The 45,X/46,XY mosaicism is a rare condition with a wide range of phenotypes, including a nearly normal male or female phenotype and variable degrees of gonadal differentiation. Dysgenetic gonads containing Y chromosome material carry an increased risk of developing gonadal germ cell tumors. However, to date, molecular analyses of testicular germ cell tumors (TGCTs) in patients with 45,X/46,XY mosaicism have not been reported. We encountered a 17-year-old male patient with 45,X/46,XY mosaicism who presented with undervirilized external genitalia. Ultrasound examination revealed an abnormality in the right testis, and subsequent orchiectomy confirmed the presence of gonadoblastoma, germ cell neoplasia in situ, and seminoma. Molecular analysis of the tumor tissue revealed a heterozygous pathogenic KIT mutation (c.2446G>T, p.(Asp816Tyr)) and copy number gains across nearly all chromosomes, including 12p. This is the first report of genetic analysis of a TGCT in a patient with 45,X/46,XY mosaicism, revealing molecular abnormalities similar to those in male patients without differences of sex development. Furthermore, we reviewed five cases of seminoma in patients with 45,X/46,XY mosaicism, including the present case. These observations suggest that seminoma may develop after puberty regardless of the degree of masculinization, testicular position, or initial biopsy findings, highlighting the need for careful long-term surveillance in these patients.

This review is aimed at clarifying the background and the meaning of new terminology "pituitary neuroendocrine tumours" (PitNETs) in WHO Classification 2022. The PitNETs share the unique structures of secretory granules (SG) with other neuroendocrine tumors, the good example of which is the pancreatic NETs which are now considered to be potentially aggressive, i.e., invasive and metastatic. The PitNETs share these features of pancreatic NETs and now are considered to be potentially aggressive tumors. The PitNETs are classified according to the functions (hormones) and transcription factors, PIT1, TPIT and SF1. The PitNETs are usually slow growing tumors with generally low (<3%) Ki-67 indices. PitNETs show some morphologic features which are more closely related to aggressive growths, such as Crooke cells. The questions how those particular PitNETs are aggressive have been approached by molecular techniques such as single cell RNA seq to clarify the genomic heterogeneity and the biology of individual tumor cells. It is expected that the PitNETs will be clarified and classified with more biologically and therapeutically oriented manner.

This randomized controlled study aimed to clarify weight loss targets for improving obesity-related disorders in individuals with overweight or obesity. A total of 294 participants with six obesity-related conditions were assigned to either a standard or intensive treatment group, with 12-month weight loss targets of ≥3% and ≥7%, respectively. The standard group followed the Japanese Guidelines for the Management of Obesity Disease 2016. The intensive group received frequent nutritional guidance, enhanced diet and exercise therapy, and additional pharmacotherapy. The primary outcome was weight loss and improvement in at least two obesity-related disorders at 12 months. Secondary outcomes included remission of health disorders, improvement in at least one health disorder, and visceral fat reduction. At 12 months, the weight loss was -2.5% in the intensive group and -1.7% in the standard group, with no significant difference in the primary outcome. However, remission of health disorders was achieved in 16.9% of the intensive group compared with 6.2% of the standard group (adjusted odds ratio 3.079; 95% CI 1.075-8.823; p = 0.036). Visceral fat reduction was greater in the intensive group (-20.46 cm[2] vs. -8.9 cm[2]; p = 0.039). Intensive treatment significantly improved blood pressure early and increased treatment motivation scores by 10.9% (95% CI: 1.2-20.6) at 24 months (p = 0.004). In both groups, ≥60% of the participants showed improvement in at least one disorder. Despite not achieving the target weight loss, resulting in no significant difference in the primary outcome, the intensive treatment increased remission percentages, improved early blood pressure control, and enhanced long-term treatment motivation. The study was registered at UMIN Clinical Trials Registry (UMIN ID: UMIN000031862).

Iodothyronine deiodinases (DIOs) are key regulators of thyroid hormone action. Three types of DIOs, including type 1 (D1), 2 (D2), and 3 (D3), coordinate the local and systemic availability of T3. D2 primarily catalyzes the activating conversion of T4 to T3, whereas D3 mainly catalyzes the inactivating conversion of T4 to reverse T3 (rT3) and T3 to diiodothyronine (T2). D1 has a relatively low affinity for T4 and contributes less to T4 activation but preferentially catalyzes the conversion of rT3 to T2. Thyroid hormones promote D1 and D3 expression, whereas D2 activity is transcriptionally regulated via several pathways such as cAMP and post-translationally through ubiquitin-dependent proteasomal degradation. Evidence from knockout and overexpressing mouse models and human genetic variants has clarified the physiological roles of DIOs in thyroid hormone economy. Reduced D1 activity increases serum rT3 levels, D2 enhances local thyroid hormone action and contributes to circulating T3 production, and D3 decreases circulating T3 and T4 levels while increasing rT3 levels. DIO dysregulation is implicated in several clinical conditions. GH-related disorders potentially alter thyroid function via D2-mediated mechanisms. In adrenal insufficiency, thyroid function may exhibit elevated serum fT3 levels without TSH suppression. Additionally, resistance to thyroid hormone β can be associated with bezafibrate-induced consumptive hypothyroidism through increased hepatic D3 expression. This review summarizes current knowledge on the biological properties and clinical implications of DIOs and highlights their significant role in the regulation of thyroid hormone action.

Immune checkpoint inhibitor (ICI)-related type 1 diabetes is a rare but potentially life-threatening immune-related adverse event, and imaging findings immediately before clinical presentation and diagnosis have rarely been documented. We report a 71-year-old woman with large cell neuroendocrine carcinoma who developed fulminant type 1 diabetes mellitus during carboplatin, nab-paclitaxel, and atezolizumab therapy. The day of clinical presentation and diagnosis was defined as Day 0. On Day -1, she developed nausea and appetite loss without abdominal pain. On Day 0, she presented with impaired consciousness and fever; laboratory evaluation showed plasma glucose 1,435 mg/dL, glycated hemoglobin (HbA1c) 6.9%, marked ketonemia, severe hyperosmolality, negative anti-glutamic acid decarboxylase (GAD) antibody, and near-complete insulin deficiency. The metabolic presentation was interpreted as diabetic ketoacidosis/hyperosmolar hyperglycemic state (DKA/HHS) overlap. Computed tomography (CT) performed on Day -2 showed radiologic enlargement of the pancreatic tail with increased peripancreatic fat attenuation, both of which had resolved on Day 0. Pancreatic volume increased from 46.0 mL at baseline to 82.5 mL on Day -2, decreased to 47.9 mL on Day 0, and further declined to 39.0 mL at 6-month follow-up. This hypothesis-generating case documents incidental transient pancreatic enlargement with peripancreatic inflammatory changes shortly before diagnosis, followed by pancreatic atrophy. This case suggests that incidental pancreatic enlargement during ICI therapy may serve as an early radiologic clue to immune-related diabetes, supporting prompt metabolic evaluation even in the absence of abdominal pain or pancreatic enzyme elevation.

Steatotic liver disease is a common metabolic disorder, and interleukin-1β (IL-1β) contributes to hepatic inflammation and lipid accumulation. ATP-binding cassette subfamily A member 1 (ABCA1) regulates cholesterol efflux and lipid homeostasis. This study examined whether IL-1β suppresses hepatic ABCA1 expression and explored the underlying signaling and transcriptional mechanisms. Primary mouse hepatocytes and HepG2 cells were treated with IL-1β. ABCA1 expression was assessed by Western blotting and RT-qPCR, and ABCA1 promoter activity was examined using luciferase reporter assays with inhibitors targeting phosphoinositide 3-kinase (PI3K), p38 mitogen-activated protein kinase (p38 MAPK), or an H-89-sensitive pathway. Prolactin regulatory element-binding protein (PREB) involvement was evaluated by nuclear protein analysis, PREB-binding-site mutation, and siRNA-mediated knockdown. Lipid accumulation was assessed by intracellular cholesterol measurement and Oil Red O staining. IL-1β decreased ABCA1 protein and mRNA expression in a dose- and time-dependent manner and suppressed ABCA1 promoter activity. Inhibition of p38 MAPK or treatment with H-89 attenuated IL-1β-induced suppression of promoter activity and endogenous ABCA1 expression. Representative immunoblotting showed that IL-1β enhanced p38 MAPK phosphorylation, whereas SB203580 attenuated this response. IL-1β reduced nuclear PREB expression, and p38 MAPK inhibition restored nuclear PREB expression. Mutation of the PREB-binding site or PREB knockdown abolished IL-1β-mediated suppression of ABCA1 expression. IL-1β also increased intracellular cholesterol content and Oil Red O-positive lipid accumulation. These findings suggest that IL-1β suppresses hepatic ABCA1 expression through p38 MAPK signaling and an H-89-sensitive pathway, at least partly involving PREB-associated transcriptional regulation, and that this suppression is associated with hepatocellular lipid accumulation.

While preserving skeletal muscle mass (SMM) is advocated in type 2 diabetes mellitus (T2DM), mass-based assessments often overlook muscle quality. This study aimed to investigate whether the balance between cellular integrity (phase angle [PhA]) and metabolic load (body fat mass [BFM]) is more clinically relevant to glycemic control than SMM-based profiling in patients with T2DM. In this cross-sectional study of 622 patients, participants were stratified into four groups based on sex-specific medians of PhA and BFM, and similarly for SMM and BFM. Multivariate logistic regression evaluated associations with glycemic targets (HbA1c <8.0% and <7.0%), adjusting for confounders. Sensitivity analyses utilized continuous Z-scores and interaction terms. High-PhA/High-BFM and High-PhA/Low-BFM groups showed significantly higher odds of HbA1c <8.0% compared with the Low-PhA/High-BFM reference group (adjusted odds ratio [OR] 2.05, 95% confidence interval [CI] 1.22-3.44; OR 2.10, 95% CI 1.21-3.64, respectively). Conversely, SMM/BFM combinations showed no significant associations. Neither profile was significantly associated with the stricter HbA1c <7.0% target. In continuous models, the PhA × BFM interaction was significantly associated with achievement of HbA1c <8.0% (p = 0.025), whereas SMM × BFM interaction was not. In conclusion, the PhA/BFM interplay shows a clearer association with glycemic control than SMM/BFM profiling in T2DM. Higher PhA may reflect a more favorable metabolic phenotype against adiposity and is associated with a lower likelihood of severe hyperglycemia (HbA1c ≥8.0%). PhA/BFM profiling offers a novel approach to identify high-risk patients overlooked by conventional mass-based assessments.

Mutations in the CACNA1H and PPP2R5D genes have been associated with functional abnormalities affecting both the endocrine and nervous systems. The CACNA1H gene encodes the T-type calcium channel CaV3.2, and pathogenic variants may alter channel activation and inactivation, resulting in increased intracellular calcium influx. Elevated intracellular calcium in adrenal zona glomerulosa cells acts as a key signal for aldosterone biosynthesis, thereby promoting excessive aldosterone secretion and contributing to the development of hypertension. The PPP2R5D gene encodes a regulatory subunit of protein phosphatase 2A (PP2A). Mutations in this gene may disrupt the regulatory function of PP2A, impairing the dephosphorylation of key neuroproteins and consequently affecting neural signal transduction and brain function. Cases of early-onset hypertension accompanied by intellectual disability associated with concurrent CACNA1H and PPP2R5D mutations remain rare. We report the case of an 18-year-old female presenting with early-onset hypertension and intellectual disability. Hypertension was first diagnosed at the age of 10 years and was accompanied by recurrent dizziness and headache. Physical examination revealed central obesity and signs of hyperandrogenism. Laboratory evaluation demonstrated elevated aldosterone levels with suppressed plasma renin activity, suggesting primary aldosteronism. Genetic analysis identified heterozygous variants in CACNA1H (c.6866C>T) and PPP2R5D (c.985A>G). Based on the clinical features and genetic findings, the patient was diagnosed with familial hyperaldosteronism type IV complicated by intellectual disability. This case highlights the importance of considering genetic forms of primary aldosteronism in young patients with early-onset hypertension and atypical clinical manifestations. Genetic testing may facilitate accurate diagnosis and guide individualized management.

Vitamin D has been linked to insulin sensitivity and glucose metabolism. However, few studies have separately examined the association between serum 25-hydroxyvitamin D2 (25(OH)D2) and 25-hydroxyvitamin D3 (25(OH)D3) levels and insulin resistance. Therefore, we investigated the associations of serum 25(OH)D2, 25(OH)D3, and total 25-hydroxyvitamin D (25(OH)D) levels with the metabolic score for insulin resistance (METS-IR) in a nationally representative sample of Korean adults. This cross-sectional study analyzed data from 9,297 adults aged ≥19 years who participated in the 2022-2023 Korea National Health and Nutrition Examination Survey. Linear regression was used to examine the associations of serum 25(OH)D2, 25(OH)D3, and total 25(OH)D levels with the METS-IR. Total 25(OH)D (β = -0.0843, 95% confidence interval [CI]: -0.0995 to -0.0691) and 25(OH)D3 levels (β = -0.0831, 95% CI: -0.0983 to -0.0680) showed significant, linear inverse associations with the METS-IR. However, serum 25(OH)D2 levels were not significantly associated with the METS-IR. Stratified analyses revealed that the inverse association between the 25(OH)D3 level and METS-IR was significantly stronger in participants with obesity, diabetes mellitus, or hypercholesterolemia than in their counterparts. These findings were consistent across all the sensitivity analyses. In this nationally representative study of Korean adults, total 25(OH)D and its principal component 25(OH)D3 were inversely associated with the METS-IR. In contrast, 25(OH)D2 was not associated, a finding most likely attributable to its very low circulating concentrations. Because total 25(OH)D performed comparably to 25(OH)D3, it remains a practical measure of vitamin D status in metabolic care.

Although randomized controlled trials have demonstrated the efficacy of real-time continuous glucose monitoring (rtCGM), evidence from routine clinical practice remains limited, particularly in Asian populations. This study aimed to evaluate the effectiveness and safety of rtCGM initiation in individuals with diabetes. This multicenter, single-arm, retrospective, observational study was conducted at 34 sites across Japan (Clinical trial registration: UMIN000054275). Adults ≥18 years of age with diabetes who began using the Dexcom G6 rtCGM system, had a baseline glycated hemoglobin (HbA1c) level ≥7.5%, and continued rtCGM for at least 26 weeks were included. Factors associated with changes in HbA1c levels were examined using multivariate linear regression models. Among 192 participants, the mean HbA1c levels at 26 weeks were significantly lower (8.62 ± 1.14% vs. 7.88 ± 1.16%, p < 0.001) than those at baseline, with a difference of -0.73 ± 1.03%. In the multivariate analysis, greater HbA1c reduction was independently associated with higher baseline HbA1c (β = -0.40; p < 0.001), longer CGM active time (β = -0.008; p = 0.043), and older age (β = -0.010; p = 0.012), whereas prior isCGM use was associated with smaller reductions (β = +0.28; p = 0.045). Sex was also independently associated with changes in HbA1c levels (p = 0.028). During the 26-week follow-up period, one patient (0.5%) experienced diabetic ketoacidosis and four individuals (2.1%) experienced severe hypoglycemia. rtCGM initiation was associated with significantly lower HbA1c levels after 26 weeks of rtCGM use. These findings support the efficacy and safety of the Dexcom G6 in routine clinical practice.

Hereditary adrenocortical unresponsiveness to adrenocorticotropin (HAUA) is a rare congenital disorder characterized by isolated glucocorticoid deficiency with preserved mineralocorticoid production. HAUA encompasses familial glucocorticoid deficiency (FGD) and triple A syndrome (AAAS) and is caused by autosomal recessive defects in ACTH-signaling-related genes, including MC2R, MRAP, AAAS, NNT, TXNRD2, and MCM4. To clarify the current clinical characteristics of HAUA (including FGD and AAAS) in Japan, we conducted a nationwide questionnaire-based survey. The primary survey identified the number of affected patients, and the secondary survey collected detailed clinical information. Fifteen patients were identified from 12 institutions. Detailed clinical data were obtained from nine patients (mean age, 40.6 years). Most patients developed symptoms during childhood [3.75 (0-8) years]. Seven presented with chronic adrenal insufficiency, and two experienced life-threatening events, hypoglycemia or encephalopathy. Genetic confirmation was obtained in four cases. All patients received glucocorticoid replacement therapy (mean hydrocortisone-equivalent dose, 13.0 mg/m[2]/day). Notably, 50% of adult patients were obese (BMI ≥25 kg/m[2]), although no clear association between glucocorticoid dose and BMI was observed. Despite the limited cohort size, this study provides detailed clinical information on HAUA (including FGD and AAAS) in Japan and suggests a potential risk of obesity in long-term management.

In adults, cases of dyshormonogenetic goiter (DG) that go undiagnosed during childhood may necessitate thyroidectomy due to unexplained thyroid enlargement, often presenting diagnostic challenges. This study aimed to characterize the histopathological features of the thyroid in adult DG cases, and to evaluate the feasibility of predicting subtypes from the findings. Fifty adult patients with DG confirmed by the presence of gene variants were included. All resected thyroids showed diffuse goiter with microscopically altered thyroid follicles throughout the gland. All patients with SLC5A5 abnormality (iodide transport defect) showed lobulation accentuated by interlobular fibrosis. Follicular cells were enlarged, except in patients with SLC26A4 abnormality (Pendred syndrome). A scant colloid was observed in all patients with thyroglobulin (TG) gene abnormality. Thyroid peroxidase (TPO) gene abnormality and SLC26A4 abnormality were characterized by large follicles with Sanderson's polsters. Multiple non-encapsulated nodular lesions were present except in two patients with SLC26A4 abnormality. These were mainly follicular thyroid adenoma-like nodules associated with TG gene abnormality, TPO gene abnormality, and SLC5A5 variant. With SLC26A4 abnormality, the nodules were follicular nodular disease-like. The proposed histological framework may be particularly valuable for adult patients undergoing thyroidectomy for unexplained diffuse enlargement or multinodularity, particularly when no prior diagnosis of DG is documented.

Dipeptidyl peptidase-4 (DPP4) is involved in immune regulation and metabolic homeostasis. Although DPP4 inhibitors are widely used in type 2 diabetes, the clinical relevance of autoantibodies against DPP4 (DPP4-Ab) remains unclear. In this study, we aimed to investigate the association between circulating DPP4-Ab levels and mortality in 274 patients with type 2 diabetes (mean age, 63 years). Serum DPP4-Ab levels were measured using amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA), and survival was assessed using Kaplan-Meier analysis and Cox proportional hazards regression analysis. During a mean follow-up of approximately 5 years, 32 deaths had occurred. Patients with elevated DPP4-Ab titers (>1,676.8 alpha counts) had a higher mortality rate than those with low titers (22.2% vs. 9.3%, p = 0.0177). In Cox proportional hazards regression analysis, DPP4-Ab titers showed a trend toward association with all-cause mortality when analyzed as a continuous variable per 100 alpha counts (a.c.) increase (hazard ratio [HR], 1.042; 95% confidence interval [CI], 0.996-1.090; p = 0.071). When patients were stratified using the predefined cutoff value of 1,676.8 a.c., the high DPP4-Ab group showed significantly higher mortality risk than the low DPP4-Ab group (HR, 2.30; 95% CI, 1.09-4.84; p = 0.028). Addition of DPP4-Ab to an age-based model only slightly improved predictive discrimination. These findings suggest that elevated DPP4-Ab titers may be associated with mortality risk; however, this association should be interpreted cautiously and warrants further investigation as a potential adjunctive immunometabolic biomarker in type 2 diabetes.