Journal of the Endocrine Society最新文献

Context: The aim of this study was to characterize the molecular genetics of 1α-hydroxylase deficiency in the highly consanguineous population of Saudi Arabia, hypothesizing that the results will show a unique CYP27B1 genotype.

Methods: We collected data on a large cohort of patients diagnosed with 1α-hydroxylase deficiency from different parts of the country. These patients underwent molecular testing for CYP27B1 mutations.

Results: A cohort of 45 patients from 29 unrelated families was studied. In 13 families (29 patients), more than one affected sibling was included (2-4 siblings) while the other 16 families had only a single patient per family. The patients included 24 females and 21 males with median age at time of presentation of 1 year and a current median age of 10 years. The clinical, biochemical and radiological profile was typical of 1α-hydroxylase deficiency. Molecular testing showed 10 mutations of different types in the 29 families. Four mutations were novel (p.(Trp257LeufsTer76), p.(Glu101Gln), p.(Gly398Ser), and p.(Arg206Cys)) while the other 6 mutations were previously described (p.(arg429Pro), p.(Phe443Profs*24), p.(Gln135Ter), p. (Gly102Glu), p.(Gln504Ter), and c.589 + 1G > A). Two of the previously reported mutations were from Saudi patients and have never been reported from other populations, increasing the number of novel/previously novel mutations to 6 of 10 mutations (60%). The most common mutation was c.1286G > C, p.(Arg429Pro) occurring in 22 patients from 15 unrelated families (51.7%).

Conclusion: The molecular genetics of 1α-hydroxylase deficiency in Saudi Arabia is unique with several novel mutations of different types and a possible founder mutation.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are effective medications for type 2 diabetes (T2D), chronic kidney disease, and chronic heart failure regardless of diabetic status. However, concerns remain about their potential to reduce skeletal muscle mass. This study clearly demonstrates that tofogliflozin (Tofo), an SGLT2 inhibitor, improves skeletal muscle mitochondrial function, morphology, and performance in a mouse model of T2D with dexamethasone (Dex)-induced muscle atrophy. Obese diabetic KK-A^y mice and nondiabetic KK mice were used. Muscle atrophy was induced in the KK-A^y mice by intraperitoneal Dex injections for 2 weeks, followed by Tofo administration (0.015%) in the diet for 2 weeks. Tofo treatment enhanced exercise endurance, restored mitochondrial morphology, increased succinate dehydrogenase activity, and elevated protein expression of optic atrophy 1 and dynamin-related protein 1. These changes were associated with AMPK (adenosine monophosphate-activated protein kinase) activation and reduced expression of the mitokine growth differentiation factor-15. Although Tofo increased muscle cross-sectional area, it did not significantly affect overall body or muscle mass, nor grip strength, suggesting a preferential effect on slow-twitch oxidative fibers. Importantly, these benefits occurred without weight loss, likely due to maintained or increased food intake. These findings suggest that Tofo specifically ameliorates mitochondrial dysfunction and improves muscle quality and endurance in diabetic sarcopenia, especially under preserved nutritional conditions. Because Tofo is a highly selective SGLT2 inhibitor with distinct pharmacokinetic properties, these results are specific to Tofo and should not be generalized to all SGLT2 inhibitors. Further studies are warranted to determine whether similar effects are observed with other agents in this class.

Objectives: To demonstrate therapeutic equivalence of the proposed denosumab biosimilar FKS518 to the originator denosumab (US-licensed Prolia®, reference product), a potent antiresorptive biologic that increases bone mineral density (BMD) and reduces the risk of fractures, in women with postmenopausal osteoporosis.

Methods: This 78-week double-blind, controlled, randomized, multicenter, multiple-dose, 2-arm, parallel-group study compared the efficacy (BMD), pharmacodynamic (bone biomarkers), safety, tolerability, and immunogenicity profiles of FKS518 with those of reference denosumab in women with postmenopausal osteoporosis. Primary-percentage change from baseline to 52 weeks in lumbar spine BMD and area under the effect curve from baseline to week 26 of serum C-terminal cross-linking telopeptide of type 1 collagen-and secondary results from the 52-week core treatment period are reported here.

Results: Postmenopausal women with osteoporosis were randomized to receive 60 mg of FKS518 (n = 277) or reference denosumab (n = 276) every 26 weeks. Demographics, baseline characteristics and medical history were similar between treatment groups. Therapeutic equivalence of FKS518 and reference denosumab was demonstrated for efficacy and pharmacodynamic characteristics. All sensitivity analyses, supportive estimands, secondary efficacy, and pharmacodynamic endpoint analyses consistently showed similarity between the 2 products. Safety outcomes were consistent with the known safety profile of denosumab and were comparable between FKS518 and reference denosumab. Immunogenicity was infrequently observed and similar between the FKS518 and the reference denosumab groups.

Conclusion: This study demonstrated therapeutic equivalence of, and comparable pharmacokinetics, safety, and immunogenicity profiles between FKS518 and reference denosumab, completing the clinical evidence to propose FKS518 as a biosimilar to denosumab.

Objective: To investigate whether prolonged embryo culture increases the risk of gestational diabetes mellitus (GDM) in pregnancies conceived via frozen embryo transfer (FET).

Research design and methods: In this retrospective cohort study, 26 100 FET pregnancies from 2018 to 2022 were analyzed. GDM was diagnosed by a 75-g oral glucose tolerance test. Embryo culture duration (day 3 vs day 5 vs day 6) and morphology were evaluated. Multivariable logistic regression adjusted for maternal age, body mass index, and fasting glucose. Interaction analyses assessed the combined effect of blastocyst transfer and maternal metabolic risk factors.

Results: GDM occurred in 14.0% of pregnancies. Blastocyst-stage transfers were associated with a significantly higher GDM risk than cleavage-stage transfers (day 3: 15.1%; day 5: 17.4%; day 6: 18.2%; P = .01). Prolonged embryo culture remained an independent risk factor in adjusted models (odds ratio, 1.045; 95% CI, 1.019-1.071; P < .01). Embryo morphology showed no significant association with GDM. The combination of blastocyst transfer and maternal metabolic risk factors further increased GDM incidence.

Conclusion: Prolonged embryo culture is an independent risk factor for GDM after FET. These findings suggest embryo development stage influences maternal glucose metabolism and should be considered in assisted reproductive technology protocols, particularly for women with existing metabolic vulnerabilities.

Objective: We examined estimated glomerular filtration rate (eGFR) in relation to cardiometabolic and glucoregulatory factors and prediabetes risk in healthy subjects.

Methods: Participants were normoglycemic Black and White offspring of parents with type 2 diabetes followed for 5 years in the Pathobiology of Prediabetes in a Biracial Cohort study. Baseline assessments included clinical examination, oral glucose tolerance test, blood chemistries, insulin sensitivity (Si-clamp), insulin secretion, and eGFR (derived from the CKD-EPI equation). We analyzed baseline eGFR in relation to metabolic syndrome (MetS), glucoregulatory function, and prediabetes risk using linear regression and Cox proportional hazards models.

Results: The participants (n = 296; 73% female; 138 Black, 158 White) were aged 45.5 ± 10.1 years; body mass index (BMI) was 30.5 ± 7.6 kg/m², and eGFR was 103 ± 18.7 mL/min. Baseline eGFR increased with cumulative MetS components (ANOVA P = .0002) and correlated significantly with waist circumference (r = 0.39, P < .0001), high-density lipoprotein cholesterol (r = -0.38, P < .0001), Si-clamp (r = -0.22; P = .003), and insulin secretion (r = 0.22; P = .0003). Higher baseline eGFR predicted lower risk of incident prediabetes: hazard ratio 0.986 (95% confidence interval 0.975-0.997, P = .012), adjusted for age, sex, ethnicity, BMI, waist circumference, glucose, insulin sensitivity, insulin secretion, and albuminuria.

Conclusion: eGFR variations within the normal range signify cardiometabolic risk status, glucoregulatory function, and incident prediabetes risk among normoglycemic persons. Further studies are needed to determine the mechanisms linking kidney function and early dysglycemia.

Animals rely on linear growth to attain their full adult size. The regulators of this multifactorial process, including environmental and endocrine cues, are still incompletely understood. Notably, GLP-1, glucagon-like peptide 1 (GLP-1) has emerged as a potential player in this process. Here, we employ semaglutide, a pharmaceutical GLP-1R agonist as a tool to mechanistically dissect the interplay between GLP-1 receptor activation, energy metabolism, and linear growth during the juvenile period, independent of its clinical applications. Using a juvenile mouse model, we show that chronic semaglutide treatment lowers blood glucose without affecting food intake or weight gain in juveniles with a normal growth pattern. However, in growth-stunted juveniles, semaglutide treatment exacerbates linear growth impairment through at least 2 concomitant mechanisms: a moderate reduction in food intake, and a decreased catabolic activity incompatible with tissue growth. These data suggest a complex interplay between GLP-1 signaling, energy metabolism, and growth during juvenile development. Overall, these findings highlight the value of semaglutide as a mechanistic tool for understanding how GLP-1 receptor activation modulates growth and metabolism in juveniles, emphasizing the importance of developmental context for interpreting its effects.

Context: Hypogonadism is a common endocrine disorder in aging men, associated with adverse cardiometabolic outcomes. Concerns about the cardiovascular (CV) safety of testosterone, an important therapy option for the condition, may be disproportionately influencing treatment decisions.

Objective: This work aimed to investigate the association between long-term testosterone therapy and major adverse CV events (MACE) in men aged 51 years and older.

Methods: This retrospective cohort study used linked health data from the National Health Service Greater Glasgow and Clyde population, accessed via the West of Scotland Safe Haven. Men aged 51 years and older as of January 1, 2012, were included. Testosterone exposure was defined as having at least a 2-year interval between the first and last prescription during a 5-year exposure window (2012-2016). Individuals were followed from January 1, 2017, to December 31, 2022. The primary outcome was time to first MACE, defined as a composite of acute myocardial infarction, unstable angina, stroke, heart failure, or CV death. Cox proportional hazards models were used to estimate associations, adjusting for age, ethnicity, socioeconomic deprivation, and comorbidities.

Results: The study included 440 testosterone-exposed and 136 051 unexposed men. Testosterone exposure was associated with a 54% increased risk of MACE in the unadjusted analysis (hazard ratio [HR]: 1.54; 95% CI, 1.18-2.00), and a 55% increased risk after adjustment (HR: 1.55; 95% CI, 1.19-2.01).

Conclusion: In this real-world cohort, long-term testosterone therapy was associated with increased CV risk. While recent trials inform short- to medium-term CV safety, this study underscores the need for more longer-term data to fully ascertain the effect of testosterone therapy.

Context: Children with diabetes mellitus (DM) have an increased risk for cardiovascular disease (CVD), a risk potentially exacerbated by elevated lipoprotein(a) (Lp(a)). While other cholesterol parameters are screened in this population, Lp(a) is often overlooked despite being an independent CVD risk factor. Lp(a) levels are historically believed to not change over an individual's life and are genetically determined, but newer literature suggests variation.

Objective: This study investigated Lp(a) levels and their relationship with glycated hemoglobin A_1c (HbA_1c) in children with incident diabetes mellitus (DM).

Methods: Children and adolescents aged 5 to 18 years with incident DM had baseline Lp(a) and lipid profiles. Repeat Lp(a) and HbA_1c were obtained 3 months later. Descriptive statistics (frequencies, proportions, means, medians) and nonparametric tests (Spearman correlation, Wilcoxon rank-sum/Kruskal-Wallis) were used. Statistical significance was set at P less than .05.

Results: Seventy-six children were included for evaluation: 76% with type 1% and 23% type 2 DM. Baseline median (Q1-Q3) Lp(a) was 43.3 nmol/L (13-73.7 nmol/L), 17 of which were elevated (≥75 nmol/L). Of the 22 participants with follow-up, 8 were abnormal: A total of 4 whose baseline Lp(a) were abnormal remained so and 4 with normal levels became abnormal. A positive correlation was found between 3-month Lp(a) values and HbA_1c (P = .004).

Conclusion: Children with DM have abnormal Lp(a) levels at a prevalence of approximately 20%, so this should be considered in CVD risk stratification. Further, observed Lp(a) fluctuations suggest value in serial Lp(a) assessments due to nongenetic influences. Without Lp(a) quantification, CVD risk characterization in children with DM may be inaccurate and should be considered for a comprehensive assessment.

Context: Current osteoporosis risk stratification relies on clinical factors and bone mineral density alone.

Objective: To determine if osteocalcin, c-terminal cross-linking telopeptide of type 1 collagen, sclerostin, and bicarbonate ("bone-related biomarkers") are associated with future fracture risk or improve risk stratification.

Design: Nested, matched case-control.

Setting: Longitudinal cohorts of health care workers.

Patients: Individuals with and without hip fracture in the Nurses' Health Study I and the Health Professionals Follow-up Study.

Main outcome measure: Hip fracture.

Results: Among 642 women in Nurses' Health Study I (mean age, 70.3 years; 29% with osteoporosis), we found no consistent associations between bone-related biomarkers and incident hip fracture, and addition of biomarkers to clinical models predicting incident hip fracture did not improve model fit. Among 586 men in Health Professionals Follow-up Study (mean age, 63.8 years; <1% with osteoporosis), higher levels of osteocalcin (odds ratio, 0.37 [95% CI, 0.13-1.04] for quintile 5 vs quintile 1; P for trend = .02) and sclerostin (odds ratio, 0.22 [95% CI, 0.09-0.54] for quintile 5 vs quintile 1; P for trend < .001) were associated with lower risk of hip fracture; however, addition of sclerostin to clinical models predicting incident hip fracture provided limited additional predictive value.

Conclusion: Osteocalcin, c-terminal cross-linking telopeptide of type 1 collagen, sclerostin, and bicarbonate were not associated with incident hip fracture among older, predominantly White women. Osteocalcin and sclerostin were associated with hip fracture among men but did not meaningfully improve the predictive accuracy of models based on clinical risk factors alone.

Context: Approximately 50% to 70% of patients with multiple endocrine neoplasia type 1 (MEN1) die of duodenopancreatic neuroendocrine tumors (NETs). While c-MET inhibitors in combination with antivascular endothelial growth factor therapy have been shown to result in longer progression-free survival in patients with sporadic NETs, data regarding their efficacy in patients with MEN1-related NETs are lacking.

Objective: We sought to characterize c-MET expression in MEN1-related NETs and evaluate its association with clinicopathologic characteristics.

Methods: Forty-three tumors from 22 genetically confirmed patients with MEN1-related metastatic NETs were identified. Of these, 15 of 22 (68%) patients had distant metastases while the remaining 7 of 22 had locoregional metastases.

Results: c-MET expression was assessed in these tumors via immunohistochemistry. A total of 19 of 43 (44%) were primary tumors (duodenum, pancreas, stomach) while the remaining were metastases. c-MET expression was scored as strongly positive in 3 of 43 (H-score >50), weakly positive in 6 of 43 (H-score: 10-50), and negative in 34 of 43 (H-score <10) tumors. All 3 tumors with strong positive c-MET expression were from patients with a distinctly aggressive clinical course. The 6 tumors with weakly positive c-MET expression were from patients with stable disease, including 4 with distant metastases. Of the 13 patients with all tumors negative for c-MET expression, all but 1 had stable disease. Age at initial NET diagnosis; tumor site, type or grade; number of sites of distant metastases; total number of surgeries for NETs; or the stability of overall tumor burden did not predict c-MET expression.

Conclusion: Our findings suggest a role for c-MET inhibition in personalizing therapy for patients with MEN1-related NETs.