Brown adipose tissue (BAT) contributes to energy expenditure through cold-induced thermogenesis and is closely linked to systemic lipid metabolism. However, the dynamic changes in circulating n-3 polyunsaturated fatty acids (PUFAs) during cold exposure and their association with BAT activity remain unclear. Healthy young men underwent controlled cold exposure, and BAT activity was quantified using fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT). Circulating levels of n-3 PUFAs, including α-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA), were measured before and after cold exposure using whole-blood lipidomics. K-means clustering based on log-transformed maximum standardized uptake value (lnSUVmax) was performed. Changes in lipid parameters were evaluated using paired t-tests and multiple regression analyses. Cold exposure significantly decreased ALA levels and the ALA/EPA ratio while increasing EPA and DPA levels and the EPA/DPA and DPA/DHA ratios. Multiple regression analyses revealed that BAT activity (lnSUVmax) was independently associated with changes in several lipid parameters. Higher SUVmax was positively associated with changes in ALA levels and the ALA/EPA ratio, whereas inverse associations were observed with changes in EPA, DPA, EPA/DPA, and DPA/DHA. Baseline lipid levels were not significant predictors of lipidomic changes. Cold-induced BAT activation is associated with dynamic remodeling of circulating n-3 fatty acids. These findings suggest that thermogenic capacity may influence systemic lipid metabolism and highlight the metabolic interplay between BAT activity and circulating n-3 PUFAs. Trial registration: University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR), UMIN000029206.

Although previous studies have described steroidogenic enzyme expression in aldosterone-producing adrenocortical carcinoma (APAC), detailed immunohistochemical evaluations of CYP11B2 at the protein level and its clinicopathological relevance remain limited. Here, we report a rare case of APAC with a comprehensive immunohistochemical analysis focusing on CYP11B2 expression. An 82-year-old woman presented with limb weakness and severe hypokalemia (serum potassium: 1.9 mmol/L). Endocrinological evaluation revealed markedly elevated plasma aldosterone levels and suppressed renin activity, indicating autonomous aldosterone secretion. Imaging identified a rapidly enlarging left adrenal mass with intratumoral hemorrhage, and adrenal venous sampling confirmed unilateral aldosterone excess. The patient underwent laparoscopic left adrenalectomy. Histopathological examination revealed a high-grade adrenocortical carcinoma with positive surgical margins. Immunohistochemical analysis demonstrated positive expression of CYP11B2, CYP11B1, and CYP17A1, whereas dehydroepiandrosterone sulfotransferase expression was absent in the tumor cells but present in the adjacent zona reticularis, suggesting disorganized steroidogenesis. Although biochemical parameters transiently improved postoperatively, the patient developed early recurrence with peritoneal dissemination and died 10 months after surgery. This case of APAC was diagnosed following severe and rapidly progressive hypokalemia, suggesting that a detailed examination of steroidogenic enzyme expression in the tumor may be valuable in elucidating the endocrine characteristics of this rare malignancy.

Oncocytic thyroid carcinoma (OCA) is a rare thyroid malignancy that has only recently been recognized as a distinct entity from follicular thyroid carcinoma. Till date, studies regarding the prognosis of OCA remain inadequate. In this retrospective study, we investigated the prognosis of OCA among 137 Japanese patients who underwent surgery at our institution. Two patients had distant metastasis before surgery (M1), and two showed distant metastasis after surgery. The 10-year and 15-year distant recurrence-free survival rates were 100%, and 92.7%, respectively. No deaths occurred owing to thyroid carcinoma. Four patients with distant metastasis/recurrence were aged ≥60 years, and their tumors were >4 cm. Further, two patients with M1 had both vascular invasion (VI) and wide capsular invasion (CI). One patient had a poorly differentiated component (approximately 30%), and one showed high cell proliferating activity (Ki-67 labeling index [LI] ≥5%). Of the two patients who developed distant metastasis after surgery, one had VI and wide CI, and although another had minimal CI and was negative for VI, the Ki-67 LI of his tumor was >5%. These findings suggest that Japanese patients with OCA generally had excellent prognosis after surgery; however, older age, large tumor size, wide CI, VI positivity, high Ki-67 LI, and the presence of a poorly differentiated component may be indicators of aggressive behavior. Further multicenter studies with larger samples and longer follow-up durations are necessary to identify clinicopathological factors accurately predicting poor prognosis in patients with OCA.

McCune-Albright syndrome (MAS) is a rare mosaic disorder caused by somatic gain-of-function variants in GNAS and frequently associated with fibrous dysplasia (FD). FD-related complications impair physical function and quality of life (QOL), yet Japanese data are lacking. We conducted a nationwide survey to characterize functional impairment and physician-perceived QOL factors in patients with MAS in Japan. Data on 43 patients were collected using a web-based questionnaire sent to council members of the Japanese Society for Pediatric Endocrinology and the Japanese Society for Bone and Mineral Research. Motor disability was assessed using the Japanese version of the modified Rankin Scale (mRS); respiratory, visual, and hearing impairments were graded using the Japanese severity criteria for designated intractable diseases. Physicians identified the single factor perceived as most affecting each patient's QOL. Motor impairment was present in 72.1%, including moderate or severe impairment (mRS ≥3) in 30.2%; other impairments were each absent in more than 80%. The most frequent QOL-affecting factor was bone pain or fractures (37.2%), followed by facial deformity or appearance changes (18.6%) and mobility or physical activity limitation (16.3%). Physician-perceived QOL factors differed by mRS group (p < 0.001): bone pain and facial deformity predominated in patients with mRS <3, whereas mobility limitation predominated in those with mRS ≥3. These findings indicate that FD-related skeletal manifestations are a major source of disability and QOL burden in Japanese patients with MAS, supporting stratified management tailored to motor disability.

The coronavirus disease 2019 (COVID-19) pandemic and associated lifestyle changes have affected metabolic status in individuals with diabetes. The impact of these changes on renal function in individuals with type 1 diabetes (T1D) remains unclear. We performed a post-hoc analysis of a multicenter retrospective cohort study (the IPRA-CKD study) including 190 Japanese individuals with T1D who were not receiving sodium-glucose cotransporter 2 inhibitors. Participants were recruited between June 2022 and July 2023, and longitudinal data over a consecutive 60-month period preceding enrollment were extracted at 6-month intervals and divided into periods before and during the pandemic. Annual rates of estimated glomerular filtration rate (eGFR) decline were compared between the periods before and during the COVID-19 pandemic using a linear mixed-effects model. The eGFR decline was not accelerated during the pandemic compared with before the pandemic; the estimated eGFR slopes were -1.54 ± 0.28 mL/min/1.73 m[2]/year before the pandemic and -1.05 ± 0.22 mL/min/1.73 m[2]/year during the pandemic (p = 0.27). Glycemic control was preserved during the pandemic, despite small but significant increases in body weight, blood pressure, and insulin dose. Exploratory subgroup analyses suggested a less steep eGFR decline during the pandemic among participants with body mass index ≥25 kg/m[2] or those receiving renin-angiotensin system inhibitors; however, these findings should be interpreted as hypothesis-generating. In this multicenter cohort of individuals with T1D, the COVID-19 pandemic was not associated with accelerated eGFR decline overall.Clinical Trial Registry (CTR) registration: UMIN-CTR000047441.

Fructose-1,6-bisphosphatase (FBPase) deficiency is a rare autosomal recessive disorder of gluconeogenesis caused by the biallelic pathogenic variants of FBP1. Recurrent episodes of hypoglycemia and lactic acidosis usually occur during childhood. Because the ketone levels during hypoglycemic attacks may vary in patients with FBPase deficiency, differentiation from fatty acid oxidation disorders can be challenging. A urinary organic acid analysis during hypoglycemic attacks, particularly the detection of glycerol and glycerol-3-phosphate, in conjunction with plasma acylcarnitine profiling, is useful for distinguishing between these disorders. Furthermore, targeted next-generation sequencing-based multigene panels for hypoglycemia and related inherited metabolic disorders have become increasingly valuable diagnostic tools in this field. At the molecular level, a useful working model is to interpret FBP1 variants along three functional dimensions: protein abundance/stability, catalytic activity, and non-canonical restraint of AKT signaling. Within this framework, many missense variants fall into two major classes: variants that preserve protein abundance, but impair the catalytic activity and variants that reduce both protein abundance and the catalytic activity through defective folding. Selected C-terminal variants additionally disrupt the AKT-regulatory scaffolding function. Emerging experimental evidence suggests that FBP1 influences hepatic lipid accumulation, fibrosis, and tumorigenesis through mechanisms beyond its canonical role in gluconeogenesis. This review summarizes the clinical features, diagnosis, genetics, and management of FBPase deficiency, with particular emphasis on the functional interpretation of FBP1 variants and the broader biological roles of FBP1.

In Japan, GH treatment (GHT) is used for short stature associated with small for gestational age (SGA), Noonan syndrome (NS), Turner syndrome (TS), achondroplasia (ACH), and hypochondroplasia (HCH). However, real-world data on these diagnoses and GHT use for these conditions in Japan remain limited. In this retrospective cohort study, we used the JMDC claims database (2005-2021) to extract data of children with SGA-related short stature or diagnosed with short stature diseases, namely NS, TS, ACH, or HCH, particularly in boys aged <17 years and girls aged <15 years. We reported the prevalence, comorbidities, age at diagnosis, time from diagnosis to treatment initiation, persistence to GHT, and proportion of days covered (PDC). We analyzed data from children with SGA-related short stature (n = 786), NS (n = 79), TS (n = 172), ACH (n = 107), and HCH (n = 30); the mean (standard deviation) age at initial diagnosis was 5.2 (3.5), 4.0 (4.0), 6.5 (4.2), 3.0 (4.1), and 4.5 (3.9) years, respectively. The prevalence (per 100,000) was 59.59, 5.45, 9.52, 8.31, and 2.12 for SGA-related short stature, NS, TS, ACH, and HCH, respectively. Mean PDC for SGA-related short stature, NS, TS, ACH, and HCH was 0.918, 0.984, 0.953, 0.941, and 1.000, respectively, demonstrating high persistence to GHT. This study provides insights into the current diagnosis and GHT use among children with short stature in Japan. The findings suggest that most Japanese children continue and adhere well to GHT. However, continued efforts toward early referral and diagnosis remain crucial.

The glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor agonist tirzepatide is available clinically. Although real-world studies of tirzepatide in Japanese people with type 2 diabetes (T2D) have been reported, data regarding low-dose tirzepatide and patient-reported outcomes in routine clinical practice remain limited. In this multicenter retrospective observational study, we evaluated changes in glycemic control, body mass index (BMI), metabolic parameters, patient-reported outcomes, and adverse events after initiation of low-dose tirzepatide in Japanese people with T2D. Eighty-eight subjects with T2D treated with an average dose of tirzepatide of 4.5 ± 1.0 mg/week for 24 weeks were retrospectively analyzed. The primary outcomes were changes in glycated hemoglobin (HbA1c) and BMI from baseline to 24 weeks. HbA1c levels and BMI decreased over 24 weeks after initiation of low-dose tirzepatide (HbA1c, -1.5%; BMI, -1.5 kg/m[2]; both p < 0.001). Additionally, serum albumin was increased, and alanine transaminase and low-density lipoprotein cholesterol were decreased significantly. In multivariable regression analysis, higher baseline HbA1c was associated with greater HbA1c reduction. In exploratory cross-sectional analyses, post-treatment Diabetes Treatment Satisfaction Questionnaire (DTSQ) scores were associated with higher baseline HbA1c, and Kanden Institute Stigma Scale (KISS) scores were associated with higher baseline BMI. Major adverse events linked with tirzepatide were gastrointestinal symptoms. In this multicenter retrospective single-arm observational study, HbA1c and BMI decreased over 24 weeks after low-dose tirzepatide initiation in Japanese people with T2D. These findings suggest that low-dose tirzepatide may be a useful treatment option in selected patients in routine clinical practice, although causal inference is limited by the observational design and lack of a control group.Trial Registration: National University Hospital Medical Information Network (UMIN Clinical Trial Registry, UMIN000053671; approval date: March 1, 2024).

A woman in her thirties presented with progressive bone pain, muscle weakness, recurrent stress fractures, and delayed fracture healing. Laboratory investigations demonstrated hypophosphatemia, renal phosphate wasting, elevated fibroblast growth factor 23 (FGF23), and inappropriately low 1,25-dihydroxyvitamin D, leading to a diagnosis of FGF23-mediated tumor-induced osteomalacia (TIO) approximately one year after symptom onset. Bone scintigraphy demonstrated multiple fractures involving the ribs and pubic bones. [18F]-fluorodeoxyglucose positron emission tomography/computed tomography ([18F]-FDG PET/CT) identified mild uptake in the left femoral head/femoral neck region, and targeted magnetic resonance imaging (MRI) confirmed a well-defined 6-mm lesion with low signal intensity on T1- and T2-weighted images and high signal intensity on short tau inversion recovery images. Somatostatin receptor scintigraphy (SRS) showed no abnormal uptake. Systemic venous sampling (SVS) demonstrated elevated FGF23 levels in the left pelvic venous drainage region. CT-guided biopsy revealed a phosphaturic mesenchymal tumor (PMT) with FGF23 immunohistochemical positivity. Complete resection would likely have required hemiarthroplasty or total hip arthroplasty because of the tumor location, and the patient declined surgery. Burosumab was therefore initiated. At 24 weeks, serum phosphate increased from 1.5 to 4.1 mg/dL, alkaline phosphatase decreased from 145 to 100 U/L, generalized bone pain and gait disturbance improved markedly, pseudofracture-related uptake disappeared on bone scintigraphy, and lumbar-spine and femoral-neck bone mineral density (BMD) improved. This case shows that multimodal localization can identify micro-TIO lesions that may escape conventional strategies, and that FGF23 blockade can be clinically effective in a localized FGF23-positive 6-mm PMT when surgery is anatomically challenging or declined.

Acquired generalized lipodystrophy (AGL) is a rare disorder characterized by progressive loss of subcutaneous and visceral adipose tissue and severe metabolic disturbances, including diabetes mellitus (DM). Although AGL is typically associated with type 2 DM, clinical experience with patients affected by both AGL and Fulminant type 1 DM (FT1DM) remains limited. We report a case of a 50-year-old man with long-standing (4-year) FT1DM who developed AGL, with histopathological and immunological evaluation and long-term follow-up after metreleptin therapy. The patient presented with rapid deterioration of glycemic control and extreme insulin resistance, requiring a marked increase in insulin dose. Imaging studies revealed generalized loss of subcutaneous and visceral adipose tissue, and skin biopsy demonstrated marked adipose tissue atrophy with infiltration of CD3[+] (cluster of differentiation 3) and CD8[+] T lymphocytes. Notably, soluble interleukin-2 receptor (sIL-2R) levels remained persistently elevated for more than 12 months, suggesting sustained systemic T-cell activation. Although metreleptin therapy resulted in partial improvement in glycemic control, hemoglobin A1c (HbA1c) did not return to the pre-AGL level during follow-up. This case raises the possibility that persistent immune activation may contribute to insulin resistance beyond leptin deficiency in some patients with AGL.

The hindbrain plays a critical role in regulating feeding, glucose metabolism, and reproductive function during malnutrition, and our previous studies suggest that hindbrain ependymal cells lining the fourth ventricle (4V) potentially contribute to the physiological responses to hindbrain glucoprivation. The present study aimed to examine the effects of 4V ependymal denudation on counterregulatory responses to hindbrain glucoprivation. Neuraminidase, an enzyme that induces ependymal denudation, was administered into the 4V of ovariectomized rats implanted with a silicone tube containing a negative feedback level of estradiol-17β (OVX + low E2 rats) to generate an ependymal cell-disrupted model, whereas vehicle administration served as the control condition. Following 4V administration of neuraminidase or vehicle, OVX + low E2 rats received 4V administration of 2-deoxy-D-glucose (2DG), a glucose utilization inhibitor, or xylose as an osmotic control, and food intake, blood glucose levels, and luteinizing hormone (LH) concentrations were measured. Administration of 2DG into the 4V increased food intake in control rats, whereas this response was absent in rats with ependymal denudation. In contrast, 4V administration of 2DG increased blood glucose levels and suppressed LH secretion in both control rats and rats with ependymal denudation. Taken together, these findings indicate that 4V ependymal cells may, at least in part, contribute to feeding responses during hindbrain glucoprivation.

Glycogen storage disease type 1a (GSD1a) is characterized by hypoglycemia in childhood; however, cases complicated by diabetes in adulthood have increasingly been reported. The clinical phenotype of GSD1a appears heterogeneous, and insulin secretory capacity in the patients has not been fully characterized. Herein, we report the case of a 20-year-old woman with GSD1a who was initially diagnosed with type 2 diabetes in early adulthood. The patient's glycemic control gradually deteriorated despite administration of oral antidiabetic agents. Longitudinal evaluation using 75-g oral glucose tolerance tests demonstrated a marked decline in insulin secretion within 10 months. Based on these findings, insulin therapy was initiated, resulting in stable glycemic control. This case suggests that rapid β-cell decompensation occurs during the clinical course of early-onset diabetes in young patients with GSD1a.

Dysthyroid optic neuropathy (DON) is a severe, vision-threatening manifestation of thyroid eye disease. We conducted a retrospective descriptive case series of consecutive patients with DON treated with teprotumumab at a single center to evaluate functional, structural, magnetic resonance imaging (MRI)-based inflammatory, and safety outcomes. Six patients (10 eyes) were included. Eye-level outcomes were assessed at baseline and during follow-up using generalized estimating equations to account for within-patient correlation. The primary outcomes were best-corrected visual acuity (BCVA), expressed as logarithm of the minimum angle of resolution (logMAR) and summed cross-sectional area of the four rectus muscles (CSA). Secondary outcomes were proptosis and mean T2 signal intensity ratio (T2-SIR) of the four rectus muscles. Estimated marginal mean BCVA improved from 0.35 logMAR at baseline to 0.04 at 3 weeks, 0.05 at 12 weeks, and -0.08 at 24 weeks. Summed rectus CSA decreased from 2.11 cm[2] at baseline to 1.48 cm[2] at 12 weeks and 1.41 cm[2] at 24 weeks. Proptosis and mean T2-SIR also decreased during follow-up. Most non-hearing-related adverse events were mild; however, treatment was discontinued in one patient because of diarrhea and in another because of fatigue and tinnitus. American Speech-Language-Hearing Association (ASHA)-defined hearing threshold shifts were identified in at least one ear in all six patients. These findings suggest that teprotumumab was associated with early concordant improvement across functional, anatomic, and MRI-based inflammatory endpoints in patients with DON. Careful monitoring, particularly audiologic assessment, remains essential.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) carry a risk of euglycemic diabetic ketoacidosis (euDKA) during acute illness. We report an educational case of a 45-year-old man with type 1 diabetes (T1D) receiving ipragliflozin who developed severe euDKA precipitated by COVID-19. During this sick-day period, he independently discontinued basal insulin-partly because his continuous glucose monitoring (CGM) readings remained within the target range-while continuing ipragliflozin. He presented to the emergency department with worsening gastrointestinal symptoms. On arrival, although blood glucose was 246 mg/dL, venous blood gas revealed severe metabolic acidosis (pH 7.040, HCO3[-] 9.6 mmol/L) and 3+ urinary ketones. Remarkably, CGM data for the 48 hours prior to ambulance arrival showed a time in range of 71%, indicating clinically acceptable glycemic control. Quantitative analysis confirmed minimal glycemic variability (coefficient of variation 15.8%; mean amplitude of glycemic excursions 77 mg/dL). To our knowledge, this is one of the first reports to quantitatively characterize CGM data, demonstrating that favorable CGM metrics do not preclude a metabolic crisis. Although reimbursement for self-monitoring of blood ketones (SMBK) for patients with T1D receiving SGLT2i has been introduced in Japan, National Database reports reveal limited utilization and structural barriers, such as restrictions on test strip supplies. While promoting SMBK is important, the concept of euDKA remains difficult for patients to grasp. Therefore, clinicians must prioritize symptom-based sick-day rules over "normal" glucose numbers to prevent false reassurance from clinically acceptable CGM metrics. This case underscores the inherent limitations of glucose-centric monitoring and the necessity of multifaceted patient education.

Maternal high fasting plasma glucose (FPG) is a well-known risk factor for large-for-gestational-age (LGA) infants. However, this association remains unclear among Japanese women with gestational diabetes mellitus (GDM). Therefore, we examined this issue in Japanese women with GDM, accounting for body mass index (BMI). This retrospective study analyzed 543 Japanese women with GDM and evaluated the associations of 1-standard deviation (SD) increments in fasting, 1-hour, and 2-hour plasma glucose and HbA1c levels with LGA. LGA was defined as birth weight above the 90th percentile for gestational age. Multivariable logistic regression was used to estimate ORs and 95% CIs for LGA per 1-SD increment in fasting, 1-hour, and 2-hour plasma glucose and HbA1c. Model 1 was adjusted for maternal age, smoking, family history of diabetes, insulin use, parity, gestational age at delivery, gestational age at diagnosis, and gestational weight gain; Model 2 was additionally adjusted for pre-pregnancy BMI. The prevalence of LGA was 9.6%. In model 1, the FPG was independently and positively associated with LGA (adjusted OR 1.44, 95% CI: 1.07-1.94). The area under the receiver operating characteristic (ROC) curve for FPG in discriminating LGA was 0.692, with an optimal cutoff of 86.0 mg/dL. After additional adjustment for pre-pregnancy BMI (model 2), FPG was no longer associated with LGA. Other glycemic parameters were not associated with low birth weight, small-for-gestational-age, or LGA. FPG at GDM diagnosis may provide limited discriminatory information for LGA. However, its association with LGA was attenuated after adjustment for pre-pregnancy BMI.