,Ruizhi Zheng,Hong Lin,Shuangyuan Wang,Mian Li,Tiange Wang,Zhiyun Zhao,Min Xu,Yuhong Chen,Yu Xu,Jieli Lu,Guang Ning,Weiqing Wang,Shan Luo,Shiu Lun Au Yeung,Yufang Bi,Jie Zheng","doi":"10.1210/clinem/dgae635","DOIUrl":"https://doi.org/10.1210/clinem/dgae635","url":null,"abstract":"INTRODUCTIONObservational study suggested SGLT2 inhibitors might promote healthy aging. However, whether brain-related phenotypes mediate this association. We applied Mendelian randomization (MR) to investigate the effect of SGLT2 inhibition on chronological, biological age and cognition and explore the mediation effects of brain imaging-derived phenotypes (IDPs).METHODSWe selected genetic variants associated with both expression levels of SLC5A2 (GTEx and eQTLGen data; N=129 to 31,684) and HbA1c levels (UK Biobank; N=344,182) and used them to proxy the effect of SGLT2 inhibition. Aging related outcomes, including parental longevity (N=389,166) and epigenetic clocks (N=34,710), and cognitive phenotypes, including cognitive function (N=300,486) and intelligence (N= 269,867) were derived from genome-wide association studies. Two-step MR were conducted to explore the associations between SGLT2 inhibition, IDPs, and aging outcomes, cognition.RESULTSSGLT2 inhibition was associated with longer father's attained age (years of life increase per SD (6.75 mmol/mol) reduction in HbA1c levels = 6.21, 95%CI 1.95 to 11.15), better cognitive function (beta = 0.17, 95%CI 0.03 to 0.31) and higher intelligence (beta = 0.47, 95%CI 0.19 to 0.75). Two-step MR identified two IDPs as mediators linking SGLT2 inhibition with chronological age (total proportion of mediation = 22.6%), where four and five IDPs were mediators for SGLT2 inhibition on cognitive function and intelligence respectively (total proportion of mediation = 61.6% and 68.6% respectively).CONCLUSIONSOur study supported that SGLT2 inhibition increases father's attained age, cognitive function and intelligence, which was mediated through brain images of different brain regions. Future studies are needed to investigate whether similar effect could be observed for users of SGLT2 inhibitors.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CONTEXTSomapacitan, a once-weekly reversible albumin-binding GH derivative, is evaluated in short children born small for gestational age (SGA).OBJECTIVEEvaluate efficacy, safety, tolerability as well as total and bioactive insulin-like growth factor-I (IGF-I) response of once-weekly somapacitan compared to daily GH in children born SGA.METHODSREAL5 is a randomized, multi-center, open-label, controlled phase 2 study comprising a 26-week main phase, 26-week extension, and an ongoing 4-year safety extension (NCT03878446).SETTINGThirty-eight sites across 12 countries.PATIENTSSixty-two GH-treatment-naïve, prepubertal short children born SGA were randomized; 61 completed 52-weeks of treatment.INTERVENTIONSPatients randomized (1:1:1:1:1) to somapacitan (0.16, 0.20 or 0.24 mg/kg/week) or daily GH (0.035 or 0.067 mg/kg/day), all administered subcutaneously.RESULTSEstimated mean height velocity (HV; cm/year) at week 52 was 8.5, 10.4 and 10.7 cm/year for somapacitan 0.16, 0.20 and 0.24 mg/kg/week, respectively, and 9.3 and 11.2 cm/year for daily GH 0.035 and 0.067 mg/kg/day, respectively. Dose-dependent increases in total IGF-I as well as peak IGF-I bioactivity were observed for both treatments and were similar between comparator groups. For somapacitan, exposure-response modelling indicated highest efficacy with 0.24 mg/kg/week after 52 weeks of treatment. Similar safety and tolerability were demonstrated across all groups.CONCLUSIONSA sustained dose-dependent growth response was demonstrated for somapacitan after 52 weeks of treatment. Overall, somapacitan 0.24 mg/kg/week provides similar efficacy, safety, and tolerability, as well as comparable bioactive and total IGF-I response, as daily GH (0.067 mg/kg/day) in children born SGA.
{"title":"Somapacitan in Children Born SGA: 52-week Efficacy, Safety, and IGF-I Response Results from the Phase 2 REAL5 Study.","authors":"Anders Juul,Philippe Backeljauw,Michael Højby,Jan Frystyk,Masanobu Kawai,Rasmus Juul Kildemoes,Anders Krogh Lemminger,Agnès Linglart,Nehama Zuckerman-Levin,Reiko Horikawa","doi":"10.1210/clinem/dgae616","DOIUrl":"https://doi.org/10.1210/clinem/dgae616","url":null,"abstract":"CONTEXTSomapacitan, a once-weekly reversible albumin-binding GH derivative, is evaluated in short children born small for gestational age (SGA).OBJECTIVEEvaluate efficacy, safety, tolerability as well as total and bioactive insulin-like growth factor-I (IGF-I) response of once-weekly somapacitan compared to daily GH in children born SGA.METHODSREAL5 is a randomized, multi-center, open-label, controlled phase 2 study comprising a 26-week main phase, 26-week extension, and an ongoing 4-year safety extension (NCT03878446).SETTINGThirty-eight sites across 12 countries.PATIENTSSixty-two GH-treatment-naïve, prepubertal short children born SGA were randomized; 61 completed 52-weeks of treatment.INTERVENTIONSPatients randomized (1:1:1:1:1) to somapacitan (0.16, 0.20 or 0.24 mg/kg/week) or daily GH (0.035 or 0.067 mg/kg/day), all administered subcutaneously.RESULTSEstimated mean height velocity (HV; cm/year) at week 52 was 8.5, 10.4 and 10.7 cm/year for somapacitan 0.16, 0.20 and 0.24 mg/kg/week, respectively, and 9.3 and 11.2 cm/year for daily GH 0.035 and 0.067 mg/kg/day, respectively. Dose-dependent increases in total IGF-I as well as peak IGF-I bioactivity were observed for both treatments and were similar between comparator groups. For somapacitan, exposure-response modelling indicated highest efficacy with 0.24 mg/kg/week after 52 weeks of treatment. Similar safety and tolerability were demonstrated across all groups.CONCLUSIONSA sustained dose-dependent growth response was demonstrated for somapacitan after 52 weeks of treatment. Overall, somapacitan 0.24 mg/kg/week provides similar efficacy, safety, and tolerability, as well as comparable bioactive and total IGF-I response, as daily GH (0.067 mg/kg/day) in children born SGA.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lulian Xu,Zhenzhen Liu,Xu Xu,Qiwen Wan,Juanying Zhen,Li Jiang,Bernard Man Yung Cheung,Chao Li
CONTEXTDietary factors are crucial in the onset and development of autoimmune thyroid disease (AITD), but the relationship between specific fatty acids and AITD remains unexplored.METHODSWe analyzed the US National Health and Nutrition Examination Survey (NHANES) 2007-2012 data on 3949 men and 3964 women aged 20 years and over with valid data on TPOAb, TgAb and details of fat intake, using multivariable regression models to examine the relationship of fat intake and specific fatty acid intake with thyroid autoimmunity.RESULTSOf the 7913 participants, 7.5% had TgAb seropositivity and 11.9% had TPOAb seropositivity. The seropositivity of TgAb and TPOAb was more common in low-fat intake participants. In the overall population and men, fats were associated with thyroid autoimmunity before and after full adjustment for age, ethnicity, body mass index, smoking status and urine iodine concentration (total fat: OR=0.64, 95% CI 0.49 to 0.83; SFA: OR=0.65, 95% CI 0.51 to 0.84; MUFA: OR=0.65, 95% CI 0.50 to 0.85; PUFA: OR=0.76, 95% CI 0.57 to 0.995, after full adjustment in men). Some specific fatty acids followed a similar pattern. The association between fats and TgAb seropositivity was significant in the overall population and men. The association between fats and TPOAb seropositivity was only found in the overall population.CONCLUSIONWe found a strong association between fat consumption and thyroid autoimmunity in the overall population and men from the nationally representative population-based survey. Fat and fatty acid consumption may be of benefit to individuals with thyroid autoimmunity.
{"title":"Thyroid autoimmunity is associated with dietary fat consumption.","authors":"Lulian Xu,Zhenzhen Liu,Xu Xu,Qiwen Wan,Juanying Zhen,Li Jiang,Bernard Man Yung Cheung,Chao Li","doi":"10.1210/clinem/dgae629","DOIUrl":"https://doi.org/10.1210/clinem/dgae629","url":null,"abstract":"CONTEXTDietary factors are crucial in the onset and development of autoimmune thyroid disease (AITD), but the relationship between specific fatty acids and AITD remains unexplored.METHODSWe analyzed the US National Health and Nutrition Examination Survey (NHANES) 2007-2012 data on 3949 men and 3964 women aged 20 years and over with valid data on TPOAb, TgAb and details of fat intake, using multivariable regression models to examine the relationship of fat intake and specific fatty acid intake with thyroid autoimmunity.RESULTSOf the 7913 participants, 7.5% had TgAb seropositivity and 11.9% had TPOAb seropositivity. The seropositivity of TgAb and TPOAb was more common in low-fat intake participants. In the overall population and men, fats were associated with thyroid autoimmunity before and after full adjustment for age, ethnicity, body mass index, smoking status and urine iodine concentration (total fat: OR=0.64, 95% CI 0.49 to 0.83; SFA: OR=0.65, 95% CI 0.51 to 0.84; MUFA: OR=0.65, 95% CI 0.50 to 0.85; PUFA: OR=0.76, 95% CI 0.57 to 0.995, after full adjustment in men). Some specific fatty acids followed a similar pattern. The association between fats and TgAb seropositivity was significant in the overall population and men. The association between fats and TPOAb seropositivity was only found in the overall population.CONCLUSIONWe found a strong association between fat consumption and thyroid autoimmunity in the overall population and men from the nationally representative population-based survey. Fat and fatty acid consumption may be of benefit to individuals with thyroid autoimmunity.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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