The Journal of clinical endocrinology and metabolism最新文献

{"title":"Genetic Risk and Transition through Preclinical Stages of Type 1 Diabetes.","authors":"Andrea K Steck, Hemang M Parikh, Taylor M Triolo, Lauric Ferrat, Lu You, Peter A Gottlieb, Richard A Oram, Suna Onengut-Gumuscu, Jeffrey P Krischer, Stephen S Rich, Maria J Redondo","doi":"10.1210/clinem/dgaf392","DOIUrl":"https://doi.org/10.1210/clinem/dgaf392","url":null,"abstract":"<p><strong>Objective: </strong>Our aim was to study the influence of type 1 diabetes (T1D) genetic risk factors on the transition through preclinical stages of T1D.</p><p><strong>Methods: </strong>In TrialNet participants who have been genotyped with the TEDDY-T1DExomeChip array (Illumina HumanCoreExome Beadarray with custom content), we evaluated the influence of the overall T1D genetic risk score (GRS2), its HLA and non-HLA components, HLA-DR3 and HLA-DR4 haplotypes and 90 single nucleotide polymorphisms previously associated with islet autoimmunity and/or T1D on three transitions between diabetes stages: from single confirmed autoantibody positive to stage 1 (N=4,314), from stage 1 to stage 2 (N=3,066), and from stage 2 to stage 3 (clinical) T1D (N=2,045).</p><p><strong>Results: </strong>The T1D GRS2 was associated with all three transitions with hazard ratios(HR) of 1.11(1.09-1.14) for single autoantibody positivity to stage 1, HR 1.05(1.03-1.08) for stage 1 to 2, and HR 1.13(1.09-1.17) for stage 2 to 3 T1D. The T1D GRS2 HLA and HLA class II components were associated with all three transitions. The HLA class I component and the HLA-DR4 haplotype were associated with the transition from single autoantibody positivity to stage 1 and from stage 2 to stage 3 T1D, while HLA-DR3 was only associated with the latter.</p><p><strong>Conclusions: </strong>Genetics influence transitions through each stage of preclinical T1D, with main contributions from HLA class II. These results increase our understanding of T1D development and support incorporating the T1D GRS2 to enhance the prediction of progression through the preclinical stages of T1D.</p>","PeriodicalId":520805,"journal":{"name":"The Journal of clinical endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144602833","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":"Near-adult height outcomes in patients treated with rhIGF-1 for severe growth failure: real-world IGFD Registry data.","authors":"Marta Ramon-Krauel, Michel Polak, Mohamad Maghnie, Joachim Woelfle, Caroline Sert, Valérie Perrot, Peter Bang","doi":"10.1210/clinem/dgaf390","DOIUrl":"https://doi.org/10.1210/clinem/dgaf390","url":null,"abstract":"<p><strong>Context: </strong>The Global Increlex® Growth Forum Database (IGFD) Registry monitors real-world effectiveness and safety of recombinant human insulin-like growth factor (rhIGF-1; Increlex® [mecasermin]) treatment in children and adolescents with severe growth failure due to severe primary insulin-like growth factor-I deficiency (SPIGFD).</p><p><strong>Objective: </strong>To report characteristics, effectiveness, and safety data from patients receiving rhIGF-1 treatment who achieved near-adult height (NAH), and determine factors that predict height gain to NAH.</p><p><strong>Methods: </strong>Descriptive analyses of patients included in the Global IGFD Registry (NCT00903110) who achieved NAH are reported for the overall population, treatment-naïve prepubertal (NPP) patients, and patients with Laron syndrome. Linear regression analyses of height gain to NAH are also reported.</p><p><strong>Results: </strong>102 patients enrolled in the Global IGFD Registry achieved NAH at data cut-off (April 20, 2023). Mean age at rhIGF-1 treatment initiation was 11.8 years; median treatment duration was 3.9 years. Mean (SD) height standard deviation score (HtSDS) gain from rhIGF-1 initiation to NAH was 0.9(1.1). In NPP patients, mean (SD) HtSDS gain was 1.4(1.0). Almost half of NPP patients reached NAH within the normal range. Despite improved height in patients with Laron syndrome, only 10.5% reached NAH within the normal range; three patients with Laron syndrome were NPP. Treatment naivety was predictive of height gain in the overall NAH population. Safety data aligned with previous reports.</p><p><strong>Conclusions: </strong>In a real-world setting, despite patients with SPIGFD initiating rhIGF-1 treatment at a relatively advanced age, rhIGF-1 treatment resulted in improved NAH. Greatest improvements in height outcomes were observed in NPP patients.</p>","PeriodicalId":520805,"journal":{"name":"The Journal of clinical endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144586188","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":"FKBP5 Methylation in Adrenal Insufficiency: New Insights into Assessing the Quality of Glucocorticoid Replacement.","authors":"Irina Chifu, Anna-Lena Richter, Juliane Lippert, Mario Detomas, Carolin Scheuermann, Sabine Herterich, Birgit Harbeck, Janik Freytag, Barbara Altieri, Stefanie Hahner","doi":"10.1210/clinem/dgaf383","DOIUrl":"https://doi.org/10.1210/clinem/dgaf383","url":null,"abstract":"<p><strong>Context: </strong>Methylation of FKBP5, a glucocorticoid(GC)-receptor co-chaperone, negatively correlates with cortisol levels in both healthy individuals and Cushing patients, potentially serving as an indicator of GC exposure.</p><p><strong>Objective: </strong>We explored whether GC replacement correlates with FKBP5 methylation in patients with adrenal insufficiency (AI), aiming to assess the adequacy of therapy.</p><p><strong>Design: </strong>Explorative cross-sectional analysis.</p><p><strong>Methods: </strong>We analysed FKBP5 gene methylation at 54 CpG sites using bisulfite pyrosequencing in 120 patients with chronic primary (n=72) and secondary (n=48) AI on hydrocortisone replacement. Results were correlated with GC replacement, salivary cortisol, 24-hour urinary cortisol, FKBP5 polymorphisms, physician-guided therapy adjustments, and a predefined clinical score for assessment of GC exposure. Methylation levels were further compared with patients with cortisol-producing adrenal adenomas (CPA, n=64).Results: Significant negative correlations were found between methylation levels and GC dose, clinical GC-replacement score, salivary and urinary cortisol levels. Patients advised to increase their GC dose showed higher methylation levels than those recommended to reduce or maintain their dose. AI patients exhibited similar or lower methylation levels compared to those with CPA.</p><p><strong>Conclusions: </strong>The correlation between FKBP5 methylation status, GC replacement dose, and clinical evaluation of therapy suggests a dose-dependent effect of GC replacement on FKBP5 methylation. This encourages further research into the added value of FKBP5 methylation analysis in assessing the quality of replacement therapy. The lower methylation levels in AI compared to CPA suggest a potential impact of the cortisol peaks arising under conventional GC treatment on FKBP5-methylation.</p>","PeriodicalId":520805,"journal":{"name":"The Journal of clinical endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144562665","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":"Approach to the patient with a difference of sexual development.","authors":"Hannes Syryn, Elfride De Baere, Martine Cools","doi":"10.1210/clinem/dgaf386","DOIUrl":"https://doi.org/10.1210/clinem/dgaf386","url":null,"abstract":"<p><p>Available pre- and postnatal tests for obtaining a molecular genetic diagnosis for differences of sexual development (DSD) have largely expanded over the last decade. More importantly, the medical management of these conditions has taken a different approach, with greater emphasis on patient autonomy, holistic care, and psychosocial support. These changes are illustrated through the discussion of two cases with a common form of DSD. While the principles and recommendations for the diagnosis and medical management of DSD are universal in nature, they need to be translated into clinical care pathways that align with the specific sociocultural background of patients and their caregivers to ensure the best possible outcome. Considering the inherent global differences in the organisation and accessibility of healthcare and available resources, this requires an individualised approach based on shared decision-making and clinical guidelines that are in line with local facilities and societal context.</p>","PeriodicalId":520805,"journal":{"name":"The Journal of clinical endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144556566","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":"Correction to: \"Medullary Thyroid Cancer: Single Institute Experience Over 3 Decades and Risk Factors for Recurrence\".","authors":"","doi":"10.1210/clinem/dgaf380","DOIUrl":"https://doi.org/10.1210/clinem/dgaf380","url":null,"abstract":"","PeriodicalId":520805,"journal":{"name":"The Journal of clinical endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144562664","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":"Effects of Acute Iso- and Hypocaloric Carbohydrate Restriction on Liver Fat and Glucose and Lipid Metabolism.","authors":"Amalie London, Amanda Schaufuss, Michal Považan, Marie-Louise Dichman, Jasmin Merhout, Carsten Dirksen, Sten Madsbad, Hartwig Roman Siebner, Annemarie Lundsgaard, Andreas Mæchel Fritzen, Bente Kiens, Kirstine Nyvold Bojsen-Møller","doi":"10.1210/clinem/dgaf382","DOIUrl":"https://doi.org/10.1210/clinem/dgaf382","url":null,"abstract":"<p><strong>Context: </strong>Liver fat is reduced within days after a low-carbohydrate diet substituted with fat to maintain isocaloric conditions.</p><p><strong>Objective: </strong>Investigate the effect of matched carbohydrate restriction during isocaloric and hypocaloric conditions on liver fat and postprandial glucose and lipid metabolism.</p><p><strong>Design: </strong>Cross-over randomized clinical trial.</p><p><strong>Setting: </strong>Research unit.</p><p><strong>Participants: </strong>15 participants with overweight/obesity (BMI 32.5 [31-34] kg/m2, median [IQR]).</p><p><strong>Intervention: </strong>Three dietary interventions; 1) two days of isocaloric control diet (CON), 2) two days of CON followed by two days of carbohydrate-restriction (∼60 g/day) during very-low calorie conditions (VLCD), and 3) two days of CON followed by two days of isocaloric conditions with low carbohydrate (∼60 g/day), high-fat (LCHF) diet.</p><p><strong>Main outcome measure: </strong>Liver fat measured using 1H-magnetic resonance spectroscopy.</p><p><strong>Results: </strong>Liver fat was -16% [-34;4] (median [IQR]) after LCHF relative to after CON (p=0.020), but did not differ between VLCD and CON. Fasting plasma concentrations of triacylglycerol, glucose, and insulin were lower after both LCHF and VLCD compared with after CON. However, postprandial plasma glucose concentrations were higher and insulinogenic index lower after both LCHF and VLCD.</p><p><strong>Conclusion: </strong>Two days of LCHF led to lower liver fat, which was not observed after VLCD. This demonstrates the dynamic regulation of liver fat and the beneficial role of substituting carbohydrates with fat to maintain energy provision. Both LCHF and VLCD had positive effects on fasting parameters for glucose metabolism, however, both diets impaired early beta-cell response resulting in deterioration in glucose handling during the meal test.</p>","PeriodicalId":520805,"journal":{"name":"The Journal of clinical endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144556567","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":"Identification of a Novel Compound Heterozygous Variant in the ALPL Gene Linked to Hypophosphatasia in a Chinese Family.","authors":"Rongmei Lu, Chuhui Chen, Zhen Yu, Qinyu Liu, Junping Wen, Gang Chen","doi":"10.1210/clinem/dgaf381","DOIUrl":"https://doi.org/10.1210/clinem/dgaf381","url":null,"abstract":"<p><strong>Context: </strong>Hypophosphatasia (HPP) is a rare inherited metabolic disorder caused by loss-of-function variant(s) of the ALPL gene, which encodes tissue-nonspecific alkaline phosphatase (TNSALP).</p><p><strong>Objective: </strong>To enrich the genetic spectrum of HPP and establish a genetic basis for the diagnosis and treatment of the proband.</p><p><strong>Methods: </strong>A detailed medical history and systematic clinical evaluation were conducted for the proband. Variants in genes relevant to the proband's clinical phenotype were identified through whole-exome sequencing and confirmed by Sanger sequencing. The effect of ALPL gene variants on TNSALP function and their dominant negative effect (DNE) was assessed by transient transfection of recombinant plasmids into HEK293T cells, followed by an analysis of enzyme specific activity (ESA).</p><p><strong>Results: </strong>Two missense variants, c.269A > G and c.787T > C, and one intronic variant, c.182-9C > T, were identified in the ALPL gene of the proband. ESA assays revealed that c.269A > G and c.182-9C > T exhibited reduced alkaline phosphatase (ALP) activity, whereas no significant change was observed for c.787T > C. Co-transfection experiments with wild-type and mutant (c.269A > G or c.182-9C > T) TNSALP revealed that both c.269A > G and c.182-9C > T have DNE.</p><p><strong>Conclusion: </strong>The compound heterozygous variant comprised of c.269A > G and c.182-9C > T in the ALPL gene may contribute to decreased ALP activity and the disease phenotype of the proband. Moreover, an experienced multidisciplinary team needs to monitor the effect of DNE on carriers and track the relevant clinical symptoms emerging at a later stage.</p>","PeriodicalId":520805,"journal":{"name":"The Journal of clinical endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144546876","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":"Letter to the Editor from Hasebe and Su: \"Adrenalectomy Reduces the Risk of Vertebral Fractures in Patients With Mild Autonomous Cortisol Secretion\".","authors":"Masashi Hasebe, Chen-Yang Su","doi":"10.1210/clinem/dgaf384","DOIUrl":"https://doi.org/10.1210/clinem/dgaf384","url":null,"abstract":"","PeriodicalId":520805,"journal":{"name":"The Journal of clinical endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144556568","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":"Response to Letter to the Editor from Hasebe and Su: \"Adrenalectomy Reduces the Risk of Vertebral Fractures in Patients With Mild Autonomous Cortisol Secretion\".","authors":"Vittoria Favero, Iacopo Chiodini","doi":"10.1210/clinem/dgaf385","DOIUrl":"https://doi.org/10.1210/clinem/dgaf385","url":null,"abstract":"","PeriodicalId":520805,"journal":{"name":"The Journal of clinical endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144556569","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":"Cord Blood DNA Methylation at CHD13 is Associated with Adiponectin Levels at 10-14 years of Age.","authors":"Monica E Bianco, Miranda G Gurra, Denise Scholtens, Marie-France Hivert, William L Lowe, Jami L Josefson","doi":"10.1210/clinem/dgaf369","DOIUrl":"https://doi.org/10.1210/clinem/dgaf369","url":null,"abstract":"<p><strong>Background: </strong>Low adiponectin levels are associated with higher insulin resistance, development of type 2 diabetes, and greater adiposity in adults, but the evidence in youth is limited. This study aimed to assess adiponectin as a biomarker of adverse metabolic health in youth and to examine whether cord blood DNA methylation (cbDNAm) is associated with child adiponectin levels.</p><p><strong>Methods: </strong>Participants from the Hyperglycemia and Adverse Pregnancy Outcome Study and Follow-up Study were included based on availability of cbDNAm, child anthropometry, child adiponectin levels, and glucose OGTT measures (N=2,265) collected at mean age 11.4 ± 1.2 years. Cross-sectional associations between child log-transformed adiponectin and child adiposity and glycemic measures were evaluated via partial correlation. Linear regression models were used for epigenome-wide analysis of cbDNAm and child adiponectin levels.</p><p><strong>Results: </strong>After adjustment for co-variates, lower child adiponectin levels were correlated with higher adiposity/dysglycemia outcomes (sum of skinfolds, r= -0.285 and glucose sum of z-scores, r= -0.070) as well as lower Matsuda (r= 0.135) and disposition (r= 0.062) indices. Linear regression was used to assess associations between cbDNAm and child adiponectin levels with covariate adjustments. cbDNAm at cg02713721, located in the CDH13 locus, was associated with child adiponectin levels (β = 0.35, Bonferroni-adjusted p=0.01).</p><p><strong>Conclusion: </strong>This study provides evidence of adiponectin as a biomarker of adverse metabolic health in youth. The association of methylation in CDH13, a gene involved in glucose regulation, with child adiponectin levels suggests a contribution to programming of future metabolic health.</p>","PeriodicalId":520805,"journal":{"name":"The Journal of clinical endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532926","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}