Journal of Clinical Endocrinology & Metabolism最新文献

Context: Aging increases fracture risk through bone loss and microarchitecture deterioration due to an age-related imbalance in bone resorption and formation during bone remodeling.

Objective: We examined the associations between levels of phosphate, calcium (Ca), and alkaline phosphatase (ALP), and fracture risk in initially healthy older individuals.

Methods: A post hoc analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) trial recruited 16 703 Australian participants aged 70 years and older and 2411 US participants aged 65 years and older. Analyses were conducted on ASPREE-Fracture substudy participants from Australia with serum calcium, phosphate, and ALP measurement. Fracture data were collected post randomization. Cox regression was used to calculate hazard ratios (HRs) and 95% CIs. Phosphate, Ca, and ALP were analyzed in deciles (D1-D10), with deciles 4 to 7 (31%-70%) as the reference category. Restricted cubic spline curves were used to identify nonlinear associations.

Results: Of the 9915 participants, 907 (9.2%) individuals had incident fractures recorded over 3.9 (SD 1.4) years. In the fully adjusted model, men in the top decile (D10) of phosphate had a 78% higher risk of incident fracture (HR 1.78; 95% CI, 1.25-2.54). No such association was observed for women (HR 1.09; 95% CI, 0.83-1.44). The population attributable fraction in men within the D10 phosphate category is 6.9%.

Conclusion: This result confirms that high-normal serum phosphate levels are associated with increased fracture risk in older men.

Objective: To investigate the association of diabetes duration with cardiovascular disease (CVD) risk and to examine the relationship between lipid levels and CVD risk over the duration.

Methods: Using the Korean National Health Insurance Service Cohort database, we identified 2 359 243 subjects with type 2 diabetes aged ≥ 20 years in 2015 to 2016. Baseline lipid levels and diabetes duration were evaluated and followed up until December 2020 (mean follow-up, 3.9 years). Subjects were categorized according to diabetes duration (new-onset, < 5 years, 5-9 years, or ≥ 10 years). We analyzed the new-onset diabetes group with low-density lipoprotein cholesterol (LDL-C) < 70 mg/dL as the reference group. The hazard ratios (HRs) and 95% CIs of myocardial infarction (MI) and ischemic stroke (IS) were estimated using a Cox proportional hazards model adjusted for potential confounders.

Results: During follow-up, 45 883 cases of MI and 53 538 cases of IS were identified. The risk of MI or IS began to increase at LDL-C ≥ 160 mg/dL in the new-onset diabetes group, and at LDL-C ≥ 130 mg/dL in the group with diabetes duration < 5 years. Among subjects with diabetes duration of 5 to 9 years, LDL-C levels of 100-129 mg/dL, 130-159 mg/dL, and ≥ 160 mg/dL were significantly associated with the risk of MI (HR [95% CI] 1.13 [1.04-1.22], 1.28 [1.17-1.39], and 1.58 [1.42-1.76], respectively). MI risk in the diabetes duration ≥ 10 years group was increased by 16%, even in the LDL-C 70-99 mg/dL population (HR [95% CI] 1.16 [1.08-1.25]).

Conclusion: This population-based longitudinal study revealed that the LDL-C cutoff level for increasing the risk of CVD varied with diabetes duration and that the target LDL-C level should depend on the duration.

Context: Low magnesium levels, which are common in people with type 2 diabetes, are associated with increased levels of proinflammatory molecules. It is unknown whether magnesium supplementation decreases this low-grade inflammation in people with type 2 diabetes.

Objective: We performed multidimensional immunophenotyping to better understand the effect of magnesium supplementation on the immune system of people with type 2 diabetes and low magnesium levels.

Methods: Using a randomized, double-blind, placebo-controlled, 2-period, crossover study, we compared the effect of magnesium supplementation (15 mmol/day) with placebo on the immunophenotype, including whole blood immune cell counts, T-cell and CD14+ monocyte function after ex vivo stimulation, and the circulating inflammatory proteome.

Results: We included 12 adults with insulin-treated type 2 diabetes (7 males, mean ± SD age 67 ± 7 years, body mass index 31 ± 5 kg/m2, HbA1c 7.5 ± 0.9%) and low magnesium levels (0.73 ± 0.05 mmol/L). Magnesium treatment significantly increased serum magnesium and urinary magnesium excretion compared with placebo. Interferon-γ production from phorbol myristate acetate/ionomycin stimulated CD8+ T-cells and T-helper 1 cells, as well as interleukin (IL) 4/IL5/IL13 production from T-helper 2 cells was lower after treatment with magnesium compared with placebo. Magnesium supplementation did not affect immune cell numbers, ex vivo monocyte function, and circulating inflammatory proteins, although we found a tendency for lower high sensitivity C-reactive protein levels after magnesium supplementation compared with placebo.

Conclusion: In conclusion, magnesium supplementation modulates the function of CD4+ and CD8+ T-cells in people with type 2 diabetes and low serum magnesium levels.

Aims: To assess adult height outcomes across levels of glycaemic control in children and adolescents with type 1 diabetes, as well as to investigate the impact of sex, age at disease onset, and timing of glycaemic control in relation to puberty.

Methods: In this population-based Swedish cohort study, we collected data on glycaemic control and height from specialist healthcare visits of all individuals with childhood-onset type 1 diabetes in the National Diabetes Register. Using linear and logistic regression, we compared suboptimal (HbA1c 53-75 mmol/mol [7.0-9.0%]) and poor (HbA1c >75 mmol/mol [>9.0%]) to optimal (HbA1c <53 mmol/mol [<7.0%]) glycaemic control in relation to final adult height and the risk of short stature.

Results: Poor glycaemic control was associated with lower final adult height (-2.91 cm [95% CI - 3.48, -2.33] for males, -1.83 cm [-2.42, -1.23] for females) as well as a higher risk of short stature in males (odds ratio 1.90 [1.07, 3.35]) but not in females (0.73 [0.36, 1.51]). For females, adult height was only lower among those with type 1 diabetes since before puberty and if the poor glycaemic control occurred before puberty. For males, adult height was lower irrespective of their age at diabetes onset, but only if they had poor glycaemic control during or after puberty.

Conclusions: Poor glycaemic control after the onset of type 1 diabetes, compared to optimal control, is associated with lower adult height in males and females. The prepubertal period seems to be more critical for females than males.

Context: Increased standing time has been associated with improved health, but the underlying mechanism is unclear.

Objectives: We herein investigate if increased weight loading increases energy demand and thereby glucose uptake (GU) locally in bone and/or muscle in the lower extremities.

Methods: In this single-center clinical trial with a randomized crossover design (ClinicalTrials.gov ID, NCT05443620), we enrolled 10 men with body mass index between 30 and 35 kg/m2. Participants were treated with both high load (standing with weight vest weighing 11% of body weight) and no load (sitting) on the lower extremities. GU was measured using whole-body quantitative positron emission tomography/computed tomography imaging. The primary endpoint was the change in GU ratio between loaded bones (ie, femur and tibia) and nonloaded bones (ie, humerus).

Results: High load increased the GU ratio between lower and upper extremities in cortical diaphyseal bone (eg, femur/humerus ratio increased by 19%, P = .029), muscles (eg, m. quadriceps femoris/m. triceps brachii ratio increased by 28%, P = .014), and certain bone marrow regions (femur/humerus diaphyseal bone marrow region ratio increased by 17%, P = .041). Unexpectedly, we observed the highest GU in the bone marrow region of vertebral bodies, but its GU was not affected by high load.

Conclusion: Increased weight-bearing loading enhances GU in muscles, cortical bone, and bone marrow of the exposed lower extremities. This could be interpreted as increased local energy demand in bone and muscle caused by increased loading. The physiological importance of the increased local GU by static loading remains to be determined.

Context: One of the major prognostic indices in neuroendocrine tumors (NETs) is Ki67 proliferation index.

Objective: To identify optimal grading Ki67 cutoffs to delineate differences in prognosis of patients with small intestinal NETs (SI-NETs).

Methods: Multicenter retrospective cohort analysis of 551 SI-NET patients diagnosed from 1993 through 2021 at 5 European referral centers with a mean (±SD) follow-up time of 51.5 (±52.9) months, measuring rates of overall survival (OS) and event-free survival (EFS).

Results: Median age at baseline was 62.3 (range, 17-90) years; 252 (45.7%) patients were female. All SI-NETs were well-differentiated, with 326 being grade 1 (G1; 59.2%), 169 G2 (30.7%), and 8 G3 (1.5), while 48 tumors were unspecified grade (8.7%). The median Ki67 was 2% (range, 1%-70%). At baseline, 247 (44.8%) patients had distant metastases (stage IV), 217 locoregional disease (41.1%; stage III), while 29 (7.1%) and 25 (4.5%) presented at stages II and I, respectively. Median OS was 214.7 (95% CI, 152.7-276.6) months and median EFS was 79.8 (68.2-91.5) months. In multivariable Cox-regression OS analysis, the proposed modified histopathological Ki67 grading system (Ki67 5%-10% group: HR = 2.2 [95% CI, 1.15-4.31], P = .018 and Ki67 ≥ 10% group: HR = 5.11 [2.87-9.09], P < .001), age (HR = 1.07 [1.04-1.09], P < .001), Charlson Comorbidity Index (HR = 1.08 [1-1.16], P = .028), and TNM stage (HR = 1.79 [1.05-3.06], P = .034) were independent predictors for death. Pertinent EFS analysis confirmed the proposed modified histopathological Ki67 grading system (Ki67 ≥ 10% group: HR = 4.01 [2.6-6.37], P < .001) and age (HR = 1.04 [1.02-1.05], P < .001) as independent predictors for recurrence, progression, and/or death.

Conclusion: Ki67 proliferation index was a strong and independent predictor of OS and EFS. A modified histopathological grading system applying Ki67 cutoffs of 5% and 10% could be superior to predict differences in SI-NET patient survival outcomes.

Purpose: This study aimed to describe the ultrasound characteristics of papillary thyroid carcinoma (PTC) harboring RET gene fusion and explore its clinical significance.

Methods: A retrospective study was conducted on 209 patients with PTC diagnosed between Aug 2021 and Jan 2024. All patients underwent ultrasound examination and were confirmed to be positive for RET fusion or BRAFV600E by pathological results. The differences in clinical characteristics and ultrasonography features between the two groups were analyzed.

Results: Among all PTCs (n=209), we detected 30 RET fusions, and 179 BRAFV600E. RET-fusion PTCs showed younger age (38.5(16.0-69.0) vs. 42.9(20.0-74.0) years, p<.05), larger tumor size (1.09(0.5-4.0) vs. 0.77(0.1-4.0) cm, p<.005), and more advanced N stage (p<.001) than BRAFV600E PTCs. RET-fusion PTCs were mainly classical and diffuse sclerosing subtypes. In terms of ultrasound performance, RET-fusion PTCs were mainly manifested as heterogeneous echogenicity (43.3%), ill-defined tumor margin (90.0%), irregular shape (83.3%) and intranodular microcalcification (83.3%), characterized by scattered microcalcification around the tumor/within thyroid gland (40.0%). In comparison, BRAFV600E PTCs were mainly characterized by hypoechogenicity (95.5%), round/oval shape (80.4%), and intranodular non-calcification (54.2%). Multivariate logistic regression analysis revealed that scattered microcalcification around the tumor/within the normal gland was an independent risk factor for lateral lymph node metastasis (LLNM) in RET-fusion PTCs (OR 9.79, 95% CI, 1.31, 72.93, P=.026).

Conclusions: Patients diagnosed with PTC harboring RET fusion presented with distinctive clinical characteristics and sonographic patterns, underscoring the unique diagnostic value of ultrasound examination. It can provide a preoperative non-invasive primary screening method for RET-fusion diagnosis, thus facilitating targeted patients with purposeful molecular sequencing to improve treatment outcomes.