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Karin Tanaka, Shu Meguro, Arata Itoh, Noriko Kodani, Hiroshi Itoh
原稿種別: Original
論文ID: EJ23-0085
発行日: 2023年
[早期公開] 公開日: 2023/06/01
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The study was aimed to investigate the seasonal variation of hemoglobin A1c (HbA1c) in adults with type 1 diabetes (T1D) and the impact of coronavirus disease 2019 (COVID-19) by comparing 2019 and 2021 data and differences in treatment modes. This was a single-center retrospective observational study including 52 adult patients with T1D who regularly visited hospital in 2019 and 2021. Twenty-five patients used multiple daily injections (MDI)/self-measurement of blood glucose (SMBG), 16 used MDI/intermittently scanned continuous glucose monitoring (isCGM), 9 used sensor-augmented pump (SAP), and 2 used continuous subcutaneous insulin infusion (CSII)/isCGM. The mean HbA1c level was calculated for each month. The correlation between monthly means of temperature and HbA1c was investigated. Similar analyses were performed for the MDI/SMBG, MDI/isCGM, and SAP + CSII/isCGM groups. HbA1c levels in 2019 decreased in summer and increased in winter and showed a significant negative correlation with temperature (r = –0.652, p = 0.022). However, HbA1c in 2021 showed no seasonal variation and no correlation with temperature (r = –0.134, p = 0.678) and tended to decline after the three emergency declarations. HbA1c in the MDI/SMBG group showed the same trend as the whole group in 2019 and 2021. However, the effect of seasonal variation in HbA1c was lower in the MDI/isCGM group and the lowest in the SAP + CSII/isCGM group in 2019. The impact of emergency declaration on HbA1c level was small for the MDI/isCGM group and smaller for the SAP + CSII/isCGM group in 2021. The COVID-19 pandemic has affected the seasonal variation of HbA1c levels in T1D; the variation differed according to the treatment mode.
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Xiaobing Dou, Xiujing Wang, Xiuhua Yu, Jiaqi Yao, Huiling Shen, Yao Xu ...
原稿種別: Original
論文ID: EJ22-0550
発行日: 2023年
[早期公開] 公開日: 2023/05/31
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Endothelial dysfunction (ED) contributes to the pathologic process underlying macrovascular complications, a common complication of type 2 diabetes mellitus (T2DM). Soluble endoglin (sEng) shed from the extracellular domain of the entire endoglin molecule blocks endothelial protection mediated by transforming growth factor-beta 1 (TGF-β1). The reactive hyperemia index (RHI), which is determined by reactive hyperemia peripheral arterial tonometry (RH-PAT), is a new index with which to evaluate ED. This study determined the changes in serum sEng levels in newly-diagnosed (untreated) T2DM patients and the correlation with the RHI. The T2DM group included 34 newly-diagnosed T2DM patients, while the control group included 53 healthy adults. The clinical data from the two groups were evaluated retrospectively. The intima-media thickness (IMT) of the common carotid artery (CCA) and the ankle-brachial index (ABI) of both legs were used to assess structural vascular changes. The serum sEng level was determined using an ELISA kit. Endothelial function was assessed using RH-PAT and the RHI was computed. The serum sEng level in the T2DM group was significantly greater than the control group, although the RHI was significantly lower in the T2DM group (p < 0.05). The serum sEng level was negatively correlated with the RHI in T2DM patents (r = 0.354, p = 0.041). The serum sEng level, CCA-IMT, and ABI were not significantly correlated with T2DM (p > 0.05). In summary, among newly-diagnosed T2DM patients, the serum sEng levels were inversely correlated with the RHI, and an elevated sEng level may be associated with ED.
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Taisuke Uchida, Hideki Yamaguchi, Yasuji Arimura, Ayako Nagayama, Kano ...
原稿種別: Original
論文ID: EJ23-0053
発行日: 2023年
[早期公開] 公開日: 2023/05/30
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There is no computed tomography (CT)-based numerical index for predicting Cushing’s syndrome (CS) in patients with adrenal incidentalomas. We tested the hypothesis that the iliopsoas muscle (Ip-M) to visceral fat (V-fat) ratio (IVR) on CT may predict CS in elderly female patients with adrenal tumors. We examined the V-fat area, subcutaneous fat (S-fat) area, Ip-M area, V-fat/S-fat ratio, and IVR at the third lumbar vertebra (L3) level using abdominal CT in female patients aged ≥50 years with cortisol-producing adrenal tumor diagnosed with CS or non-functioning adrenal tumor (NFT) in the derivation cohort. We performed receiver operating characteristic (ROC) analysis to evaluate the diagnostic value of the V-fat/S-fat ratio and IVR for predicting CS. We assessed the usefulness of the IVR in a separate validation cohort. In the derivation cohort, the IVR was significantly lower in the 9 patients with CS than in the 15 patients with NFT (p < 0.001). In ROC analysis with a cut-off value of 0.067, the IVR showed a sensitivity of 100%, specificity of 80.0%, positive likelihood ratio (PLR) of 5.000, and negative likelihood ratio (NLR) of 0.000. The area under the curve was significantly higher for the IVR than for the V-fat/S-fat ratio (0.933 vs. 0.704, respectively, p = 0.036). In 23 patients in the validation cohort, the IVR demonstrated a PLR of 5.714 and an NLR of 0.327. The novel IVR index, based on single-slice CT at the L3 level, predicted CS in elderly female patients with adrenal tumors.
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Takumi Kitamoto, Domenico Accili
原稿種別: State-of-the-Art Review in Endocrinology
論文ID: EJ23-0150
発行日: 2023年
[早期公開] 公開日: 2023/05/27
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Over 100 years have passed since insulin was first administered to a diabetic patient. Since then great strides have been made in diabetes research. It has determined where insulin is secreted from, which organs it acts on, how it is transferred into the cell and is delivered to the nucleus, how it orchestrates the expression pattern of the genes, and how it works with each organ to maintain systemic metabolism. Any breakdown in this system leads to diabetes. Thanks to the numerous researchers who have dedicated their lives to cure diabetes, we now know that there are three major organs where insulin acts to maintain glucose/lipid metabolism: the liver, muscles, and fat. The failure of insulin action on these organs, such as insulin resistance, result in hyperglycemia and/or dyslipidemia. The primary trigger of this condition and its association among these tissues still remain to be uncovered. Among the major organs, the liver finely tunes the glucose/lipid metabolism to maintain metabolic flexibility, and plays a crucial role in glucose/lipid abnormality due to insulin resistance. Insulin resistance disrupts this tuning, and selective insulin resistance arises. The glucose metabolism loses its sensitivity to insulin, while the lipid metabolism maintains it. The clarification of its mechanism is warranted to reverse the metabolic abnormalities due to insulin resistance. This review will provide a brief historical review for the progress of the pathophysiology of diabetes since the discovery of insulin, followed by a review of the current research clarifying our understanding of selective insulin resistance.
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Ryota Terashima, Tomotaka Tani, Keitaro Sakakibara, Shiro Kurusu, Mits ...
原稿種別: Original
論文ID: EJ23-0080
発行日: 2023年
[早期公開] 公開日: 2023/05/19
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The secretion of several hypothalamic peptide hormones is activated during the preovulatory period. Hypothalamic thyrotropin-releasing hormone (TRH) is one such hormone with reproductive and/or metabolic significance. However, it remains unclear whether thyroid-stimulating hormone (TSH)-producing thyrotrophs are produced during the preovulatory period. We previously found a transient increase in the expression of the nuclear receptor NR4A3, a well-known immediate early gene, in the proestrus afternoon in the anterior pituitary glands of rats. To investigate the relationship between TRH secretion and pituitary NR4A3 expression during proestrus, we used proestrus and thyroidectomized rats to identify NR4A3-expressing cells and examined the regulation of Nr4a3 gene expression via the hypothalamus-pituitary-thyroid (HPT) axis. The percentage of NR4A3-expressing cells increased in thyrotrophs at 14:00 h of proestrus. Incubation of rat primary pituitary cells with TRH transiently stimulated Nr4a3 expression. Thyroidectomy to attenuate the negative feedback effects led to increased serum TSH levels and Nr4a3 gene expression in the anterior pituitary, whereas thyroxine (T4) administration conversely suppressed Nr4a3 expression. Additionally, the administration of T4 or TRH antibodies significantly suppressed the increase in Nr4a3 expression at 14:00 h of proestrus. These results demonstrate that pituitary NR4A3 expression is regulated by the HPT axis, and that TRH stimulates thyrotrophs and induces NR4A3 expression during the proestrus afternoon. This suggests the potential involvement of NR4A3 in the regulation of the HPT axis during pre- and post-ovulatory periods.
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Daisuke Hagiwara, Yoshinori Azuma, Yohei Kawaguchi, Takashi Miyata, Hi ...
原稿種別: Review
論文ID: EJ23-0193
発行日: 2023年
[早期公開] 公開日: 2023/05/19
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Arginine vasopressin (AVP) is an antidiuretic hormone synthesized principally in the hypothalamic supraoptic and paraventricular nuclei. The immunoglobulin heavy chain binding protein (BiP), one of the most abundant endoplasmic reticulum (ER) chaperones, is highly expressed in AVP neurons, even under basal conditions. Moreover, its expression is upregulated in proportion to the increase in AVP expression under dehydration. These data suggest that AVP neurons are constantly exposed to ER stress. BiP knockdown in AVP neurons induces ER stress and autophagy, resulting in AVP neuronal loss, indicating that BiP is pivotal in maintaining the AVP neuron system. Furthermore, inhibition of autophagy after BiP knockdown exacerbates AVP neuronal loss, suggesting that autophagy induced under ER stress is a protective cellular mechanism by which AVP neurons cope with ER stress. Familial neurohypophysial diabetes insipidus (FNDI) is an autosomal dominant disorder caused by mutations in the AVP gene. It is characterized by delayed-onset progressive polyuria and eventual AVP neuronal loss. In AVP neurons of FNDI model mice, mutant protein aggregates are confined to a specific compartment of the ER, called the ER-associated compartment (ERAC). The formation of ERACs contributes to maintaining the function of the remaining intact ER, and mutant protein aggregates in ERACs undergo autophagic-lysosomal degradation without isolation or translocation from the ER, representing a novel protein degradation system in the ER.
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Takuya Kitamura, Yuki Ishihara, Toru Kusakabe, Mika Tsuiki, Kazutaka N ...
原稿種別: Note
論文ID: EJ22-0564
発行日: 2023年
[早期公開] 公開日: 2023/05/12
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Osteogenesis imperfecta (OI) is a rare hereditary bone fragility disorder that affects 6–7 per 100,000 populations, and pituitary stalk interruption syndrome (PSIS) is a rare congenital defect with varying degrees of pituitary hormone deficiency, affecting approximately 0.5 in every 100,000 births. Currently, only two cases of these complications have been reported. A 46-year-old male who had experienced more than 20 fractures (peripheral and vertebral) during adolescence visited our hospital for close examination. He presented with blue sclerae and long bone deformations. We suspected OI because his mother and sister, who were being treated for osteoporosis, also had blue sclerae. Genetic testing identified a heterozygous variant (c.757C > T, p.Arg253Ter) in the COL1A1 gene, leading to the diagnosis of OI. His mother and sister also had the same variant. Considering that he underwent GH replacement therapy for his short stature during his childhood, his pituitary hormone levels were also evaluated to know if GH deficiency impacted low bone density; hypopituitarism was then suspected. The pituitary function test results led to the diagnoses of hypothalamic GH deficiency, hypogonadism, hypothyroidism, and hypoadrenocorticism. Furthermore, magnetic resonance imaging showed anterior pituitary atrophy, pituitary stalk loss, and ectopic posterior pituitary, leading to the diagnosis of PSIS. The combination of OI and hypopituitarism may have caused further bone fragility. Therefore, although rare, clinicians should keep in mind that patients with OI can possibly have concomitant pituitary insufficiency, which can lead to developmental and growth retardation.
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Masanori Hasebe, Shinobu Satoh, Kohei Ito, Haruka Tamura, Yasuo Terauc ...
原稿種別: Original
論文ID: EJ22-0562
発行日: 2023年
[早期公開] 公開日: 2023/05/11
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We investigated the pathophysiology of the dawn phenomenon by examining the effects of changes in blood glucose levels from late night to early morning on various hormones in a group taking glargine BS and a group taking Lantus XR, with the goal of achieving better glycemic control. Patients with types 1 and 2 diabetes scheduled for inpatient education were divided into BS and XR groups. Blood glucose levels were tracked from 0:00 to 7:00, while blood samples were extracted at 3:00 and 7:00 to measure glucose levels and hormones related to the dawn phenomenon. Overall, we analyzed blood sample and intermittently scanned Continuous Glucose Monitoring data of 43 and 40 patients, respectively. From 0:00 to 7:00, the mean blood glucose was significantly lower in the BS group, although the fluctuation was similar (p < 0.0001). The BS group also exhibited significantly higher ∆ACTH (p = 0.0215) and ∆ cortisol (p = 0.0430) than the XR group. In the BS group, ∆Glu exhibited a significant negative correlation with ∆ACTH and ∆cortisol (p = 0.0491). Similar findings were not observed in the XR group. These results suggest that XR may be a better choice for long-acting insulin since it is less likely to induce cortisol secretion. Further, analysis of the dawn phenomenon and non-dawn phenomenon groups showed the mean CPR levels at 3:00 and 7:00 were significantly higher in the latter (p = 0.0135). This supports the conventional belief that appropriate basal insulin replacement therapy is a beneficial treatment for the dawn phenomenon.
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Yan Wang, Jie Su, Peng Zhou, Xiao-yu Pan, Gao-xiang Huang, Li-juan Yin ...
原稿種別: Original
論文ID: EJ21-0787
発行日: 2023年
[早期公開] 公開日: 2023/05/09
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Glucocorticoids (GCs) are the important stress hormones and widely prescribed as drugs. Although stress has been suggested as a promoter of tumor progression, the direct influence of GCs on metastasis of tumor is not fully understood. Metastasis is a major cause of death in pancreatic cancer patients. In the present study, we investigated the effect of GCs on progression of pancreatic cancer and elucidated the underlying mechanism. It was found that GCs significantly promote cell adhesion, migration, and invasion of pancreatic cancer cells in vitro and their lung metastasis in vivo. Further mechanistic studies showed that GCs notably up-regulate the expression of a trans-membrane glycoprotein, mucin 1 (MUC1) and increase the activation of AKT. Inhibiting MUC1 expression not only attenuates the activation of AKT, but also significantly reduces the promoting effects of GCs on cell adhesion, migration, invasion, and lung metastasis of pancreatic cancer cells. Moreover, GCs not only significantly up-regulate expression of Rho-associated kinase 1/2 (ROCK1/2) and matrix metalloproteinase 3 and 7 (MMP3/7), but also activate ROCK2, which are also involved in the pro-migratory and pro-invasive effects of GCs in pancreatic cancer cells. Taken together, our findings reveal that GCs promote metastasis of pancreatic cancer cells through complex mechanism. MUC1-PI3K/AKT pathway, ROCK1/2 and MMP3/7 are involved in the promoting effect of GCs on cell migration, invasion and metastasis in pancreatic cancer cells. These results suggest the importance of reducing stress and GCs administration in patients with pancreatic cancer to avoid an increased risk of cancer metastasis.
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Mari Matsushiro, Daisuke Harada, Kaoru Ueyama, Hiroko Kashiwagi, Yoshi ...
原稿種別: Original
論文ID: EJ22-0620
発行日: 2023年
[早期公開] 公開日: 2023/05/09
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Osteogenesis imperfecta (OI) is an inherited disease characterized by bone fragility due to impaired type I collagen. Although orthopedic management is improving, other complications are poorly understood. We describe three patients with OI with unruptured intracranial aneurysm (IA) detected by magnetic resonance angiography (MRA) screening of 14 patients. Case 1 was a 73-year-old woman with type 1 OI with blue sclera, vertebral compression fractures, and impaired hearing. Lumbar spine bone mineral density (BMD) was preserved (young adult mean (YAM): 86%). MRA revealed an IA in the right internal carotid artery. Case 2 was a 43-year-old man with type 4 OI and leg-length discrepancy due to left femoral neck fracture. Lumbar spine BMD was decreased (YAM: 61%). MRA showed an IA in the left anterior cerebral artery. Case 3 was a 35-year-old woman with type 3 OI with blue sclera, dentinogenesis imperfecta, deformity of the long bones, and severe scoliosis. She had undergone spine surgery and needed wheelchair assistance. The YAM of the femoral neck BMD was 71%. MRA indicated an IA in the right posterior communicating artery. The prevalence of IA in our series of patients with OI was 21%, which is higher than the reported prevalence of unruptured IA in the Japanese general population (2.2%), suggesting that IA may be a complication of OI. Our literature review revealed no cases of OI with unruptured IA, but 11 cases of OI with subarachnoid hemorrhage. IA seems unrelated to OI type, sex, or age. We recommend MRA of adults with OI.
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Wei Shi, Daofei Song, Dan Chen, Wei Duan, Jing Zhang
原稿種別: Original
論文ID: EJ22-0643
発行日: 2023年
[早期公開] 公開日: 2023/04/21
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This study was established to explore the association of thyroid parameters including thyroid hormone and thyroid sensitivity indices with chronic kidney disease (CKD) in euthyroid patients with type 2 diabetes (T2D). CKD markers were defined by estimated glomerular filtration rate (eGFR) based on serum creatinine (Scr) (eGFRcr), eGFR based on cystatin C (cys C) (eGFRcys), and urinary albumin-to-creatinine ratio (UACR). Thyroid parameters, including triiodothyronine (FT3), free thyroxin (FT4), thyroid-stimulating hormone (TSH), FT3/FT4 ratio, TSH index (TSHI), and thyrotroph T4 resistance index (TT4RI), were measured. The prevalence rates of CKD defined by eGFRcys, eGFRcr, and UACR was 19.9%, 14.1%, and 50.6%, respectively. The eGFRcys and eGFRcr levels increased with increasing FT3 and FT3/FT4 tertiles, while the UACR levels increased with decreasing FT3 tertiles. Spearman’s analysis demonstrated that FT3 and FT3/FT4 were positively associated with eGFRcys and eGFRcr, and negatively associated with UACR. In logistic regression analyses, compared with the lowest FT3 tertile (≤4.12 pmol/L), the adjusted ORs for CKD (eGFRcys <60 mL/min/1.73 m2) in the middle FT3 tertile (4.12–4.74 pmol/L) and higher FT3 tertile (>4.74 pmol/L) were 0.248 and 0.153, respectively, but prominent associations of thyroid parameters with eGRFcr <60 mL/min/1.73 m2 and UACR were not observed after adjustment. Linear regression analysis demonstrated that eGFRcys was more strongly associated with FT3 than eGFRcr or UACR in the adjusted model. Among euthyroid patients with T2D, FT3 in the normal range was the independent factor most strongly related to CKD. Additionally, eGFRcys rather than eGFRcr or UACR was the CKD marker most associated with FT3.
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Masanori Adachi, Sakura Motegi, Keiko Nagahara, Ayako Ochi, Junya Toyo ...
原稿種別: Original
論文ID: EJ22-0607
発行日: 2023年
[早期公開] 公開日: 2023/04/19
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Pseudohypoaldosteronism (PHA) type II (PHA2) is a genetic disorder that leads to volume overload and hyperkalemic metabolic acidosis. PHA2 and PHA type I (PHA1) have been considered to be genetic and pediatric counterparts to type IV renal tubular acidosis (RTA). Type IV RTA is frequently found in adults with chronic kidney disease and is characterized by hyperchloremic hyperkalemic acidosis with normal anion gap (AG). However, we recently observed that PHA1 was not always identical to type IV RTA. In this study, we focused on the aid–base balance in PHA2. Through a literature search published between 2008–2020, 46 molecularly diagnosed cases with PHA2 were identified (median age of 14 years). They comprised 11 sets of familial and 16 sporadic cases and the pathology was associated with mutations in WNK 4 (n = 1), KLHL3 (n = 17), and CUL3 (n = 9). The mean potassium (K+) level was 6.2 ± 0.9 mEq/L (n = 46, range 4.0–8.6 mEq/L), whereas that of chloride (Cl–) was 110 ± 3.5 mEq/L (n = 41, 100–119 mEq/L), with 28 of 41 cases identified as hyperchloremic. More than half of the cases (18/35) presented with metabolic acidosis. Although AG data was obtained only in 16 cases, all but one cases were within normal AG range. Both Cl– and HCO3– levels showed significant correlations with K+ levels, which suggested that the degree of hyperchloremia and acidosis reflect the clinical severity, and is closely related to the fundamental pathophysiology of PHA2. In conclusion, our study confirmed that PHA2 is compatible with type IV RTA based on laboratory findings.
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Tetsuro Izumi
原稿種別: State-of-the-Art Review in Endocrinology
論文ID: EJ23-0112
発行日: 2023年
[早期公開] 公開日: 2023/04/19
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ALK7, a type I receptor for the transforming growth factor-β superfamily, is known to be predominantly expressed in adipocytes in both mice and humans. The present review describes recent findings suggesting that ALK7 plays a major role in regulating lipid metabolism and fat mass. Furthermore, the ligands and upstream regulators that activate ALK7 signaling are discussed. The focus is on findings in mice and their derivative tissues and cells that harbor the mutations of ALK7 and related molecules. Particular attention is paid to the contradictory nature of the current literature about the loss-of-function phenotypes and the relationship with insulin secretion and sensitivity. Additional attention is paid to the ALK7 gene variants found in humans and their associated traits. The goal is to seek a parsimonious, and preferably singular and unified, description of the underlying mechanism. This review also introduces recent promising findings about ALK7 neutralizing treatment to obese mice.
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Miwa Makino, Nobuyuki Koriyama, Nami Kojima, Takuya Tobo, Yoshihiko Ni ...
原稿種別: Case Report with Review of Literature
論文ID: EJ22-0622
発行日: 2023年
[早期公開] 公開日: 2023/04/15
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We report an extremely rare case of a 61-year old woman with food-dependent Cushing’s syndrome (FDC) due to unilateral adrenocortical adenoma (UAA) with cortisol (CORT) secretion without ACTH elevation detected in peripheral blood by the CRH test. She was on oral medications for hypertension and depression, and presented weight gain, general fatigue, muscle weakness, and hypokalemia. Despite the fact that the diurnal variation of ACTH was always suppressed, a diurnal variation in CORT was observed, in the form of low levels in the early morning and high levels in the afternoon. An increase in CORT was shown in a 75 g-oral glucose tolerance test (OGTT) and in a mixed meal tolerance test, but no change in CORT levels was seen in intravenous glucose tolerance tests. Elevated CORT levels were observed in response to intravenous injection of CRH, although ACTH levels were always below the measured sensitivity. Laparoscopic left adrenalectomy was performed, which resulted in postoperative improvement in potassium and ACTH levels and disappearance of the CORT secretory response in the OGTT. Clear expression of glucose-dependent insulinotropic polypeptide receptor (GIPR), CRH and CRH receptor 2 (CRHR2) were confirmed in the surgically-resected UAA specimen by molecular and immunohistochemical analyses, suggesting the involvement of not only GIPR, but also CRH and CRHR2 in FDC.
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Keitaro Kawada, Shunbun Kita, Shiro Fukuda, Keita Fukuoka, Tomonori Ok ...
原稿種別: Original
論文ID: EJ22-0665
発行日: 2023年
[早期公開] 公開日: 2023/04/15
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The fat-derived factor, adiponectin, is considered a salutary circulating factor. We recently demonstrated that native adiponectin binds T-cadherin and promotes intracellular biogenesis and secretion of the exosome. Exosomes play important roles in various aspects of homeostasis, including glucose and energy metabolism. However, it remains unclear whether and how the promotion of exosome production by adiponectin in vivo is beneficial for glucose and lipid metabolism. In the present study, overexpression of human adiponectin in mice resulted in an increased number of circulating exosomes, but it did not significantly improve glucose metabolism, change body weights, or change triglyceride clearance under a high-fat diet. Multiple small doses of streptozotocin increased blood glucose and decreased triglyceride clearance similarly in both wild-type and transgenic mice. Thus, these results indicated that human adiponectin overexpression in mice increases plasma exosomes but does not significantly influence glucose and lipid metabolism.
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Satoshi Tanaka, Hiroyuki Akagawa, Kenkou Azuma, Kaoru Watanabe, Sayaka ...
原稿種別: Original
論文ID: EJ22-0541
発行日: 2023年
[早期公開] 公開日: 2023/04/13
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Glucokinase is a glycolytic enzyme that catalyzes the phosphorylation of glucose to glucose-6-phospate in the first step of the glycolytic pathway. It also regulates the threshold for insulin secretion from pancreatic beta cells by catalyzing the phosphorylation of glucose and plays an important role as a glucose sensor. Pathogenic variants in the glucokinase gene (GCK) cause non-progressive but persistent mild fasting hyperglycemia, also recognized as maturity-onset diabetes of the young 2 (MODY2). This report presents the case of two Japanese siblings with MODY2, who were initially diagnosed with impaired glucose intolerance at 20 and 17 years of age, and later developed diabetes mellitus. They had no history of obesity, were negative for islet-related autoantibodies and their serum C-peptide level were within the normal range. Diabetic complications were not observed. Next-generation sequencing revealed a novel heterozygous variant in GCK (NM_000162.5: c.1088A>G, p.Asp363Gly) in both siblings. This variant has not been reported previously. In silico functional analyses, using SIFT and MutationTaster, suggested that the variant was damaging. To confirm the functional impact of the mutated GCK, the HiBiT-tagged p.Asp363Gly variant and the wild-type GCK were transiently expressed in HEK293T cells. The cells expressing the variant GCK exhibited 79% less bioluminescence, compared to those expressing the wild-type GCK, suggesting that the pathophysiology of the variant was a result of haploinsufficiency.
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An Murai, Naoki Shinojima, Genki Ikuta, Kazutaka Ozono, Yutaka Ueda, H ...
原稿種別: Original
論文ID: EJ22-0637
発行日: 2023年
[早期公開] 公開日: 2023/04/13
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Lymphocytic hypophysitis (LYH) is a rare chronic inflammatory disease characterized by lymphocytic infiltration of the anterior or posterior pituitary gland and hypothalamus. LYH is subdivided into lymphocytic adenohypophysitis (LAH), lymphocytic infundibulo-neurohypophysitis (LINH), and lymphocytic panhypophysitis (LPH) depending on the primary site. Most cases occur in adults, with few cases reported in children, and it is especially important to distinguish LYH from suprasellar malignancies, such as germ cell tumors and other neoplastic diseases. Although a biopsy is necessary for definitive diagnosis, it is desirable to be able to diagnose the disease without biopsy if possible, especially in children, because of the surgical invasiveness of the procedure. Recently, serum anti-rabphilin-3A antibodies have attracted attention as diagnostic markers for LYH, especially in LINH, but there are only a few reports on pediatric patients. In the present study, we experienced two children with LPH and LAH, respectively, who tested positive for anti-rabphilin-3A antibodies. This is the first report of children with LYH other than LINH positive for anti-rabphilin-3A antibodies, and anti-rabphilin-3A antibodies may be a useful non-invasive diagnostic marker not only for LINH but also for LYH in general. We also discuss the sensitivity and specificity of anti-rabphilin-3A antibody testing in cases where histological diagnosis has been made.
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Yutaka Takahashi
原稿種別: State-of-the-Art Review in Endocrinology
論文ID: EJ23-0050
発行日: 2023年
[早期公開] 公開日: 2023/04/13
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Paraneoplastic syndromes are defined by symptoms or signs resulting from damage to organs or tissues that are remote from the site of malignant neoplasms or its metastasis. They are due to tumor secretion of functional hormones or peptides or are related to immune cross-reactivity with the host tissue. In particular, paraneoplastic endocrine syndromes are mainly caused by ectopic hormone production by the tumor such as PTHrP in humoral hypercalcemia in malignancy and ACTH in ectopic ACTH syndrome. Recently, it has been reported that a specific form of hypophysitis is caused as an immune-mediated paraneoplastic syndrome; paraneoplastic autoimmune hypophysitis, in which an ectopic pituitary antigen expression in the tumor evoked autoimmunity against pituitary-specific antigens, resulting in hypophysitis and exhibiting the injury of specific anterior pituitary cells by cytotoxic T cells. This novel clinical entity, paraneoplastic autoimmune hypophysitis consists of several conditions such as anti-PIT-1 hypophysitis and a part of isolated ACTH deficiency and immune checkpoint inhibitor-related hypophysitis with common mechanisms. These conditions can explain at least in part, the underlying mechanisms of acquired specific pituitary hormone deficiencies. In addition, it is important to apply a comprehensive discipline of onco-immuno-endocrinology to understand the pathophysiology and this approach; the expansion and application of immune-mediated paraneoplastic syndrome to endocrine diseases may give a new clue to understand pathophysiology of the autoimmunity against endocrine organs.
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Hisamitsu Ide
原稿種別: State-of-the-Art Review in Endocrinology
論文ID: EJ22-0604
発行日: 2023年
[早期公開] 公開日: 2023/04/12
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Testosterone plays a key role in the maintenance of physical and mental functions in men. Age-related testosterone decline is closely associated with sarcopenia and muscle deterioration, while testosterone decline is linked with the etiology and prevention of diseases such as angina pectoris, arteriosclerosis, obesity, metabolic syndrome, and dementia. Late-onset hypogonadism (LOH) is defined as a disease characterized by age-related testosterone decline and associated clinical symptoms. Testosterone replacement therapy improves health-related QOL in patients with LOH.
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Liangmiao Chen, Enling Ye, Mengli Sun, Hai Lin, Lechu Yu, Zhenzhen Lin ...
原稿種別: Original
論文ID: EJ22-0528
発行日: 2023年
[早期公開] 公開日: 2023/04/08
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To study the effects of third trimester maternal isolated hypothyroxinemia (serum low free thyroxine and normal thyroid stimulating hormone level) on pregnancy outcomes, we performed a retrospective cohort study in women with singleton pregnancy between February 2009 and June 2012. Pregnant women were assigned to two groups, a hypothyroxinemia group (with maternal isolated hypothyroxinemia in the third trimester and normal thyroid function in the first and second trimesters) and a control group (with normal serum thyroid functions). The pregnancy outcomes, including preterm birth, fetal distress, birth weight, premature rupture of membranes, and Apgar score at one minute after the birth, were recorded and compared between the two groups. A total of 3,945 pregnant women (median age 26 year old) were included in the study, with 195 women in the hypothyroxinemia group and 3,750 women in the control group. Compared with the women in the control group, women in the hypothyroxinemia group had higher incidences of premature rupture of membranes and low Apgar score at one minute after the birth. The multivariate logistic regression analysis showed that the low third trimester serum thyroxine level was the independent risk factor for the premature rupture of membranes and low Apgar score. There were no statistically significant differences in preterm birth, macrosomia, and intrauterine fetal distress between two groups. Third trimester maternal isolated hypothyroxinemia was associated with adverse pregnancy outcomes. The maternal serum thyroxine level should be monitored during late pregnancy and necessary management should be applied to improve the pregnancy outcomes.
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Lulu Liu, Danting Li, Chuan Peng, Rufei Gao, Xuan Li, Linkun Zhang, Qi ...
原稿種別: Original
論文ID: EJ22-0288
発行日: 2023年
[早期公開] 公開日: 2023/04/05
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Adipocyte apoptosis is a key initial event that contributes to macrophage infiltration into adipose tissue (AT) and thus triggers AT inflammation in obesity. MicroRNA-27a (miR-27a) was shown to mediate the pathological processes of many metabolic disorders; however, whether miR-27a is involved in adipocyte apoptosis of obese AT remains unknown. The present study aimed to investigate the alteration of miR-27a in obese individuals and its antiapoptotic function in adipocytes. In vivo, serum samples and omental adipose tissue from humans as well as epididymal fat pads from mice were collected to detect miR-27a expression. In vitro, 3T3-L1 preadipocytes and mature adipocytes were treated with TNF-α to induce apoptosis and transfected with a mimic for overexpressing miR-27a-3p. The results showed that miR-27a was markedly decreased in the serum and AT of obese human patients and in the AT of high-fat diet-fed mice. Regression analyses revealed that the serum level of miR-27a was correlated with metabolic parameters in human obesity. Notably, TNF-α induced cell apoptosis in both preadipocytes and mature adipocytes, as evidenced by the upregulation of cleaved caspase 3 and cleaved caspase 8 and the ratio of Bax to Bcl-2, while these effects were partly diminished by miR-27a overexpression. In addition, TUNEL and Hoechst 33258 staining verified that miR-27a overexpression markedly inhibited the apoptosis of adipocytes under TNF-α stimulation. Thus, miR-27a was downregulated in the AT of obese subjects with proapoptotic status, and overexpression of miR-27a exerted an antiapoptotic effect on preadipocytes, providing a novel potential target for preventing AT dysfunction.
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Yuki Abe, Tatsuhiko Urakami, Junichi Suzuki, Satoshi Morita, Mariko Ar ...
原稿種別: Original
論文ID: EJ22-0379
発行日: 2023年
[早期公開] 公開日: 2023/04/04
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Prevention of hypoglycemia is an important strategy for glycemic management in patients with type 1 diabetes mellitus (T1D). Hypoglycemia is difficult to recognize at night while sleeping, particularly when using multiple daily injection (MDI) insulin therapy rather than sensor-augmented insulin-pump therapy. Therefore, it is possible that patients with T1D are at higher risk of nocturnal hypoglycemia when insulin is administered using an MDI regimen. We investigated nocturnal hypoglycemia in 50 pediatric patients with T1D on MDI insulin therapy using data from an intermittently scanned continuous glucose monitoring (isCGM) system. Hypoglycemia was observed on 446 of the 1,270 nights studied. Most of the hypoglycemic episodes were severe (blood glucose <54 mg/dL). On nights when hypoglycemia occurred, the blood glucose concentrations measured using finger-stick blood glucose monitoring (FSGM) before sleep and the next morning were lower than nights when hypoglycemia did not occur. However, few values were below the normal blood glucose range, suggesting that FSGM alone may be insufficient to detect nocturnal hypoglycemia. Approximately 7% of time was spent below the normal glucose range during the 10 hours from 21:00 to 7:00 the next morning. This result suggests that the patients on MDI insulin therapy could end up spending more time in hypoglycemia than is recommended by the American Diabetes Association (time below range <4.0% of time per day). Monitoring glucose levels overnight using an isCGM sensor may improve glycemic management via automatic detection of blood glucose peaks and troughs.
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Keigo Murata, Yuri Ishiuchi-Sato, Taku Nedachi
原稿種別: Original
論文ID: EJ22-0611
発行日: 2023年
[早期公開] 公開日: 2023/03/11
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電子付録
The skeletal muscle is an endocrine organ that produces proteins and peptides, collectively termed as myokines. The temperature of skeletal muscles varies during exercise and/or with changes in ambient temperature. However, whether myokine secretion is regulated by heat stimulation is unclear. Thus, we aimed to explore the effects of environmental heat stimulation on myokine secretion. We initially investigated the secretome of C2C12 myotubes and identified several novel heat-responsive myokines. The concentration of C-C motif chemokine ligand 5 (CCL5) dramatically decreased by 0.3-fold in response to heat stress. After 3 h heat stimulation of C2C12 cells, the expression of heat shock protein 70 was induced, and the gene expression and secretion of CCL5 was significantly attenuated in C2C12 cells. We then examined the effects of acute heat stress on serum CCL5 levels in mice and Ccl5 gene expression in skeletal muscles. Mice were maintained at 23°C, exposed to 45°C for 30 min, and then returned to the 23°C chamber for recovery. The expression of Ccl5 in the skeletal muscle significantly decreased after 3 h of recovery. Serum CCL5 levels increased by approximately 1.9-fold after 30 min of heat exposure and then significantly decreased by approximately 0.7-fold after 23 h of recovery. This study suggests that heat stimulation decreases CCL5 secretion from the skeletal muscle in vitro and in vivo. Given its fundamental role in inflammation by recruiting several immune cells, CCL5 has a potential role in controlling inflammatory responses in the body after heat stimulation.
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Keiko Nagata, Kazuhiko Hayashi, Keisuke Kumata, Yukio Satoh, Mitsuhiko ...
原稿種別: Original
論文ID: EJ22-0609
発行日: 2023年
[早期公開] 公開日: 2023/03/10
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Epstein-Barr virus (EBV) is a human herpes virus that latently infects B lymphocytes. When EBV is reactivated, host B cells differentiate into plasma cells and produce IgM-dominant antibodies as well as many progeny virions. The aims of the present study were to confirm the IgM dominance of thyrotropin-receptor antibodies (TRAbs) produced by EBV reactivation and investigate the roles of TRAb-IgM in Graves’ disease. Peripheral blood mononuclear cells (PBMCs) containing TRAb-producing cells were stimulated for EBV reactivation, and TRAb-IgM and TRAb-IgG were measured by ELISA. TRAb-IgM were purified and TSH-binding inhibitory activities were assessed using a radio-receptor assay. Porcine thyroid follicular epithelial cells were cultured with TRAb-IgM and/or complements to measure the intracellular levels of cAMP and the amount of LDH released. TRAb-IgM/TRAb-IgG (the MG ratio) was examined in sequential serum samples of Graves’ disease and compared among groups of thyroid function. The results obtained showed that IgM-dominant TRAb production was induced by EBV reactivation. TRAb-IgM did not inhibit TSH binding to TSH receptors and did not transduce hormone-producing signals. However, it destroyed thyroid follicular epithelial cells with complements. The MG ratio was significantly higher in samples of hyperthyroidism or hypothyroidism than in those with normal function or in healthy controls. A close relationship was observed between TRAb-IgM produced by EBV reactivation and the development and exacerbation of Graves’ disease. The present results provide novel insights for the development of prophylaxis and therapeutics for Graves’ disease.
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Momoe Sakurai, Tetsuji Wakabayashi, Yasuyuki Kondo, Eriko Ikeda, Koich ...
原稿種別: Original
論文ID: EJ22-0578
発行日: 2023年
[早期公開] 公開日: 2023/03/09
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Vasoactive intestinal peptide-secreting tumors (VIPomas) are extremely rare functional pancreatic neuroendocrine neoplasms (p-NENs) characterized by watery diarrhea, hypokalemia, and achlorhydria. Here, we report the case of a 51-year-old female patient with VIPoma that recurred after a long-term disease-free interval. This patient had been asymptomatic for approximately 15 years after the initial curative surgery for pancreatic VIPoma, with no metastasis. The patient underwent a second curative surgery for the locally recurrent VIPoma. Whole-exome sequencing of the resected tumor revealed a somatic mutation in MEN1, which is reportedly responsible not only for multiple endocrine neoplasia type 1 (MEN1) syndrome but also sporadic p-NENs. Symptoms were controlled with lanreotide before and after surgery. The patient is alive with no relapse following 14 months after surgery. This case demonstrates the importance of long-term observation of patients with VIPoma.
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Satoshi Ida, Ryutaro Kaneko, Kanako Imataka, Kaoru Okubo, Kentaro Azum ...
原稿種別: Original
論文ID: EJ22-0548
発行日: 2023年
[早期公開] 公開日: 2023/03/01
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We used a consensus statement to diagnose sarcopenic obesity, evaluated incidence of sarcopenic obesity in older patients with diabetes, and examined whether sarcopenic obesity was associated with their higher-level functional capacity. Outpatients with diabetes (age, ≥65 years) undergoing treatment at Ise Red Cross Hospital were included. The Tokyo Metropolitan Institute of Gerontology Index of Competence (TMIG-IC)—a self-administered questionnaire—was used to assess their higher-level functional capacity. Sarcopenic obesity was evaluated based on the consensus statement diagnostic criteria—i.e., presence or absence of decreased skeletal muscle mass was evaluated based on appendicular skeletal muscle mass/body weight and obesity was assessed based on body fat mass percentage. To calculate the adjusted β coefficient of sarcopenic obesity for higher-level functional capacity, multiple regression analyses were performed using TMIG-IC scores as the dependent variable and four categories (non-sarcopenia/non-obesity was used as a reference) that included sarcopenia and obesity as the predictor and moderator variables. Among the 310 patients included, the sarcopenic obesity incidence was 13.1% and 14.2% in men and women, respectively. When the non-sarcopenia/non-obesity group was used as a reference, the adjusted β coefficient of sarcopenic obesity for scores of the TMIG-IC was –2.09 (p = 0.014) in men. However, the women showed no relationship between sarcopenic obesity and TMIG-IC scores. In older men with diabetes, sarcopenic obesity was associated with a decline in higher-level functional capacity.
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Nuri Karadurmus, Mehmet Ilkin Naharci, Sinasi Erol Bolu, Aydogan Aydog ...
論文ID: RET10-1
発行日: 2010年
[早期公開] 公開日: 2010/11/12
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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 ...
論文ID: K10E-195
発行日: 2010年
[早期公開] 公開日: 2010/09/22
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This article was retracted. See the Notification.
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Chengjiang LI, Mingzhi XU, Qing GU
論文ID: K08E-187
発行日: 2008年
[早期公開] 公開日: 2008/11/20
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This article was retracted. See the Notification.
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