Endocrine Journal
Online ISSN : 1348-4540
Print ISSN : 0918-8959
Advance online publication
Showing 1-28 articles out of 28 articles from Advance online publication
  • Hongliang Wei, Meiling Huang, Jing Fan, Ting Wang, Rui Ling
    Type: Original
    Article ID: EJ18-0363
    Published: 2018
    [Advance publication] Released: December 05, 2018
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    To explore new methods for intraoperative identification of parathyroid glands, 86 thyroid cancer patients, admitted to Xijing hospital from July 2017 to July 2018, were included. During lymph node dissection, parathyroid glands were firstly judged by clinician eyeballing, based on his clinical experience. Then, cytological detection was used for rapid identification via Diff-quik staining. PTH monitoring was performed by PTH detection kit. Finally, frozen pathology was examined and regarded as the golden standard. In this study, 172 suspicious parathyroid glands were observed. According to frozen pathology outcome, the accuracy, sensitivity and specificity of clinician eyeballing were calculated as 63.3%, 100%, and 13.9%. Kappa test showed poor consistency (kappa = 0.156), AUC area was 0.569 ± 0.045, 95%CI = (0.480–0.658), p = 0.123. For cytological and PTH detection, the accuracy, sensitivity and specificity were 91.7% vs. 92.3%, 93.6% vs. 93.8% and 89.0% vs. 90.3%. Kappa value was 0.829 vs. 0.842, indicating good consistency. AUC area was 0.908 ± 0.027 vs. 0.918 ± 0.025, 95%CI = (0.856–0.960) vs. (0.869–0.966), p < 0.001, indicating higher diagnositic value. Besides, compared with frozen pathology, cytological detection was easily and rapid. The time-taking between frozen pathology and cytological detection or PTH detection were 39.0 ± 6.59 min vs. 5.02 ± 0.78 min and 39.0 ± 6.59 min vs. 6.1 ± 1.23 min, p < 0.001. In conclusion, intra-operative cytological detection maybe potential for in-situ preservation of parathyroid glands.

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  • Satoko Nagao, Nahoko Iwata, Yoshiaki Soejima, Takaaki Takiguchi, Tamam ...
    Type: Original
    Article ID: EJ18-0423
    Published: 2018
    [Advance publication] Released: December 05, 2018
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    A functional link between clock gene expression and ovarian steroidogenesis was studied using human granulosa KGN cells. Similarities between changes in the mRNA and protein expression levels of Bmal1 and Clock and those of Per2 and Cry1 were found in KGN cells after treatment with forskolin. Among the interrelationships between the expression levels of clock and steroidogenic factors, Clock mRNA had a strongly positive correlation with P450arom and a negative correlation with 3βHSD. Knockdown of Clock gene by siRNA resulted in a significant reduction of estradiol production by inhibiting P450arom expression, while it induced a significant increase of progesterone production by upregulating 3βHSD in KGN cells treated with forskolin. Moreover, BMP-7 had an enhancing effect on the expression of Clock mRNA and protein in KGN cells. Thus, the expression levels of Clock, being upregulated by forskolin and BMP-7, were functionally linked to estradiol production and progesterone suppression by human granulosa cells.

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  • Song Bai, Zichuan Yao, Xianqing Zhu, Zidong Li, Yunzhong Jiang, Rongzh ...
    Type: Original
    Article ID: EJ18-0402
    Published: 2018
    [Advance publication] Released: December 04, 2018
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    Surgical resection is the primary treatment strategy for pheochromocytoma; however, it carries a high risk of morbidity and mortality, especially with respect to cardiovascular complications, which is the most common kinds of morbidity. The risk factors for morbidity remain unclear and require further exploration, moreover no studies focus on risk factors for cardiovascular morbidity. Herein we identified the risk factors for cardiovascular morbidity after pheochromocytoma surgery in Chinese patients. We retrospectively reviewed 262 patients who underwent unilateral surgical resection of pheochromocytoma at our center between 1 January 2007 and 31 December 2016. Patient demographics and extensive perioperative data were recorded and evaluated. Adjusted odds ratios and 95% confidence intervals were determined by multivariate logistic regression. Cut-off values and the area under the curve for continuous risk factors were calculated based on receiver operating characteristic curve analysis. A p-value <0.05 was considered statistically significant. Of the 262 patients, 63 (24.0%) had cardiovascular morbidity. The independent risk factors for cardiovascular morbidity were low body mass index, large radiographic tumor size, coronary heart disease, no preoperative crystal/colloid administration, and intraoperative hemodynamic instability; the corresponding odds ratio were 0.762 (p < 0.001), 1.208 (p = 0.010), 2.378 (p = 0.012), 2.720 (p = 0.011), and 4.764 (p = 0.001), respectively. The optimal cut-off values for body mass index and radiographic tumor size were 24.59 kg/m2 and 6.05 cm. We found that cardiovascular morbidity is common in patients after pheochromocytoma surgery. We identified five independent risk factors for cardiovascular morbidity. Identification of these risk factors may help to improve treatment strategies.

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  • Yoshifumi Tamura
    Type: Review
    Article ID: EJ18-0435
    Published: 2018
    [Advance publication] Released: December 04, 2018
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    Although metabolic abnormalities commonly occur in non-obese Asians, their pathogenesis is not fully understood. Proton magnetic resonance spectroscopy has been used to analyze intracellular lipids in humans, and results suggest that ectopic fat accumulation in muscle and liver may induce insulin resistance in each tissue independently of obesity. Thus, measurement of ectopic fat currently plays an important role in the study of insulin resistance in non-obese Asians. In addition, studies using 2-step hyperinsulinemic euglycemic clamp with a glucose tracer may clarify how tissue-specific insulin resistance in muscle, liver, and adipose tissue contributes to the development of metabolic disease in non-obese Japanese. Although numerous studies have elucidated the pathophysiology of insulin resistance in obese subjects, research on “metabolic gradation,” defined as the gradual transition from an insulin-sensitive to an insulin-resistant state, is less common, especially in terms of early metabolic changes. This review addresses a simple question: when and how is insulin resistance induced in non-obese East Asians? Several studies revealed that impaired insulin clearance and hyperinsulinemia not only compensated for insulin resistance, but also secondarily facilitated insulin resistance and weight gain. In this regard, we recently found that impaired insulin clearance and hyperinsulinemia could occur in apparently healthy subjects without significant insulin resistance, suggesting that this change may be an initial trigger that drives subsequent insulin resistance and weight gain. Further research is required to clarify the pathogenesis of metabolic gradation in non-obese Asians.

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  • Yoshihiro Niitsu, Isao Minami, Hajime Izumiyama, Koshi Hashimoto, Taka ...
    Type: Original
    Article ID: EJ18-0353
    Published: 2018
    [Advance publication] Released: November 30, 2018
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    Diazoxide is recognized as an effective medical treatment for insulinoma. However, due to its adverse effects, such as fluid retention, it is sometimes difficult to employ diazoxide at an effective dose in clinical practice. This study aimed to clarify the clinical factors, which may affect efficacy and safety of the diazoxide treatment. We retrospectively evaluated the medical records of 20 patients with insulinoma including 4 malignant cases. The patients were divided into two groups according to the presence or absence of favorable outcomes or adverse effects, and the clinical features of both groups were compared. Diazoxide was effective and ineffective in each 9 patients, respectively. In other 2 cases, the efficacy could not be determined. In the effective group, all patients had benign insulinoma. Additionally, the tumor size determined by imaging test was tended to smaller than the ineffective group but not statistically significant when malignant cases were excluded (p = 0.065). Fluid retention was observed more frequently in females than in males (p = 0.025). Five patients displayed unacceptable thrombocytopenia within a few weeks after the administration of diazoxide. In these patients, the diazoxide dose was significantly higher than that in the other patients [400 mg/day (250–500 mg/day) vs. 225 mg/day (50–425 mg/day), p = 0.027]. These findings may be informative in determining the indication and dose of diazoxide against insulinoma. In addition, a careful evaluation of platelet count would be required for a few weeks after the initiation of diazoxide treatment.

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  • Aki Tanaka, Mitsuyoshi Hirokawa, Miyoko Higuchi, Risa Kanematsu, Ayana ...
    Type: Original
    Article ID: EJ18-0422
    Published: 2018
    [Advance publication] Released: November 21, 2018
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    Concerning the needle size for thyroid fine needle aspiration cytology (FNAC), 25–27-gauge needles are generally used in Western countries. However, in Japan, the use of larger needles (21–22-gauge needles) is common. The aim of our study was to determine the optimal needle size for thyroid FNAC. We performed ultrasound-guided FNAC for 200 thyroid nodules in 200 patients using two different-sized needles (22 and 25 gauge). For each nodule, two passes with the different-sized needles were performed. The order of needle sizes was reversed for the second group of 100 nodules. The second aspiration was more painful than the first, regardless of the needle size. An association with more severe blood contamination was more frequently observed with the use of 22-gauge needles (32.0%) than with the use of 25-gauge needles (17.5%) and in the second aspiration (37.5%) than in the initial aspiration (12.0%). The initial aspiration samples were more cellular than the second aspiration samples. Regarding the unsatisfactory and malignancy detection rates, there was no statistical difference between the needles. In three of seven markedly calcified nodules, it was difficult to insert 25-gauge needles into the nodules. In terms of the diagnostic accuracy and pain, either needle size can be used. We recommend using 22-gauge needles for markedly calcified nodules because 25-gauge needles bend more easily in such cases. We demonstrated that the initial aspiration tended to obtain more cellular samples and to be less contaminated. Thus, the initial aspiration is more important and should be closely attended.

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  • Hao Hu, Guoyue Yuan, Xinchen Wang, Jin Sun, Zhaohua Gao, Tingting Zhou ...
    Type: Original
    Article ID: EJ18-0191
    Published: 2018
    [Advance publication] Released: November 15, 2018
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    Angiopoietin-like protein 8 (ANGPTL8) is a newly discovered adipokine plays an important role in energy homoeostasis, obesity and type 2 diabetes (T2D). Although lifestyle modification in obesity and T2D is known to offer metabolic benefits, there is paucity of comprehensive data on change in ANGPTL8. We investigated the effect of lifestyle intervention on ANGPTL8 concentrations. 384 obese/overweight adults with newly diagnosed T2D were randomly assigned (1:1:1) to diet (n = 128), diet + activity (n = 128) or usual care (control, n = 128) groups. All patients received usual care. Besides, the diet group received a calorie-restricted diet aiming for a weight loss of 5–10%. The diet + activity group additionally received a pedometer-based walking program. Primary outcome was change in ANGPTL8 concentration at 6 months. Data were analyzed according to intention-to-treat. From baseline to 6 months, the median ANGPTL8 level changed from 804.38 pg/mL to 792.86 pg/mL in control group. Compared with control, ANGPTL8 decreased with diet (baseline-adjusted between-group difference was –121.00 pg/mL, 95% CI –177.47 to –64.53; p < 0.0001) and diet + activity (–126.16 pg/mL, –181.21 to –71.11; p < 0.0001). There was no greater effect of diet + activity compared with diet (–5.16 pg/mL, –53.63 to 43.31; p = 0.8348). Both effects disappeared after adjusting for change in body fat, but did not differ significantly when adjusting for physical activity. A 6-month intervention inducing weight loss by a calorie-restricted diet or diet + activity, resulted in significant decrease on ANGPTL8 concentration. These effects were established by change in total body fat, and not by change in physical activity.

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  • Yu Ding, Bo-Hou Xia, Guang-Chao Zhuo, Cai-Juan Zhang, Jian-Hang Leng
    Type: Original
    Article ID: EJ18-0308
    Published: 2018
    [Advance publication] Released: November 06, 2018
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    Premature ovarian insufficiency (POI) is a common endocrine disorder featured by the triad constituting of amenorrhea for at least four months, to date, the molecular pathogenesis of POI is largely undetermined. Despite several investigations have reported an increase in reactive oxygen species (ROS) content in idiopathic POI, the role of mitochondrial DNA (mtDNA) mutations/variants in the progression of POI has not been widely investigated. The current study aimed to explore the association between mt-tRNA mutations/variants and POI; we first used the PCR-Sanger sequencing to detect the mutations/variants in mt-tRNA genes from 50 POI patients and 30 healthy subjects. In addition, we evaluated the mitochondrial functions by using trans-mitochondrial cybrid cells containing these potential pathogenic mt-tRNA mutations. Consequently, five mutations: tRNALeu(UUR) C3303T, tRNAMet A4435G, tRNAGln T4363C, tRNACys G5821A and tRNAThr A15951G were identified. Notably, these mutations occurred at the extremely conserved nucleotides of the corresponding mt-tRNAs and may result the failure in mt-tRNA metabolism and subsequently lead to the impairment in mitochondrial protein synthesis. Furthermore, biochemical and molecular analyses of the cybrid cells containing these mutations showed a significantly lower level of ATP production when compared with the controls, whereas the ROS levels were much higher in POI patients carrying these mt-tRNA mutations, strongly indicated that these mt-tRNA mutations may cause the mitochondrial dysfunction, and play active roles in the progression and pathogensis of POI. Together, this study shaded additional light on the molecular mechanism of POI that was manifestated by mt-tRNA mutations.

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  • Yaping Liang, Xiaojia Xu, Mingjuan Yin, Yan Zhang, Lingfeng Huang, Ruo ...
    Type: Original
    Article ID: EJ18-0109
    Published: 2018
    [Advance publication] Released: November 03, 2018
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    We conducted a systematic review and meta-analysis to evaluate the effect of Berberine on glucose in patients with type 2 diabetes mellitus and identify potential factors may modifying the hypoglycemic effect. We searched PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure, and Wanfang Database to identify randomized controlled trials that investigated the effect of Berberine. We calculated weighted mean differences (WMD) and 95% confidence interval (CI) for fasting plasma glucose (FPG), postprandial plasma glucose (PPG) and glycated haemoglobin (HbA1c) levels. Twenty-eight studies were identified for analysis, with a total of 2,313 type 2 diabetes mellitus (T2DM) patients. The pool data showed that Berberine treatment was associated with a better reduction on FPG (WMD = –0.54 mmol/L, 95% CI: –0.77 to –0.30), PPG (WMD = –0.94 mmol/L, 95% CI: –1.27 to –0.61), and HbA1c (WMD = –0.54 mmol/L, 95% CI: –0.93 to –‍0.15) than control groups. Subgroup-analyses indicated that effects of Berberine on blood glucose became unremarkable as the treatment lasted more than 90 days, the daily dosage more than 2 g/d and patients aged more than 60 years. The efficiency of Berberine combined with hypoglycaemics is better than either Berberine or hypoglycaemic alone. The dosage and treatment duration of Berberine and patients’ age may modify the effect.

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  • Hiromi Tabuchi, Hiroshi Maegawa, Kazuyuki Tobe, Ichiro Nakamura, Satos ...
    Type: Original
    Article ID: EJ18-0217
    Published: 2018
    [Advance publication] Released: November 03, 2018
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    This subgroup analysis of STELLA-LONG TERM, an ongoing 3-year post-marketing surveillance study on the long-term efficacy and safety of ipragliflozin, assessed the effect of ipragliflozin on liver function in type 2 diabetes mellitus (T2DM) patients. Patients were divided according to baseline liver function (normal [male: ALT ≤30, female: ALT ≤20], abnormal [male: ALT ≥31, female: ALT ≥21]). We evaluated changes in aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase (γ-GTP), alkaline phosphatase (ALP), and fatty liver index (FLI) at 3 months of treatment; the proportion of patients with abnormal liver function whose liver function normalized after 3 months of treatment; and correlations between changes in ALT levels and efficacy variables/laboratory values. Liver function was normal in 2,570 and abnormal in 3,239 patients. Only patients with abnormal liver function showed a statistically/clinically significant decrease in AST, ALT, γ-GTP, and ALP levels at 3 months (all p < 0.05 vs. baseline). The FLI significantly decreased from 63.2677 ± 26.4363 (baseline) to 56.7137 ± 27.6484 (3 months) (p < 0.05) in the overall patient population. Liver function normalized in 20.5% (543/2,648) of patients with abnormal liver function. There was no obvious correlation between changes in ALT and changes in efficacy/laboratory parameters. Liver function improved after 3-month treatment with ipragliflozin in T2DM patients with abnormal liver function.

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  • Shin Kawanabe, Yoshio Nagai, Yuta Nakamura, Ami Nishine, Tomoko Nakaga ...
    Type: Original
    Article ID: EJ18-0252
    Published: 2018
    [Advance publication] Released: November 03, 2018
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    This study assessed the association of muscle mass with insulin resistance, evaluated from the insulin sensitivity index (ISI), in Japanese patients with gestational diabetes mellitus (GDM). Consecutive patients with GDM (n = 96) admitted to St. Marianna University Hospital between October 2015 and March 2018 for initial education and glycemic control were enrolled in a prospective observational study. Insulin resistance was evaluated by measuring the ISI and body composition was assessed by bioelectrical impedance analysis. The subjects were aged 34.4 ± 4.8 years (mean ± SD) and their body mass index (BMI) before pregnancy was 22.3 ± 4.0 kg/m2. Fifty-three patients (55.2%) had a history of diabetes in first-degree relatives. The ISI was 7.2 ± 3.3, appendicular skeletal muscle mass (ASM) was 17.0 ± 2.1 kg, and fat mass (FM) was 18.8 ± 8.2 kg. The ASM/FM ratio was 1.02 ± 0.34. There was a positive correlation between FM and ASM (r = 0.734, p < 0.001). To adjust for confounders when evaluating the association of ASM with ISI, multivariate analysis was conducted using age, family history of diabetes, and BMI as variables. In this analysis, the ASM/FM ratio showed a significant positive correlation with ISI (β = 0.303, p = 0.020). These findings suggest that inadequate ASM/FM ratio is important for the development of insulin resistance in Japanese patients with GDM. Excessive emphasis on dieting rather than health might increase the risk of GDM by reducing the muscle mass below the level that maintains normal glucose metabolism.

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  • Satoko Tsuchiya, Shojiro Sawada, Kana Takeda, Kenji Takahashi, Takeko ...
    Type: Note
    Article ID: EJ18-0356
    Published: 2018
    [Advance publication] Released: November 02, 2018
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    Soft-drink diabetic ketosis, characterized by acute onset ketosis induced by excessive ingestion of sugar-containing drinks, is often seen in obese, young patients, even with undiagnosed type 2 diabetes. We herein report a 15-year-old obese patient with the apolipoprotein E4/2 phenotype, in whom eruptive xanthomas lead to a diagnosis of soft-drink diabetic ketosis. He developed multiple asymptomatic yellowish papules on the auricles, back, buttocks and the extensor surfaces of the elbows and knees. He initially visited a dermatology clinic and his blood triglyceride and HbA1c levels were found to be 6,490 mg/dL and 16.5%, respectively. He was referred to our hospital for treatment of hyperglycemia and hypertyriglyceridemia. On admission, he had ketonuria and increased blood levels of 3-hydroxybutylate and acetoacetate. He habitually drank 1–3 litters of sweet beverages daily to quench his thirst. Therefore, “soft-drink diabetic ketosis” was diagnosed. Severe hypertriglyceridemia was considered to have been a consequence of impaired insulin action and his apolipoprotein E4/2 phenotype. We treated the diabetic ketosis and hypertriglyceridemia with intensive insulin therapy and a fat-restricted diet. At discharge, he no longer required insulin therapy and his blood glucose levels were controlled with metformin and voglibose. Along with amelioration of the hyperglycemia, triglyceride levels decreased to 247 mg/dL without administration of anti-hyperlipidemia agents. The eruptive xanthoma lesions gradually diminished in size and number and eventually disappeared by 12 months. This case provides an instructive example of eruptive xanthomas serving as a sign of severe dysregulation, not only of lipid, but also glucose, metabolism.

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  • Liu Yang, Kwang Won Jeong
    Type: Original
    Article ID: EJ18-0343
    Published: 2018
    [Advance publication] Released: October 26, 2018
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    The human homologue of flightless-I (FLII) belong to the gelsolin protein family and contain a gelsolin-like domain at the C-terminus and a leucine-rich repeat (LRR) domain at the N-terminus. FLII regulates estrogen receptor alpha (ERα) and glucocorticoid receptor (GR)-mediated transcription by direct interaction through different domains, suggestive of its potential role in the crosstalk between the ERα and GR signaling pathway. Here, we demonstrate that FLII plays a critical role in GR-mediated repression of ERα target gene expression. In FLII-depleted cells, the reduction in 17-β-estradiol (E2)-induced ERα occupancy following treatment with dexamethasone (Dex) at the estrogen responsive element (ERE) site of the ERα target gene was significantly inhibited. The ERE binding of GR by the cotreatment with E2 and Dex was significantly inhibited by FLII depletion, indicating that FLII is required for the recruitment of GR at the ERE sites of ERα target genes. In addition, the recruitment of ERα-induced FLII to ERE sites was significantly reduced by Dex treatment. In protein binding assays, GR inhibited the E2-induced interaction between ERα and FLII, suggesting that GR interferes with the binding of ERα and FLII at the ERα target genes, resulting in the release of ERα and FLII from EREs. Taken together, our data reveal an unknown mechanism by which the transcription coactivator FLII regulates the GR-mediated repression of ERα target gene expression in MCF-7 cells.

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  • Mohammad Saiful Islam, Noriyuki Namba, Yasuhisa Ohata, Makoto Fujiwara ...
    Type: Original
    Article ID: EJ18-0251
    Published: 2018
    [Advance publication] Released: October 25, 2018
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    Monocarboxylate transporter 8 (MCT8) facilitates T3 uptake into cells. Mutations in MCT8 lead to Allan-Herndon-Dudley syndrome (AHDS), which is characterized by severe psychomotor retardation and abnormal thyroid hormone profile. Nine uncharacterized MCT8 mutations in Japanese patients with severe neurocognitive impairment and elevated serum T3 levels were studied regarding the transport of T3. Human MCT8 (hMCT8) function was studied in wild-type (WT) or mutant hMCT8-transfected human placental choriocarcinoma cells (JEG3) by visualizing the locations of the proteins in the cells, detecting specific proteins, and measuring T3 uptake. We identified 6 missense (p.Arg445Ser, p.Asp498Asn, p.Gly276Arg, p.Gly196Glu, p.Gly401Arg, and p.Gly312Arg), 2 frameshift (p.Arg355Profs*64 and p.Tyr550Serfs*17), and 1 deletion (p.Pro561del) mutation(s) in the hMCT8 gene. All patients exhibited clinical characteristics of AHDS with high free T3, low-normal free T4, and normal-elevated TSH levels. All tested mutants were expressed at the protein level, except p.Arg355Profs*64 and p.Tyr550Serfs*17, which were truncated, and were inactive in T3 uptake, excluding p.Arg445Ser and p.Pro561del mutants, compared with WT-hMCT8. Immunocytochemistry revealed plasma membrane localization of p.Arg445Ser and p.Pro561del mutants similar with WT-hMCT8. The other mutants failed to localize in significant amount(s) in the plasma membrane and instead localized in the cytoplasm. These data indicate that p.Arg445Ser and p.Pro561del mutants preserve residual function, whereas p.Asp498Asn, p.Gly276Arg, p.Gly196Glu, p.Gly401Arg, p.Gly312Arg, p.Arg355Profs*64, and p.Tyr550Serfs*17 mutants lack function. These findings suggest that the mutations in MCT8 cause loss of function by reducing protein expression, impairing trafficking of protein to plasma membrane, and disrupting substrate channel.

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  • Saki Nagai, Kazuhiro Ikeda, Kuniko Horie-Inoue, Satoru Takeda, Satoshi ...
    Type: Original
    Article ID: EJ17-0548
    Published: 2018
    [Advance publication] Released: October 17, 2018
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    Estrogen deficiency has been known to associate with musculoskeletal diseases in women, based on the clinical observations of frequent susceptibility to osteoporosis and sarcopenia among postmenopausal women. In skeletal muscles, estrogen has been assumed to play physiological roles in maintaining muscle mass and strength, although its precise molecular mechanism remains to be elucidated. We have previously shown that estrogen regulates energy metabolism through the downregulation of mitochondrial uncoupling protein 3 (UCP3) in skeletal muscles, which may contribute to the prolonged exercise endurance in female mice. In the present study, we investigated the effects of estrogen on the expression levels of all members of the nuclear receptor superfamily. Microarray analysis showed that the mRNA level of nuclear receptor subfamily 4 group A member 1 (Nr4a1) was upregulated by the transduction of a recombinant adenovirus expressing constitutively active estrogen receptor α (caERα) in differentiated myoblastic C2C12 cells. Thus we assumed that NR4A1 may be an estrogen-inducible gene in myoblastic cells. We also demonstrated that caERα increases the cellular ATP content along with an increase in mitochondrial DNA content in differentiated myoblastic C2C12 cells. In contrast, the knockdown of Nr4a1 using siRNA exhibited reduced ATP generation as well as a decrease in mitochondrial DNA content. Overall, the present study indicates a crosstalk between estrogen signaling and NR4A1 in skeletal muscle cells. We consider that estrogen-dependent NR4A1 upregulation could increase efficient ATP generation in skeletal muscle cells partly through enhancing mitochondrial functions.

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  • Kenji Kohara, Atsushi Obata, Tomohiko Kimura, Masashi Shimoda, Saeko M ...
    Type: Original
    Article ID: EJ18-0203
    Published: 2018
    [Advance publication] Released: October 17, 2018
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    It is known that long-chain fatty acids bind to free fatty acid receptor 1 (Ffar1), also known as G protein-coupled receptor 40 (GPR40), and amplify glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells and that Ffar1 agonists facilitates insulin secretion and ameliorates glycemic control. On the other hands, pancreatic and duodenal homeobox factor 1 (Pdx1) is an important transcription factor for various β-cell-related genes including insulin gene and thereby contributes to the maintenance of mature β-cell function. The aim of this study was to evaluate how Ffar1 expression in β-cells is altered under diabetic conditions. In this study, we used male obese type 2 diabetic mice and control mice. We evaluated Ffar1 and Pdx1 mRNA and protein expression levels in both mice. In addition, we examined whether Pdx1 is a possible regulator of Ffar1 expression using small interfering RNA for Pdx1 (siPdx1) in β-cell-derived cell line. As the results, Ffar1 mRNA and protein expression in β-cells were significantly lower in obese type 2 diabetic db/db mice compared to control mice which was accompanied by the decreased expression of Pdx1. In addition, down-regulation of Pdx1 expression using siPdx1 suppressed Ffar1 expression. Furthermore, adenoviral Pdx1 overexpression significantly increased Ffar1 expression. In conclusion, Ffar1 expression is markedly down-regulated under diabetic conditions which is accompanied by decreased expression of Pdx1. Furthermore, it is likely that Pdx1 is a regulator of Ffar1 expression in β-cells.

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  • Mitsuyoshi Takahara, Toshihiko Shiraiwa, Naoto Katakami, Yoshifumi Mae ...
    Type: Original
    Article ID: EJ18-0313
    Published: 2018
    [Advance publication] Released: October 11, 2018
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    The aim of this study was to investigate whether daily glycemic profiles and treatment satisfaction would be changed after switching from once-daily 25-mg alogliptin plus twice-daily 250-mg metformin to the fixed-dose combination of 25-mg alogliptin and 500-mg metformin once daily in type 2 diabetic patients. Twenty adult Japanese type 2 diabetic patients in whom once-daily 25-mg alogliptin plus twice-daily 250-mg metformin were switched to the fixed-dose combination of 25-mg alogliptin and 500-mg metformin once daily participated. Before and one month after the switch, participants were asked to perform one day of seven-point self-monitoring of blood glucose (SMBG), to wear a sensor of flash glucose monitoring for up to 14 days, and to respond to a questionnaire for treatment satisfaction. As a result, the SMBG profiles were significantly changed after the switch (p = 0.021); blood glucose levels 2 hours after breakfast were significantly elevated (p = 0.022), whereas those 2 hours after lunch were significantly reduced (p = 0.036). The flash glucose monitoring also demonstrated a significant change of daily glucose profiles (p < 0.001). The risk of glucose levels <80 mg/dL were decreased from evening to morning, while the risk of glucose levels ≥140 mg/dL were increased. Mean 24-hour glucose values were increased by 5 mg/dL on average (p < 0.001). Treatment satisfaction was significantly improved after the switch (p < 0.001). In conclusion, daily glycemic profiles were significantly changed after switching from once-daily 25-mg alogliptin plus twice-daily 250-mg metformin to the once-daily fixed-dose combination in Japanese type 2 diabetic patients. Treatment satisfaction was significantly improved after the switch.

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  • Takeshi Nishimura, Masami Tanaka, Yoshifumi Saisho, Kei Miyakoshi, Mam ...
    Type: Original
    Article ID: EJ17-0533
    Published: 2018
    [Advance publication] Released: October 10, 2018
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    We aimed to clarify the pathophysiological significance of total bilirubin (TB) in gestational diabetes mellitus (GDM). This was a cross-sectional study that included 616 pregnant Japanese women (368 normal glucose tolerance [NGT] and 248 GDM). Serum TB concentration, homeostasis model assessment of insulin resistance (HOMA-IR), and other clinical parameters were compared in NGT and GDM women. TB concentration was also compared according to the number of abnormal OGTT values. Logistic regression analysis was used to evaluate the association between TB and GDM prevalence. A multiple linear regression model was used to evaluate the association between TB and HOMA-IR. TB concentrations were significantly lower in GDM women than in NGT women. This result did not change after adjustments for TB sampling timing were made. Out of 248 GDM women, the prevalences of 1- and 2/3- abnormal OGTT values (1- and 2/3-AV) GDM were 72.2% (n = 179) and 27.8% (n = 69), respectively. In the multiple comparisons, TB concentrations were significantly lower in women with 2/3-AV GDM than in women with NGT and 1-AV GDM. Multiple logistic regression analysis showed that TB was a significantly associated factor for 2/3-AV, but not for total GDM. HOMA-IR was significantly higher in GDM women than in NGT women. The univariate, but not multivariate, analysis showed that TB was a significantly associated factor for HOMA-IR. Our findings suggest that hypobilirubinemia may be involved in the pathogenesis of GDM.

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  • Miyoko Higuchi, Mitsuyoshi Hirokawa, Risa Kanematsu, Aki Tanaka, Ayana ...
    Type: Original
    Article ID: EJ18-0290
    Published: 2018
    [Advance publication] Released: October 03, 2018
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    The Bethesda System for Reporting Thyroid Cytopathology has recently been revised in 2017 (TBSRTC 2017). This study aimed to evaluate the impact of modifying the diagnostic criteria in TBSRTC 2017 at a single institute. We retrospectively reviewed cytological specimens of 10,399 thyroid nodules submitted for thyroid fine-needle aspiration cytology. Among them, 56 atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS) nodules, 16 suspicious for malignancy (SFM) nodules, and 8 malignant nodules were re-categorized into follicular neoplasm or suspicious for a follicular neoplasm (FN/SFN). The incidence of FN/SFN was increased by 0.8%, while that of AUS/FLUS, SFM, and malignant nodule was decreased by 0.5%, 0.2%, and 0.1%, respectively. In nine (60%) of the 15 nodules that were re-classified from AUS/FLUS to FN/SFN nodules and re-aspiration was performed, it was possible to judge whether they were benign or malignant. Of the 24 patients with FN/SFN nodules originally diagnosed with SFM or malignant, 16 were followed up without surgical resection. In conclusion, TBSRTC 2017 only caused minor changes in the incidence of each diagnostic category. TBSRTC 2017 was revised to avoid false positives owing to noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) that account for >10% of papillary thyroid carcinomas; however, it is not necessary in low frequency NIFTP institutes or countries. In Japan, we propose active surveillance as an accepted option for clinically managing AUS/FLUS, FN/SFN, SFM, or malignant nodules having favorable benign clinical findings or being part of the low-risk group.

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  • Tadashi Yamamuro, Kana Inoue, Yasuki Nagai, Daisuke Azuma, Aya Yamamot ...
    Type: Original
    Article ID: EJ18-0052
    Published: 2018
    [Advance publication] Released: September 20, 2018
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Ectopic ACTH syndrome (EAS) is a potentially fatal endocrine disease that results from a variety of neuroendocrine tumors (NETs), such as small cell lung cancer (SCLC) and bronchial typical carcinoid. Typical carcinoid is usually slow growing, not associated with plasma progastrin releasing peptide (ProGRP) elevation. Here, we report a 47-year-old female smoker with progressive typical carcinoid and plasma ProGRP elevation. Several types of Cushingoid features were found on physical examination. In addition, laboratory examination showed elevated plasma ACTH and serum cortisol levels. These findings indicated ACTH-dependent Cushing’s syndrome. Moreover, the serum cortisol level was not suppressed by overnight high-dose dexamethasone treatment, suggesting the presence of an extra-pituitary tumor. Contrast-enhanced brain MRI revealed no pituitary adenoma, which also supported the idea that EAS occurred in the present case. Strikingly, chest computed tomographic (CT) scan showed a single 18-mm peripheral nodule in the right middle lobe of the lung. Tumor marker analysis revealed an elevation in plasma ProGRP. These data suggested a possibility that SCLC secreted ACTH and caused EAS in this patient. Of note, the plasma ACTH level was increased (1.7 fold) in l-desamino-8-D-arginine vasopressin (DDAVP) test, also suggesting the specific clinical feature in this case. After additional imaging examinations, we performed surgical resection with the suspicion of limited SCLC. As a result, pathological examination revealed a vasopressin receptor Ib (V1b) receptor-negative bronchial typical carcinoid with ACTH production and mediastinal lymphatic metastasis. In summary, we present a case of EAS caused by progressive bronchial typical carcinoid with plasma ProGRP elevation. We propose a novel subtype of lung typical carcinoid.

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  • Daisuke Tadotsu, Noritoshi Kawate, Hiromichi Tamada
    Type: Note
    Article ID: EJ18-0302
    Published: 2018
    [Advance publication] Released: September 19, 2018
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    The present study examined the effects of progesterone (P) and 17β-estradiol (E2) on fetal damage and intrauterine pressure in ovariectomized pregnant mice. The mice were ovariectomized on gestational day (GD) 9 (copulation plug = GD 0), and daily subcutaneous injection of various doses of P (2, 3 or 4 mg) or 4 mg P plus E2 (0.05 or 0.1 μg) was given thereafter. Although P alone increased percentage of normal fetuses on GD 17 dose-dependently, fetal injury with edematous hematomata on their extremities was frequently observed. In the group treated with 4 mg P, the injured fetus was found at the highest percentage (18%) and intrauterine pressure was significantly higher than that in intact pregnant mice (controls). No injured fetus on GD 17 was found by the treatment with 4 mg P plus 0.05 or 0.1 μg E2, and the treatments decreased the intrauterine pressure to the level of controls. Percentage of normal fetuses in the ovariectomized mice treated with 4 mg P plus 0.05 μg E2 was similar to that of controls, while that in the ovariectomized mice treated with 4 mg P plus 0.1 μg E2 markedly decreased. The results suggest that estrogen decreases intrauterine pressure to defend fetal damage in ovariectomized P-treated mice, and a high estrogen level interrupted pregnancy while keeping this estrogen action.

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  • Masanori Adachi, Tomonobu Hasegawa, Yukichi Tanaka, Yumi Asakura, Junk ...
    Type: Original
    Article ID: EJ18-0218
    Published: 2018
    [Advance publication] Released: September 15, 2018
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    A heterozygous NR5A1 mutation is one of the most frequent causes of 46,XY DSD (disorders of sex development). We here reported a NR5A1-related 46,XY DSD patient, who first received endocrinological attention at 10 years of age for clitoromegaly. The patient had been reared as a girl, and no signs of virilization had been detected before. On examination, her clitoris was 35 mm long and 10 mm wide, with Tanner 3° pubic hair. Urogenital sinus and labial fusion was absent, while her uterus was found to be severely hypoplastic. Her basal testosterone level was 94.8 ng/dL, suggesting the presence of functioning Leydig cells. Gonadal histology revealed bilateral dysplastic testes consisting of mostly Sertoli cell-only tubules and Leydig cell hyperplasia. Novel heterozygous Arg313Leu substitution in NR5A1 was identified in the patient. Literature search confirmed twelve other cases of this scenario, namely, severe under-virilization in utero followed by spontaneous virilization around puberty in NR5A1-related 46,XY DSD. Of interest, Leydig cell hyperplasia was documented in 6 out of 9 patients for whom testicular histology was available. To keep in mind about the possible restoration of Leydig cell function around puberty, even in patients without discernible in utero androgen effect, may be of clinical significance, because it will give a great impact on the judgement about sex assignment.

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  • Eunyoung Kim, Min Jae Chung, Yoonyoung Chung, Yonghyun Jun
    Type: Original
    Article ID: EJ18-0181
    Published: 2018
    [Advance publication] Released: September 14, 2018
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Early onset puberty and irregular estrous cycles occur more frequently in rats which are fed a high-fat diet. Kisspeptin is an essential factor for the regulation of sexual maturation and is co-expressed with neurokinin B in neurons in the hypothalamic arcuate nucleus. However, the effects of a diet change on kisspeptin neuronal signaling are not well-understood. Therefore, in this study, we examined the immunoreactivity pattern of the kisspeptin/kiss1-receptor (KISS1R) and neurokinin B/neurokinin3-receptor (R). Pups born to high-fat diet rats were exposed to a high-fat diet until the onset of puberty. From puberty, the offspring originally exposed to a high–fat diet were fed a normal diet up to 85 postnatal days (PND 85). We examined kisspeptin/Kiss1-receptor and neurokinin B/neurokinin3-receptor immunoreactivity (IR) in the arcuate nucleus of the pups. The onset of puberty in the high-fat group was significantly earlier than the control group. At the onset of puberty, the densities of kisspeptin and neurokinin B IR cells were significantly higher in the high-fat diet group than in the control group; however, the densities of KISS1 and neurokinin 3-receptor IR cells did not differ between the two groups. At PND 85, the density of kisspeptin and neurokinin B IR cells did not differ between control and high fat group. The density of densities of KISS1 and neurokinin 3-receptor IR cells also did not differ between groups at this stage. These data suggest that a high-fat diet can influence puberty onset and the immunoreactivity of kisspeptin and neurokinin B. These effects can be modified by dietary control.

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  • Ayana Suzuki, Mitsuyoshi Hirokawa, Nami Takada, Miyoko Higuchi, Aki Ta ...
    Type: Original
    Article ID: EJ18-0282
    Published: 2018
    [Advance publication] Released: September 12, 2018
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Follicular cell-derived thyroid carcinomas, including thyroid squamous cell carcinomas (SCCs) and anaplastic carcinomas, are immunoreactive for paired-box gene 8 (PAX8), while non-follicular cell-derived thyroid carcinomas stain negative for the PAX8 antibody. Intrathyroid thymic carcinoma (ITTC) arising from the intrathyroidal ectopic thymus exhibits moderate-to-strong nuclear reactivity for polyclonal PAX8. This is difficult to understand given that PAX8 is not associated with embryonic thymic development. We aimed to determine the diagnostic significance of monoclonal PAX8 antibody in distinguishing ITTCs from follicular cell-derived thyroid carcinomas. Ten ITTCs, 14 poorly differentiated thyroid carcinomas (PDTCs), 14 thyroid SCCs, 7 thymic tissue specimens, 7 thymomas, and 1 thymic carcinoma were analyzed using antibodies against polyclonal and monoclonal PAX8, thyroid transcription factor-1, p63, and CD5. Four ITTCs (40.0%) stained positive for polyclonal PAX8; none stained positive for monoclonal PAX8. All PDTCs and 92.9% of SCCs were immunoreactive for both polyclonal and monoclonal PAX8. All PDTCs, 46.2% of SCCs, and none of the ITTCs were immunoreactive for thyroid transcription factor-1. Eight ITTCs (80.0%), but none of the PDTCs and SCCs, were immunoreactive for CD5. We are the first to show that ITTCs stain negative for monoclonal PAX8. Monoclonal PAX8 is a more reliable marker than polyclonal PAX8 for determining follicular cell origin. We conclude that monoclonal PAX8 is a useful marker for distinguishing ITTCs from PDTCs and SCCs. Monoclonal PAX8 negativity is additional evidence in support of ITTCs not being follicular cell-derived thyroid carcinomas, but having a thymic origin.

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  • Yumie Takeshita, Chisato Teramura, Toshinari Takamura
    Type: Original
    Article ID: EJ18-0119
    Published: 2018
    [Advance publication] Released: September 08, 2018
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    A 45-year-old male suddenly experienced left-flank abdominal pain. Echocardiography revealed akinesis of the ‘takotsubo cardiomyopathy’ type. He experienced a sudden haemodynamic collapse (blood pressure, 324/154 mmHg; pulse rate, 180 beats/min) during emergency cardiac catheterisation. An abdominal computed tomography (CT) revealed expansion of a soft tissue mass 64 × 33 mm in dimension in the left adrenal region, with accumulation of fluid surrounding the left pararenal space. Three days after the attack, his urinary catecholamine concentrations were slightly elevated. We suspected the patient as having a pheochromocytoma followed by acute haemorrhagic rupture, based on signatures of adrenal mass, ‘takotsubo cardiomyopathy’, and the hypertensive crisis. Over the next few weeks, he recovered well as an outpatient, and his blood pressure remained around 110/60 mmHg without medication. Three weeks after the attack, an abdominal CT showed shrinkage of the ruptured adrenal mass (to a diameter of 30 mm) and absorption of the retroperitoneal hematoma. On day 190 after the attack, abdominal CT did not detect any left adrenal mass. This is the first report of the case showing a complete vanishing of ruptured adrenal mass with takotsubo cardiomyopathy. Although surgical approaches for ruptured adrenal mass involve either emergency or elective surgery, the patients did not need even the elective surgery. Accumulation of the similar cases may unravel clinical factors predicting self-limiting of the ruptured adrenal mass to avoid unnecessary risky surgery.

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  • Nuri Karadurmus, Mehmet Ilkin Naharci, Sinasi Erol Bolu, Aydogan Aydog ...
    Article ID: RET10-1
    Published: 2010
    [Advance publication] Released: November 12, 2010
    JOURNALS FREE ACCESS ADVANCE PUBLICATION
    This article released online on September 22, 2010 as advance publication was withdrawn at the request of the authors.
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  • Nuri Karadurmus, Mehmet Ilkin Naharci, Sinasi Erol Bolu, Aydogan Aydog ...
    Article ID: K10E-195
    Published: 2010
    [Advance publication] Released: September 22, 2010
    JOURNALS FREE ACCESS ADVANCE PUBLICATION
    This article was retracted. See the Notification.
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  • Chengjiang LI, Mingzhi XU, Qing GU
    Article ID: K08E-187
    Published: 2008
    [Advance publication] Released: November 20, 2008
    JOURNALS FREE ACCESS ADVANCE PUBLICATION
    This article was retracted. See the Notification.
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