Endocrine Journal

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ISSN / EISSN : 0918-8959 / 1348-4540
Published by: Japan Endocrine Society (10.1507)
Total articles ≅ 3,847
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Nao Shibata, Hiromi Nyuzuki, Sunao Sasaki, Yohei Ogawa, Masayasu Okada, Keisuke Nagasaki
Published: 17 July 2021
by 10.1507
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Minoru Kihara, Akira Miyauchi, Mitsuyoshi Hirokawa, Hiroo Masuoka, Takuya Higashiyama, Naoyoshi Onoda, Yasuhiro Ito, Akihiro Miya
Published: 16 July 2021
by 10.1507
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Jiajun Li, Yue Wang, Xiao Zheng, Jie Sheng, Hui Guo, Wenlin Long, Yao Xu
Published: 1 January 2021
Endocrine Journal, Volume 68, pp 153-162; https://doi.org/10.1507/endocrj.ej20-0239

Abstract:
Type 2 diabetes (T2D) is a chronic endocrine disorder with rapidly increasing prevalence worldwide. Genetic instability leading to metabolic dysfunction plays an important role in T2D susceptibility and progression. Structural alteration in genome, that is, copy number variation (CNV) is emerging as the inherent marker for disease identification. Previous genomic CNV array revealed that protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene was overlapped with a CNV region, however, whether this CNV affected T2D risk remains to be further elucidated. In this study, we first identified divergent distributions of the PTPN22 copy number (CN) between T2D patients and healthy controls in Chinese population (p < 0.01). Risk assessment analysis revealed that the CN gain (OR = 3.28, p < 0.001) was the promising risk factor for T2D. Also, significantly positive correlations of the PTPN22 CNV with fasting plasma glucose and glycated hemoglobin were demonstrated in T2D patients. Statistical association analysis investigated that the T2D individuals carrying CN gain showed higher plasma glucose and lower insulin levels than those carrying CN normal and loss at 60 min/120 min/180 min during an OGTT test. In addition, the PTPN22 CNV had an effect on total cholesterol, and the CN gain presented higher values than the other two CN types. These results suggested that the CN gain types of the PTPN22 gene accompany with the glycometabolism dysregulation, and finally predispose their carriers to T2D; therefore, the PTPN22 CNV may be a promising biomarker for predicting T2D risk, or a clinical target for T2D diagnosis and therapy.
Kazunori Kageyama, Rie Hagiwara, Kanako Niioka, Shinobu Takayasu, Makoto Daimon
Published: 1 January 2021
Endocrine Journal, Volume 68, pp 163-170; https://doi.org/10.1507/endocrj.ej20-0251

Abstract:
Autonomous production of adrenocorticotropic hormone (ACTH) from pituitary corticotroph adenomas is the primary cause of Cushing’s disease. Somatostatin receptor, a G protein-coupled receptor (GPCR), types 2 (SSTR2) and 5 (SSTR5) mRNA expression is greater than that of other SSTR subtypes in human corticotroph adenomas. Further, the multiligand SOM230 shows potent effects in decreasing ACTH plasma levels and urinary free cortisol levels in patients with Cushing’s disease. We previously showed that both Sstr2 and Sstr5 mRNA levels were unaffected by SOM230 treatment, suggesting that both receptors might not be downregulated by the agonist. Intracellular molecules, such as β-arrestins, modulate ligand activated-receptor responses. In the present study, we determined regulation of β-arrestin1 and β-arrestin2 by SOM230 and dexamethasone in murine AtT-20 corticotroph tumor cells. In addition, we examined the effects of β-arrestin1 and β-arrestin2 on Sstr mRNA and their protein levels. SOM230 treatment increased β-arrestin1 mRNA levels and did not alter β-arrestin2 mRNA levels. SOM230 treatment could induce β-arrestin1 production in corticotroph tumor cells. Dexamethasone treatment decreased β-arrestin2 mRNA levels. β-arrestin2 knockdown increased proopiomelanocortin, and both Sstr2 and Sstr5 mRNA and their protein levels. The β-arrestin2 knockdown-increased proopiomelanocortin mRNA levels were canceled by SOM230 treatment.
Tetsuro Niri, Ichiro Horie, Hiromi Kawahara, Takao Ando, Noriaki Fukuhara, Hiroshi Nishioka, Naoko Inoshita, Haruki Fujisawa, Atsushi Suzuki, Yoshihisa Sugimura, et al.
Published: 1 January 2021
Endocrine Journal, Volume 68, pp 119-127; https://doi.org/10.1507/endocrj.ej20-0300

Abstract:
Idiopathic hypothalamitis is a rare condition that can cause anterior pituitary dysfunction and central diabetes insipidus (CDI), occasionally accompanied by a disturbance of autonomic regulation known as hypothalamic syndrome. This condition has been described as a subtype of autoimmune (lymphocytic) hypophysitis; however, some cases of isolated hypothalamic involvement with no inflammatory lesions in either the pituitary gland or infundibulum have been reported. The detailed epidemiology and pathophysiology of isolated hypothalamitis have not been clarified. We herein report a case of a solitary hypothalamic lesion in a young woman who showed spontaneous development of CDI and panhypopituitarism accompanied by hyperphagia. The hypothalamic lesion increased from 11 × 7 to 17 × 7 mm over 16 months based on the sagittal slices of magnetic resonance imaging examinations. The negative results for anti-pituitary antibodies and anti-Rabphilin-3A antibodies suggested that upward extension of lymphocytic adenohypophysitis or infundibulo-neurohypophysitis was unlikely. Infectious disease, granulomatosis, Langerhans cell histiocytosis, vasculitis, and systemic neoplastic diseases were excluded by the findings of a laboratory investigation, cerebrospinal fluid examination, and imaging studies. To make a definitive diagnosis, we performed a ventriculoscopic biopsy of the hypothalamic lesion. Histology revealed an infiltration of nonspecific lymphoplasmacytes with no evidence of neoplasm, which was consistent with a diagnosis of idiopathic hypothalamitis. Subsequently, the patient was treated with methylprednisolone pulse therapy followed by oral prednisolone. The hypothalamic lesion improved and remained undetectable after withdrawal of the prednisolone, suggesting that the glucocorticoid treatment was effective for isolated hypothalamitis while the patient remains dependent on the replacement of multiple hormones.
Guoqiang Fan, Yanfei Li, Fuli Ma, Ruqian Zhao, Xiaojing Yang
Published: 1 January 2021
Endocrine Journal, Volume 68, pp 53-62; https://doi.org/10.1507/endocrj.ej20-0179

Abstract:
Skeletal muscle is the most abundant tissue in the adult body and plays an essential role in maintaining heat production for the entire body. Recently, muscle-derived non-shivering thermogenesis under cold conditions has received much attention. Zinc-α2-glycoprotein (ZAG) is an adipokine that was shown to influence energy metabolism in the adipose tissue. We used ZAG knock-out (ZAG KO) and wild-type (WT) mice to investigate the effect of ZAG on the lipid metabolism of skeletal muscle upon exposure to a low temperature (6°C) for one week. The results show that cold stress significantly increases the level of lipolysis, energy metabolism, and fat browning-related proteins in the gastrocnemius muscle of WT mice. In contrast, ZAG KO mice did not show any corresponding changes. Increased expression of β3-adrenoceptor (β3-AR) and protein kinase A (PKA) might be involved in the ZAG pathway in mice exposed cold stress. Furthermore, expression of lipolysis-related proteins (ATGL and p-HSL) and energy metabolism-related protein (PGC1α, UCP2, UCP3 and COX1) was significantly enhanced in ZAG KO mice after injection of ZAG-recombinant plasmids. These results indicate that ZAG promotes lipid-related metabolism in the skeletal muscle when the animals are exposed to low temperatures. This finding provides a promising target for the development of new therapeutic approaches to improve skeletal muscle energy metabolism.
Norio Wada, Arina Miyoshi, Hiroaki Usubuchi, Satoshi Terae, Yui Shibayama, Bunya Takahashi, Shuhei Baba, Hajime Sugawara, Shinji Obara
Published: 1 January 2021
Endocrine Journal, Volume 68, pp 45-51; https://doi.org/10.1507/endocrj.ej20-0329

Abstract:
Captopril challenge test (CCT) is a simple and safe confirmatory test for primary aldosteronism (PA). We investigated the effectiveness of the indices after captopril administration for prediction of unilateral hyperaldosteronism (UHA) on adrenal vein sampling (AVS). We studied 238 patients with PA who had CCT and successful AVS between July 2007 and December 2019 in Sapporo City General Hospital. Receiver operating characteristic (ROC) curve analysis showed that the diagnostic performance for prediction of UHA on AVS in regard to the reduction rate of plasma aldosterone concentration (PAC) after captopril administration was inferior to aldosterone to renin ratio (ARR) and PAC (area under the ROC curve 0.72 vs. 0.84, 0.72 vs. 0.89, respectively, both p < 0.01). Based on the optimal cut-off values in ARR (897 pg/mL/ng/mL/h, sensitivity 64.6%, specificity 93.0%) and PAC (203 pg/mL, sensitivity 73.9%, specificity 93.0%) after captopril administration, the patients were divided into three groups: (1) both positive, (2) one positive, and (3) both negative. The prevalence of UHA on AVS in the three groups were 90.0%, 52.9%, and 7.3%, respectively. In the first group, 31 of 32 patients with unilateral nodular lesion on CT had an ipsilateral unilateral AVS. In conclusion, the combination of post-captopril ARR and PAC is useful for prediction of laterality diagnosis on AVS. AVS is strongly recommended in patients with both positive or one positive results for the optimal cut-off values of post-captopril ARR and PAC and is weakly recommended in patients with both negative results.
Naoki Fukuda, Kazuhisa Toda, Xiaofei Wang, Akihiro Ohmoto, Naomi Hayashi, Tetsuya Urasaki, Yasuyoshi Sato, Kenji Nakano, Makiko Ono, Junichi Tomomatsu, et al.
Published: 1 January 2021
Endocrine Journal, Volume 68, pp 639-647; https://doi.org/10.1507/endocrj.ej20-0754

Abstract:
Lenvatinib is a standard therapy for radioiodine-refractory differentiated thyroid cancer (RR-DTC). However, because of the high incidence of adverse events resulting from this treatment, it is not easy to maintain the dose intensity of lenvatinib, especially in Japanese patients. Although the prognostic impact of lenvatinib dose interruption has been reported, the target dose intensity of lenvatinib to optimize survival benefits remains unknown. We therefore propose a target dose intensity of lenvatinib during the first 8 weeks of treatment. We retrospectively analyzed 42 RR-DTC patients who were treated with lenvatinib for more than 8 weeks. We performed receiver operating characteristic curve analysis to determine the cut-off value of 8 weeks’ relative dose intensity (8w-RDI) to predict treatment response, and identified that the optimal cut-off value of 8w-RDI was 60% (sensitivity: 81.8%; specificity: 80.6%). Median progression-free survival (PFS) (not reached [NR] vs. 11.0 months; hazard ratio [HR] 0.29; 95% confidence interval [CI] 0.11–0.72; p < 0.01) and overall survival (NR vs. 27.6 months; HR 0.44; 95% CI 0.11–0.91; p = 0.03) were longer in the higher 8w-RDI (≥60%) patients than in the lower 8w-RDI (<60%) patients. Multivariate analysis revealed that 8w-RDI at ≥60% was an independent prognostic factor for PFS (HR 0.29; 95% CI 0.09–0.96; p = 0.04). Targeting for ≥60% of the relative dose intensity during the first 8 weeks of lenvatinib treatment can be sufficient to achieve significant tumor shrinkage and prolong PFS in RR-DTC patients.
Yi Wang, Yawen Zhang, Xiangyu Gao, Jiali Qian, Jia Yang, Wanwan Sun, Hao Wang, Yehong Yang
Published: 1 January 2021
Endocrine Journal, Volume 68, pp 461-468; https://doi.org/10.1507/endocrj.ej20-0343

Abstract:
Vascular muscle cells (VSMCs) participate in the pathophysiology of atherosclerosis. Resistin-like molecule beta (Relmβ) contributes to atherosclerosis development by activating macrophage. This study aims to investigate whether Relmβ regulates VSMC phenotypic modulation under high glucose environment. Human aortic vascular smooth muscle cells were cultured and treated with Relmβ in the presence or absence of high glucose. VSMC phenotypic modulation was assessed by expression of related markers. The migration of VSMCs was detected by wound healing assay and transwell assay. The proliferation of VSMCs was measured using CCK-8 assay. In this study, we observed that Relmβ modulated VSMC phenotypic modulation by down-regulating expression of smooth muscle α-actin (α-SMA), smooth muscle myosin heavy chain (SM-MHC), and calponin while up-regulating expression of osteopontin (OPN). Relmβ increased the expression of inflammatory genes in VSMCs. Relmβ also augmented VSMCs migration as well as proliferation. It is worth noting that all the effects of VSMCs were enhanced upon high glucose stimulation. The phosphorylation levels of p38MAPK and ERK1/2 were increased by co-treatment with Relmβ and high glucose. The p38 MAPK pathway inhibitor RWJ64809 and pERK1/2 inhibitor PD98059 significantly inhibited the proliferation of VSMCs induced by Relmβ and high glucose. Our results provide evidence that Relmβ augments phenotypic modulation and migration of human aortic smooth muscle cell induced by high glucose. Relmβ might be a potential target for treatment of atherosclerosis induced by hyperglycemia.
Jingjing Ma, Zhenghua Kan
Published: 1 January 2021
Endocrine Journal, Volume 68, pp 543-552; https://doi.org/10.1507/endocrj.ej20-0453

Abstract:
CircRNAs have been implicated in the progression of human cancers, including papillary thyroid carcinoma (PTC). Although circ_0008274 has been demonstrated as a potential oncogenic circRNA in PTC, our understanding of its molecular determinants is limited. The levels of circ_0008274, miR-154-3p and solute carrier family 7 member 11 (SLC7A11) mRNA were determined by quantitative real-time polymerase chain reaction (qRT-PCR). SLC7A11 protein level was assessed by western blot. Cell apoptosis, migration, and adhesion capacities were examined by flow cytometry, transwell and cell adhesion assays, respectively. The targeted correlations among circ_0008274, miR-154-3p and SLC7A11 were confirmed by a dual-luciferase reporter assay. Animal studies were performed to observe the role of circ_0008274 in tumor growth in vivo. Our data showed that the high levels of circ_0008274 and SLC7A11 were associated with poor prognosis of PTC patients. The knockdown of circ_0008274 or SLC7A11 enhanced PTC cell apoptosis and repressed cell migration and adhesion in vitro. Circ_0008274 knockdown suppressed tumor growth in vivo. Mechanistically, circ_0008274 modulated SLC7A11 expression by acting as a sponge of miR-154-3p. SLC7A11 was a functional mediator of circ_0008274 in regulating PTC cell apoptosis, migration and adhesion in vitro, and miR-154-3p overexpression repressed PTC progression in vitro by targeting SLC7A11. Our findings identified that the knockdown of circ_0008274 repressed PTC malignant progression at least in part through regulating the miR-154-3p/SLC7A11 axis, providing a promising therapeutic opportunity for PTC treatment.
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