Endocrine Journal
Online ISSN : 1348-4540
Print ISSN : 0918-8959
ISSN-L : 0918-8959
Advance online publication
Displaying 1-24 of 24 articles from this issue
  • Akiho Yamashita, Masayuki Kaku, Takuya Ideguchi, Shuhei Nishida, Hiroy ...
    Article type: Original
    Article ID: EJ24-0486
    Published: 2025
    Advance online publication: February 05, 2025
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION

    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.

    Download PDF (1974K)
  • Yuji Hataya, Yuko Fujishima, Kanta Fujimoto, Toshio Iwakura, Naoki Mat ...
    Article type: Note
    Article ID: EJ24-0417
    Published: 2025
    Advance online publication: February 01, 2025
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION

    Serum thyroglobulin (Tg) levels are highly sensitive and specific tumor markers in patients with thyroid cancer who have undergone total thyroidectomy and radioiodine (RAI) therapy. Recently, we reported a case wherein serum Tg levels fluctuated according to hemoglobin A1c (HbA1c) levels, demonstrating a strong correlation between serum Tg and HbA1c levels. However, whether this association exists broadly in other patients with thyroid cancer remains unclear. Therefore, we retrospectively investigated this association in six patients with thyroid cancer and diabetes who underwent total thyroidectomy and RAI therapy at our institution. Two patients exhibited a significant correlation between serum Tg and HbA1c levels (r = 0.53, p < 0.01 and r = 0.66, p = 0.01). In these patients, a gradual decrease in serum Tg levels was observed, along with improved glycemic control. Two other patients showed a non-significant correlation between serum Tg and HbA1c levels (r = 0.72, p = 0.11 and r = 0.54, p = 0.17). In these patients, a rapid increase in serum Tg levels was observed, with HbA1c levels showing only small fluctuations. In the remaining two patients, no correlation was found; in these patients, the fluctuations in serum Tg levels were only small, despite fluctuations in HbA1c levels. In conclusion, serum Tg levels may be associated with HbA1c levels in some patients with thyroid cancer and diabetes. The correlation between serum Tg and HbA1c levels was more evident in patients with gradual fluctuations in Tg levels. Future studies with larger cohorts are necessary to clarify the underlying mechanism by which glycemic control influences Tg levels and establish appropriate monitoring methods.

    Download PDF (3217K)
  • Shih-Peng Mao, Chen-Yu Wang, Chi-Hao Liu, Chung-Bao Hsieh, Dee Pei, Ta ...
    Article type: Original
    Article ID: EJ24-0449
    Published: 2025
    Advance online publication: February 01, 2025
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION

    Insulin resistance (IR) is the core for type 2 diabetes and metabolic syndrome. The homeostasis assessment model is a straightforward and practical tool for quantifying insulin resistance (HOMA-IR). Multiple adaptive regression spline (MARS) is a machine learning method used in many research fields but has yet to be applied to estimating HOMA-IR. This study uses MARS to build an equation to estimate HOMA-IR in pre-menopausal Chinese women based on a sample of 4,071 healthy women aged 20–50 with no major diseases and no medication use for blood pressure, blood glucose or blood lipids. Thirty variables were applied to build the HOMA-IR model, including demographic, laboratory, and lifestyle factors. MARS results in smaller prediction errors than traditional multiple linear regression (MLR) methods, and is thus more accurate. The model was established based on key impact factors including waist-hip ratio (WHR), C reactive protein (CRP), uric acid (UA), total bilirubin (TBIL), leukocyte (WBC), serum glutamic oxaloacetic transaminase (GOT), high-density lipoprotein cholesterol (HDL-C), systolic blood pressure (SBP), serum glutamic pyruvic transaminase (GPT), and triglycerides (TG). The equation is as following:

    HOMA-IR = 6.634 – 1.448MAX(0, 0.833 – WHR) + 10.152MAX(0, WHR – 0.833) – 1.351MAX(0, 0.7 – CRP) – 0.449MAX(0, CRP – 0.7) + 1.062MAX(0, UA – 8.5) + +1.047(MAX(0, 0.83 – TBIL) + 0.681MAX(0, WBC – 11.53) – 0.071MAX(0, 11.53 – WBC) + 0.043MAX(0, 24 – GOT) – 0.017MAX(0, GOT – 24) + 0.021MAX(0, 59 – HDL) – 0.005MAX(0, HDL – 59) – 0.013MAX(0, 141 – SBP) – 0.033MAX(0, 100 – GPT) + 0.013MAX(0, GPT – 100) – 0.004MAX(303 – TG)

    Results indicate that MARS is a more precise tool than fasting plasma insulin (FPI) levels, and could be used in the daily practice, and further longitudinal studies are warranted.

    Download PDF (2900K)
  • Yusuke Shibata, Ako Oiwa, Hiroki Tanaka, Satoshi Kubota, Ken-ichi Ito, ...
    Article type: Original
    Article ID: EJ24-0494
    Published: 2025
    Advance online publication: February 01, 2025
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION

    Although antithyroid drugs (ATDs) are the first-line treatment for patients with Graves’ disease (GD) in Japan and other countries, some patients do not achieve remission due to drug resistance, leading to surgery. Even if ATD doses are increased, they often have uncontrolled thyroid function and enlarged goiters, necessitating high-risk emergency surgical treatment. In this study, we aimed to identify the characteristics of patients resistant to ATDs who underwent thyroidectomy and those who achieved remission. We retrospectively analyzed 45 patients with GD who underwent thyroidectomy and 73 patients who achieved remission with ATDs at Shinshu University Hospital between April 1, 2015 and September 30, 2023. In patients who underwent surgery, the drug-resistant patients (DR group; n = 15) had longer disease durations (8.0 vs. 3.0 years, respectively; p = 0.013), higher free triiodothyronine (FT3) / free thyroxine (FT4) ratios (5.54 vs. 3.52, respectively; p = 0.005), higher anti-TSH receptor antibody (TRAb) levels (39.16 vs. 13.31 IU/L, respectively; p = 0.002), and larger thyroid glands (251.00 vs. 54.80 g, respectively; p < 0.001) than non-drug-resistant patients (NDR group; n = 30). Compared with patients who achieved remission with ATDs (Remission group; n = 73), the DR group had higher FT3/FT4 ratios (5.54 vs. 2.99, respectively; p < 0.001) and higher TRAb levels (39.16 vs. 5.9 IU/L, respectively; p < 0.001). Notably, most of the patients in the DR group had a combination of these factors. This suggests that in patients with large thyroid, high FT3/FT4 ratios, and high TRAb levels, early consideration of definitive-curative treatment such as surgery or RI therapy may be warranted instead of continuing prolonged ineffective ATDs treatment.

    Download PDF (1723K)
  • Noriko Kimura, Koji Muroya, Masato Yonamine, Kazuhiro Takekoshi, Takes ...
    Article type: Original
    Article ID: EJ24-0584
    Published: 2025
    Advance online publication: February 01, 2025
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION

    Pediatric patients with pheochromocytoma (PCC)/paraganglioma (PGL) (PPGL) are rare, and clinicopathological investigations, especially the relationship between gene analysis and histological features, are insufficient. We comprehensively examined the clinical data, germline/somatic variants (mutations), and pathological characteristics of operated tumors using immunohistochemical expression and histological grading by Grading of Adrenal PCC and PGL score. This study included 28 patients (15 males and 13 females) aged <19 years. The age at the diagnosis was 12.8 ± 4.5 years. The included patient often had multiple PPGLs, with 39 tumors, including 21 PCCs and 18 PGLs, with average tumor sizes of 45.0 ± 22.8 and 42.6 ± 23.6 mm, respectively. Genomic types examined by gene mutations and immunohistochemistry of CA9 for VHL, SDHB for SDHx, and MAX for MAX, classified them into 14 VHL (50%), ten SDHx (35.7%), one MAX (3.6%), and three unknown (10.7%) types. Tumor metastasis was limited to two SDHB-related PPGLs, but not to VHL-related PPGLs. In both patients, the metastatic sites were the bones. The average GAPP score of the PPGLs was 2.9 ± 1.5 in VHL and 5.3 ± 1.7 in SDHB, and histological grades were well-differentiated in VHL and moderately differentiated in SDHB. SSTR2 expression was positive in 90% of SDHB-related PPGLs, but negative in 75% and weakly or focally positive in 25% of VHL-related PPGLs. Most pediatric PPGLs (90%) demonstrated mutations in VHL, SDHB, and MAX, with histological features depending on the mutation type. Combined genetic and immunohistochemical examination is desirable for accurate genomic diagnosis, and clinicopathological study.

    Download PDF (13590K)
  • Seiji Nishikage, Masaaki Yamamoto, Takahiro Niikura, Yuiko Inaba, Tomo ...
    Article type: Case Report with Review of Literature
    Article ID: EJ24-0431
    Published: 2025
    Advance online publication: January 29, 2025
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION

    The use of asfotase alfa, a bone-targeted recombinant alkaline phosphatase (ALP) enzyme, for the treatment of adult-onset hypophosphatasia (HPP) remains controversial, particularly in patients without evident bone abnormalities. We report the case of a 41-year-old woman with a history of Graves’ disease, who presented with progressive joint pain and severe fatigue. Despite the absence of bone lesions, the patient was diagnosed with HPP based on persistently low alkaline phosphatase levels, family history, and a novel heterozygous ALPL variant (p.Ala205Thr). Functional analysis revealed a dominant-negative effect for this variant. Her symptoms significantly interfered with her daily activities owing to uncontrolled pain and loss of motor function and were so exacerbated that high doses of acetaminophen and NSAIDs were ineffective. Treatment with asfotase alfa was initiated based on multidisciplinary team consensus. Within 3 months of treatment initiation, her pain improved significantly, as indicated by reduced scores on the visual analog scale from 6.6 to 0.9, and elimination of the need for analgesics. Additionally, her grip strength increased, and her urinary phosphoethanolamine levels and serum pyridoxal 5'-phosphate/pyridoxal ratio decreased from 90.4 to 57.8 μmol/g·creatinine and from 4.6 to 0.4, respectively. These improvements have been maintained for more than 2 years. This case highlights the potential of asfotase alfa in effectively alleviating symptoms in patients with adult-onset HPP without bone lesions, emphasizing the importance of patient selection and outcome monitoring. We also discuss the key considerations for future treatment, supported by a literature review of asfotase alfa in adult patients with HPP.

    Download PDF (2001K)
  • Ai Yoshihara, Jaeduk Yoshimura Noh, Kosuke Inoue, Masakazu Koshibu, Re ...
    Article type: Original
    Article ID: EJ24-0578
    Published: 2025
    Advance online publication: January 23, 2025
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION

    We investigated the association between a 500 MBq dose of radioactive iodine treatment (RAIT) and both thyroid nodule volume and thyroid function in patients with a single autonomous functioning thyroid nodule (AFTN). We retrospectively studied 201 patients with an AFTN who received RAIT at a dose of 500 MBq and were followed up for more than 2 years. Thyroid function at diagnosis, thyroid antibody positivity, treatment with antithyroid drugs before RAIT, cystic components of the nodule, and 131I uptake outside the nodule were assessed. Nodule enlargement was observed in 18 patients (9%), persistent hyperthyroidism in 13 patients (6.5%), and hypothyroidism in 45 patients (22.3%). Nodule volume before RAIT was significantly larger in the nodule enlargement group compared to the non-enlargement group. The risk factors for persistent hyperthyroidism were larger nodule volume and absence of a cystic component in multivariate analysis. The cutoff nodule volume before RAIT for predicting nodule enlargement was 15.5 mL, and for predicting persistent hyperthyroidism was 16.6 mL. Nodule volume decreased to 47% in the first year and continued to gradually decrease thereafter. This study provided long-term outcome data regarding nodule volume change and thyroid function in AFTN patients following single fixed-dose RAIT, and it identified risk factors for nodule enlargement and persistent hyperthyroidism after RAIT. Nodule volume before treatment was a good predictor of treatment response.

    Download PDF (1631K)
  • Yuki Taki, Takashi Kono, Tatsuma Matsuda, Ryunosuke Kozu, Masanori Fuj ...
    Article type: Case Report with Review of Literature
    Article ID: EJ24-0548
    Published: 2025
    Advance online publication: January 22, 2025
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION

    Pasireotide (PAS), a multireceptor somatostatin analog, has been demonstrated to effectively control hormone levels, including those of growth hormone (GH) and insulin-like growth factor 1 (IGF-1), in patients with acromegaly. However, it induces hyperglycemia by inhibiting insulin secretion via somatostatin receptor 5 (SSTR5). Despite the extensive literature on the occurrence of PAS-induced hyperglycemia, there is still no consensus on the optimal first-line treatment for this complication. Herein, we present two cases of acromegaly treated with PAS and highlight its short- and long-term effects on glucose metabolism. In the first case, postprandial hyperglycemia manifested rapidly following the commencement of PAS treatment and was effectively managed with dulaglutide under continuous glucose monitoring (CGM). In the second case, long-term PAS therapy resulted in a dose-dependent glycemic response that was controlled by different GLP-1 receptor agonists (GLP-1RAs), including semaglutide. CGM facilitated the early detection of significant glycemic fluctuations, underscoring the necessity for close monitoring in patients receiving PAS therapy. These cases demonstrate the efficacy of GLP-1RAs in managing PAS-induced hyperglycemia and highlights the value of CGM in early detection and intervention. Our findings suggest that GLP-1RAs, particularly semaglutide, are a valuable treatment option for this condition. Further research is needed to determine the optimal treatment strategy, particularly in East Asian populations, and to establish a clear consensus on the first-line therapy for PAS-induced hyperglycemia.

    Download PDF (9339K)
  • Tomomi Taguchi, Shiori Ito, Rei Fujishima, Naoya Shimizu, Wataru Hagiw ...
    Article type: Original
    Article ID: EJ24-0481
    Published: 2025
    Advance online publication: January 09, 2025
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION

    Adult growth hormone deficiency (AGHD) is often accompanied with metabolic dysfunction-associated steatotic liver disease (MASLD). Although some studies reported that MASLD is ameliorated by growth hormone replacement therapy (GHRT), the characteristics of AGHD that are associated with an improvement of hepatic steatosis by GHRT remain unknown. We aimed to investigate whether GHRT affects hepatic lipid accumulation as well as biochemical parameters, and investigated the association between these parameters (UMIN000044989). Thirty people with AGHD were recruited, and assigned to either the GHRT group or the non-GHRT group. Serum laboratory data were analyzed before and after GHRT. Hepatic lipid content was evaluated using magnetic resonance imaging-proton density fat fraction (MRI-PDFF). Correlations between MRI-PDFF and other clinical parameters were investigated. Twenty-nine people completed this study (19 in the GHRT group and 10 in the non-GHRT group). In the GHRT group, significant decreases in MRI-PDFF and serum levels of aspartate aminotransferase, alanine aminotransferase, and γ-glutamyl transpeptidase were observed after the treatment. The decrease in MRI-PDFF levels after GHRT significantly correlated with initial MRI-PDFF, triglyceride (TG), lactate dehydrogenase, and ALT levels, and age. Multiple regression analysis demonstrated that younger age and high serum TG levels were independent predictors of a decrease in MRI-PDFF levels. GHRT in people with AGHD significantly reduced lipid accumulation in the liver on MRI, and improved serum liver parameters. Age and serum TG levels were found to be associated with the effectiveness of GHRT.

    Download PDF (1430K)
  • Yuichiro Iwamoto, Shuhei Nakanishi, Masahiro Komi, Yuto Kimura, Yuki W ...
    Article type: Original
    Article ID: EJ24-0397
    Published: 2025
    Advance online publication: January 07, 2025
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION

    Nerve conduction studies (NCS) are the standard method for diagnosing diabetic polyneuropathy. Because a clear association between handgrip strength and diabetic neuropathy can serve as a screening tool, the present study evaluated the association between handgrip strength and NCS and diabetes-related complications. A total of 436 patients with type 2 diabetes (T2D) who were admitted to our hospital between April 1, 2018 and March 31, 2023, and evaluated using Baba’s diabetic neuropathy classification (BDC) were included. The participants were grouped by sex using the grip strength tertile method to assess correlations with the prevalence of diabetic microvascular complications in the high-handgrip group (HG), middle-handgrip group (MG), and low-handgrip group (LG). The percentage of BDC-0 was 65% in the HG, 54% in the MG, and 36% in the LG. Furthermore, none of the participants in the HG had BDC-3/4, whereas 4% in the MG and 15% in the LG had BDC-3/4. The morbidity progression of diabetic neuropathy was seen in the order of LG, MG, and HG (p < 0.001). Patients with T2D and advanced diabetic neuropathy had decreased handgrip strength. Early evaluation of BDC and other NCS should be considered if decreased handgrip strength is evident.

    Download PDF (1814K)
  • Fangfang Wu, Lixia Wang, Hongju Zuo, Hanbing Tian
    Article type: Original
    Article ID: EJ24-0440
    Published: 2025
    Advance online publication: January 07, 2025
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION

    Nerve aberrations and vascular lesions in the distal lower limbs are the etiological factors for diabetic foot ulcers (DFUs). This study aimed to understand the regulatory mechanism of angiogenesis in patients with DFU by examining lncRNA, as well as to explore effective targets for diagnosing and treating DFU. The serum levels of A1BG-AS1 and miR-214-3p and the predictive power of A1BG-AS1 for DFU were determined by quantitative PCR and ROC analysis. The correlation of A1BG-AS1 with clinical characteristics was examined using chi-square tests. The risk factors for DFU in patients with type 2 diabetes mellitus (T2DM) were identified using the logistic regression model. Furthermore, the binding sites of A1BG-AS1 and miR-214-3p were determined. Next, A1BG-AS1 interference plasmid and miR-214-3p inhibitor were co-transfected into high glucose-induced cells to investigate their effects on the expression of angiogenesis-related genes and cell proliferation. The A1BG-AS1 levels were upregulated, whereas the miR-214-3p levels were downregulated in patients with DFU. The upregulation of A1BG-AS1 was significantly associated with both blood glucose levels and ulcer grades. A1BG-AS1 served as a crucial biomarker for diagnosing DFU and evaluating the risk of DFU occurrence in patients with T2DM. Co-transfection experiments revealed that the inhibition of miR-214-3p effectively recovered the suppressive effects of A1BG-AS1 on angiogenesis-related gene expression, endothelial cell differentiation, and proliferation. The sponging effect of A1BG-AS1 on miR-214-3p impaired angiogenesis in patients with DFU. Thus, A1BG-AS1 is a potential therapeutic target for DFU.

    Download PDF (3062K)
  • Katsuya Sakai, Yuki Nakazato, Yuki Shiimura, Weidong Zhang, Masamitsu ...
    Article type: State-of-the-Art Review in Endocrinology
    Article ID: EJ24-0543
    Published: 2024
    Advance online publication: December 27, 2024
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION

    Ghrelin produced in the stomach promotes food intake and GH secretion, and acts as an anabolic peptide during starvation. Ghrelin binds to the growth hormone secretagogue receptor, a G protein-coupled receptor (GPCR), whose high-resolution complex structures have been determined in the apo state and when bound to an antagonist. Anamorelin, a low-molecular-weight ghrelin agonist, has been launched in Japan for the treatment of cancer cachexia, and its therapeutic potential has attracted attention due to the various biological activities of ghrelin. In 2019, liver-expressed antimicrobial peptide (LEAP2), initially discovered as an antimicrobial peptide produced in the liver, was identified to be upregulated in the stomach of diet-induced obese mice after vertical sleeve gastrectomy. LEAP2 binds to the GHSR and antagonizes ghrelin’s activities. The serum concentrations of human LEAP2 are positively correlated with body mass index, body fat accumulation, and fasting serum concentrations of glucose and triglyceride. Serum LEAP2 elevated and ghrelin reduced in obesity. Ghrelin and LEAP2 regulate body weight, food intake, and GH and blood glucose concentrations, and other physiological phenomena through their interactions with the same receptor, GHSR.

    Download PDF (2869K)
  • Kazuhisa Akiba, Keiko Matsubara, Atsushi Hattori, Maki Fukami
    Article type: Case Report with Review of Literature
    Article ID: EJ24-0355
    Published: 2024
    Advance online publication: December 21, 2024
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION
    Supplementary material

    Over 70 intragenic copy-number variations (CNVs) of PHEX have been identified in patients with X-linked hypophosphatemia (XLH). However, the underlying mechanism of these CNVs has been poorly investigated. Furthermore, although PHEX undergoes X chromosome inactivation (XCI), the association between XLH in women with heterozygous PHEX variants and skewed XCI remains unknown. In this study, we determined the precise genomic structure and the XCI status of a girl with XLH who showed short stature and bowing of the legs at 2 years old. Laboratory tests revealed low levels of serum phosphate and elevated levels of alkaline phosphatase and fibroblast growth factor 23. Multiplex ligation-dependent probe amplification and targeted long-read sequencing revealed that she carried a 24.6-kb intragenic duplication of PHEX. The duplication was tandemly aligned in a head-to-tail orientation. The duplication breakpoints shared a 2-bp microhomology, indicating that this CNV resulted from a replication-based error. Trio sequencing results showed that the duplication was a de novo CNV that occurred on the paternally-derived allele. DNA methylation analysis demonstrated random XCI. A literature review of 12 previously reported cases of intragenic CNVs of PHEX revealed that the deletions/duplications can be ascribed to replication-based errors. Our findings and those of previous studies indicate that XLH-causative CNVs in PHEX predominantly arise from replication-based errors. Thus, the genomic region surrounding PHEX may be vulnerable to replication-based errors during gametogenesis or early embryogenesis. Our study provides supporting evidence that heterozygous PHEX variants can lead to XLH in women with random XCI.

    Download PDF (2694K)
  • Lou-yan Ma, Song-fang Liu, Zheng-quan Ma, Ya-gang Guo, Mo Li, Yuan Gao ...
    Article type: Original
    Article ID: EJ23-0723
    Published: 2024
    Advance online publication: December 07, 2024
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION

    Diabetes has been regarded as an independent risk factor for Alzheimer’s disease (AD). Liraglutide could improve cognition in AD mouse models, but its precise mechanism remains unclear. In this study, we used STZ-induced diabetic rats and HT-22 cells to investigate the effects of liraglutide. The MWM test, MTT assay, ELISA, western blot, and immunofluorescence were used in this research. Diabetic rats induced by STZ displayed a longer escape latency and entered the target zone less frequently (p < 0.05) in the MWM test. Intraperitoneal injection of liraglutide improved the cognition of diabetic rats (p < 0.05) and reduced Aβ42 expression in the hippocampus (p < 0.05). In vivo experiments showed that HT-22 cell viability decreased in the HG group, but liraglutide (100 nmol/L and 1 μmol/L) enhanced HT-22 cell viability (p < 0.05). Oxidative stress markers were upregulated in HT-22 cells in the HG group, while liraglutide treatment significantly reduced these markers (p < 0.05). Western blot and immunofluorescence analyses demonstrated increased levels of Aβ, BACE1, and γ-secretase in HT-22 cells in the HG group (p < 0.05), whereas these levels were reduced in the liraglutide treatment group (p < 0.05). These effects were reversed by the nuclear factor kappa B (NF-κB) and extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitors (p < 0.05). These findings suggest that liraglutide improved the cognition of diabetic rats and might exert its protective effects by reducing oxidative stress, downregulating BACE1 and γ-secretase expression, and decreasing Aβ deposition via the NF-κB and ERK1/2 pathways.

    Download PDF (4284K)
  • Shinichiro Sano, Taemi Ogura, Takayuki Takachi, Yuki Murai, Yasuko Fuj ...
    Article type: Case Report with Review of Literature
    Article ID: EJ24-0457
    Published: 2024
    Advance online publication: December 04, 2024
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION

    Glutamic acid decarboxylase (GAD) is an enzyme that catalyzes the conversion of glutamic acid into γ-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the central nervous system (CNS). GAD is widely expressed in the CNS and pancreatic β-cells. GABA produced by GAD plays a role in regulating insulin secretion in pancreatic islets. Anti-GAD antibody is an established marker of type 1 diabetes mellitus (T1DM) and is also associated with stiff-person syndrome (SPS) and several other neurological disorders, including ataxia, cognitive impairment, limbic encephalitis, and epilepsy, collectively referred to as GAD antibody-spectrum disorders (GAD-SD). We report the case of a 17-year-old male patient who developed GAD-SD and T1DM after allogeneic hematopoietic cell transplantation (HCT). He presented with memory disorders, including feelings of déjà vu, accompanied by vomiting and headaches, and exhibited abnormal brain magnetic resonance imaging and electroencephalogram results. In addition to elevated fasting plasma glucose and glycated hemoglobin levels, markedly elevated anti-GAD antibody levels were detected in the serum and cerebrospinal fluid. Based on these findings, the patient was diagnosed with GAD-SD and T1DM and treated with methylprednisolone, followed by multiple daily insulin injections. We also reviewed previously reported cases of GAD-SD following HCT and multiple positive islet-related antibodies.

    Download PDF (1459K)
  • Daisuke Aono, Toshiaki Kato, Akina Morisawa, Sakuya Kimata, Seigo Koni ...
    Article type: Case Report with Review of Literature
    Article ID: EJ24-0346
    Published: 2024
    Advance online publication: November 30, 2024
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION

    Recently, the usefulness of circulating tumor DNA (ctDNA) analysis in various malignancies has been reported. However, reports on ctDNA analysis in adrenocortical carcinoma (ACC) are few. Therefore, this study aimed to examine the detectability of genetic mutations in ctDNA and the association between ctDNA allelic ratio and disease progression in a patient with post-operative recurrence of ACC. A 77-year-old woman presented with a 5.4 cm left adrenal mass, which was clinically diagnosed as subclinical cortisol-producing ACC on close examination. She underwent left adrenalectomy and was diagnosed with stage II (T2N0M0) ACC. Post-operatively, adjuvant chemotherapy with mitotane was commenced because of histologically high-grade ACC. However, 17 months post-operatively, she had a local recurrence at the left adrenalectomy site. FoundationOne® CDx Cancer Genome Profile showed CTNNB1 G34A mutation in the resected adrenal tumor. She had heart failure and interstitial pneumonia and was treated with radiotherapy for local recurrence. Subsequently, lung and liver metastasis appeared post-operatively at 21 and 23 months, respectively. Serum dehydroepiandrosterone sulfate and computed tomography findings at 27 months post-operatively showed disease progression. We collected the peripheral blood at 23 and 27 months post-operatively and analyzed 18 genes associated with adrenal disease in plasma cell-free DNA and the resected adrenal tumor using a next-generation sequencer. At both time-points, CTNNB1 mutations consistent with the primary tumor were observed in ctDNA, with the allelic ratio increasing over time from 8% to 27%. In conclusion, monitoring the ctDNA allelic ratio may be useful for evaluating disease progression in advanced ACC.

    Download PDF (4101K)
  • Yuri Kadowaki, Tomohisa Aoyama, Yusuke Hada, Masakazu Aihara, Mika Saw ...
    Article type: Original
    Article ID: EJ24-0315
    Published: 2024
    Advance online publication: November 28, 2024
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION
    Supplementary material

    The Japan Society for the Study of Obesity recommends a weight loss of 3% of body weight over a period of 3–6 months. However, the effects of rapid weight loss on the body composition have not yet been adequately studied. Therefore, we observed the changes in the body composition induced by rapid weight loss and its effects on the pathophysiological mechanisms involved in obesity. The subjects were people with obesity admitted to our institution. The goal was to achieve a 3–5% body weight loss in the subjects by combining a carbohydrate-controlled therapeutic diet of 25–30 kcal/day per kg target body weight, exercise therapy, and pharmacotherapy. The body composition was measured at admission and at discharge by the dual bioelectrical impedance analysis. After 2 weeks, the participants’ body weight decreased by 4.2%; the visceral fat area decreased by 16.7%, the subcutaneous fat area by 2.4%, and the lean area by 4.0%. The moderate weight loss, moderate energy restriction and adequate protein intake significantly reduced the visceral fat area while allowing the lean area to be preserved. Improvements were also noted in the peripheral white blood cell count and C-reactive protein level. However, no statistically significant changes in homeostasis model assessment for insulin resistance and the adiponectin level were noted. Regarding clinical parameters, improvements of the systolic and diastolic blood pressures, fasting plasma glucose, triglycerides, low-density lipoprotein cholesterol, and degree of microalbuminuria were observed. Short-term comprehensive treatment produced beneficial body composition changes, and improvements in the pathophysiological mechanisms involved in obesity.

    Download PDF (2099K)
  • Jie Li, Jun Xie, Yi Han, Wei Zhang, Yilei Wang, Zhitao Jiang
    Article type: Original
    Article ID: EJ24-0286
    Published: 2024
    Advance online publication: November 27, 2024
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION

    Tirzepatide is a novel drug for the treatment of type 2 diabetes mellitus and chronic weight management, and there is an urgent need to explore its safety profile. The FDA Adverse Event Reporting System (FAERS) database provides a reliable pathway for adverse event (AE) disproportionality analysis. Data regarding AEs registered in the FAERS between Q2 2022 and Q4 2023 were collected for this study. The reporting odds ratio (ROR) method was applied to analyse the association between tirzepatide use and the risk of developing AEs. The occurrence of ≥3 AEs with an ROR value 95% confidence interval (CI) lower limit >1 was considered to indicate statistical significance. Data on 638,153 AEs were collected from the FAERS database, and tirzepatide use was implicated for 8,096 of those AEs. A total of 98 preferred terms (PTs) were detected as positive signals for tirzepatide use. Frequently observed expected AEs included injection site pain, nausea, injection site haemorrhage, diarrhoea, and vomiting. Some unexpected AEs that were frequently observed included incorrect doses, off-label use, the administration of extra doses, an inappropriate schedule of product administration, and increased blood glucose. In this study, we identified potential novel and unexpected AE signals associated with tirzepatide use. Our findings confirm the importance of real-world disproportionality analysis in identifying the safety profile of new drugs, ultimately contributing to the safe clinical application of tirzepatide.

    Download PDF (1013K)
  • Tomoya Onishi, Hiroshi Sakai, Hideaki Uno, Iori Sakakibara, Akiyoshi U ...
    Article type: Original
    Article ID: EJ24-0410
    Published: 2024
    Advance online publication: November 22, 2024
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION
    Supplementary material

    Androgen is widely acknowledged to regulate skeletal muscle mass. However, the specific mechanism driving muscle atrophy resulting from androgen deficiency remains elusive. Systemic androgen receptor knockout (ARKO) mice exhibit reduction in both muscle strength and muscle mass while skeletal muscle fiber specific ARKO mice have decreased muscle strength without affecting skeletal muscle mass in the limbs. Therefore, androgens may indirectly regulate skeletal muscle mass through effects on non-myofibers. Considering this, our investigation focused on blood fluid factors that might play a role in the regulation of skeletal muscle mass under the influence of androgens. Using a male mouse model of sham, orchidectomy and DHT replacement, mass spectrometry for serum samples of each group identified epidermal growth factor receptor (EGFR) as a candidate protein involving the regulation of skeletal muscle mass affected by androgens. Egfr expression in both liver and epididymal white adipose tissue correlated with androgen levels. Furthermore, Egfr expression in these tissues was predominantly elevated in male compared to female mice. Interestingly, male mice exhibited significantly elevated serum EGFR concentrations compared to their female counterparts, suggesting a connection with androgen levels. Treatment of EGFR to C2C12 cells promoted phosphorylation of AKT and its downstream S6K, and enhanced the protein synthesis in vitro. Furthermore, the administration of EGFR to female mice revealed a potential role in promoting an increase in skeletal muscle mass. These findings collectively enhance our understanding of the complex interplay among androgens, EGFR, and the regulation of skeletal muscle mass.

    Download PDF (6058K)
  • Minako Tokunaga, Yuko Seki, Tatsushi Horiguchi, Kiwako Miura, Haruna K ...
    Article type: Case Report with Review of Literature
    Article ID: EJ24-0180
    Published: 2024
    Advance online publication: November 21, 2024
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION

    Liddle syndrome (LS) is an autosomal dominant genetic disorder characterized by early onset hypertension, hypokalemia, and low plasma aldosterone or renin concentration. It is caused by mutations in subunits of the epithelial sodium channel (ENaC). The clinical phenotypes of LS are variable and nonspecific, making it prone to both misdiagnosis and missed diagnosis. Genetic analysis is necessary to confirm the diagnosis of LS. Herein, we report the case of a 42-year-old male with LS and a 30-year history of hypertension. He was being treated for possible primary aldosteronism (PA) over the preceding 7 years; however, his hypertension was poorly controlled despite intensive combination therapy. His 13-year-old son served as a proband for a diagnosis of LS, as he had hypertension, hypokalemia, and a significant family history of hypertension. Genetic testing revealed a heterozygous pathological variant in the SCNN1B gene. This led to a diagnosis of LS, as the father was found to harbor the same mutation. Both were treated with ENaC inhibitors and a salt-restricted diet, which improved their symptoms markedly. The son’s genetic diagnosis facilitated the subsequent proper diagnosis and treatment of his father. LS causes early onset hypertension; hence, its early diagnosis and treatment can prevent complications. Hereditary hypertension should be considered in cases of early onset hypertension with a significant family history. Patients diagnosed with PA using outdated criteria may have concomitant LS and require careful evaluation of biochemical and endocrine tests according to the current criteria.

    Download PDF (436K)
  • Yuto Yamazaki, Yuta Tezuka, Yoshikiyo Ono, Fumitoshi Satoh, Hironobu S ...
    Article type: State-of-the-Art Review in Endocrinology
    Article ID: EJ24-0466
    Published: 2024
    Advance online publication: November 12, 2024
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION

    Discerning malignancy in adrenocortical tumors is clinically pivotal in the management of patients but has also been one of the most difficult areas in both clinical and pathology settings. The recently published WHO 5th edition “Endocrine and Neuroendocrine Tumours” recommends a diagnostic algorithm employing not only one but several proposed histopathological criteria—including the Weiss criteria and its revision and the Helsinki criteria—in addition to the Reticulin algorithm, the Ki-67 proliferative index, and others depending upon their histopathological features. On the other hand, the risk classification proposed by ENSAT (European Network of Study for Adrenal Tumors) in 2018 was primarily based on the Ki-67 proliferative index of carcinoma cells, especially focusing on whether or not postoperative or adjuvant chemotherapy could be administered. The recently reported results of the ADIUVO study, although preliminary, discuss the necessity of postoperative therapy with mitotane in patients with low-grade adrenocortical carcinomas (ACCs) after complete resection. In addition, recently reported comprehensive genetic analyses attempted to classify ACCs into four major molecular subtypes: (i) the Wnt/-catenin pathway, (ii) the p53/Rb1 pathway, (iii) the chromosomal maintenance/chromatin remodeling pathway, and (iv) the MMR (Mismatch repair) pathway. Among those, groups (i) and (ii) are more commonly detected in high-grade ACCs but it is also true that specific therapeutic targets based on the molecular characteristics of tumors have remained limited. In addition, possible effects of glucocorticoid excess in functional ACCs on the tumor microenvironment have also been examined, and the utility of immune checkpoint inhibitors is being explored at this juncture.

    Download PDF (14889K)
  • Nuri Karadurmus, Mehmet Ilkin Naharci, Sinasi Erol Bolu, Aydogan Aydog ...
    Article ID: RET10-1
    Published: 2010
    Advance online publication: November 12, 2010
    JOURNAL FREE ACCESS ADVANCE PUBLICATION
    This article released online on September 22, 2010 as advance publication was withdrawn at the request of the authors.
    Download PDF (408K)
  • Nuri Karadurmus, Mehmet Ilkin Naharci, Sinasi Erol Bolu, Aydogan Aydog ...
    Article ID: K10E-195
    Published: 2010
    Advance online publication: September 22, 2010
    JOURNAL FREE ACCESS ADVANCE PUBLICATION
    This article was retracted. See the Notification.
    Download PDF (701K)
  • Chengjiang LI, Mingzhi XU, Qing GU
    Article ID: K08E-187
    Published: 2008
    Advance online publication: November 20, 2008
    JOURNAL FREE ACCESS ADVANCE PUBLICATION
    This article was retracted. See the Notification.
    Download PDF (111K)
feedback
Top