Endocrine journal最新文献

Type 2 diabetes mellitus (T2DM) is a persistent condition typically defined by prolonged hyperglycemia resulting from beta-cell impairment and insulin resistance. Glucokinase activators (GKAs) are new medications that target glucokinase (GK) to increase glucose utilization in both the pancreas and liver. Its effectiveness and safety are inconsistent across various doses and types. The meta-analysis assessed the effectiveness and safety of GKAs in T2DM on glycemic control (hemoglobin A1c [HbA1c], fasting plasma glucose [FPG], postprandial plasma glucose [PPG]) as well as metabolic parameters (lipids, body weight, safety outcomes) stratified by dosage, type, and intervention time. The study involved a comprehensive analysis of 3,854 participants drawn from 11 randomized controlled trials (RCTs). Standardized mean differences (SMDs) and risk ratios (RRs) were computed employing random-effects models, alongside conducting sensitivity and subgroup analyses. GKAs effectively lowered HbA1c and PPG, especially high-dose (HbA1c: SMD = -0.43, 95% CI: -0.62 to -0.24) and dual-acting GKAs. Medium and high-dose GKAs were associated with increased risk of hypoglycemia (RR = 1.50; 1.63). At 24 weeks, GKAs led to increases in triglycerides, body weight, and liver enzymes, with the majority of these effects subsiding by 52 weeks. GKAs provide favorable glycemic control but carry dose-dependent concerns. While dual-acting GKAs demonstrate impressive efficacy, hepatoselective GKAs reveal improved safety. There exists a pressing need for further longitudinal studies and customized treatment approaches concerning the utilization of GKAs.PROSPERO registration: CRD42020188517.

Impaired linear growth is an important morbidity in childhood cancer survivors (CCS); however, chemotherapy-associated factors that affect height outcomes remain elusive. Accordingly, we conducted a single-center, retrospective cohort study that included survivors of childhood-onset acute lymphoblastic leukemia (ALL) diagnosed between 2002 and 2021 who achieved complete remission through chemotherapy alone. Anthropometric parameters and treatment protocols were evaluated based on medical records. Individuals with background disorders or impaired growth were excluded from the study. Associations between anthropometric parameters during chemotherapy and height standard deviation scores (height-SDS) at the current visit were investigated. The results are expressed as the median (interquartile range). Seventy-three individuals (males, N = 44) were included in the study. The median age (years) at diagnosis, end of chemotherapy, and current visit were 4.2 (3.2 to 7.9), 6.3 (5.1 to 10.0), and 15.9 (11.4 to 19.2), respectively. Height-SDS at diagnosis was -0.25 (-0.65 to 0.35), which significantly declined during chemotherapy and recovered thereafter, resulting in a current height-SDS of -0.31 (-0.84 to 0.22). The height-SDS at the investigated time points and its changes during chemotherapy did not differ among the treatment protocols. Multivariate analysis revealed that height-SDS at the current visit was positively associated with changes in body mass index (BMI)-SDS during chemotherapy (β = 0.22, p = 0.01) after adjusting for sex, current age, height-SDS at diagnosis, changes in height-SDS during chemotherapy, and treatment protocols. Since changes in BMI are potentially influenced by nutritional status, our results may underscore the importance of nutritional status during chemotherapy on height outcomes in childhood ALL survivors.

Sarcomatoid adrenal cortical carcinoma (SACC) is an extremely rare histological subtype accounting for only 0.2% of all adrenal cortical carcinomas. Most reported cases of SACC are nonfunctional, showing a biphasic histological pattern with both epithelial adrenocortical carcinoma and sarcomatous components, which are often associated with poor prognosis. Herein, we report a unique case of SACC with characteristics distinct from those previously documented. A 66-year-old man presented with uncontrolled hypertension, night sweats, exertional dyspnea, and palpitations. Imaging revealed an 11 cm mass in the left adrenal gland. Laboratory results indicated hypokalemia with suppressed plasma renin and aldosterone levels and the presence of mineralocorticoid intermediates, notably elevated deoxycorticosterone (DOC), detected via LC-MS/MS. The patient underwent a left adrenalectomy. Histologically, the tumor consisted solely of spindle cells without the typical adrenocortical carcinoma components. Immunohistochemical analysis demonstrated partial positivity for steroidogenic enzymes, including 3β-hydroxysteroid dehydrogenase, cytochrome P450 family 21 subfamily A member 2 (CYP21A2) and cytochrome P450 family 11 subfamily B member 1 (CYP11B1). This finding was consistent with RNA expression analysis, supporting the synthesis of mineralocorticoid intermediates within the tumor. However, the discrepancy between the measured steroid intermediate metabolites and enzyme expression patterns in the tumor, as indicated by immunostaining and mRNA levels, suggests that the steroid production pathway in this tumor remains partially unclear. Two years postoperatively, the patient has remained free from recurrence or metastasis. This case holds particular value, as it is the first report to describe hormone production in a SACC composed solely of spindle cells.

When adrenal incidentalomas are detected, diagnostic procedures are complicated by the need for endocrine-stimulating tests and imaging using various modalities to evaluate whether the tumor is a hormone-producing adrenal tumor. This study aimed to develop a machine-learning-based clinical model that combines computed tomography (CT) imaging and clinical parameters for adrenal tumor classification. This was a retrospective cohort study involving 162 patients who underwent hormone testing for adrenal incidentalomas at our institution. Nominal logistic regression analysis was used to identify the predictive factors for hormone-producing adrenal tumors, and three random forest classification models were developed using clinical and imaging parameters. The study included 55 patients with non-functioning adrenal tumors (NFAT), 44 with primary aldosteronism (PA), 22 with mild autonomous cortisol secretion (MACS), 18 with Cushing's syndrome (CS), and 23 with pheochromocytoma (Pheo). A random forest classification model combining the adrenal tumor diameter on CT, early morning hormone measurements, and several clinical parameters was constructed, and showed high diagnostic accuracy for PA, Pheo, and CS (area under the curve: 0.88, 0.85, and 0.80, respectively). However, sufficient diagnostic accuracy has not yet been achieved for MACS. This model provides a noninvasive and efficient tool for adrenal tumor classification, potentially reducing the need for additional hormonal stimulation tests. However, further validation studies are required to confirm the clinical utility of this method.

Hepatic carbohydrate and lipid metabolism is strictly regulated by hormones such as insulin, glucagon, cortisol, and adrenaline, dynamically adapting to diet and stress. Metabolic zonation, a key feature of liver function, has been studied for decades. It refers to the spatial arrangement of hepatocytes with distinct metabolic roles along the portal-to-central vein axis, shaped by nutrient and oxygen gradients, as well as signaling molecules. However, traditional methods have struggled to reveal the spatial regulation of gene expression and signaling within these zones. Recent advances in single-cell and spatial omics technologies now allow detailed analysis of gene expression, signaling pathways, and cell-cell interactions with spatial resolution, providing new insights beyond classical models. Metabolic zonation research is rapidly advancing, and the concept of immune zonation, describing the spatial distribution of immune cells, has gained attention for its role in liver metabolism. These findings have improved our understanding of metabolic changes in conditions like fatty liver disease and diabetes. However, many questions remain, including the dynamic effects of diet and hormones and disease-related alterations. This review summarizes past and recent findings on metabolic zonation, explores the role of immune zonation and hormonal regulation, and discusses the latest technologies and future challenges.

Twin studies offer a powerful approach for disentangling genetic and environmental influences on human traits. By comparing monozygotic twins with identical genetic makeup, researchers can more accurately identify the environmental contributions to phenotypic variation. Structural equation modeling provides a theoretical framework for estimating the relative contributions of additive genetic effects, shared environmental factors, and unique environmental influences. This model allows researchers to determine the most suitable parameters for explaining the observed data in twin populations. In addition, bioinformatic tools enable in-depth analyses of phenotypically discordant monozygotic twin pairs, helping to uncover both environmental sensitivities and genetic predispositions. This review examines the advantages and limitations of twin study methodologies in research on endocrine disorders, lipid metabolism, and thyroid function. Findings from twin cohorts have enhanced our understanding of heritability, environmental modifiers, and epigenetic factors, offering valuable insights into gene-environment interactions. Overall, twin studies remain critical tools in genetics, endocrinology, and obesity research. In the future, genetic information may enable the development of optimal personalized environments, ultimately providing valuable insights that contribute to physical, mental, and social well-being throughout the lifespan.

Hypercalcemia is an oncologic metabolic emergency in cancer patients, primarily caused by local osteolytic hypercalcemia and humoral hypercalcemia of malignancy. Hormones associated with oncologic metabolic emergency include parathyroid hormone and parathyroid hormone-related peptide (PTHrP), but 1,25-dihydroxyvitamin D (1,25(OH)₂D) is rarely the cause. We report the case of an 87-year-old man with hypercalcemic crisis owing to 1,25(OH)₂D overproduction from a high-grade intranasal non-intestinal-type adenocarcinoma. 1,25(OH)₂D and corrected Ca levels normalized after tumor resection and did not re-elevate subsequently. Serum PTH was suppressed and PTHrP not detected, suggesting the hypercalcemia was not due to the PTH pathway. Immunohistochemistry for CYP27B1, a key enzyme that converts 25-hydroxyvitamin D (25(OH)D) to 1,25(OH)₂D, showed positivity in the cytosol of about 20% of tumor cells, but only about 1% of the macrophages. On the other hand, CYP24A1, a 1,25(OH)₂D-degrading enzyme, was diffusely expressed in the cytosol of about 80% of tumor cells. These findings may suggest overproduction of CYP27B1 mRNA. The balance between synthesis and degradation of 1,25(OH)₂D in tumor tissue is thought to be implicated in the development of 1,25(OH)₂D-producing solid tumors. Further case accumulation and studies will be needed to confirm this hypothesis. Nonetheless, in diagnosing 1,25(OH)₂D-producing solid tumors, it is important to evaluate not only CYP27B1 expression but also CYP24A1.

Body mass index (BMI) can be used to define obesity-a global health concern and a risk factor for various complications. However, it does not accurately represent body composition. Furthermore, a correlation between BMI and the frequency of comorbidities in patients with acromegaly, a condition that affects body composition, remains unclear. This study aimed to investigate the association between BMI and frequency of metabolic complications in patients with acromegaly. This single-center, retrospective, cross-sectional study included patients with untreated acromegaly. The patients were divided into two groups: BMI <25 kg/m² and BMI ≥25 kg/m², and the prevalence of metabolic complications was compared between the groups. Of the 66 patients, the BMI <25 kg/m² group included 39 patients (BMI: 22.7 [20.0-24.1], insulin-like growth factor-1 [IGF-1] standard deviation score [SDS]: 6.7 [4.7-7.9]), and the BMI ≥25 kg/m² group included 27 patients (BMI: 27.6 [25.9-29.8], IGF-1 [SDS]: 8.5 [6.0-10.2]). The prevalence of metabolic complications did not differ between the groups, except for a lower incidence of fatty liver in the BMI <25 kg/m² group (8% vs. 29%, p = 0.04). In these patients, BMI was positively correlated with serum IGF-1 levels (r = 0.29, p = 0.01). Our results suggest that BMI is not useful in predicting metabolic complications in individuals with acromegaly, except for fatty liver disease.

Immune cells undergo substantial metabolic rewiring during differentiation and activation to satisfy the energy demands of an appropriate immune response. Lipids serve as energy sources and function as essential components of cellular membranes and signaling molecules. Recent studies have revealed that reprogramming of lipid metabolism, including lipid uptake, de novo synthesis of cholesterol and fatty acids, and fatty acid oxidation, leads to dynamic alterations in the quantity and quality of intracellular lipids. These metabolic changes play crucial roles in shaping immune cell functions, promoting anti-inflammatory responses, and facilitating the resolution of inflammation. Conversely, dysregulation of lipid metabolism can result in immune cell dysfunction, contributing to the onset and progression of chronic inflammatory diseases such as autoimmune diseases and metabolic syndrome. Notably, cholesterol and fatty acid metabolism influence immune responses by modulating membrane lipid composition and downstream inflammatory signaling. Given these insights, targeting lipid metabolism has emerged as a promising therapeutic approach for restoring immune homeostasis and treating chronic inflammatory diseases.

Rising nicotinamide adenine dinucleotide (NAD⁺) levels mitigate the onset and progression of age-related diseases including metabolic disorders. Several studies have demonstrated that NAD⁺ levels can be efficiently replenished via nicotinamide mononucleotide (NMN) intake and thereby prevent metabolic disorders. However, the acute effects of NMN administration on metabolism remain unclear. We observed metabolic dynamics after a single bolus injection of NMN. Sirt1 and Nampt mRNA levels were increased in the liver suggesting that intracellular NAD⁺ increased after injection. During OGTT, glucose tolerance and insulin secretion did not change significantly in response to NMN administration, while during ITT, increased insulin sensitivity was observed in muscle. NMN administration decreased serum non-esterified free fatty acid (NEFA) concentrations, which would presumably be responsible for the increased muscle insulin sensitivity. Furthermore, NMN administration reduced the respiratory quotient, confirming that NMN promotes utilization of lipids as an energy source. Our data demonstrate acute effects of NMN on metabolism and raise the possibility of NMN as a treatment for metabolic disorders.