Endocrine journal最新文献

This study investigated the role of scutellarin (Scu) and Nrf2 in diabetic atherosclerosis, focusing on their effects on FBXL2 and NLRP3 ubiquitination. Human umbilical vein endothelial cells were treated with high glucose (HG) to model diabetic atherosclerosis in vitro. Cell viability, cytotoxicity, pyroptosis, and inflammatory cytokine levels were assessed, and gene interactions were examined by dual-luciferase reporter assays. Ubiquitination and protein levels were analyzed through immunoprecipitation and western blotting. The results revealed that HG treatment decreased Nrf2 and FBXL2 levels and enhanced NLRP3-mediated pyroptosis. However, Scu treatment increased Nrf2 expression, improved cell viability, and inhibited pyroptosis. Nrf2 knockdown downregulated FBXL2 and reversed the protective effects of Scu. Additionally, FBXL2 promoted the ubiquitination-mediated degradation of NLRP3 and suppressed pyroptosis. The activation of NLRP3 reversed the protective effects of Scu on diabetic atherosclerosis. These findings suggest that Scu alleviated diabetic atherosclerosis by increasing Nrf2 and FBXL2 expression, promoting NLRP3 ubiquitination-mediated degradation, and suppressing pyroptosis.

To determine the prognosis of Graves' disease initially presenting with severe subclinical hyperthyroidism, we investigated 110 patients with Graves' disease with normal FT3 and FT4 levels and TSH below 0.1 μU/mL. Graves' disease was diagnosed based on the diffuse accumulation of radioiodine in the thyroid in 83 patients, while the other 27 patients were diagnosed based on positive anti-TSH receptor antibodies. Seventy patients did not receive immediate medical treatment for the hyperthyroidism. Forty-four patients developed overt hyperthyroidism after 1-131 (median 3) months. In 19 patients, TSH levels returned to normal after 1-43 (median 6) months. One patient developed persistent hypothyroidism after two months, and another six had subclinical hyperthyroidism during the observation period. The positivity of TSH receptor antibodies was significantly higher (p = 0.0445) in patients who developed overt hyperthyroidism (86.0%) than in other patients (65.4%). Seventeen patients were treated immediately after diagnosis. Seven patients remitted after 2-94 (median 9) months of medical treatment. Another 10 patients remained euthyroid under the continuous administration of small amounts of medication. Some patients with severe subclinical hyperthyroidism due to Graves' disease develop overt hyperthyroidism. If patients are at risk due to cardiovascular diseases, osteoporotic fractures, or an older age, then immediate treatment can be considered. Otherwise, careful monitoring of the thyroid function without treatment for 6 months is considered to be reasonable. TRAb has been suggested to play a role in the progression of subclinical hyperthyroidism due to Graves' disease.

Hyperuricemia reflects increased insulin resistance, and uric acid (UA) may serve as a predictive marker for the development of metabolic dysfunction-associated steatotic liver disease (MASLD); however, few studies have investigated this condition in the Japanese population. Thus, this retrospective observational study aimed to investigate the association of hyperuricemia with the risk of MASLD or metabolic and alcohol-related liver disease (MetALD) in individuals undergoing health checkups. A cross-sectional analysis was performed on 58,110 individuals, dividing them into quartile groups according to UA values for men and women (Q1 being the lowest and Q4 being the highest), and examining the complication rate of MASLD/MetALD. Subsequently, among 22,364 individuals without MASLD/MetALD, the relationship between UA at baseline and MASLD/MetALD development during follow-up was investigated using Cox proportional hazard models. In the cross-sectional analysis, the higher UA group had a higher complication rate of MASLD/MetALD in both men and women. In the follow-up analysis, both genders in the higher UA quartiles had a significantly higher incidence of MASLD/MetALD than those in the lower quartiles. Multivariate Cox proportional hazards analysis revealed that Q4 had a significantly higher hazard ratio than Q1 for both genders. These trends were the same in the time-dependent body mass index (BMI) model, which incorporated BMI as a time-dependent variable. High UA levels may serve as a predictive marker for MASLD/MetALD development. UA monitoring during health checkups could enable early detection and provision of intervention, improving patient outcomes.

Inorganic iodine has long been used as a treatment for Graves' disease. It is currently a treatment option for mild Graves' disease, but there have been no data suggesting the validity of continuing low-dose iodine treatment after improvement in thyrotoxicosis. For this prospective observational study, we recruited patients with Graves' disease treated only with low-dose iodine (potassium iodine ≤25 mg/day). These patients were then divided into two groups: those who continued with low-dose iodine (C group) and those who discontinued it (DC) group. We compared the 2-year thyrotoxicosis relapse rate between the two groups and investigated anthropometric variables associated with relapse. Of 2,159 patients on iodine treatment, 56 patients met the selection criteria but 4 who gave consent dropped out, leaving 25 in the C group and 27 in the DC group. Regarding baseline characteristics, the C group had a longer duration of Graves' disease, lower therapeutic iodine doses, and lower TSH levels than the DC group. During the 2-year follow-up period, the relapse rate in the C and DC groups was 32.0% and 22.2%, respectively (p = 0.536). Furthermore, patients who relapsed had significantly higher therapeutic iodine doses, FT4 levels, and TSAb levels at baseline than patients who did not relapse. Multiple logistic regression showed that relapse is positively associated with therapeutic iodine dose and TSAb levels. The present study failed to show the efficacy of continuing low-dose iodine in patients with Graves' disease after improvement in thyrotoxicosis. The relapse rate seems to be affected by residual immune activity. UMIN000047660.

Limited real-world data are available on persistence to growth hormone replacement therapy (GHRT) in Japan. Therefore, we used the Japan Medical Data Center claims database to retrospectively investigate persistence with GHRT in patients with pediatric growth hormone deficiency (pGHD). We identified 1,020 patients with pGHD treated with GHRT. The mean age at initial diagnosis was 7.5 ± 3.8 years, and we found a bimodal pattern in age, with peaks at 3 and 12 to 13 years of age; the peaks were more pronounced in male patients. After excluding patients with early withdrawal, 1,016 patients were eligible for persistence analysis. The time to initial treatment discontinuation, i.e., the first prescription-free period of 182 days (6 months) or more, for 50% of the patients was 2,526 days, which was similar to that of treatment completion (2,626 days). Most patients persisted with GHRT until they completed treatment, but 24 out of 1,016 (2.4%) had a treatment discontinuation. The mean proportion of days covered was 89.8%. Being female (hazard ratio [95% CI]: 1.85 [1.36-2.51]) and older age at diagnosis (1.50 [1.41-1.60]) were associated with shorter time to discontinuation. This finding suggests that most patients persist with GHRT until puberty. In conclusion, although most Japanese patients with pGHD appear to persist well with GHRT, some complete GHRT before puberty. Additionally, there are patients diagnosed and starting treatment just before puberty. Therefore, continued efforts towards early referral and diagnosis are important.

High-mobility group AT-hook 2 (HMGA2) is a nuclear protein involved in the differentiation and proliferation of epithelial-derived tumors and also considered to be involved in the growth and differentiation of various malignant tumors, including thyroid cancer. Immunohistochemistry (IHC) for HMGA2 has been reported to show diffuse positivity in several follicular thyroid carcinoma (FTC) cases. This study aimed to investigate whether positive immunohistochemical staining for HMGA2 in primary tumors can be used to predict the prognosis and detect prognostic factors in malignant thyroid tumors associated with metastatic recurrence in FTC. Formalin-fixed, paraffin-embedded (FFPE) resected specimens used for the IHC for HMGA2. The association of positive HMGA2 staining with metastasis and recurrence, along with the potential of HMGA2 as a prognostic marker of metastatic recurrence, was statistically determined. HMGA2 staining was positive in most malignant tissues, whereas benign tissues were unstained. HMGA2 staining of the marginal and invasive regions was observed in FTC tissues. The association of HMGA2 staining with metastasis and recurrence was significant (p = 0.018). Kaplan-Meier curves showed an association of negative HMGA2 staining with metastasis and disease-free survival (p = 0.090). Tumor size (>4 cm) and wide invasion were also significant factors (p = 0.043, p < 0.001). The risk ratio without HMGA2 was significantly reduced by 30% compared to that with HMGA2. In primary tumors, positive HMGA2 staining can be used to predict prognosis in malignant thyroid tumors associated with metastatic recurrence in FTC and negative HMGA2 staining may indicate longer disease-free survival after surgery.

The prevalence of obesity is increasing rapidly worldwide, particularly in Asia. Visceral obesity, characterized by intra-abdominal fat accumulation, is a precursor to metabolic syndrome, encompassing hyperglycemia, dyslipidemia, and hypertension, which elevate the risk of atherosclerosis and cardiovascular disease. A visceral fat area (VFA) of ≥100 cm² is a recognized threshold for diagnosing obesity-related metabolic syndrome. This study aimed to identify independent risk factors for VFA ≥100 cm² in middle-aged Chinese individuals from the general population. We analyzed data from 148 participants (mean age: 49.3 ± 10.8 years; 54% male) who underwent health check-ups. VFA and subcutaneous fat area were assessed using computed tomography, while arterial stiffness and fatty liver were evaluated via brachial-ankle pulse wave velocity (baPWV) and abdominal ultrasonography, respectively. Between-group comparisons (VFA ≥100 cm² vs. VFA <100 cm²) were conducted using unpaired t-tests and Mann-Whitney U tests, and logistic regression analysis identified risk factors. Multivariable regression analysis revealed that baPWV ≥1,400 cm/s (odds ratio [OR] = 5.71, p = 0.011), waist circumference ≥85 cm (OR = 5.46, p = 0.026), fasting blood glucose (FBG) ≥100 mg/dL (OR = 5.69, p = 0.030), male sex (OR = 12.79, p = 0.029), and fatty liver (OR = 3.99, p = 0.042) were significant independent risk factors for VFA ≥100 cm². Among these, baPWV ≥1,400 cm/s was the most significant, showing a positive correlation with VFA (r = 0.365, p < 0.001). Visceral obesity (VFA ≥100 cm²) is a critical target for interventions addressing metabolic syndrome, metabolic dysfunction-associated fatty liver disease (MAFLD), and cardiovascular disease, particularly in males.

Pheochromocytomas occur in the adrenal medulla and present with various symptoms associated with excessive catecholamine production. Although pheochromocytomas associated with ectopic ACTH-producing tumors and hyper-interleukin-6emia (hyper-IL-6emia) have been reported, those associated with both diseases simultaneously have not been reported. In pheochromocytomas with ectopic ACTH-producing tumors and hyper-IL-6emia, the disease characteristics and relationship between each hormone and cytokine are unknown. Herein, we report a case of a 56-year-old woman with stroke whose computed tomography scans of the abdomen revealed a right adrenal tumor on systemic examination. Endocrinological examination revealed elevated plasma levels of catecholamines and their metabolites in the urine and elevated levels of plasma ACTH, serum cortisol, and serum dehydroepiandrosterone sulfate, leading to a diagnosis of right pheochromocytoma and associated ectopic ACTH-producing tumor. Furthermore, hyper-IL-6emia was detected as a key indicator of anemia due to inflammatory hematopoietic disorders. The patient's general condition improved with drug therapy, including 1,000 mg/d of metyrapone, 2 mg/h of phentolamine, 8 mg/d of doxazosin, and systemic management. Dexamethasone suppression tests demonstrated suppressed serum cortisol and IL-6 levels, and dexamethasone dose-dependently increased plasma adrenaline and noradrenaline levels. These findings indicate that excess glucocorticoids play a stimulatory role in catecholamine secretion and a concentration-suppressive role in serum IL-6 levels in pheochromocytomas associated with ectopic ACTH-producing tumors and hyper-IL-6emia. The presence of rare comorbidities should be considered if the clinical findings cannot be explained by the pathophysiology of a pheochromocytoma alone because pheochromocytomas can be associated with the production of other hormones and cytokines.

In Japan, the guidelines for gestational weight gain (GWG) were revised in 2021. Under the new guidelines, pregnant women are recommended to increase their GWG. The aim of this study was to compare the incidence of adverse pregnancy outcomes (APOs), large for gestational age (LGA), and postpartum glucose tolerance in gestational diabetes mellitus (GDM) patients before and after the revised GWG standards. This retrospective cohort study enrolled 1,021 GDM patients who underwent prenatal glycemic control and a postpartum 75-g oral glucose tolerance test. The endpoint was the incidence of APOs, LGA, and postpartum impaired glucose tolerance (IGT) and diabetes mellitus (DM). There was no significant difference in the incidence of APOs and postpartum IGT and DM in GDM patients before and after the revised GWG standards. On the other hand, when the new GWG standards were applied to GDM patients, the incidence of LGA increased (adjusted odds ratio [aOR]; 1.764, 95% confidence interval [CI]; 1.180-2.637). In particular, when classified by pre-pregnancy body mass index, the incidence of LGA increased in the obese group (aOR; 5.944, 95% CI; 1.847-19.129). Future prospective cohort studies are needed to verify the efficacy and safety of appropriate GWG in Japanese GDM patients.

Obesity resulting from long-term sedentary a significant threat to human health. This study explores the effects of exercise snack intervention on body composition and plasma metabolomics in sedentary obese adults. Participants in the snack group were subjected to 4 days of sprint exercises by stair-climbing per week for 12 weeks. Systemic and regional fat mass, epicardial adipose tissue (EAT), abdominal visceral (AVFA) and subcutaneous (ASFA) fat area and plasma metabolomics data were measured before and after intervention. A higher improvement of EAT, AVFA and ASFA in the snack group compared to that in the control group, with a significant interaction effect (p < 0.05). The key differential metabolites between the two groups include isoleucine, glycine and serine. The proposed exercise snack effectively reduced the amount of AVFA and EAT. The change in body composition may be associated with the altered pathways of isoleucine, glycine, and serine metabolism.