Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Clinical Endocrinology and Metabolism  

CONTEXT: Prolonged exposure to pathological cortisol, as in Cushing's syndrome causes various age-related disorders, including sarcopenia. However, it is unclear whether mild cortisol excess, for example, accelerates sarcopenia due to aging or chronic stress. OBJECTIVE: We used Mendelian randomization (MR) analysis to assess whether cortisol was causally associated with muscle strength and mass. METHODS: Three single-nucleotide polymorphisms associated with plasma cortisol concentrations in the CORtisol NETwork consortium (n = 12 597) were used as instrumental variables. Summary statistics with traits of interest were obtained from relevant genome-wide association studies. For the primary analysis, we used the fixed-effects inverse-variance weighted analysis accounting for genetic correlations between variants. RESULTS: One SD increase in cortisol was associated with SD reduction in grip strength (estimate, -0.032; 95% CI -0.044 to -0.020; P = 3e-04), whole-body lean mass (estimate, -0.032; 95% CI, -0.046 to -0.017; P = 0.004), and appendicular lean mass (estimate, -0.031; 95% CI, -0.049 to -0.012; P = 0.001). The results were supported by the weighted-median analysis, with no evidence of pleiotropy in the MR-Egger analysis. The association of cortisol with grip strength and lean mass was observed in women but not in men. The association was attenuated after adjusting for fasting glucose in the multivariable MR analysis, which was the top mediator for the association in the MR Bayesian model averaging analysis. CONCLUSION: This MR study provides evidence for the association of cortisol with reduced muscle strength and mass, suggesting the impact of cortisol on the development of sarcopenia.

DOI： 10.1210/clinem/dgab862

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Language：English   Publishing type：Research paper (scientific journal)  

CONTEXT: 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors demonstrate antimetabolic and antisarcopenic effects in Cushing's syndrome (CS) and autonomous cortisol secretion (ACS) patients. OBJECTIVE: To confirm the efficacy and safety of S-707106 (11β-HSD1 inhibitor) administered to CS and ACS patients. DESIGN: A 24-week single-center, open-label, single-arm, dose-escalation, investigator-initiated clinical trial on a database. SETTING: Kyushu University Hospital, Kurume University Hospital, and related facilities. PATIENTS: Sixteen patients with inoperable or recurrent CS and ACS, with mildly impaired glucose tolerance. INTERVENTION: Oral administration of 200 mg S-707106 after dinner, daily, for 24 weeks. In patients with insufficient improvement in oral glucose tolerance test results at 12 weeks, an escalated dose of S-707106 (200 mg twice daily) was administered for the residual 12 weeks. MAIN OUTCOME MEASURES: The rate of participants responding to glucose tolerance impairment, defined as those showing a 25&#37; reduction in the area under the curve (AUC) of plasma glucose during the 75-g oral glucose tolerance test at 24 weeks. RESULTS: S-707106 administration could not achieve the primary endpoint of this clinical trial (>20&#37; of responsive participants). AUC glucose decreased by -7.1&#37; [SD, 14.8 (90&#37; CI -14.8 to -1.0), P = 0.033] and -2.7&#37; [14.5 (-10.2 to 3.4), P = 0.18] at 12 and 24 weeks, respectively. S-707106 administration decreased AUC glucose significantly in participants with a high body mass index. Body fat percentage decreased by -2.5&#37; [1.7 (-3.3 to -1.8), P < 0.001] and body muscle percentage increased by 2.4&#37; [1.6 (1.7 to 3.1), P < 0.001]. CONCLUSIONS: S-707106 is an effective insulin sensitizer and antisarcopenic and antiobesity medication for these patients.

DOI： 10.1210/clinem/dgab450

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: Dehydroepiandrosterone sulfate (DHEAS) from the adrenal cortex substantially decreases with age, which may accelerate osteoporosis. However, the association of DHEAS with bone mineral density (BMD) and fracture is inconclusive. We conducted a Mendelian randomization (MR) analysis to investigate the role of DHEAS in age-related changes in BMD and fracture risk. METHODS: Single nucleotide polymorphisms (SNPs) associated with serum DHEAS concentrations were used as instrumental variables (4 SNPs for main analysis; 4 SNPs for men and 5 SNPs for women in sex-related analysis). Summary statistics were obtained from relevant genome-wide association studies. RESULTS: A log-transformed unit (µmol/L) increase in serum DHEAS concentrations was associated with an SD increase in estimated BMD at the heel (estimate, 0.120; 95&#37; CI, 0.081-0.158; P = 9 × 10-10), and decreased fracture (odds ratio, 0.989; 95&#37; CI, 0.981-0.996; P = 0.005), consistent with dual-energy X-ray absorptiometry-derived BMD at the femoral neck and lumbar spine. Their associations remained even after adjusting for height, body mass index, testosterone, estradiol, sex hormone-binding globulin, and insulin-like growth factor 1. The association of DHEAS with fracture remained after adjusting for falls, grip strength, and physical activity but was attenuated after adjusting for BMD. The MR-Bayesian model averaging analysis showed BMD was the top mediating factor for association of DHEAS with fracture. The association between DHEAS and BMD was observed in men but not in women. CONCLUSION: DHEAS was associated with increased BMD and decreased fracture. DHEAS may play a protective role in decreasing fracture risk, mainly by increasing bone mass.

DOI： 10.1210/clinem/dgab459

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: Dehydroepiandrosterone sulfate (DHEAS) from the adrenal cortex substantially decreases with age, which may accelerate osteoporosis. However, the association of DHEAS with bone mineral density (BMD) and fracture is inconclusive. We conducted a Mendelian randomization (MR) analysis to investigate the role of DHEAS in age-related changes in BMD and fracture risk. METHODS: Single nucleotide polymorphisms (SNPs) associated with serum DHEAS concentrations were used as instrumental variables (4 SNPs for main analysis; 4 SNPs for men and 5 SNPs for women in sex-related analysis). Summary statistics were obtained from relevant genome-wide association studies. RESULTS: A log-transformed unit (μmol/L) increase in serum DHEAS concentrations was associated with SD increase in estimated BMD at the heel (estimate, 0.120; 95&#37; confidence interval [CI], 0.081-0.158; P = 9 × 10 -10), and decreased fracture (odds ratio [OR], 0.989; 95&#37;CI, 0.981-0.996; P = 0.005), consistent with dual-energy X-ray absorptiometry-derived BMD at the femoral neck and lumbar spine. Their associations remained even after adjusting for height, body mass index, testosterone, estradiol, sex hormone-binding globulin, and IGF-1. The association of DHEAS with fracture remained after adjusting for falls, grip strength, and physical activity but was attenuated after adjusting for BMD. The MR-Baysian model averaging analysis showed BMD was the top mediating factor for association of DHEAS with fracture. The association between DHEAS and BMD was observed in men but not in women. CONCLUSION: DHEAS was associated with increased BMD and decreased fracture. DHEAS may play a protective role in decreasing fracture risk, mainly by increasing bone mass.

DOI： 10.1210/clinem/dgab459

Language：English   Publishing type：Research paper (scientific journal)  

Primary aldosteronism (PA) is associated with an increased risk of cardiometabolic diseases, especially in unilateral subtype. Despite its high prevalence, the case detection rate of PA is limited, partly because of no clinical models available in general practice to identify patients highly suspicious of unilateral subtype of PA, who should be referred to specialized centers. The aim of this retrospective cross-sectional study was to develop a predictive model for subtype diagnosis of PA based on machine learning methods using clinical data available in general practice. Overall, 91 patients with unilateral and 138 patients with bilateral PA were randomly assigned to the training and test cohorts. Four supervised machine learning classifiers; logistic regression, support vector machines, random forests (RF), and gradient boosting decision trees, were used to develop predictive models from 21 clinical variables. The accuracy and the area under the receiver operating characteristic curve (AUC) for predicting of subtype diagnosis of PA in the test cohort were compared among the optimized classifiers. Of the four classifiers, the accuracy and AUC were highest in RF, with 95.7&#37; and 0.990, respectively. Serum potassium, plasma aldosterone, and serum sodium levels were highlighted as important variables in this model. For feature-selected RF with the three variables, the accuracy and AUC were 89.1&#37; and 0.950, respectively. With an independent external PA cohort, we confirmed a similar accuracy for feature-selected RF (accuracy: 85.1&#37;). Machine learning models developed using blood test can help predict subtype diagnosis of PA in general practice.

DOI： 10.1038/s41598-021-88712-8

Language：English   Publishing type：Research paper (scientific journal)  

CONTEXT: Current clinical guidelines recommend confirmation of a positive result in at least one confirmatory test in the diagnosis of primary aldosteronism (PA). Clinical implication of multiple confirmatory tests has not been established, especially when patients show discordant results. OBJECTIVE: The aim of the present study was to explore the role of 2 confirmatory tests in subtype diagnosis of PA. DESIGN AND SETTING: A retrospective cross-sectional study was conducted at two referral centers. PARTICIPANTS AND METHODS: We identified 360 hypertensive patients who underwent both a captopril challenge test (CCT) and a saline infusion test (SIT) and exhibited at least one positive result. Among them, we studied 193 patients with PA whose data were available for subtype diagnosis based on adrenal vein sampling (AVS). MAIN OUTCOME MEASURE: The prevalence of bilateral subtype on AVS according to the results of the confirmatory tests was measured. RESULTS: Of patients studied, 127 were positive for both CCT and SIT (double-positive), whereas 66 were positive for either CCT or SIT (single-positive) (n = 34 and n = 32, respectively). Altogether, 135 were diagnosed with bilateral subtype on AVS. The single-positive patients had milder clinical features of PA than the double-positive patients. The prevalence of bilateral subtype on AVS was significantly higher in the single-positive patients than in the double-positive patients. (63/66 [95.5&#37;] vs 72/127 [56.7&#37;], P < .01). Several clinical parameters were different between CCT single-positive and SIT single-positive patients. CONCLUSION: Patients with discordant results between CCT and SIT have a high probability of bilateral subtype of PA on AVS.

DOI： 10.1210/clinem/dgaa812

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© Endocrine Society 2019. All rights reserved. Context: The current clinical guidelines suggest that confirmatory tests for primary aldosteronism (PA) may be excluded in some of patients who have elevated plasma aldosterone concentration (PAC) under plasma renin suppression. However, this has low-priority evidence and is under debate in use of serum potassium. Objective: This study aimed to investigate an appropriate setting for sparing confirmatory tests in PA. Design and Setting: A retrospective cross-sectional study in a single referral center. Participants: This study included 327 patients who had hypertension under plasma renin suppression and underwent the captopril challenge test (CCT) between January 2007 and April 2019. CCT results were used to diagnose PA. Main Outcome Measure: Diagnostic value of PAC and serum potassium in confirmation of PA. Results: Of the studied patients, 252 of 327 (77&#37;) were diagnosed with PA. All 61 patients with PAC > 30 ng/dL were diagnosed with PA. In patients with PAC between 20 and 30 ng/dL, 44 of 55 (80&#37;) were diagnosed with PA, while all 26 with PAC between 20 to 30 ng/dL who had spontaneous hypokalemia were diagnosed with PA. The proportion of unilateral PA determined by adrenal vein sampling (AVS) was higher in patients who had PAC > 30 ng/dL or those with spontaneous hypokalemia who had PAC between 20 and 30 ng/dL than those who did not meet the criteria (76&#37; vs. 17&#37;, P <.001). Conclusion: Confirmatory tests in PA could be spared in patients who have typical features of PA and these patients had a high probability of unilateral PA on AVS.

DOI： 10.1210/clinem/dgz148

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OBJECTIVE: Expression of corticotropin-releasing factor type 1 receptor (CRFR1) has been shown on pancreatic β cells, and its activation potentiates glucose-stimulated insulin secretion (GSIS). However, the roles of CRFR1 in energy metabolism beyond insulin release remain elusive. MATERIALS/METHODS: We characterized the metabolic phenotypes of mice lacking CRFR1 (CRFR1KO mice) under conditions of energy excess. RESULTS: When fed a normal diet, the glucose profile of CRFR1KO mice in response to a glucose tolerance test was similar to that of wild-type (WT) mice, while serum insulin levels were significantly lower in CRFR1KO mice, reflecting high insulin sensitivity in part due to very low glucocorticoid levels. Histology of the pancreas revealed islet hypoplasia in CRFR1KO mice, suggesting a role of CRFR1 in maintaining the β cell mass in a manner similar to incretins. In response to a high-fat diet, CRFR1KO mice showed insulin resistance, but serum insulin levels during glucose challenge remained at a low level, indicating defective GSIS. In addition, CRFR1KO mice showed resistance to diet-induced obesity and hepatic steatosis. Although total food intake was not different between CRFR1KO and WT mice, oxygen consumption was significantly increased in CRFR1KO mice. The increased energy expenditure may explain the lean phenotype of CRFR1KO mice under conditions of energy excess. CONCLUSIONS: Our results suggest that CRFR1 plays important roles in whole body energy homeostasis, providing compelling evidence of the close relationship between energy homeostasis and the function of the hypothalamic-pituitary-adrenal axis.

DOI： 10.1016/j.metabol.2013.08.005

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Activin, a transforming growth factor β family member, has a wide range of physiological roles during embryonic development and organogenesis. In the ovary, activin, secreted from ovarian granulosa cells, not only acts on the pituitary gland to regulate the gonadotropin secretion from the pituitary gland in an endocrine manner but also acts on granulosa cells in a paracrine/autocrine manner to regulate folliculogenesis. Previously, we showed that activin signals through activin type IB receptor (ActRIB) and up-regulates follicle-stimulating hormone receptor expression and P450 aromatase activity in human ovarian granulose cell-like KGN cells. In the current study, we demonstrate the direct involvement of Smad2 as a downstream signal mediator of ActRIB in the transcriptional regulation of the P450 aromatase gene (CYP19A) in KGN cells. Upon activin stimulation, Smad2 activation and an increase in P450 aromatase messenger RNA (mRNA) were observed in KGN cells. Interestingly, Smad2 phosphorylation correlated well with the increase in P450 aromatase mRNA. Reciprocally, knockdown of Smad2 mRNA in KGN cells led to a decrease in the P450 aromatase mRNA expression, suggesting that Smad2 regulates CYP19A gene expression. Further analysis of CYP19A promoter activity revealed that the 5' upstream region between -2069 and -1271bp is required for the activation by Smad2. Finally, we provide compelling evidence that Smad2 shows follicular stage-specific expression, which is high in granulosa cells of preantral or early antral follicles in mice. Our results suggest that activin signaling through the ActRIB-Smad2 pathway plays a pivotal role in CYP19A expression and thus in follicular development.

DOI： 10.1016/j.bbrc.2013.05.124

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Smad2 is a critical mediator of TGF-beta signals that are known to play an important role in a wide range of biological processes in various cell types. Its role in the development of the CNS, however, is largely unknown. Mice lacking Smad2 in the CNS (Smad2-CNS-KO) were generated by a Cre-loxP approach. These mice exhibited behavioral abnormalities in motor coordination from an early postnatal stage and mortality at approximately 3 weeks of age, suggestive of severe cerebellar dysfunction. Gross observation of Smad2-CNS-KO cerebella demonstrated aberrant foliations in lobule IX and X. Further analyses revealed increased apoptotic cell death, delayed migration and maturation of granule cells, and retardation of dendritic arborization of Purkinje cells. These findings indicate that Smad2 plays a key role in cerebellar development and motor function control.

DOI： 10.1074/jbc.M111.223271

Language：Japanese   Publisher：The Japan Endocrine Society  

DOI： 10.1507/endocrine.101.s.update_6

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Language：English   Publisher：Diabetology International  

It is rare for a patient to have minimal change nephrotic syndrome, slowly progressive insulin-dependent diabetes mellitus, and Graves’ disease in combination. In this case, a patient developed idiopathic nephrotic syndrome at the age of 11 years. She was diagnosed with frequently relapsing nephrotic syndrome and steroid-dependent nephrotic syndrome after repeated increases in urinary protein levels with prednisolone reduction. At the age of 14 years, steroid-induced diabetes was suspected because she was negative for anti-glutamic acid decarboxylase (GAD) antibody, and her glycemic control improved after medication. At the age of 16 years, her nephrotic syndrome was in remission, but even after discontinuation of cyclosporine, her glycemic control did not improve. Decreased insulin secretion and positive anti-insulinoma-associated protein-2 (IA2) antibody were found, and therefore she was diagnosed as having slowly progressive insulin-dependent diabetes mellitus (SPIDDM). Although her glycemic control was stable with insulin therapy, she was diagnosed with asymptomatic Graves’ disease at the age of 28 years and started treatment. Human leukocyte antigen testing (HLA) was performed to evaluate the etiology of the disease, which revealed A*02:01, B*35:01, DQA1*03:01, DQB1*03:02, DQB1*04:01, DRB1*04:05, DRB1*08:02, and DPB1*05:01, suggesting genetic involvement of HLA for each disease susceptibility.

DOI： 10.1007/s13340-024-00787-6

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Language：English   Publisher：シュプリンガー・ジャパン(株)  

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CONTEXT: Diabetic retinopathy (DR) is a common microvascular complication of diabetes, and identifying the risk factors for severe DR is important. OBJECTIVE: We aimed to investigate the relationship between severe DR and the extracellular water to total body water ratio (ET ratio). DESIGN: Retrospective cross-sectional study. SETTING: Department of Endocrinology, Metabolism, and Diabetes at Kyushu University Hospital. PATIENTS: A total of 205 adults with type 2 diabetes (T2D) were included. The patients were divided into two groups: non-proliferative DR (non-PDR; n = 161, 126 with no DR and 35 with simple DR) and proliferative DR (PDR; n = 44, 18 with pre-proliferative DR and 26 with PDR). MAIN OUTCOME MEASURE: The ET ratio was measured using bioelectrical impedance analysis. RESULTS: The ET ratio was significantly higher in the PDR group than in the non-PDR group (0.390 vs. 0.398; P < .0001). Multivariate logistic regression analysis showed that the ET ratio was significantly associated with PDR, independent of known risk factors for DR progression. In the subgroup analysis by age, multivariate logistic regression analysis revealed a significant association between the ET ratio and PDR, independent of known risk factors for DR progression in patients younger than 60 years. However, in patients 60 years and older, only the urinary albumin to creatinine ratio (UACR) showed a significant association with PDR in a model using the UACR and the ET ratio. CONCLUSION: In patients with T2D younger than 60 years, the ET ratio may be a useful indicator for identifying severe DR.

DOI： 10.1210/clinem/dgae768

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of the Endocrine Society  

CONTEXT: Adrenal incidentalomas, including nonfunctioning adrenal incidentalomas (NFAI), are associated with a high prevalence of diabetes mellitus (DM). While NFAI is diagnosed by exclusion when no hormone excess exists, subtle cortisol secretion may exist and contribute to DM development. However, it alone cannot explain the increased risk, and whether other steroid metabolites are involved remains unclear. PURPOSE: To investigate steroid metabolites associated with DM in patients with NFAI using plasma steroid profiles. METHODS: Using liquid chromatography-tandem mass spectrometry, 22 plasma steroid metabolites were measured in 68 patients with NFAI (31 men and 37 women). Data were adjusted for age before normalization. RESULTS: Discriminant analysis showed that plasma steroid profiles discriminated between patients with and without DM in men (n = 10 and = 21, respectively) but not women: 11β-hydroxytestosterone, an adrenal-derived 11-oxygenated androgen, contributed most to this discrimination and was higher in patients with DM than in those without DM (false discovery rate = .002). 11β-hydroxytestosterone was correlated positively with fasting plasma glucose (r = .507) and hemoglobin A1c (HbA1c) (r = .553) but negatively with homeostatic model assessment of β-cell function (HOMA2-B) (r = -.410). These correlations remained significant after adjusting for confounders, including serum cortisol after the 1-mg dexamethasone suppression test. Bayesian kernel machine regression analysis verified the association of 11β-hydroxytestosterone with HbA1c and HOMA2-B in men. MAIN CONCLUSION: Plasma steroid profiles differed between those with and without DM in men with NFAI. 11β-hydroxytestosterone was associated with hyperglycemia and indicators related to pancreatic β-cell dysfunction, independently of cortisol.

DOI： 10.1210/jendso/bvae140

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Molecular Metabolism  

OBJECTIVE: The human adrenal cortex comprises three functionally and structurally distinct layers that produce layer-specific steroid hormones. With aging, the human adrenal cortex undergoes functional and structural alteration or "adrenal aging", leading to the unbalanced production of steroid hormones. Given the marked species differences in adrenal biology, the underlying mechanisms of human adrenal aging have not been sufficiently studied. This study was designed to elucidate the mechanisms linking the functional and structural alterations of the human adrenal cortex. METHODS: We conducted single-cell RNA sequencing and spatial transcriptomics analysis of the aged human adrenal cortex. RESULTS: The data of this study suggest that the layer-specific alterations of multiple signaling pathways underlie the abnormal layered structure and layer-specific changes in steroidogenic cells. We also highlighted that macrophages mediate age-related adrenocortical cell inflammation and senescence. CONCLUSIONS: This study is the first detailed analysis of the aged human adrenal cortex at single-cell resolution and helps to elucidate the mechanism of human adrenal aging, thereby leading to a better understanding of the pathophysiology of age-related disorders associated with adrenal aging.

DOI： 10.1016/j.molmet.2024.101954

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Language：English   Publisher：Elsevier BV  

Background: The human adrenal cortex consists of three functionally and structurally distinct layers; zona glomerulosa, zona fasciculata (zF), and zona reticularis (zR), and produces adrenal steroid hormones in a layer-specific manner; aldosterone, cortisol, and adrenal androgens, respectively. Cortisol-producing adenomas (CPAs) occur mostly as a result of somatic mutations associated with the protein kinase A pathway. However, how CPAs develop after adrenocortical cells acquire genetic mutations, remains poorly understood. Methods: We conducted integrated approaches combining the detailed histopathologic studies with genetic, RNA-sequencing, and spatially resolved transcriptome (SRT) analyses for the adrenal cortices adjacent to human adrenocortical tumours. Findings: Histopathological analysis revealed an adrenocortical nodular structure that exhibits the two-layered zF- and zR-like structure. The nodular structures harbour GNAS somatic mutations, known as a driver mutation of CPAs, and confer cell proliferative and autonomous steroidogenic capacities, which we termed steroids-producing nodules (SPNs). RNA-sequencing coupled with SRT analysis suggests that the expansion of the zF-like structure contributes to the formation of CPAs, whereas the zR-like structure is characterised by a macrophage-mediated immune response. Interpretation: We postulate that CPAs arise from a precursor lesion, SPNs, where two distinct cell populations might contribute differently to adrenocortical tumorigenesis. Our data also provide clues to the molecular mechanisms underlying the layered structures of human adrenocortical tissues. Funding: KAKENHI, The Uehara Memorial Foundation, Daiwa Securities Health Foundation, Kaibara Morikazu Medical Science Promotion Foundation, Secom Science and Technology Foundation, ONO Medical Research Foundation, and Japan Foundation for Applied Enzymology.

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Language：English   Publisher：(一社)日本内分泌学会  

新型コロナウイルス感染症(COVID-19)の流行が日本の内分泌および代謝疾患の管理に及ぼした影響を検討した。日本内分泌学会認定内分泌専門医薬2700名を対象に全国横断質問紙調査を実施した。質問紙は多肢選択式項目と自由記述項目の計109項目で構成された。528名(19.5%)から回答を得た。249名(47%)がCOVID-19後またはワクチン接種後の患者に内分泌異常を診断したことがあると回答した。特に、甲状腺疾患、糖代謝疾患/糖尿病、視床下部下垂体疾患に関連する症状がみられた。COVID-19の管理に糖尿病や肥満が負の影響を与えたと回答した参加者はそれぞれ455名(86%)と382名(72%)と多かった。COVID-19の医療への正の影響に関する回答のテキストマイニング分析では、外食が減ったことによる生活習慣改善、リモートワークに関連する生活習慣の変化、COVID-19予防や後遺症管理に関わる疾患理解の向上、遠隔診療の拡大などが挙げられた。

Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：THE JAPAN DIABETES SOCIETY  

<p>We herein report a 67-year-old man with type 1 diabetes mellitus receiving combination immune checkpoint inhibitor (ICI) therapy. He was being treated with nivolumab and ipilimumab for lung metastasis from renal cancer. After one cycle, hyperthyroidism was detected, which evolved into manifest hypothyroidism over the next few weeks, requiring levothyroxine substitution therapy. Eight weeks after initiating ICI therapy, he presented at the emergency department with thirst, weight loss, and generalized weakness. Hyperglycemia (1,234 mg/dL), anion gap metabolic acidosis (pH 7.112), and ketonemia (<i>β</i>-hydroxybutyrate 1,590 <i>μ</i>mol/L) were observed. The glycated hemoglobin level was 9.1 %. Islet-related autoantibodies were all negative. The glucagon tolerance test revealed attenuated secretion of insulin. Human leukocyte antigen was heterozygous for the DRB1*0405-DQB1*0401 haplotype. We compared these findings with those of four cases of type 1 diabetes related to blockade of the cytotoxic T-lymphocyte antigen 4 (CTLA-4) or programmed cell death 1 (PD-1) receptor or its ligand (PD-L1) or combination (ICI) therapy at our institution. All patients showed the DRB1*0405 or DRB1*0901 HLA haplotype, which has been shown to be associated with type 1 diabetes in Japan.</p>

DOI： 10.11213/tonyobyo.66.850

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PLoS ONE  

The Cre-loxP strategy for tissue-specific gene inactivation has become a widely employed tool in several research studies. Conversely, inadequate breeding and genotyping without considering the potential for non-specific Cre-recombinase expression may lead to misinterpretations of results. Nestin-Cre transgenic mice, widely used for the selective deletion of genes in neurons, have been observed to have an incidence of Cre-line germline recombination. In this study, we attempted to generate neuron-specific Glucagon-like peptide 1 receptor (Glp1r) knock-out mice by crossing mice harboring the Nestin-Cre transgene with mice harboring the Glp1r gene modified with loxP insertion, in order to elucidate the role of Glp1r signaling in the nervous system. Surprisingly, during this breeding process, we discovered that the null allele emerged in the offspring irrespective of the presence or absence of the Nestin-Cre transgene, with a high probability of occurrence (93.6%). To elucidate the cause of this null allele, we conducted breeding experiments between mice carrying the heterozygous Glp1r null allele but lacking the Nestin-Cre transgene. We confirmed that the null allele was inherited by the offspring independently of the Nestin-Cre transgene. Furthermore, we assessed the gene expression, protein expression, and phenotype of mice carrying the homozygous Glp1r null allele generated from the aforementioned breeding, thereby confirming that the null allele indeed caused a global knock-out of Glp1r. These findings suggest that the null allele in the NestinCre-Glp1r floxed breeding arose due to germline recombination. Moreover, we demonstrated the possibility that germline recombination may occur not only during the spermatogenesis at testis but also during epididymal sperm maturation. The striking frequency of germline recombination in the Nestin-Cre driver underscores the necessity for caution when implementing precise breeding strategies and employing suitable genotyping methods.

DOI： 10.1371/journal.pone.0296006

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Endocrinology (United States)  

Pancreatic islet inflammation plays a crucial role in the etiology of type 2 diabetes (T2D). Macrophages residing in pancreatic islets have emerged as key players in islet inflammation. Macrophages express a plethora of innate immune receptors that bind to environmental and metabolic cues and integrate these signals to trigger an inflammatory response that contributes to the development of islet inflammation. One such receptor, Dectin-2, has been identified within pancreatic islets; however, its role in glucose metabolism remains largely unknown. Here we demonstrated that mice lacking Dectin-2 exhibit local inflammation within islets, along with impaired insulin secretion and β-cell dysfunction. Our findings indicate that these effects are mediated by pro-inflammatory cytokines, such as IL-1α and IL-6, which are secreted by macrophages that have acquired an inflammatory phenotype because of the loss of Dectin-2. This study provides novel insights into the mechanisms underlying the role of Dectin-2 in the development of islet inflammation.

DOI： 10.1210/endocr/bqad181

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Cachexia, Sarcopenia and Muscle  

BACKGROUND: Diabetes is associated with an increased risk of deleterious changes in muscle mass and function or sarcopenia, leading to physical inactivity and worsening glycaemic control. Given the negative energy balance during sodium-glucose cotransporter-2 (SGLT2) inhibition, whether SGLT2 inhibitors affect skeletal muscle mass and function is a matter of concern. However, how SGLT2 inhibition affects the skeletal muscle function in patients with diabetes remains insufficiently explored. We aimed to explore the effects of canagliflozin (CANA), an SGLT2 inhibitor, on skeletal muscles in genetically diabetic db/db mice focusing on the differential responses of oxidative and glycolytic muscles. METHODS: Db/db mice were treated with CANA for 4 weeks. We measured running distance and handgrip strength to assess skeletal muscle function during CANA treatment. At the end of the experiment, we performed a targeted metabolome analysis of the skeletal muscles. RESULTS: CANA treatment improved the reduced endurance capacity, as revealed by running distance in db/db mice (414.9 ± 52.8 vs. 88.7 ± 22.7 m, P < 0.05). Targeted metabolome analysis revealed that 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranosyl 5'-monophosphate (AICARP), a naturally occurring AMP-activated protein kinase (AMPK) activator, increased in the oxidative soleus muscle (P < 0.05), but not in the glycolytic extensor digitorum longus muscle (P = 0.4376), with increased levels of AMPK phosphorylation (P < 0.01). CONCLUSIONS: This study highlights the potential role of the AICARP/AMPK pathway in oxidative rather than glycolytic skeletal muscles during SGLT2 inhibition, providing novel insights into the mechanism by which SGLT2 inhibitors improve endurance capacity in patients with type 2 diabetes.

DOI： 10.1002/jcsm.13350

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

67歳男性.糖尿病歴なし.腎癌肺転移に対しニボルマブとイピリムマブ併用療法開始し14日後に免疫関連副作用(immune-related Adverse Events:irAE)による破壊性甲状腺炎を発症し,65日後に糖尿病性ケトアシドーシスを発症し,救急搬送後の随時血糖1234mg/dL,HbA1c 9.1%,グルカゴン負荷後の血中CPR測定感度未満,膵島関連自己抗体は陰性であり,またヒト白血球抗原(HLA)検査でDRB1*04:05-DQB1*04:01のヘテロ接合を認めた.本症例を含めたirAEでの1型糖尿病発症自験例4例を比較したところ,全症例において日本人における1型糖尿病発症との関連が示されているDRB1*0405もしくはDRB1*0901のHLAハプロタイプを示し,抗PD-1抗体と抗CTLA-4抗体併用療法では抗PD-1抗体単独治療と比較し発症までの期間は明らかに短縮していた.(著者抄録)

Publisher：Scientific Reports  

This study aimed to develop a machine-learning algorithm to diagnose aldosterone-producing adenoma (APA) for predicting APA probabilities. A retrospective cross-sectional analysis of the Japan Rare/Intractable Adrenal Diseases Study dataset was performed using the nationwide PA registry in Japan comprised of 41 centers. Patients treated between January 2006 and December 2019 were included. Forty-six features at screening and 13 features at confirmatory test were used for model development to calculate APA probability. Seven machine-learning programs were combined to develop the ensemble-learning model (ELM), which was externally validated. The strongest predictive factors for APA were serum potassium (s-K) at first visit, s-K after medication, plasma aldosterone concentration, aldosterone-to-renin ratio, and potassium supplementation dose. The average performance of the screening model had an AUC of 0.899; the confirmatory test model had an AUC of 0.913. In the external validation, the AUC was 0.964 in the screening model using an APA probability of 0.17. The clinical findings at screening predicted the diagnosis of APA with high accuracy. This novel algorithm can support the PA practice in primary care settings and prevent potentially curable APA patients from falling outside the PA diagnostic flowchart.

DOI： 10.1038/s41598-023-29653-2

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Language：Japanese   Publisher：(一社)日本肥満学会  

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Language：Japanese   Publisher：(一社)日本肥満学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Publisher：Journal of Human Hypertension  

The incidence of atrial fibrillation (AF) and risk of cardiovascular events are reportedly higher in patients with primary aldosteronism (PA) than essential hypertension. However, associated factors of comorbid AF and cardiovascular events in PA patients after PA treatment remain unclear. This nationwide registration study included PA patients ≥20 years old. Incident cardiovascular events were observed with a mean follow-up of approximately 3 years. A total of 3654 patients with PA were included at the time of analysis. Prevalence of AF was 2.4%. PA patients with AF were older, more frequently male and had longer duration of hypertension than those without AF. No significant difference in basal plasma and adrenal venous aldosterone concentration, renin activity, potassium concentration, confirmatory tests of PA, laterality or surgery rate were seen between groups. Logistic regression analysis showed age, male sex, cardiothoracic ratio, past history of coronary artery disease and heart failure were independent factors associated with AF. PA patients with AF showed a higher frequency of cardiovascular events than those without AF (P < 0.001). Multivariate Cox analyses demonstrated AF in addition to older age, duration of hypertension, body mass index and chronic kidney disease as independent prognostic factors for cardiovascular events after PA treatment. Incidence of cardiovascular events were significantly lower in PA patients with AF than AF patients from the Fushimi registry during follow-up after adjusting age, sex and systolic blood pressure. Early diagnosis of PA may prevent AF and other cardiovascular events in PA patients by shortening the duration of hypertension and appropriate PA treatment.

DOI： 10.1038/s41371-022-00753-2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

BACKGROUND: Autonomous cortisol secretion (ACS), resulting from cortisol-producing adenomas (CPA), causes endogenous steroid-induced osteoporosis (SIOP). However, the risk of endogenous SIOP cannot be explained by cortisol excess alone, and how other steroid metabolites affect bone status is unclear. METHODS: ACS was diagnosed as serum cortisol ≥1.8 μg/dL after the 1-mg dexamethasone suppression test (DST-cortisol). Using liquid chromatography tandem mass spectrometry, 21 plasma steroid metabolites were measured in 73 patients with ACS and 85 patients with non-functioning adrenal tumors (NFAT). Expression of steroidogenic enzymes and relevant steroid metabolites were analyzed in some of CPA tissues. FINDINGS: Discriminant and principal component analyses distinguished steroid profiles between the ACS and NFAT groups in premenopausal women. Premenopausal women with ACS exhibited higher levels of a mineralocorticoid metabolite, 11-deoxycorticosterone (11-DOC), and lower levels of androgen metabolites, dehydroepiandrosterone-sulfate, and androsterone-glucuronide. In premenopausal women with ACS, DST-cortisol negatively correlated with trabecular bone score (TBS). Additionally, 11-DOC negatively correlated with lumbar spine-bone mineral density, whereas androsterone-glucuronide positively correlated with TBS. The CPA tissues showed increased 11-DOC levels with increased expression of CYP21A2, essential for 11-DOC synthesis. Adrenal non-tumor tissues were atrophied with reduced expression of CYB5A, required for androgen synthesis. INTERPRETATION: This study demonstrates that unbalanced production of adrenal steroid metabolites, derived from both adrenal tumor and non-tumor tissues, contributes to the pathogenesis of endogenous SIOP in premenopausal women with ACS. FUNDING: JSPS KAKENHI, Secom Science and Technology Foundation, Takeda Science Foundation, Japan Foundation for Applied Enzymology, AMED-CREST, JSTA-STEP, JST-Moonshot, and Ono Medical Research Foundation.

DOI： 10.1016/j.ebiom.2023.104733

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Language：Japanese  

Language：Japanese   Publisher：日本筋学会・筋ジストロフィー医療研究会  

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：American Diabetes Association  

Background: Diabetes is associated with loss of skeletal muscle mass and function. Specifically, diabetes may affect the function of oxidative muscle fibers with lower fatigability and higher oxidative capacity in skeletal muscle. The effects of SGLT2 inhibition on skeletal muscle metabolism and function in patients with type 2 diabetes remain unclear.

Methods: Male db/db (diabetic) and db/+ (non-diabetic) mice at 8 weeks of age were fed a normal chow diet or a diet containing canagliflozin (CANA) for 4 weeks. Grip strength and running distance were assessed during CANA treatment. At the end of CANA treatment, we measured muscle weight and analyzed metabolites in skeletal muscle.

Results: The weights of the oxidative soleus and glycolytic extensor digitorum longus muscles were reduced by approximately 50% in the diabetic group compared to the non-diabetic group, but neither was altered by CANA treatment. Grip strength did not differ between the CANA-treated diabetic, diabetic, and non-diabetic groups. However, the running distance decreased in the diabetic group compared to the non-diabetic group (89 ± 60 m vs. 1980 ± 276 m). This was partially restored by CANA treatment (89 ± 60 m vs. 415 ± 140 m). Metabolomic analysis revealed that long-chain acyl-CoA increased and medium-chain and short-chain acyl-CoA decreased in diabetic soleus muscle. In contrast, CANA treatment increased medium-chain and short-chain acyl-CoA. Furthermore, CANA increased 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranosyl 5’-monophosphate (AICARP), an endogenous AMPK activator, by approximately 3-fold in diabetic soleus muscle with increased levels of AMPK phosphorylation (Thr172).

Conclusion: These results suggest that SGLT2 inhibitors may activate the AICARP/AMPK pathway and improve impaired oxidative muscle function in patients with type 2 diabetes.

Disclosure

S. Nakamura: None. Y. Miyachi: None. H. Yokomizo: None. H. Otsuka: None. R. Sakamoto: None. M. Takahashi: None. Y. Izumi: None. T. Miyazawa: None. T. Bamba: None. Y. Ogawa: None.

DOI： 10.2337/db23-266-lb

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DOI： 10.3390/reports6020018

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Language：Japanese   Publisher：The Japan Endocrine Society  

DOI： 10.1507/endocrine.99.s.update_14

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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症例は68歳男性で、左眼瞼下垂、視力低下を主訴に、前医の頭部MRIにて下垂体部の腫瘍を指摘され、手術目的に当院紹介となった。下垂体腫瘍に対し外科的腫瘍摘出術を施行し、病理組織学的にトルコ鞍内脊索腫と診断された。術前後の内分泌学的所見を評価すると、術前に認めた下垂体前葉ホルモン基礎値の広範な低下は、術後にはPRLを除いて改善し、術後はホルモン補充療法を行わず経過観察する方針とした。また、眼瞼下垂と視力低下は術後改善し、術後7ヵ月の時点で再発は認めなかった。

Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：THE JAPAN DIABETES SOCIETY  

<p>We report the case of a 95-year-old woman who had been diagnosed with diabetes mellitus with HbA1c 9.7 % and a fasting blood glucose level of 199 mg/dL at 94 years of age. Despite the administration of oral hypoglycemic therapy for 5 months, her blood glucose was poorly controlled. On admission, we found that her HbA1c was 11.0 %, her casual blood glucose was 394 mg/dL and her glutamic acid decarboxylase antibody titer was 1740 U/mL (ELISA); she was then diagnosed with SPIDDM. While the development of SPIDDM is commonly reported in patients in their 40s to 50s, recent studies showed that around 10 % of elderly patients who developed diabetes were diagnosed with SPIDDM. We searched clinical characteristics of latter-stage elderly patients who developed SPIDDM and found that majority were female and showed reduced insulin secretion with poor glycemic control. It is important to consider the possibility of type 1 diabetes, including SPIDDM, even in elderly patients who have developed diabetes with poor glycemic control.</p>

DOI： 10.11213/tonyobyo.66.139

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

症例は95歳,女性.X-1年11月にHbA1c 9.7%,空腹時血糖199mg/dLであり,糖尿病と診断された.X年4月にHbA1c 11.0%,随時血糖394mg/dL,空腹時血中Cペプチド0.92ng/mL,GAD抗体(ELISA法)1740U/mLであり,緩徐進行1型糖尿病(SPIDDM)と診断された.SPIDDMは40,50歳代の発症が多いが,65歳以上の高齢発症糖尿病においても10%程度の割合で存在する.後期高齢で糖尿病を発症し,その後SPIDDMと診断された症例を検索した結果,女性に多く,インスリン分泌能が低下している症例が多かった.記載のある全例(1例を除く)が診断時HbA1c 8.0%以上であった.高齢発症糖尿病患者においても,緩徐進行型を含む1型糖尿病が存在するため,血糖コントロール不良の症例は1型糖尿病も鑑別に精査を行う必要がある.(著者抄録)

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Bone Reports  

Purpose: Bone and vascular diseases are considered to share pathogenic mechanisms. Excess glucocorticoids, key regulators of cardiovascular and metabolic homeostasis, may promote both diseases simultaneously. We used endogenous Cushing's syndrome (CS) to investigate whether glucocorticoid excess underlies coexisting bone and vascular diseases. Methods: We included 194 patients with adrenal tumors (ATs): autonomous cortisol secretion (ACS, n = 97) and non-functional AT (n = 97). ACS was further classified into overt CS (n = 17) and subclinical CS (SCS, n = 80). Arterial stiffness was defined as a brachial-ankle pulse wave velocity (baPWV) ≥ 1800 cm/s. Results: Patients with ACS had higher coexistence rates of vertebral fracture and arterial stiffness (23 % vs. 2 %; p < 0.001) and vertebral fracture and abdominal aortic calcification (22 % vs. 1 %; p < 0.001) than those with non-functional AT. In patients with ACS, baPWV was negatively correlated with trabecular bone score (TBS, r = -0.33; p = 0.002), but not with bone mineral density, and vertebral fracture was associated with arterial stiffness in the logistic regression analysis. In the multivariate analysis of variance, the degree of cortisol excess (defined as CS, SCS, and non-functional AT) determined the correlation between TBS and baPWV (partial η2 = 0.07; p < 0.001). In the analysis of covariance, patients with coexisting vertebral fracture and arterial stiffness had higher levels of serum cortisol after the 1-mg dexamethasone suppression test than those without. Conclusion: In endogenous glucocorticoid excess, bone and vascular diseases frequently coexisted, and deteriorated bone quality, not bone loss, was related to arterial stiffness. Thus, glucocorticoid excess may perturb the bone-vascular axis.

DOI： 10.1016/j.bonr.2022.101610

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Clinical Endocrinology  

OBJECTIVE: The clinical practice guideline for primary aldosteronism (PA) places a high value on confirmatory tests to sparing patients with false-positive results in case detection from undergoing adrenal venous sampling (AVS). However, it is unclear whether multiple types of confirmatory tests are more useful than a single type. To evaluate whether the machine-learned combination of two confirmatory tests is more useful in predicting subtypes of PA than each test alone. DESIGN: A retrospective cross-sectional study in referral centres. PATIENTS: This study included 615 patients with PA randomly assigned to the training and test data sets. The participants underwent saline infusion test (SIT) and captopril challenge test (CCT) and were subtyped by AVS (unilateral, n = 99; bilateral, n = 516). MEASUREMENTS: The area under the curve (AUC) and clinical usefulness using decision curve analysis for the subtype prediction in the test data set. RESULTS: The AUCs for the combination of SIT and CCT, SIT alone and CCT alone were 0.850, 0.813 and 0.786, respectively, with no significant differences between them. The AUC for the baseline clinical characteristics alone was 0.872, whereas the AUCs for these combined with SIT, combined with CCT and combined with both SIT and CCT were 0.868, 0.854 and 0.855, respectively, with no significant improvement in AUC. The additional clinical usefulness of the second confirmatory test was unremarkable on decision curve analysis. CONCLUSIONS: Our data suggest that patients with positive case detection undergo one confirmatory test to determine the indication for AVS.

DOI： 10.1111/cen.14854

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Language：English   Publisher：シュプリンガー・ジャパン(株)  

食道運動障害性疾患(EMD)を診断するための新たな2所見を用いたバリウム食道造影検査(BE)によるスクリーニングを評価した。2013年1月から2020年10月にEMDが疑われ高解像度マノメトリー検査(HRM)とBEの両方が施行された244例を対象とした。EMDの診断はシカゴ分類第3.0版を用いてHRM所見に基づいて行った。BEは硫酸バリウムを用いて食道連続撮影を行った。従来からのBE所見(ニボー、数珠状/コルク栓抜き様所見、蠕動の消失/減弱)に加え、新規2所見(蠕動波出現、胃食道接合部上膨隆所見)を診断に用いた。新規2所見と従来の3所見を診断に用いた場合のBEスクリーニングの感度は79.4%、特異度は88%であった(受信者動作特性曲線下領域(AUC)=0.837)。新規2所見を診断に用いない場合には、感度は63.9%、特異度は96%(AUC=0.800)であった。アカラシアはニボー形成と特に関連性が強かった(88.7%)。収縮の消失は蠕動の消失/減弱と強く関連していた(85.7%)。遠位食道痙攣と数珠状/コルク栓抜き様所見との間(60%)およびアカラシアと蠕動波出現(59.7%)との間には比較的高い関連性が認められた。個々のBE所見の観察者内再現性、観察者間一致率はそれぞれ84.4%、75%であった。蠕動波出現は積算弛緩圧(IRP)高値および遠位潜時短縮と関連していた。食道胃接合部上膨隆はIRP高値と関連していた。新規の2所見を追加したBEスクリーニングによるEMDの診断は一般診療において有用である可能性が示された。

Language：Japanese   Publisher：(一社)日本肥満学会  

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Language：Japanese   Publisher：(一社)日本肥満学会  

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Language：Japanese   Publisher：(一社)日本肥満学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Gastroenterology  

BACKGROUND: High-resolution manometry (HRM) is the gold standard for diagnosing esophageal motility disorders (EMDs); however, it requires specialized equipment. The development of more accessible screening examinations is expected. We evaluated the utility of barium esophagography (BE) screening using two novel findings to diagnose EMDs. METHODS: Between January 2013 and October 2020, 244 patients with suspected EMDs who underwent both HRM and BE were analyzed. The EMD diagnosis was based on HRM findings using Chicago Classification version 3.0. BE was performed using sequential esophagography with barium sulfate. Three conventional BE findings (air-fluid level, rosary-bead/corkscrew appearance, and absent/weak peristalsis) and two novel BE findings (wave appearance and supra-junctional ballooning) were used for diagnosis. RESULTS: The sensitivity and specificity of BE screening using the two novel findings and conventional findings to diagnose EMDs were 79.4% and 88%, respectively [area under the receiver-operating characteristic curve (AUC) = 0.837]. Without these novel findings, they were 63.9% and 96%, respectively (AUC = 0.800), respectively. Achalasia was highly correlated with the air-fluid level (88.7%). Absent contractility was highly correlated with absent/weak peristalsis (85.7%). Relatively high correlations were observed between distal esophageal spasm and rosary-bead/corkscrew appearance (60%), and between achalasia and wave appearance (59.7%). The intra-observer reproducibility and inter-observer agreement for individual BE findings were 84.4% and 75%, respectively. Wave appearance was associated with higher integrated relaxation pressure (IRP) and shorter distal latency. Supra-junctional ballooning was associated with higher IRP. CONCLUSIONS: BE screening using two additional novel findings to diagnose EMDs could be useful in general practice.

DOI： 10.1007/s00535-022-01913-4

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

A recent report stated that patients with primary aldosteronism who remain renin suppressed during mineralocorticoid receptor antagonist treatment might have a higher risk of developing cardiovascular disease than those with unsuppressed renin activity. We retrospectively investigated the incidence of composite cardiovascular disease and risk factors for cardiovascular disease in 1115 Japanese patients with primary aldosteronism treated with mineralocorticoid receptor antagonists. The median follow-up period was 3.0 years, and the incidence of cardiovascular events was very low (2.1%) throughout 5 years of follow-up. Changes in plasma renin activity from before to after mineralocorticoid receptor antagonist treatment were divided into three groups based on tertile, low, intermediate, and high plasma renin activity change groups, with incidences of cardiovascular disease events of 2.1%, 0.5%, and 3.7%, respectively. Multivariate Cox regression analysis revealed age (adjusted hazard ratio, 1.07; 95% confidence interval, [1.02–1.12]) and body mass index (adjusted hazard ratio, 1.13 [1.04–1.23]) as independent risk factors for cardiovascular disease. The high plasma renin activity change group had significantly higher cardiovascular disease risk with mineralocorticoid receptor antagonist treatment than the intermediate plasma renin activity change group (adjusted hazard ratio, 5.71 [1.28–25.5]). These data suggest that a high change in renin level after mineralocorticoid receptor antagonist treatment may not necessarily predict a better prognosis of cardiovascular disease in patients with primary aldosteronism.

DOI： 10.1038/s41440-022-00960-x

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Other Link： https://www.nature.com/articles/s41440-022-00960-x

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(公財)大和証券ヘルス財団  

骨粗鬆症の早期診断法を開発するため、骨量正常にもかかわらず脆弱性骨折を引き起こす骨質劣化型骨粗鬆症に着目し、副腎由来ホルモンにおける骨粗鬆症への病態生理学的意義を検討した。副腎由来ホルモン過剰モデルであるヒト副腎腫瘍を対象とした観察研究、健常人を対象としたゲノムワイド関連研究を用いたメンデルランダム化研究、健常人の血液検体を対象とした網羅的ステロイドミクス解析を行った。その結果、副腎由来ホルモンは骨質制御に重要な役割を担っていることが明らかになった。さらに、生理的濃度の副腎由来ホルモンの変動も骨粗鬆症の進展に影響すること、健常人において副腎由来ホルモンに個人差を認めることも明らかになった。副腎由来ホルモンは有用な骨質サロゲート指標になり得ると考えられた。

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers in Endocrinology  

Whole transcriptome profiling is a promising technique in adrenal studies; however, whole transcriptome profiling of adrenal disease using formalin-fixed paraffin-embedded (FFPE) samples has to be further explored. The aim of this study was to evaluate the utility of transcriptome data from FFPE samples of adrenocortical tumors. We performed whole transcriptome profiling of FFPE and fresh frozen samples of adrenocortical carcinoma (ACC, n = 3), aldosterone-producing adenoma (APA, n = 3), and cortisol-producing adenoma (CPA, n = 3), and examined the similarity between the transcriptome data. We further examined whether the transcriptome data of FFPE samples could be used to distinguish tumor types and detect marker genes. The number of read counts was smaller in FFPE samples than in fresh frozen samples (P < 0.01), while the number of genes detected was similar (P = 0.39). The gene expression profiles of FFPE and fresh frozen samples were highly correlated (r = 0.93, P < 0.01). Tumor types could be distinguished by consensus clustering and principal component analysis using transcriptome data from FFPE samples. In the differential expression analysis between ACC and APA-CPA, known marker genes of ACC (e.g., CCNB2, TOP2A, and MAD2L1) were detected in FFPE samples of ACC. In the differential expression analysis between APA and CPA, known marker genes of APA (e.g., CYP11B2, VSNL1, and KCNJ5) were detected in the APA of FFPE samples. The results suggest that FFPE samples may be a reliable alternative to fresh frozen samples for whole transcriptome profiling of adrenocortical tumors.

DOI： 10.3389/fendo.2022.808331

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Biochemical Journal  

There has been a concern that sodium-glucose cotransporter 2 (SGLT2) inhibitors could reduce skeletal muscle mass and function. Here, we examine the effect of canagliflozin (CANA), an SGLT2 inhibitor, on slow and fast muscles from nondiabetic C57BL/6J mice. In this study, mice were fed with or without CANA under ad libitum feeding, and then evaluated for metabolic valuables as well as slow and fast muscle mass and function. We also examined the effect of CANA on gene expressions and metabolites in slow and fast muscles. During SGLT2 inhibition, fast muscle function is increased, as accompanied by increased food intake, whereas slow muscle function is unaffected, although slow and fast muscle mass is maintained. When the amount of food in CANA-treated mice is adjusted to that in vehicle-treated mice, fast muscle mass and function are reduced, but slow muscle was unaffected during SGLT2 inhibition. In metabolome analysis, glycolytic metabolites and ATP are increased in fast muscle, whereas glycolytic metabolites are reduced but ATP is maintained in slow muscle during SGLT2 inhibition. Amino acids and free fatty acids are increased in slow muscle, but unchanged in fast muscle during SGLT2 inhibition. The metabolic effects on slow and fast muscles are exaggerated when food intake is restricted. This study demonstrates the differential effects of an SGLT2 inhibitor on slow and fast muscles independent of impaired glucose metabolism, thereby providing new insights into how they should be used in patients with diabetes, who are at a high risk of sarcopenia.

DOI： 10.1042/BCJ20210700

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

糖尿病(DM)患者の左室拡張能障害に対する血中コルチゾール値の影響について検討した。対象は心エコー図検査を施行したDM患者109名と非DM患者104名である。拡張能の指標として拡張早期血流速度と僧帽弁輪部拡張早期速度の比(E/e')を算出し、各種臨床指標との関連を解析した。E/e'はDM群が非DM群に比べ高値であった(10.4 vs 8.3、P<0.001)。DM群の対数変換(log)E/e'は、年齢(β=0.22、P=0.017)、log収縮期血圧(β=0.25、P=0.004)、コルチゾール値(β=0.18、P=0.037)、推算糸球体濾過量(β=-0.21、P=0.016)、およびナトリウム・グルコース共輸送体2阻害薬使用(β=-0.18、P=0.042)と相関した。非DM群ではE/e'とコルチゾールの間に関連はみられなかった。DM患者のコルチゾール高値は、拡張能障害のリスク上昇と関連する可能性がある。

Language：English  

DOI： 10.1111/jdi.13658

Web of Science

PubMed

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：English   Publishing type：Research paper (scientific journal)  

AIMS/HYPOTHESIS: Mitochondria are highly dynamic organelles continuously undergoing fission and fusion, referred to as mitochondrial dynamics, to adapt to nutritional demands. Evidence suggests that impaired mitochondrial dynamics leads to metabolic abnormalities such as non-alcoholic steatohepatitis (NASH) phenotypes. However, how mitochondrial dynamics are involved in the development of NASH is poorly understood. This study aimed to elucidate the role of mitochondrial fission factor (MFF) in the development of NASH. METHODS: We created mice with hepatocyte-specific deletion of MFF (MffLiKO). MffLiKO mice fed normal chow diet (NCD) or high-fat diet (HFD) were evaluated for metabolic variables and their livers were examined by histological analysis. To elucidate the mechanism of development of NASH, we examined the expression of genes related to endoplasmic reticulum (ER) stress and lipid metabolism, and the secretion of triacylglycerol (TG) using the liver and primary hepatocytes isolated from MffLiKO and control mice. RESULTS: MffLiKO mice showed aberrant mitochondrial morphologies with no obvious NASH phenotypes during NCD, while they developed full-blown NASH phenotypes in response to HFD. Expression of genes related to ER stress was markedly upregulated in the liver from MffLiKO mice. In addition, expression of genes related to hepatic TG secretion was downregulated, with reduced hepatic TG secretion in MffLiKO mice in vivo and in primary cultures of MFF-deficient hepatocytes in vitro. Furthermore, thapsigargin-induced ER stress suppressed TG secretion in primary hepatocytes isolated from control mice. CONCLUSIONS/INTERPRETATION: We demonstrated that ablation of MFF in liver provoked ER stress and reduced hepatic TG secretion in vivo and in vitro. Moreover, MffLiKO mice were more susceptible to HFD-induced NASH phenotype than control mice, partly because of ER stress-induced apoptosis of hepatocytes and suppression of TG secretion from hepatocytes. This study provides evidence for the role of mitochondrial fission in the development of NASH.

DOI： 10.1007/s00125-021-05488-2

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Diabetes Investigation  

AIMS/INTRODUCTION: Diabetes mellitus is a major risk factor for the development of cardiovascular diseases. Heart failure with preserved ejection fraction is characterized by left ventricular diastolic dysfunction (LVDD). It has been reported that excess cortisol found in patients with Cushing's syndrome was associated with the development of LVDD. However, the relationship between cortisol concentration and LVDD in patients with diabetes mellitus has not been addressed. MATERIALS AND METHODS: We enrolled 109 patients with diabetes mellitus and 104 patients without diabetes mellitus who had undergone echocardiographic examination at Kyushu University Hospital, Fukuoka, Japan, between November 2016 and March 2019. Left ventricular function was evaluated and the ratio of early diastolic velocity from transmitral inflow to early diastolic velocity (E/e') was used as an index of diastolic function. Plasma cortisol concentrations, glycemic control, lipid profiles, treatment with antidiabetic drugs and other clinical characteristics were evaluated, and their associations with E/e' were determined using univariate and multivariate analyses. RESULTS: Multivariate linear regression analysis showed that log E/e' was positively correlated with age (P = 0.017), log systolic blood pressure (P = 0.004) and cortisol (P = 0.037), and negatively correlated with estimated glomerular filtration rate (P = 0.016) and the use of sodium-glucose cotransporter 2 inhibitors (P = 0.042) in patients with diabetes mellitus. Multivariate analysis showed that cortisol was positively correlated with age (P = 0.016) and glycated hemoglobin (P = 0.011). There was no association between E/e' and cortisol in patients without diabetes mellitus. CONCLUSIONS: Increased cortisol levels might increase the risk of developing LVDD in diabetes mellitus patients.

DOI： 10.1111/jdi.13653

Web of Science

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Vascular complications are the main cause of morbidity and mortality in diabetic patients, and advanced glycation end products (AGEs) play a critical role in promoting diabetic vascular dysfunction. The human homolog of scavenger receptor class B type I (SR-BI), CD36, and LIMPII analog-1 (hSR-BI/CLA-1) facilitates the cellular uptake of cholesterol from HDL. In endothelial cells, HDL activates endothelial nitric oxide synthase (eNOS) via hSR-BI/CLA-1. In this study, we elucidated the effects of AGEs on hSR-BI/CLA-1 expression in human umbilical vein endothelial cells (HUVECs). HSR-BI/CLA-1 expression was examined by real-time PCR, western blot analysis, and reporter gene assay in HUVECs incubated with AGEs. eNOS activity was assessed by detecting the phosphorylation (Ser 1179) of eNOS. Our results showed that AGEs decreased the endogenous expression of hSR-BI/CLA-1. AGEs also inhibited the activity of the hSR-BI/CLA-1 promoter and its mRNA expression via receptor RAGE. We identified the binding site for Smad1 on the hSR-BI/CLA-1 promoter: Smad1 bound to its promoter. AGE treatment stimulated the transcriptional activity of Smad1, and mutation of the Smad1 binding site inhibited the effect of AGEs on the hSR-BI/CLA-1 promoter. HDL-treatment enhanced the phosphorylation of eNOS at Ser 1179, but pretreatment with AGEs inhibited the phosphorylation of eNOS Ser 1179. These results suggested that AGEs downregulate the expression of the endothelial hSR-BI/CLA-1 via the Smad1 pathway, which may be a therapeutic target for diabetic endothelial dysfunction.

DOI： 10.1530/JME-20-0177

Language：English   Publishing type：Research paper (scientific journal)  

Pathological excess of fibroblast growth factor 23 (FGF23) causes mineral and bone disorders. However, the causality of FGF23 in the development of osteoporosis remains unknown. Whether FGF23 has systemic effects on cardiometabolic disorders beyond regulating mineral metabolism is also controversial. In this study, we investigated the causal effect of FGF23 on osteoporosis and cardiometabolic disorders using Mendelian randomization (MR) analysis. Summary statistics for single-nucleotide polymorphisms with traits of interest were obtained from the relevant genome-wide association studies. As a result, FGF23 was found to be inversely associated with femoral neck-BMD (odds ratio [OR] 0.682, 95&#37; confidence interval [CI] 0.546-0.853, p = 8e-04) and heel estimated BMD (eBMD) (OR 0.898, 95&#37;CI 0.820-0.985, p = 0.022) in the inverse-variance-weighted analysis, but not lumbar spine-BMD and fractures. The results were supported by the weighted-median analysis, and there was no evidence of pleiotropy in the MR-Egger analysis. FGF23 was associated with FN-BMD and eBMD after adjustment for estimated glomerular filtration rate, height, and body mass index in multivariable MR analysis. On the other hand, there was no association between FGF23 and cardiometabolic traits including cardio artery disease, brachial-ankle pulse wave velocity, intima-media thickness of carotid arteries, systolic and diastolic blood pressure, fasting glucose, high and low-density lipoprotein cholesterol, and triglycerides. Therefore, this MR study established that FGF23 was involved in bone loss and, in contrast, was not involved in cardiometabolic disorders. Our findings provide important insights into the role of FGF23 in the pathogenesis of osteoporosis and cardiometabolic disorders.

DOI： 10.1016/j.bone.2020.115777

Language：English   Publishing type：Research paper (scientific journal)  

CONTEXT: The success rate of cannulation of the right adrenal vein is limited. The aldosterone gradient within the same adrenal vein branch is specific for aldosterone-producing adenoma. OBJECTIVE: This study was performed to investigate whether the absolute aldosterone gradient within the left adrenal vein (left-AV absolute aldosterone gradient) indicates unilateral excess aldosterone. DESIGN AND SETTING: A retrospective cross-sectional study in a single referral centre. PATIENTS AND METHODS: In total, 123 consecutive patients with primary aldosteronism who had successful adrenal vein sampling (AVS) data were examined. The left-AV absolute aldosterone gradient was considered significant when a gradient of >4:1 in the aldosterone-to-cortisol ratio between the common trunk vein and central vein was found. MAIN OUTCOME MEASURE: The prevalence of the unilateral subtype in patients with a significant left-AV absolute aldosterone gradient. RESULTS: The prevalence of the unilateral subtype was higher in patients with than without a significant left-AV absolute aldosterone gradient (88.2% [15/17] vs 21.7% [23/106], P < .001). Of 60 patients with spontaneous hypokalemia, left unilateral disease on computed tomography, or both, a significant left-AV absolute aldosterone gradient was present only in patients with the unilateral subtype on AVS (42.9% [15/35]), but not in those with the bilateral subtype (0.0% [0/25]). These data were validated in an external cohort. CONCLUSION: The presence of a significant left-AV absolute aldosterone gradient can be used to diagnose the left unilateral subtype of primary aldosteronism on AVS in patients with spontaneous hypokalemia, left unilateral disease on computed tomography or both.

DOI： 10.1111/cen.14320

Language：English   Publishing type：Research paper (scientific journal)  

CONTEXT: Pheochromocytoma (PHEO) and paraganglioma (PGL) (PHEO and PGL: PPGLs), catecholamine-producing tumors, represent an emerging cause of secondary osteoporosis. However, despite decreased bone mineral density (BMD), vertebral fracture (VF) is not associated with BMD in PPGLs. OBJECTIVE: To evaluate whether deteriorated bone quality is involved in the development of osteoporosis in PPGLs. PARTICIPANTS: Trabecular bone score (TBS), used to assess trabecular bone quality, was examined in 56 patients with PPGLs and 52 with non-functional adrenal tumors (AT). Radiograph of the spine was carried out in 35 patients with PPGLs, and TBS was analyzed in 18 patients with PPGLs at follow-up. MAIN OUTCOME MEASURE: TBS and BMD at the lumbar spine in patients with PPGLs with and without VF. RESULTS: PPGLs had a lower TBS (n = 56, 1.338 [1.294-1.420]) than non-functional AT (n = 52, 1.394 [1.342-1.444]; p = 0.033). Among those with PPGLs, patients with VF (n = 14, 1.314 [1.289-1.346]) had a lower TBS than those without VF (n = 21, 1.383 [1.324-1.426]; p = 0.046), despite no significant difference in BMD at the lumbar spine between the two groups (p = 0.501). An optimal cut-off level of TBS for diagnosing VF in PPGLs was 1.323, and its area under the curve was 0.702. The severity of catecholamine excess and maximal size of tumor were associated with decreased TBS in PPGLs patients (p = 0.016 and p = 0.020, respectively). Surgical resection of PPGLs improved TBS at follow-up, with 2.5&#37; increase (p = 0.007). CONCLUSIONS: This study provides evidence for the importance of deteriorated bone quality rather than decreased bone mass in the development of VF in PPGLs.

DOI： 10.1016/j.bone.2020.115607

Language：Others   Publishing type：Research paper (scientific journal)  

© 2020, International Osteoporosis Foundation and National Osteoporosis Foundation. Summary: Osteoporosis and atherosclerosis frequently coexist in patients with pheochromocytoma. The presence of osteoporosis may predict that of atherosclerosis and vice versa in patients with PHEO. These findings have implications for the long-term management of the pheochromocytoma and its potential chronic complications. Introduction: Pheochromocytoma (PHEO), a catecholamine-producing tumor, is often found incidentally, and it may be present for years before it is diagnosed. However, long-term exposure to catecholamines excess may induce chronic complications, such as osteoporosis and atherosclerosis. We aimed to evaluate concomitant osteoporosis and atherosclerosis in patients with PHEO. Methods: Fifty-one patients with PHEO and 51 patients with a non-functional adrenal tumor were compared radiographically for the prevalence of vertebral fracture (VF), a typical osteoporotic fracture, and abdominal aortic calcification (AAC). Results: In patients with PHEO, the prevalence of AAC was higher in those with VF (58%) than in those without (6%, p < 0.001). AAC was associated with VF after adjusting for age and sex (odds ratio, 1.53; 95% confidence interval, 1.07–2.46; p = 0.003) in patients with PHEO. The degree of catecholamine excess correlated with the presence of VF and AAC (p = 0.007). The prevalence of VF was higher in patients with PHEO (37%) than those with non-functional AT (12%, p = 0.005), but the prevalence of AAC was comparable between the two groups (25% and 19%, p = 0.636). VF and AAC more frequently coexisted in patients with PHEO (22%) than in those with non-functional AT (2%, p = 0.003). Conclusion: This study represents the first demonstration that osteoporosis and atherosclerosis frequently coexist in patients with PHEO. The presence of osteoporosis may predict that of atherosclerosis and vice versa in patients with PHEO. These findings have implications for the long-term management of the PHEO and its potential chronic complications.

DOI： 10.1007/s00198-020-05527-5

Language：English   Publishing type：Research paper (scientific journal)  

Left ventricular hypertrophy (LVH) is often seen in patients with primary aldosteronism (PA), and the prevalence of LVH is reportedly higher among patients with PA than patients with essential hypertension. However, the correlation between aldosterone levels and LVH is undefined, and how aldosterone affects LVH in patients with PA remains unclear. We, therefore, retrospectively assessed a large PA database established by the multicenter JPAS (Japan Primary Aldosteronism Study) to reveal the factors associated with LVH in patients with PA without suspected autonomous cortisol secretion. In the 1186 patients with PA studied, the basal plasma aldosterone concentration, plasma renin activity, and the aldosterone-to-renin ratio did not significantly correlate with left ventricular LV mass index (LVMI) in single or multiple regression analyses. However, the plasma aldosterone concentration after the captopril challenge test or saline-infusion test, which are associated with autonomous aldosterone secretion, correlated significantly with LVMI, even after adjusting for patients' backgrounds, including age and blood pressure. In addition, hypokalemia and the unilateral subtype also correlated with LVMI. Longitudinal subanalysis of medically or surgically treated patients with PA showed significant reductions in LVMI in both the surgery (63.0±18.1 to 55.3±19.5 g/m2.7, P<0.001) and drug treatment (56.8±14.1 to 52.1±13.5 g/m2.7, P<0.001) groups. Our results suggest the autonomous aldosterone secretion level, not the basal aldosterone level itself, is relevant to LVH in patients with PA. In addition, the elevated LVMI seen in patients with PA is at least partially reversible with surgical or medical treatment.

DOI： 10.1161/HYPERTENSIONAHA.119.14601

Language：English  

DOI： 10.1080/10428194.2020.1725507

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Immune checkpoint inhibitors (ICPis) induce various immune-related adverse events (irAEs), despite their beneficial effects in treating various advanced cancers. ICPi-induced secondary adrenal insufficiency is described as a prevalent and serious 'pituitary irAE.' However, its precise mechanism remains unclear, and no definitive predictive markers have been reported. PATIENTS AND METHODS: We enrolled and studied 11 patients with advanced cancer (aged 39-70 years; 6 male patients) receiving nivolumab, pembrolizumab or ipilimumab who developed pituitary irAEs. Their clinical data, including endocrine functions, were retrospectively assessed and human leucocyte antigen (HLA) genotypes were determined to compare the HLA allele frequencies in these patients and healthy controls. RESULTS: Among 11 patients, 7, 3 and 1 patients exhibited malignant melanoma, non-small-cell lung cancer and gastric cancer, respectively. HLA type screening results revealed that HLA-DR15, B52 and Cw12 were observed in 9, 7, and 7 patients with pituitary irAE, respectively. DR15, B52 and Cw12 were significantly more prevalent in our group than in the healthy control group from the Japanese HLA-haplotype database (this study vs healthy control group); DR15: 81.8&#37; vs 33.5&#37; (n = 11, P = 0.0014), B52: 63.6&#37; vs 21.0&#37; (n = 11, P = 0.0026) and Cw12: 70&#37; vs 21.3&#37; (n = 10, P = 0.0013). CONCLUSIONS: HLA-DR15, B52 and Cw12 are possible predisposing factors for pituitary irAEs. HLA-DR15 is reportedly associated with autoimmune disease via interleukin-17 regulation, suggesting its involvement in pituitary irAE development. Using HLA haplotypes as pituitary irAE predictive markers, we could provide safe ICPi treatment and understand irAE pathogenesis.

DOI： 10.1016/j.ejca.2020.02.049

Language：English   Publishing type：Research paper (scientific journal)  

Background: Immune checkpoint inhibitors (ICPis) induce various immune-related adverse events (irAEs), despite their beneficial effects in treating various advanced cancers. ICPi-induced secondary adrenal insufficiency is described as a prevalent and serious ‘pituitary irAE.’ However, its precise mechanism remains unclear, and no definitive predictive markers have been reported. Patients and methods: We enrolled and studied 11 patients with advanced cancer (aged 39–70 years; 6 male patients) receiving nivolumab, pembrolizumab or ipilimumab who developed pituitary irAEs. Their clinical data, including endocrine functions, were retrospectively assessed and human leucocyte antigen (HLA) genotypes were determined to compare the HLA allele frequencies in these patients and healthy controls. Results: Among 11 patients, 7, 3 and 1 patients exhibited malignant melanoma, non–small-cell lung cancer and gastric cancer, respectively. HLA type screening results revealed that HLA-DR15, B52 and Cw12 were observed in 9, 7, and 7 patients with pituitary irAE, respectively. DR15, B52 and Cw12 were significantly more prevalent in our group than in the healthy control group from the Japanese HLA-haplotype database (this study vs healthy control group); DR15: 81.8% vs 33.5% (n = 11, P = 0.0014), B52: 63.6% vs 21.0% (n = 11, P = 0.0026) and Cw12: 70% vs 21.3% (n = 10, P = 0.0013). Conclusions: HLA-DR15, B52 and Cw12 are possible predisposing factors for pituitary irAEs. HLA-DR15 is reportedly associated with autoimmune disease via interleukin-17 regulation, suggesting its involvement in pituitary irAE development. Using HLA haplotypes as pituitary irAE predictive markers, we could provide safe ICPi treatment and understand irAE pathogenesis.

DOI： 10.1016/j.ejca.2020.02.049

Language：English   Publishing type：Research paper (scientific journal)  

© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc. Background: Hypokalemic periodic paralysis (HypoPP) is an autosomal dominant disease characterized by the episodic weakness of skeletal muscles and hypokalemia. More than half patients with HypoPP carry mutations in CACNA1S, encoding alpha-1 subunit of calcium channel. Few reports have documented the non-neuromuscular phenotypes of HypoPP. Methods: The proband is a Japanese woman who developed HypoPP at 6 years of age. An excessive insulin secretion with the oral glucose tolerance test rationalized that she had experienced frequent attacks of paralysis on high-carbohydrate diets. Results: Voglibose and acetazolamide effectively controlled her paralytic episodes. Her 8-year-old son and 2-year-old daughter started showing the paralytic symptoms from 4 and 2 years of age, respectively. Laboratory tests revealed high concentrations of creatinine kinase in serum and elevated renin activities in plasma of these children. The targeted sequencing confirmed that these three patients had an identical heterozygous mutation (p.V876E) in CACNA1S. Conclusion: Our data indicate that the p.V876E mutation in CACNA1S contributes to the early onset of neuromuscular symptoms and unusual clinical phenotypes of HypoPP.

DOI： 10.1002/mgg3.1175

Language：English   Publishing type：Research paper (scientific journal)  

CONTEXT: Pheochromocytoma (PHEO) and paraganglioma (PGL) (PHEO and PGL: PPGLs) are catecholamine-producing neuroendocrine tumors, which are known to be associated with low bone mineral density (BMD). However, it remains unknown whether PPGLs are associated with high prevalence of osteoporotic fracture and if so, whether their surgical resection improves BMD has been addressed. OBJECTIVE: To evaluate the risk of vertebral fracture (VF) in PPGLs and the improvement of BMD after surgery. DESIGN AND SETTINGS: A retrospective cross-sectional study in a single referral center. PARTICIPANTS: This study included the following patients: 1) 49 patients with PPGLs and 61 patients with non-functional AT who were examined radiograph of the spine, 2) 23 patients with PPGLs who were examined BMD at follow-up. INTERVENTION: 1) The prevalence of VF was evaluated between PPGLs and non-functional AT. 2) In PPGLs, BMD was evaluated at baseline and after surgery. RESULTS: PPGLs had a higher prevalence of VF (43&#37; [21/49]) than non-functional AT (16&#37; [10/61]; p = 0.002). PPGLs were associated with VF after adjusting for age and sex (odds ratio, 4.47; 95&#37; confidence interval, 1.76-11.3; p = 0.001). In PPGLs, BMD at the lumber spine was improved (before: 0.855 ± 0.198 g/cm2, after: 0.888 ± 0.169 g/cm2, mean of the difference: 0.032 g/cm2, p = 0.026), with 3.8&#37; increase. CONCLUSION: This study demonstrates that PPGLs was associated with VF and that their surgical resection contributes to the improvement of BMD in the trabecular bone. These observations support the notion that PPGLs are an emerging cause of secondary osteoporosis.

DOI： 10.1016/j.bone.2020.115221

Language：English   Publishing type：Research paper (scientific journal)  

Background: Hypokalemic periodic paralysis (HypoPP) is an autosomal dominant disease characterized by the episodic weakness of skeletal muscles and hypokalemia. More than half patients with HypoPP carry mutations in CACNA1S, encoding alpha-1 subunit of calcium channel. Few reports have documented the non-neuromuscular phenotypes of HypoPP. Methods: The proband is a Japanese woman who developed HypoPP at 6 years of age. An excessive insulin secretion with the oral glucose tolerance test rationalized that she had experienced frequent attacks of paralysis on high-carbohydrate diets. Results: Voglibose and acetazolamide effectively controlled her paralytic episodes. Her 8-year-old son and 2-year-old daughter started showing the paralytic symptoms from 4 and 2 years of age, respectively. Laboratory tests revealed high concentrations of creatinine kinase in serum and elevated renin activities in plasma of these children. The targeted sequencing confirmed that these three patients had an identical heterozygous mutation (p.V876E) in CACNA1S. Conclusion: Our data indicate that the p.V876E mutation in CACNA1S contributes to the early onset of neuromuscular symptoms and unusual clinical phenotypes of HypoPP.

DOI： 10.1002/mgg3.1175

Language：English   Publishing type：Research paper (scientific journal)  

CONTEXT: The current clinical guidelines suggest that confirmatory tests for primary aldosteronism (PA) may be excluded in some of patients who have elevated plasma aldosterone concentration (PAC) under plasma renin suppression. However, this has low-priority evidence and is under debate in use of serum potassium. OBJECTIVE: This study aimed to investigate an appropriate setting for sparing confirmatory tests in PA. DESIGN AND SETTING: A retrospective cross-sectional study in a single referral center. PARTICIPANTS: This study included 327 patients who had hypertension under plasma renin suppression and underwent the captopril challenge test (CCT) between January 2007 and April 2019. CCT results were used to diagnose PA. MAIN OUTCOME MEASURE: Diagnostic value of PAC and serum potassium in confirmation of PA. RESULTS: Of the studied patients, 252 of 327 (77%) were diagnosed with PA. All 61 patients with PAC > 30 ng/dL were diagnosed with PA. In patients with PAC between 20 and 30 ng/dL, 44 of 55 (80%) were diagnosed with PA, while all 26 with PAC between 20 to 30 ng/dL who had spontaneous hypokalemia were diagnosed with PA. The proportion of unilateral PA determined by adrenal vein sampling (AVS) was higher in patients who had PAC > 30 ng/dL or those with spontaneous hypokalemia who had PAC between 20 and 30 ng/dL than those who did not meet the criteria (76% vs. 17%, P < .001). CONCLUSION: Confirmatory tests in PA could be spared in patients who have typical features of PA and these patients had a high probability of unilateral PA on AVS.

DOI： 10.1210/clinem/dgz148

Language：English   Publishing type：Research paper (scientific journal)  

Context: Pheochromocytoma (PHEO) and paraganglioma (PGL) (PHEO and PGL: PPGLs) are catecholamine-producing neuroendocrine tumors, which are known to be associated with low bone mineral density (BMD). However, it remains unknown whether PPGLs are associated with high prevalence of osteoporotic fracture and if so, whether their surgical resection improves BMD has been addressed. Objective: To evaluate the risk of vertebral fracture (VF) in PPGLs and the improvement of BMD after surgery. Design and settings: A retrospective cross-sectional study in a single referral center. Participants: This study included the following patients: 1) 49 patients with PPGLs and 61 patients with non-functional AT who were examined radiograph of the spine, 2) 23 patients with PPGLs who were examined BMD at follow-up. Intervention: 1) The prevalence of VF was evaluated between PPGLs and non-functional AT. 2) In PPGLs, BMD was evaluated at baseline and after surgery. Results: PPGLs had a higher prevalence of VF (43% [21/49]) than non-functional AT (16% [10/61]; p = 0.002). PPGLs were associated with VF after adjusting for age and sex (odds ratio, 4.47; 95% confidence interval, 1.76–11.3; p = 0.001). In PPGLs, BMD at the lumber spine was improved (before: 0.855 ± 0.198 g/cm², after: 0.888 ± 0.169 g/cm², mean of the difference: 0.032 g/cm², p = 0.026), with 3.8% increase. Conclusion: This study demonstrates that PPGLs was associated with VF and that their surgical resection contributes to the improvement of BMD in the trabecular bone. These observations support the notion that PPGLs are an emerging cause of secondary osteoporosis.

DOI： 10.1016/j.bone.2020.115221

Language：English   Publishing type：Research paper (scientific journal)  

Context: Primary aldosteronism (PA) is known to increase vertebral fracture (VF), although the detailed mechanism remains to be elucidated. We hypothesized that the PA subtype is associated with VF. Objective: To evaluate whether unilateral PA is associated with the prevalence of VF. Design: This was a retrospective cross-sectional study in a single referral centre. Patients: We identified 210 hypertensive patients whose clinical data were available for case-detection results. One hundred and fifty-two patients were diagnosed with PA using captopril challenge tests. Measurements: We measured the prevalence of VF, according to PA subtype. Results: One hundred thirteen patients with PA were subtype classified by adrenal vein sampling. Of these, 37 patients had unilateral PA, 76 patients had bilateral PA, 58 patients had non-PA; 39 patients with PA were not subtype-classified. Patients with PA had a higher prevalence of VF (29%, 44/152) than those with non-PA (12%, 7/58; P =.011). Moreover, unilateral PA had a higher prevalence of VF (46%, 17/37) than bilateral PA (20%, 15/76; P =.021). There was no significant difference in the prevalence of VF between bilateral PA and non-PA. Unilateral PA was an independent risk factor for VF after adjusting for age and sex (OR: 3.16, 95% confidence interval: 1.12-8.92; P =.017). Among patients with unilateral PA, serum cortisol concentrations after 1-mg dexamethasone suppression test were higher in those with VF (1.32 ± 0.67 g/dL) than those without (0.96 ± 0.33 g/dL; P =.048). Conclusions: Unilateral PA is an independent risk factor for VF.

DOI： 10.1111/cen.14145

Language：English   Publishing type：Research paper (scientific journal)  

Objectives: We investigated the clinical significance of ACTH stimulation during adrenal venous sampling (AVS) by surgical outcome of primary aldosteronism (PA). Design: Multicenter retrospective study by Japan PA study. Method: We allocated 314 patients with both basal and ACTH-stimulated AVS data who underwent adrenalectomy to three groups: basal lateralization index (LI) ≥2 with ACTH-stimulated LI ≥4 on the ipsilateral side (Unilateral (U) to U group, n = 245); basal LI <2 with ACTH-stimulated LI ≥4 (Bilateral (B) to U group, n = 15); and basal LI ≥2 with ACTH-stimulated LI <4 (U to B group, n = 54). We compared surgical outcomes among the groups using the Primary Aldosteronism Surgical Outcome (PASO) criteria. Results: Compared with U to U group, U to B group had poor clinical and biochemical outcomes and low rates of adrenal adenoma as pathological findings (P = 0.044, 0.006, and 0.048, respectively), although there were no significant differences between U to U and B to U groups. All patients in U to B group with clinical and biochemical benefits, however, had adrenal adenoma as pathological findings and could be well differentiated from those with poor surgical outcomes via basal LI (>8.3), but not ACTH-stimulated LI. These results were similar even when we defined each group based on a cut-off value of 4 for basal LI. Conclusions: Although PA patients in U to B group had worse surgical outcomes than did those in U to U group, basal LI could discriminate among patients with better surgical outcomes in U to B group.

DOI： 10.1530/EJE-19-0860

Language：English   Publishing type：Research paper (scientific journal)  

© 2019 John Wiley & Sons Ltd Context: Primary aldosteronism (PA) is known to increase vertebral fracture (VF), although the detailed mechanism remains to be elucidated. We hypothesized that the PA subtype is associated with VF. Objective: To evaluate whether unilateral PA is associated with the prevalence of VF. Design: This was a retrospective cross-sectional study in a single referral centre. Patients: We identified 210 hypertensive patients whose clinical data were available for case-detection results. One hundred and fifty-two patients were diagnosed with PA using captopril challenge tests. Measurements: We measured the prevalence of VF, according to PA subtype. Results: One hundred thirteen patients with PA were subtype classified by adrenal vein sampling. Of these, 37 patients had unilateral PA, 76 patients had bilateral PA, 58 patients had non-PA; 39 patients with PA were not subtype-classified. Patients with PA had a higher prevalence of VF (29&#37;, 44/152) than those with non-PA (12&#37;, 7/58; P =.011). Moreover, unilateral PA had a higher prevalence of VF (46&#37;, 17/37) than bilateral PA (20&#37;, 15/76; P =.021). There was no significant difference in the prevalence of VF between bilateral PA and non-PA. Unilateral PA was an independent risk factor for VF after adjusting for age and sex (OR: 3.16, 95&#37; confidence interval: 1.12-8.92; P =.017). Among patients with unilateral PA, serum cortisol concentrations after 1-mg dexamethasone suppression test were higher in those with VF (1.32 ± 0.67 g/dL) than those without (0.96 ± 0.33 g/dL; P =.048). Conclusions: Unilateral PA is an independent risk factor for VF.

DOI： 10.1111/cen.14145

Language：Others   Publishing type：Research paper (scientific journal)  

© 2019, The Author(s), under exclusive licence to Springer Nature Limited. Primary aldosteronism (PA) is a common curable cause of hypertension. Adrenal venous sampling (AVS) is recommended for subtype diagnosis but is a difficult procedure. Recently, an increased prevalence of PA was reported, creating a greater demand for treatment of the condition in clinical facilities. The aim of the present study was to identify the historical changes over time and the differences between facilities in the success rate and subtype diagnosis of PA. The database of the PA registry developed by the Japan PA Study (JPAS) was used. A total of 2599 patients with PA who underwent AVS were evaluated. The overall success rate of AVS was 88%. The bilateral subtype was the dominant subtype, comprising 69% of cases. During the period 2004−2011 to 2011−2017, there were significant changes in the total number of AVS procedures (from 562 to 1732), ratio of ACTH administration with AVS (75 to 97%), success rate (79 to 90%), and proportion with bilateral subtype diagnosis (53 to 72%). There were also significant inter-facility differences in the number of AVS procedures (6 to 322), success rate (59 to 97%), and proportion with the bilateral subtype (44 to 86%). The principal enrolled department was Endocrinology (86%), and the ratio of unilateral PA was significantly higher in this department than in others (32% vs. 25%). In conclusion, the number of AVS procedures performed, the success rate, and the proportion with the bilateral subtype increased over time after normalizing the centre difference. Significant differences were observed between the centres.

DOI： 10.1038/s41371-019-0229-4

Language：English   Publishing type：Research paper (scientific journal)  

Primary aldosteronism (PA) is a common curable cause of hypertension. Adrenal venous sampling (AVS) is recommended for subtype diagnosis but is a difficult procedure. Recently, an increased prevalence of PA was reported, creating a greater demand for treatment of the condition in clinical facilities. The aim of the present study was to identify the historical changes over time and the differences between facilities in the success rate and subtype diagnosis of PA. The database of the PA registry developed by the Japan PA Study (JPAS) was used. A total of 2599 patients with PA who underwent AVS were evaluated. The overall success rate of AVS was 88%. The bilateral subtype was the dominant subtype, comprising 69% of cases. During the period 2004−2011 to 2011−2017, there were significant changes in the total number of AVS procedures (from 562 to 1732), ratio of ACTH administration with AVS (75 to 97%), success rate (79 to 90%), and proportion with bilateral subtype diagnosis (53 to 72%). There were also significant inter-facility differences in the number of AVS procedures (6 to 322), success rate (59 to 97%), and proportion with the bilateral subtype (44 to 86%). The principal enrolled department was Endocrinology (86%), and the ratio of unilateral PA was significantly higher in this department than in others (32% vs. 25%). In conclusion, the number of AVS procedures performed, the success rate, and the proportion with the bilateral subtype increased over time after normalizing the centre difference. Significant differences were observed between the centres.

DOI： 10.1038/s41371-019-0229-4

Language：English   Publishing type：Research paper (scientific journal)  

Objectives: We investigated the clinical significance of ACTH stimulation during adrenal venous sampling (AVS) by surgical outcome of primary aldosteronism (PA). Design: Multicenter retrospective study by Japan PA study. Method: We allocated 314 patients with both basal and ACTH-stimulated AVS data who underwent adrenalectomy to three groups: basal lateralization index (LI) ≥2 with ACTH-stimulated LI ≥4 on the ipsilateral side (Unilateral (U) to U group, n = 245); basal LI <2 with ACTH-stimulated LI ≥4 (Bilateral (B) to U group, n = 15); and basal LI ≥2 with ACTH-stimulated LI <4 (U to B group, n = 54). We compared surgical outcomes among the groups using the Primary Aldosteronism Surgical Outcome (PASO) criteria. Results: Compared with U to U group, U to B group had poor clinical and biochemical outcomes and low rates of adrenal adenoma as pathological findings (P = 0.044, 0.006, and 0.048, respectively), although there were no significant differences between U to U and B to U groups. All patients in U to B group with clinical and biochemical benefits, however, had adrenal adenoma as pathological findings and could be well differentiated from those with poor surgical outcomes via basal LI (>8.3), but not ACTH-stimulated LI. These results were similar even when we defined each group based on a cut-off value of 4 for basal LI. Conclusions: Although PA patients in U to B group had worse surgical outcomes than did those in U to U group, basal LI could discriminate among patients with better surgical outcomes in U to B group.

DOI： 10.1530/EJE-19-0860

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1080/10428194.2020.1725507

Language：English   Publishing type：Research paper (scientific journal)  

© 2019 Takei et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Objective Although previous studies have reported a negative relationship between serum bilirubin concentration and the development of diabetes mellitus (DM), the relationship between bilirubin and insulin resistance has not been thoroughly assessed. This study was designed to determine the relationships between bilirubin, body fat distribution, and adipose tissue inflammation in patients with type 2 DM and the effect of bilirubin in an obese animal model. Method Body fat distribution was measured using an abdominal dual bioelectrical impedance analyzer in patients with type 2 DM. We also measured glycemic control, lipid profile, serum bilirubin concentration and other clinical characteristics, and determined their relationships with body fat distribution. In the animal study, biliverdin (20 mg/kg daily) was orally administered to high-fat diet (HFD)-induced obese (DIO) mice for 2 weeks, after which intraperitoneal insulin tolerance testing was performed. Then, adipocyte area, adipocytokine expression, and macrophage polarization were evaluated in epididymal adipose tissues. Results In the clinical study, univariate analysis showed that a lower bilirubin concentration was significantly correlated with higher body mass index, waist circumference, triglyceride, uric acid, creatinine, visceral fat area and lower HDL-C. In multivariate analyses, bilirubin concentration significantly correlated with diastolic blood pressure, creatinine, and visceral fat area. However, there was no association between bilirubin concentration and subcutaneous fat area. In the animal study, DIO mice treated with biliverdin had smaller adipocytes than untreated DIO mice and biliverdin improved HFD-induced insulin resistance. Biliverdin treatment reversed the higher gene expression of Cd11c, encoding an M1 macrophage marker, and Tnfa, encoding the proinflammatory cytokine tumor necrosis factor-α, in the adipose tissues of DIO mice. These data suggest biliverdin administration alleviates insulin resistance by ameliorating inflammation and the dysregulation of adipocytokine expression in adipose tissues of DIO mice. Conclusions Bilirubin may protect against insulin resistance by ameliorating visceral obesity and adipose tissue inflammation.

DOI： 10.1371/journal.pone.0223302

Language：Japanese  

Language：English   Publishing type：Research paper (scientific journal)  

© 2019 Naruse et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background Based on non-clinical data, it is expected that azilsartan, an angiotensin II receptor blocker, will help improve insulin resistance in addition to its hypotensive action. The present study is aimed to explore the effect of azilsartan compared to telmisartan on insulin sensitivity in hypertensive patients in the clinical setting. Methods This multicenter, randomized, open-label, parallel-group exploratory study was conducted in Japan. We randomized adult patients (20 years old) with grade I or II essential hypertension and coexisting type 2 diabetes (1:1) to receive either oral azilsartan (20 mg/day;17 patients) or telmisartan (40 mg/day;16 patients) for 12 weeks. The primary endpoint was the change in the homeostasis model assessment ratio of insulin resistance (HOMA-R) from the baseline at the end of the treatment period. We also evaluated its safety and efficacy on other diabetes-related variables and blood pressure. Findings The mean changes in HOMA-R at the end of treatment were 0.22 (95% CI, −1.09–1.52) in the azilsartan group and −0.23 (95% CI, −0.72–0.27) in the telmisartan group. We found no clinically remarkable changes between the groups in diabetes-related variables such as fasting blood glucose, fasting insulin, HbA1c (NGSP), HOMA-β, or 1,5-anhydroglucitol. Reductions in clinic systolic and diastolic blood pressure were observed at week 4 and the reduced levels were maintained throughout the treatment period in both groups. No serious treatment-emergent adverse events (TEAEs) were observed. Only one drug-related TEAE (mild decrease in blood pressure) was reported in one patient in the azilsartan group. Conclusion Neither azilsartan nor telmisartan had any clinically remarkable effects on insulin resistance parameters when administered for 12 weeks to patients with grade I or II essential hypertension and coexisting type 2 diabetes mellitus. Azilsartan (20 mg/day) and telmisartan (40 mg/ day) exerted comparable antihypertensive effects.

DOI： 10.1371/journal.pone.0214727

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Background Based on non-clinical data, it is expected that azilsartan, an angiotensin II receptor blocker, will help improve insulin resistance in addition to its hypotensive action. The present study is aimed to explore the effect of azilsartan compared to telmisartan on insulin sensitivity in hypertensive patients in the clinical setting. Methods This multicenter, randomized, open-label, parallel-group exploratory study was conducted in Japan. We randomized adult patients (20 years old) with grade I or II essential hypertension and coexisting type 2 diabetes (1:1) to receive either oral azilsartan (20 mg/day;17 patients) or telmisartan (40 mg/day;16 patients) for 12 weeks. The primary endpoint was the change in the homeostasis model assessment ratio of insulin resistance (HOMA-R) from the baseline at the end of the treatment period. We also evaluated its safety and efficacy on other diabetes-related variables and blood pressure. Findings The mean changes in HOMA-R at the end of treatment were 0.22 (95% CI, −1.09–1.52) in the azilsartan group and −0.23 (95% CI, −0.72–0.27) in the telmisartan group. We found no clinically remarkable changes between the groups in diabetes-related variables such as fasting blood glucose, fasting insulin, HbA1c (NGSP), HOMA-β, or 1,5-anhydroglucitol. Reductions in clinic systolic and diastolic blood pressure were observed at week 4 and the reduced levels were maintained throughout the treatment period in both groups. No serious treatment-emergent adverse events (TEAEs) were observed. Only one drug-related TEAE (mild decrease in blood pressure) was reported in one patient in the azilsartan group. Conclusion Neither azilsartan nor telmisartan had any clinically remarkable effects on insulin resistance parameters when administered for 12 weeks to patients with grade I or II essential hypertension and coexisting type 2 diabetes mellitus. Azilsartan (20 mg/day) and telmisartan (40 mg/ day) exerted comparable antihypertensive effects.

DOI： 10.1371/journal.pone.0214727

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Nivolumab, an anti-PD-1 antibody, is now considered an important therapeutic agent in several advanced malignancies. However, immune-related adverse events such as endocrinopathies have been reported with its use. Thyroid disorder and isolated adrenocorticotropic hormone deficiency have frequently been reported as nivolumab-induced immune-related adverse events. Another endocrinopathy is nivolumab-induced type 1 diabetes mellitus (t1dm), described as diabetes mellitus with rapid onset and complete insulin insufficiency, at times leading to fulminant t1dm. We report the case of a 68-year-old woman who developed pancreatic islet-related autoantibody-negative t1dm, possibly induced by nivolumab, under continuous glucocorticoid administration. She was treated with nivolumab for advanced malignant melanoma, concomitant with 10 mg prednisolone daily for thrombophlebitis tapered to 5 mg after 13 courses of nivolumab therapy. At approximately the 27th course of nivolumab therapy, she showed elevated plasma glucose levels despite preserved insulin secretion. A month later, she developed diabetic ketoacidosis. Her insulin secretion decreased and finally was exhausted. She was diagnosed with acute-onset rather than fulminant t1dm because of a rapidly progressive course to diabetic ketoacidosis during just more than 1 week. She is currently receiving insulin replacement. There has been no recurrence of the melanoma. Thus, nivolumab might induce autoimmune diabetes mellitus, with patients having t1dm-sensitive human leucocyte antigen being more susceptible even when receiving glucocorticoids. Physicians should be aware that nivolumab could potentially induce t1dm as a critical immune-related adverse event.

DOI： 10.3747/co.26.4130

Language：English   Publishing type：Research paper (scientific journal)  

Nivolumab, an anti-PD-1 antibody, is now considered an important therapeutic agent in several advanced malignancies. However, immune-related adverse events such as endocrinopathies have been reported with its use. Thyroid disorder and isolated adrenocorticotropic hormone deficiency have frequently been reported as nivolumab-induced immune-related adverse events. Another endocrinopathy is nivolumab-induced type 1 diabetes mellitus (t1dm), described as diabetes mellitus with rapid onset and complete insulin insufficiency, at times leading to fulminant t1dm. We report the case of a 68-year-old woman who developed pancreatic islet-related autoantibody-negative t1dm, possibly induced by nivolumab, under continuous glucocorticoid administration. She was treated with nivolumab for advanced malignant melanoma, concomitant with 10 mg prednisolone daily for thrombophlebitis tapered to 5 mg after 13 courses of nivolumab therapy. At approximately the 27th course of nivolumab therapy, she showed elevated plasma glucose levels despite preserved insulin secretion. A month later, she developed diabetic ketoacidosis. Her insulin secretion decreased and finally was exhausted. She was diagnosed with acute-onset rather than fulminant t1dm because of a rapidly progressive course to diabetic ketoacidosis during just more than 1 week. She is currently receiving insulin replacement. There has been no recurrence of the melanoma. Thus, nivolumab might induce autoimmune diabetes mellitus, with patients having t1dm-sensitive human leucocyte antigen being more susceptible even when receiving glucocorticoids. Physicians should be aware that nivolumab could potentially induce t1dm as a critical immune-related adverse event.

DOI： 10.3747/co.26.4130

Language：English   Publishing type：Research paper (scientific journal)  

Objective: Unusual clinical course Background: Ipilimumab is a therapeutic human monoclonal antibody that targets the T-cell inhibitory molecule, cytotoxic T-lymphocyte antigen-4 (CTLA-4), and is classified as an immune checkpoint inhibitor that has been shown to improve prognosis in patients with advanced melanoma. However, several immune-related adverse events have been reported to be associated with ipilimumab Treatment. A case of acute exacerbation of chronic adrenal insufficiency is presented that highlights that glucocorticoid dosage for patients undergoing steroid treatment at the time of ipilimumab treatment has yet to be established. Case Report: A 50-year-old Japanese woman was diagnosed with malignant melanoma on the sole of her right foot. During her second course of ipilimumab treatment, she developed acute adrenal insufficiency caused by isolated adrenocorticotropic hormone (ACTH) deficiency, which required treatment with oral hydrocortisone. However, the symptoms of her adrenal insufficiency worsened, and she commenced treatment with 12 courses of nivolumab, a therapeutic human monoclonal antibody that blocks programmed cell death protein 1 (PD-1) on the surface of T-cells. She did not require corticosteroid support during nivolumab treatment. Conclusions: This case report highlights the risk of exacerbating adrenal insufficiency during treatment with ipilimumab. The differences in clinical outcome in this patient between ipilimumab and nivolumab treatment might be explained by the different mechanisms between ipilimumab and nivolumab on immune function.

DOI： 10.12659/AJCR.913021

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© 2019 The Author(s). Background: Increased urinary free cortisol in response to the oral administration of dexamethasone is a paradoxical reaction mainly reported in patients with primary pigmented nodular adrenocortical disease. Here, we describe the first case of subclinical Cushing's syndrome represented by autonomous cortisol secretion and paradoxical response to oral dexamethasone administration, harboring an activating mutation in the α subunit of the stimulatory G protein (GNAS). Case presentation: A 65-year-old woman was diagnosed with subclinical Cushing's syndrome during an evaluation for bilateral adrenal masses. Tumors of unknown origin were found in the heart, brain, thyroid gland, colon, pancreas, and both adrenal glands. Adenocarcinoma of the sigmoid colon and systemic brown-patchy skin pigmentation were also present. Her urinary cortisol levels increased in response to oral dexamethasone, while serum dehydroepiandrosterone-sulfate was not suppressed. After right adrenalectomy, genetic analysis of the resected tumor revealed the somatic GNAS activating mutation, p.R201H. Paradoxical urinary cortisol response persisted even after unilateral adrenal resection, although serum and urinary cortisol levels were attenuated. Conclusions: This patient harbored a GNAS activating mutation, and presented with a mild cortisol- and androgen-producing adrenal adenoma. Administration of oral dexamethasone paradoxically increased cortisol levels, possibly via the stimulation of the cyclic adenosine monophosphate-dependent protein kinase A signaling pathway, which is seen in patients with pigmented nodular adrenocortical disease or Carney complex. GNAS mutations may provide clues to the mechanisms of hyper-function and tumorigenesis in the adrenal cortex, especially in bilateral adrenal masses accompanied by multiple systemic tumors. Examining GNAS mutations could help physicians detect extra-adrenal malignancies, which may contribute to an improved prognosis for patients with this type of Cushing's syndrome.

DOI： 10.1186/s12902-019-0345-8

Language：English   Publishing type：Research paper (scientific journal)  

Objective Although previous studies have reported a negative relationship between serum bilirubin concentration and the development of diabetes mellitus (DM), the relationship between bilirubin and insulin resistance has not been thoroughly assessed. This study was designed to determine the relationships between bilirubin, body fat distribution, and adipose tissue inflammation in patients with type 2 DM and the effect of bilirubin in an obese animal model. Method Body fat distribution was measured using an abdominal dual bioelectrical impedance analyzer in patients with type 2 DM. We also measured glycemic control, lipid profile, serum bilirubin concentration and other clinical characteristics, and determined their relationships with body fat distribution. In the animal study, biliverdin (20 mg/kg daily) was orally administered to high-fat diet (HFD)-induced obese (DIO) mice for 2 weeks, after which intraperitoneal insulin tolerance testing was performed. Then, adipocyte area, adipocytokine expression, and macrophage polarization were evaluated in epididymal adipose tissues. Results In the clinical study, univariate analysis showed that a lower bilirubin concentration was significantly correlated with higher body mass index, waist circumference, triglyceride, uric acid, creatinine, visceral fat area and lower HDL-C. In multivariate analyses, bilirubin concentration significantly correlated with diastolic blood pressure, creatinine, and visceral fat area. However, there was no association between bilirubin concentration and subcutaneous fat area. In the animal study, DIO mice treated with biliverdin had smaller adipocytes than untreated DIO mice and biliverdin improved HFD-induced insulin resistance. Biliverdin treatment reversed the higher gene expression of Cd11c, encoding an M1 macrophage marker, and Tnfa, encoding the proinflammatory cytokine tumor necrosis factor-α, in the adipose tissues of DIO mice. These data suggest biliverdin administration alleviates insulin resistance by ameliorating inflammation and the dysregulation of adipocytokine expression in adipose tissues of DIO mice. Conclusions Bilirubin may protect against insulin resistance by ameliorating visceral obesity and adipose tissue inflammation.

DOI： 10.1371/journal.pone.0223302

Language：English   Publishing type：Research paper (scientific journal)  

Background: Increased urinary free cortisol in response to the oral administration of dexamethasone is a paradoxical reaction mainly reported in patients with primary pigmented nodular adrenocortical disease. Here, we describe the first case of subclinical Cushing's syndrome represented by autonomous cortisol secretion and paradoxical response to oral dexamethasone administration, harboring an activating mutation in the α subunit of the stimulatory G protein (GNAS). Case presentation: A 65-year-old woman was diagnosed with subclinical Cushing's syndrome during an evaluation for bilateral adrenal masses. Tumors of unknown origin were found in the heart, brain, thyroid gland, colon, pancreas, and both adrenal glands. Adenocarcinoma of the sigmoid colon and systemic brown-patchy skin pigmentation were also present. Her urinary cortisol levels increased in response to oral dexamethasone, while serum dehydroepiandrosterone-sulfate was not suppressed. After right adrenalectomy, genetic analysis of the resected tumor revealed the somatic GNAS activating mutation, p.R201H. Paradoxical urinary cortisol response persisted even after unilateral adrenal resection, although serum and urinary cortisol levels were attenuated. Conclusions: This patient harbored a GNAS activating mutation, and presented with a mild cortisol- and androgen-producing adrenal adenoma. Administration of oral dexamethasone paradoxically increased cortisol levels, possibly via the stimulation of the cyclic adenosine monophosphate-dependent protein kinase A signaling pathway, which is seen in patients with pigmented nodular adrenocortical disease or Carney complex. GNAS mutations may provide clues to the mechanisms of hyper-function and tumorigenesis in the adrenal cortex, especially in bilateral adrenal masses accompanied by multiple systemic tumors. Examining GNAS mutations could help physicians detect extra-adrenal malignancies, which may contribute to an improved prognosis for patients with this type of Cushing's syndrome.

DOI： 10.1186/s12902-019-0345-8

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1200/JOP.18.00076

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1200/JOP.18.00076

Language：English   Publishing type：Research paper (scientific journal)  

© 2018 The Author(s). Background: Nivolumab, an anti-programmed cell death-1 monoclonal antibody, has improved the survival of patients with malignant melanoma. Despite its efficacy, nivolumab inconsistently induces thyroid dysfunction as an immune-related adverse event (irAE). This study aimed to evaluate nivolumab-induced thyroid dysfunction to determine the risks and mechanisms of thyroid irAEs. Methods: After excluding 10 patients, data of 24 patients with malignant melanoma (aged 17-85years; 54% female) were retrospectively analyzed. Results: Thyroid irAEs were observed in seven patients (29%). Three patients had hypothyroidism after preceding transient thyrotoxicosis, and the other four patients had hypothyroidism without thyrotoxicosis. Levothyroxine-Na replacement was required in three patients. Antithyroid antibody (ATA) titer was elevated in one of four assessable patients. The average (±SD) time to onset of thyroid irAE was 33.6 (±21.9) weeks. The administration period of nivolumab was longer in patients with thyroid irAEs than in those without thyroid irAEs (P<0.01). There were no significant differences between patients with and without thyroid irAEs regarding age, sex, tumor stage, response to nivolumab therapy, baseline thyroid function, antithyroid peroxidase antibody (anti-TPO Ab) and antithyroglobulin antibody (anti-Tg Ab). Conclusions: Thyroid dysfunction was a common irAE of nivolumab in malignant melanoma. Neither anti-TPO Ab nor anti-Tg Ab was associated with the risk for nivolumab-induced thyroid dysfunction. A conventional ATA-independent mechanism might be involved in thyroid irAEs. Further studies are required to clarify the mechanism and identify the predictive factors of thyroid irAEs.

DOI： 10.1186/s12902-018-0267-x

Language：English   Publishing type：Research paper (scientific journal)  

Background: Nivolumab, an anti-programmed cell death-1 monoclonal antibody, has improved the survival of patients with malignant melanoma. Despite its efficacy, nivolumab inconsistently induces thyroid dysfunction as an immune-related adverse event (irAE). This study aimed to evaluate nivolumab-induced thyroid dysfunction to determine the risks and mechanisms of thyroid irAEs. Methods: After excluding 10 patients, data of 24 patients with malignant melanoma (aged 17-85years; 54% female) were retrospectively analyzed. Results: Thyroid irAEs were observed in seven patients (29%). Three patients had hypothyroidism after preceding transient thyrotoxicosis, and the other four patients had hypothyroidism without thyrotoxicosis. Levothyroxine-Na replacement was required in three patients. Antithyroid antibody (ATA) titer was elevated in one of four assessable patients. The average (±SD) time to onset of thyroid irAE was 33.6 (±21.9) weeks. The administration period of nivolumab was longer in patients with thyroid irAEs than in those without thyroid irAEs (P<0.01). There were no significant differences between patients with and without thyroid irAEs regarding age, sex, tumor stage, response to nivolumab therapy, baseline thyroid function, antithyroid peroxidase antibody (anti-TPO Ab) and antithyroglobulin antibody (anti-Tg Ab). Conclusions: Thyroid dysfunction was a common irAE of nivolumab in malignant melanoma. Neither anti-TPO Ab nor anti-Tg Ab was associated with the risk for nivolumab-induced thyroid dysfunction. A conventional ATA-independent mechanism might be involved in thyroid irAEs. Further studies are required to clarify the mechanism and identify the predictive factors of thyroid irAEs.

DOI： 10.1186/s12902-018-0267-x

Language：Japanese  

ミネラルコルチコイド受容体拮抗薬(MRA)使用下での副腎静脈サンプリング(AVS)の局在診断精度の検討

Language：English   Publishing type：Research paper (scientific journal)  

Subtype diagnosis of primary aldosteronism (PA) by adrenal vein sampling (AVS) is recommended as a mandatory step for indicating adrenal surgery. It is a technically demanding procedure, especially in the right adrenal vein. The aim of the study was to predict the subtype diagnosis in the absence of values from the right AVS. From the databases of nine centers (WAVES-J), 308 patients with PA who underwent successful AVS were studied. Based on the ipsilateral ratio (IR) (aldosterone/cortisol ratio of the left adrenal vein [A/C_{left AV}] / aldosterone/cortisol ratio of the inferior vena cava [A/C_IVC]), the patients were divided into two groups: the patients with IR ≥ 1.0 (n = 262) and those with IR < 1.0 (n = 46). In patients with IR > 1.0, the A/C_{left AV} was significantly higher in patients with the left unilateral subtype than in patients with the bilateral subtype. Receiver operating characteristic (ROC) curve analysis revealed that an A/C_{left AV} cutoff >68 showed 70.8% sensitivity and 93.5% specificity for the left unilateral subtype. On the other hand, in patients with IR < 1.0, the A/C_{left AV} was significantly lower in patients with the right unilateral subtype. ROC analysis revealed that an A/C_{left AV} cutoff <9 showed 86.7% sensitivity and 75.0% specificity for the right unilateral subtype. Hence, the combination of the IR and A/C ratio in the left adrenal vein is useful for predicting the subtype. The present results provide important information for patients with PA in whom AVS was unsuccessful in the right adrenal vein.

DOI： 10.1038/s41371-017-0015-0

Language：English   Publishing type：Research paper (scientific journal)  

© 2017 The Author(s) 2017, under exclusive licence to Macmillan Publishers Limited, part of Springer Nature. Subtype diagnosis of primary aldosteronism (PA) by adrenal vein sampling (AVS) is recommended as a mandatory step for indicating adrenal surgery. It is a technically demanding procedure, especially in the right adrenal vein. The aim of the study was to predict the subtype diagnosis in the absence of values from the right AVS. From the databases of nine centers (WAVES-J), 308 patients with PA who underwent successful AVS were studied. Based on the ipsilateral ratio (IR) (aldosterone/cortisol ratio of the left adrenal vein [A/Cleft AV] / aldosterone/cortisol ratio of the inferior vena cava [A/CIVC]), the patients were divided into two groups: the patients with IR ≥ 1.0 (n = 262) and those with IR < 1.0 (n = 46). In patients with IR > 1.0, the A/Cleft AV was significantly higher in patients with the left unilateral subtype than in patients with the bilateral subtype. Receiver operating characteristic (ROC) curve analysis revealed that an A/Cleft AV cutoff >68 showed 70.8&#37; sensitivity and 93.5&#37; specificity for the left unilateral subtype. On the other hand, in patients with IR < 1.0, the A/Cleft AV was significantly lower in patients with the right unilateral subtype. ROC analysis revealed that an A/Cleft AV cutoff <9 showed 86.7&#37; sensitivity and 75.0&#37; specificity for the right unilateral subtype. Hence, the combination of the IR and A/C ratio in the left adrenal vein is useful for predicting the subtype. The present results provide important information for patients with PA in whom AVS was unsuccessful in the right adrenal vein.

DOI： 10.1038/s41371-017-0015-0

Language：English   Publishing type：Research paper (scientific journal)  

Hyperkalemia is an important complication of adrenalectomy for patients with primary aldosteronism (PA). The frequency of hyperkalemia after medication using mineralocorticoid receptor antagonists (MRAs) for PA is unclear. The aim of this study is to investigate the frequency and the risk factors of hyperkalemia after surgery and medication for PA. The data of 376 patients with PA registered in a multicentre-collaborative study in Japan, including surgically treated patients (group A; n=142) and medically treated patients with MRAs (group B; n=234) were studied. The prevalence of hyperkalemic patients (serum potassium >5.0 mEq l -1) after treatment was higher in group A than group B (9.9 vs 3.8%, P<0.01). At diagnosis, the hyperkalemic patients were older and had a poorer renal function than the non-hyperkalemic patients in both groups (P<0.05). The hyperkalemic patients had severer PA in group A and milder PA in group B. The independent risk factor by a logistic regression analysis was only age in both groups. After treatment, the percentages of patients withdrawing antihypertensive drugs and the normalization of aldosterone renin ratio were not different between hyperkalemic and non-hyperkalemic patients in group A. The type and dose of MRAs and the combination of other antihypertensive drugs were not different between hyperkalemic and non-hyperkalemic patients in group B. In conclusion, the potential occurrence of hyperkalemia should be considered after medical as well as surgical treatment for PA, especially in patients with older age (>60 years) and impaired renal function (estimated glomerular filtration rate <70 ml min -1 per 1.73 m 2) at diagnosis.

DOI： 10.1038/jhh.2017.38

Language：English   Publishing type：Research paper (scientific journal)  

Hyperkalemia is an important complication of adrenalectomy for patients with primary aldosteronism (PA). The frequency of hyperkalemia after medication using mineralocorticoid receptor antagonists (MRAs) for PA is unclear. The aim of this study is to investigate the frequency and the risk factors of hyperkalemia after surgery and medication for PA. The data of 376 patients with PA registered in a multicentre-collaborative study in Japan, including surgically treated patients (group A; n = 142) and medically treated patients with MRAs (group B; n = 234) were studied. The prevalence of hyperkalemic patients (serum potassium > 5.0 mEq l(-1)) after treatment was higher in group A than group B (9.9 vs 3.8%, P < 0.01). At diagnosis, the hyperkalemic patients were older and had a poorer renal function than the non-hyperkalemic patients in both groups (P < 0.05). The hyperkalemic patients had severer PA in group A and milder PA in group B. The independent risk factor by a logistic regression analysis was only age in both groups. After treatment, the percentages of patients withdrawing antihypertensive drugs and the normalization of aldosterone renin ratio were not different between hyperkalemic and non-hyperkalemic patients in group A. The type and dose of MRAs and the combination of other antihypertensive drugs were not different between hyperkalemic and non-hyperkalemic patients in group B. In conclusion, the potential occurrence of hyperkalemia should be considered after medical as well as surgical treatment for PA, especially in patients with older age (> 60 years) and impaired renal function (estimated glomerular filtration rate < 70 ml min(-1) per 1.73 m(2)) at diagnosis.

DOI： 10.1038/jhh.2017.38

Language：English   Publishing type：Research paper (scientific journal)  

Although laterality assessed by computed tomography (CT) in primary aldosteronism (PA) is not always concordant with that assessed by adrenal vein sampling (AVS), it is unclear whether all patients diagnosed with PA should undergo AVS for subtype classification. The aim of the current study was to investigate the accuracy of CT in subtype classification and to develop a prediction score for bilateral subtype in patients without adrenal tumour. As part of the WAVES-J study, 393 patients with PA were analysed. Subtyping using CT was concordant with that using AVS in 68% (269/393) of patients in the total sample, and in 38% (68/156) of patients with unilateral tumours, 56% (5/9) of patients with bilateral tumours and 89% (204/228) of patients without tumour. In patients without tumour, female gender, plasma aldosterone concentration (pg ml(-1)) to plasma renin activity ratio. 550 and serum potassium. 3.8 mEq l (-1) were shown to be independent predictors for bilateral subtype. A prediction score based on these three variables was constructed with one point attributed to each variable. A score of three points had 29% sensitivity and 96% specificity in a receiver operating characteristic curve analysis. The results suggest that although CT is not sufficiently accurate for subtype classification in patients with adrenal tumours, it is sufficient to determine bilateral subtype in patients without tumour. Moreover, using our clinical prediction score in patients without tumour could be useful in determining the necessity of AVS for subtype classification.

DOI： 10.1038/jhh.2016.61

Language：English   Publishing type：Research paper (scientific journal)  

Although laterality assessed by computed tomography (CT) in primary aldosteronism (PA) is not always concordant with that assessed by adrenal vein sampling (AVS), it is unclear whether all patients diagnosed with PA should undergo AVS for subtype classification. The aim of the current study was to investigate the accuracy of CT in subtype classification and to develop a prediction score for bilateral subtype in patients without adrenal tumour. As part of the WAVES-J study, 393 patients with PA were analysed. Subtyping using CT was concordant with that using AVS in 68% (269/393) of patients in the total sample, and in 38% (68/156) of patients with unilateral tumours, 56% (5/9) of patients with bilateral tumours and 89% (204/228) of patients without tumour. In patients without tumour, female gender, plasma aldosterone concentration (pg ml^-1) to plasma renin activity ratio ≤550 and serum potassium ≥3.8 mEq l^-1 were shown to be independent predictors for bilateral subtype. A prediction score based on these three variables was constructed with one point attributed to each variable. A score of three points had 29% sensitivity and 96% specificity in a receiver operating characteristic curve analysis. The results suggest that although CT is not sufficiently accurate for subtype classification in patients with adrenal tumours, it is sufficient to determine bilateral subtype in patients without tumour. Moreover, using our clinical prediction score in patients without tumour could be useful in determining the necessity of AVS for subtype classification.

DOI： 10.1038/jhh.2016.61

Language：English   Publishing type：Research paper (scientific journal)  

Objective: Although corticotropin is a representative secretagogue of aldosterone, the utility of the cosyntropin stimulation test (C-ST) in diagnosing primary aldosteronism (PA) has not been elucidated. Aim of the study was to evaluate the clinical utility of C-ST for confirmatory testing and subtype classification of PA. Design, Setting and Patients: In this retrospective study, we identified patients with hypertension and positive case-detection results for PA who underwent C-ST and saline infusion testing (SIT) between 2006 and 2013 at eight referral centres in Japan. PA and essential hypertension (EH) were distinguished based on SIT results. PA subtype classification was determined by adrenal venous sampling (AVS). Plasma aldosterone concentration (PAC) was measured before and 30 and 60 min after intravenous cosyntropin administration. The ability of C-ST to distinguish PA from EH and to distinguish unilateral from bilateral disease was assessed by the area under the receiver operating characteristic curve. Results: Of 205 patients with hypertension and positive case-detection results, 139 (68%) had PA based on SIT results. Eighteen patients in whom AVS was unsuccessful were excluded from analysis. The baseline PAC before C-ST was significantly higher (P < 0·01) in patients with PA than in those with EH. However, the degree of difference in PAC between patients with PA and EH was not enhanced by the administration of cosyntropin. In addition, the administration of cosyntropin did not improve the distinction between bilateral and unilateral PA subtypes. Conclusions: C-ST has no utility as a confirmatory and subtype testing of PA when the diagnosis of PA is based on the positive results in SIT.

DOI： 10.1111/cen.13167

Language：English   Publishing type：Research paper (scientific journal)  

ObjectiveAlthough corticotropin is a representative secretagogue of aldosterone, the utility of the cosyntropin stimulation test (C-ST) in diagnosing primary aldosteronism (PA) has not been elucidated. Aim of the study was to evaluate the clinical utility of C-ST for confirmatory testing and subtype classification of PA.Design, Setting and PatientsIn this retrospective study, we identified patients with hypertension and positive case-detection results for PA who underwent C-ST and saline infusion testing (SIT) between 2006 and 2013 at eight referral centres in Japan. PA and essential hypertension (EH) were distinguished based on SIT results. PA subtype classification was determined by adrenal venous sampling (AVS). Plasma aldosterone concentration (PAC) was measured before and 30 and 60 min after intravenous cosyntropin administration. The ability of C-ST to distinguish PA from EH and to distinguish unilateral from bilateral disease was assessed by the area under the receiver operating characteristic curve.ResultsOf 205 patients with hypertension and positive case-detection results, 139 (68&#37;) had PA based on SIT results. Eighteen patients in whom AVS was unsuccessful were excluded from analysis. The baseline PAC before C-ST was significantly higher (P < 001) in patients with PA than in those with EH. However, the degree of difference in PAC between patients with PA and EH was not enhanced by the administration of cosyntropin. In addition, the administration of cosyntropin did not improve the distinction between bilateral and unilateral PA subtypes.ConclusionsC-ST has no utility as a confirmatory and subtype testing of PA when the diagnosis of PA is based on the positive results in SIT.

DOI： 10.1111/cen.13167

Language：English   Publishing type：Research paper (scientific journal)  

Context: In adrenal vein sampling (AVS) for patients with primary aldosteronism, the contralateral ratio of aldosterone/cortisol (A/C) between the nondominant adrenal vein and the inferior vena cava is one of the best criteria for determining lateralized aldosterone secretion. Despite successful cannulation in some patients, the A/C ratios in the adrenal veins are bilaterally lower than that in the inferior vena cava (bilateral aldosterone suppression; BAS). Objectives: To investigate the prevalence of BAS in AVS and how to resolve this condition. Design and setting: Retrospective study involving nine referral centres. Patients: Four hundred and ninety-one patients who were confirmed as having primary aldosteronism and had an AVS between January 2006 and December 2013. Measurements: The prevalence of BAS before and after ACTH stimulation was compared. In addition, we investigated other methods for overcoming BAS. Results: In 304 patients with successful AVS before ACTH stimulation, BAS was observed in 29 (9·5%). BAS was resolved after ACTH stimulation in 22 patients. In 276 patients with successful AVS both before and after ACTH stimulation, the frequency of BAS was significantly reduced after ACTH (8·7% vs 2·5%, P < 0·01). In a few patients, BAS was also resolved by adding a sampling point at the common trunk of the left adrenal vein and by an alternative drainage vein from the adrenal tumour. Conclusions: BAS sometimes occurs in AVS without ACTH stimulation. ACTH stimulation significantly reduces BAS with a single AVS procedure.

DOI： 10.1111/cen.13090

Language：English   Publishing type：Research paper (scientific journal)  

CONTEXT: In adrenal vein sampling (AVS) for patients with primary aldosteronism, the contralateral ratio of aldosterone/cortisol (A/C) between the nondominant adrenal vein and the inferior vena cava is one of the best criteria for determining lateralized aldosterone secretion. Despite successful cannulation in some patients, the A/C ratios in the adrenal veins are bilaterally lower than that in the inferior vena cava (bilateral aldosterone suppression; BAS). OBJECTIVES: To investigate the prevalence of BAS in AVS and how to resolve this condition. DESIGN AND SETTING: Retrospective study involving nine referral centres. PATIENTS: Four hundred and ninety-one patients who were confirmed as having primary aldosteronism and had an AVS between January 2006 and December 2013. MEASUREMENTS: The prevalence of BAS before and after ACTH stimulation was compared. In addition, we investigated other methods for overcoming BAS. RESULTS: In 304 patients with successful AVS before ACTH stimulation, BAS was observed in 29 (9·5%). BAS was resolved after ACTH stimulation in 22 patients. In 276 patients with successful AVS both before and after ACTH stimulation, the frequency of BAS was significantly reduced after ACTH (8·7% vs 2·5%, P < 0·01). In a few patients, BAS was also resolved by adding a sampling point at the common trunk of the left adrenal vein and by an alternative drainage vein from the adrenal tumour. CONCLUSIONS: BAS sometimes occurs in AVS without ACTH stimulation. ACTH stimulation significantly reduces BAS with a single AVS procedure.

DOI： 10.1111/cen.13090

Language：English   Publishing type：Research paper (scientific journal)  

Adrenal venous sampling is considered to be the most reliable diagnostic procedure to lateralize aldosterone excess in primary aldosteronism (PA). However, normative criteria have not been established partially because of a lack of data in non-PA hypertensive patients. The aim of the study was to investigate aldosterone concentration and its gradient in the adrenal vein of non-PA hypertensive patients. We retrospectively studied the results of cosyntropin-stimulated adrenal venous sampling in 40 hypertensive patients who showed positive screening testing but negative results in 2 confirmatory tests/captopril challenge test and saline infusion test. Plasma aldosterone concentration, aldosterone/cortisol ratio, its higher/lower ratio (lateralization index) in the adrenal vein with cosyntropin stimulation were measured. Median plasma aldosterone concentration in the adrenal vein was 25 819 pg/mL (range, 5154-69 920) in the higher side and 12 953 (range, 1866-36 190) pg/mL in the lower side (P<0.001). There was a significant gradient in aldosterone/cortisol ratio between the higher and the lower sides (27.2 [5.4-66.0] versus 17.3 [4.0-59.0] pg/mL per mu g/dL; P<0.001) with lateralization index ranging from 1.01 to 3.87. The aldosterone lateralization gradient was between 1 to 2 in 32 patients and 2 to 4 in 8 patients. None of the patients showed lateralization index >= 4. The present study demonstrated that plasma aldosterone concentration in the adrenal veins showed significant variation and lateralization gradient even in non-PA hypertensive patients. Adrenal venous sampling aldosterone lateralization gradients between 2 and 4 should be interpreted with caution in patients with PA because these gradients can be found even in patients with negative confirmatory testing for PA.

DOI： 10.1161/HYPERTENSIONAHA.115.06607

Language：English   Publishing type：Research paper (scientific journal)  

Adrenal venous sampling is considered to be the most reliable diagnostic procedure to lateralize aldosterone excess in primary aldosteronism (PA). However, normative criteria have not been established partially because of a lack of data in non-PA hypertensive patients. The aim of the study was to investigate aldosterone concentration and its gradient in the adrenal vein of non-PA hypertensive patients. We retrospectively studied the results of cosyntropin-stimulated adrenal venous sampling in 40 hypertensive patients who showed positive screening testing but negative results in 2 confirmatory tests/captopril challenge test and saline infusion test. Plasma aldosterone concentration, aldosterone/cortisol ratio, its higher/lower ratio (lateralization index) in the adrenal vein with cosyntropin stimulation were measured. Median plasma aldosterone concentration in the adrenal vein was 25 819 pg/mL (range, 5154-69 920) in the higher side and 12 953 (range, 1866-36 190) pg/mL in the lower side (P<0.001). There was a significant gradient in aldosterone/cortisol ratio between the higher and the lower sides (27.2 [5.4-66.0] versus 17.3 [4.0-59.0] pg/mL per μg/dL; P<0.001) with lateralization index ranging from 1.01 to 3.87. The aldosterone lateralization gradient was between 1 to 2 in 32 patients and 2 to 4 in 8 patients. None of the patients showed lateralization index ≥4. The present study demonstrated that plasma aldosterone concentration in the adrenal veins showed significant variation and lateralization gradient even in non-PA hypertensive patients. Adrenal venous sampling aldosterone lateralization gradients between 2 and 4 should be interpreted with caution in patients with PA because these gradients can be found even in patients with negative confirmatory testing for PA.

DOI： 10.1161/HYPERTENSIONAHA.115.06607

Language：English   Publishing type：Research paper (scientific journal)  

Primary aldosteronism (PA) is associated with a higher rate of cardiovascular events than essential hypertension. Although adrenalectomy has been reported to reduce carotid intima-media thickness (IMT) in patients with PA, the effects of the selective aldosterone blocker, eplerenone, on vascular damage in these patients remains unclear. To evaluate the effects of eplerenone on vascular status in PA patients, we sequentially measured carotid IMT (using computer software to calculate an average IMT for accurate and reproducible evaluation) in 22 patients including 8 patients treated by unilateral adrenalectomy and 14 patients treated with eplerenone for 12 months. Patients who underwent adrenalectomy showed significant reductions in aldosterone concentration (from 345 ± 176 pg/mL to 67 ± 34 pg/mL; P<0.01) and IMT (from 0.67 ± 0.07 mm to 0.63 ± 0.09 mm; P<0.05) 6 months after surgery. Patients treated with eplerenone showed significant reductions in IMT from baseline (0.75 ± 0.10 mm) to 6 (0.71 ± 0.11 mm; P<0.05) and 12 (0.65 ± 0.09 mm; P<0.01) months, although plasma aldosterone level increased significantly, from 141 ± 105 pg/mL to 207 ± 98 pg/mL (P<0.05). Eplerenone treatment of patients with PA reduces blood pressure, increases serum potassium level, and improves vascular status. Carotid IMT may be a useful marker for evaluating the effectiveness of eplerenone in patients with PA.

DOI： 10.1507/endocrj.EJ15-0362

Language：English   Publishing type：Research paper (scientific journal)  

Context Although adrenal vein sampling (AVS) is the standard method for subtype diagnosis in primary aldosteronism (PA), protocol details including the sampling position in the adrenal vein are not standardized. Objective To establish the optimum sampling position in the left adrenal vein based on postoperative outcome in PA patients. Design and Setting Retrospective study in nine referral centres. Participants Of 496 consecutive PA patients who underwent AVS between 2006 and 2013, 217 with successful AVS under cosyntropin stimulation, and with concomitant data from two positions: proximal (common trunk) and distal (central vein) to the junction with the inferior phrenic vein, were included. Main outcome measures Discordant rate of subtype diagnosis between common trunk and central vein, and postoperative outcomes in patients with discordant results. Results Subtype diagnosis using common trunk and central vein was discordant in 10 (4·6%) of the 217 patients (κ = 0·87, P < 0·05). Of these 10 patients, eight with left unilateral subtype and two with bilateral subtype using common trunk data showed bilateral subtype and unilateral subtype, respectively, using central vein data. Five patients with left unilateral subtype and one with bilateral subtype by common trunk data underwent unilateral adrenalectomy. All six patients were cured of PA after adrenalectomy, resulting in false-negative rates of 17% (1/6) by common trunk data, and 83% (5/6) by central vein data. Conclusion In view of its better potential diagnostic accuracy, technical ease, lower cost and lower risk of vein rupture, blood sampling from the common trunk of the left adrenal vein may be preferable as the standard method of AVS in patients with PA, although additional studies in a larger number of cases are required.

DOI： 10.1111/cen.12847

Language：English   Publishing type：Research paper (scientific journal)  

Context Although adrenal vein sampling (AVS) is the standard method for subtype diagnosis in primary aldosteronism (PA), protocol details including the sampling position in the adrenal vein are not standardized.Objective To establish the optimum sampling position in the left adrenal vein based on postoperative outcome in PA patients.Design and Setting Retrospective study in nine referral centres.Participants Of 496 consecutive PA patients who underwent AVS between 2006 and 2013, 217 with successful AVS under cosyntropin stimulation, and with concomitant data from two positions: proximal (common trunk) and distal (central vein) to the junction with the inferior phrenic vein, were included.Main outcome measures Discordant rate of subtype diagnosis between common trunk and central vein, and postoperative outcomes in patients with discordant results.Results Subtype diagnosis using common trunk and central vein was discordant in 10 (4.6%) of the 217 patients (kappa = 0.87, P < 0.05). Of these 10 patients, eight with left unilateral subtype and two with bilateral subtype using common trunk data showed bilateral subtype and unilateral subtype, respectively, using central vein data. Five patients with left unilateral subtype and one with bilateral subtype by common trunk data underwent unilateral adrenalectomy. All six patients were cured of PA after adrenalectomy, resulting in false-negative rates of 17% (1/6) by common trunk data, and 83% (5/6) by central vein data.Conclusion In view of its better potential diagnostic accuracy, technical ease, lower cost and lower risk of vein rupture, blood sampling from the common trunk of the left adrenal vein may be preferable as the standard method of AVS in patients with PA, although additional studies in a larger number of cases are required.

DOI： 10.1111/cen.12847

Language：Japanese  

PA局在診断におけるAVSの左副腎静脈採血部位の意義

Language：English   Publishing type：Research paper (scientific journal)  

Objectives Adrenal vein sampling (AVS) is the standard criterion for the subtype diagnosis in primary aldosteronism (PA). Although lateralized index (LI) >= 4 after cosyntropin stimulation is the commonly recommended cut-off for unilateral aldosterone hypersecretion, many of the referral centres in the world use LI cut-off of <4 without sufficient evidence for its diagnostic accuracy.Aim The aim of the study was to establish the diagnostic significance of contralateral (CL) aldosterone suppression for the subtype diagnosis in patients with LI <4 in AVS.Design and patients A retrospective multicentre study was conducted in Japan. Of 124 PA patients subjected to unilateral adrenalectomy after successful AVS with cosyntropin administration, 29 patients with LI < 4 were included in the study. The patients were divided into Group A with CL suppression (n = 16) and Group B (n = 13) without CL suppression. Three outcome indices were assessed after 6 months postoperatively: normalization/significant improvement of hypertension, normalization of the aldosterone to renin ratio (ARR) and normalization of hypokalaemia.Results The normalization/significant improvement of hypertension was 81% in Group A and 54% in Group B (P = 0.2). The normalization of ARR was 100% in Group A and 46% in Group B (P = 0.004). Hypokalaemia was normalized in all patients of both groups. The overall cure rate of PA based on meeting all the three criteria was 81% in Group A and 31% in Group B (P = 0.01).Conclusions In patients with PA, where the LI is < 4 on AVS, CL suppression of aldosterone is an accurate predictor of a unilateral source of aldosterone excess. CL suppression data should be interpreted in conjunction with computed tomographic adrenal imaging findings to guide surgical management.

DOI： 10.1111/cen.12761

Language：Japanese  

副腎静脈サンプリングにおける左副腎静脈採血部位が原発性アルドステロン症の局在診断に及ぼす影響 WAVES-J研究における解析

Language：Japanese  

若年者原発性アルドステロン症の局在診断におけるCT所見の意義

Language：Japanese  

原発性アルドステロン症におけるCT画像による病側診断率および副腎静脈サンプリングの適応に関する検討 WAVES-J研究より

Language：English   Publishing type：Research paper (scientific journal)  

Objectives Adrenal vein sampling (AVS) is the standard criterion for the subtype diagnosis in primary aldosteronism (PA). Although lateralized index (LI) ≥4 after cosyntropin stimulation is the commonly recommended cut-off for unilateral aldosterone hypersecretion, many of the referral centres in the world use LI cut-off of <4 without sufficient evidence for its diagnostic accuracy. Aim The aim of the study was to establish the diagnostic significance of contralateral (CL) aldosterone suppression for the subtype diagnosis in patients with LI <4 in AVS. Design and patients A retrospective multicentre study was conducted in Japan. Of 124 PA patients subjected to unilateral adrenalectomy after successful AVS with cosyntropin administration, 29 patients with LI < 4 were included in the study. The patients were divided into Group A with CL suppression (n = 16) and Group B (n = 13) without CL suppression. Three outcome indices were assessed after 6 months postoperatively: normalization/significant improvement of hypertension, normalization of the aldosterone to renin ratio (ARR) and normalization of hypokalaemia. Results The normalization/significant improvement of hypertension was 81% in Group A and 54% in Group B (P = 0·2). The normalization of ARR was 100% in Group A and 46% in Group B (P = 0·004). Hypokalaemia was normalized in all patients of both groups. The overall cure rate of PA based on meeting all the three criteria was 81% in Group A and 31% in Group B (P = 0·01). Conclusions In patients with PA, where the LI is <4 on AVS, CL suppression of aldosterone is an accurate predictor of a unilateral source of aldosterone excess. CL suppression data should be interpreted in conjunction with computed tomographic adrenal imaging findings to guide surgical management.

DOI： 10.1111/cen.12761

Language：English   Publishing type：Research paper (other academic)  

Language：Japanese  

Language：English   Publishing type：Research paper (scientific journal)  

Objective The treatment for asymptomatic primary hyperparathyroidism (PHPT) remains controversial. In 2008, the Third International Workshop on the Management of Asymptomatic PHPT proposed a set of guidelines for the management of asymptomatic PHPT. We therefore evaluated the application of the Workshop recommendations in Japanese patients with asymptomatic PHPT.
Methods We analyzed each parameter of the guidelines in 87 Japanese patients with asymptomatic PHPT who underwent methoxy-isobutyl-isonitrile (MIBI) scintigraphy.
Results Fewer than 10% of the patients were less than 50 years of age. The bone mineral density T-score was below -2.5 SD in 20 women (46.5% of all women analyzed) and in none of the men. The eGFR was <60 mL/min/1.73 m² in 17 patients. A majority of patients (43) satisfied only one parameter, while 25 patients satisfied none of the parameters. Furthermore, the MIBI-positive and surgically treated patients tended to satisfy a larger number of the parameters. The Workshop criteria and levels of PTH, daily Ca excretion, serum ALP and 1,25(OH)2 Vitamin D were further analyzed in relation to the findings of MIBI scans, and almost all of the parameters were found to be significantly correlated with the results of the MIBI studies.
Conclusion Our results suggest the need to reassess the Workshop guidelines for the treatment of hyperparathyroidism in Japanese patients. It is desirable that MIBI scintigraphy be performed whenever possible, as this modality is anticipated to play an important role in determining whether or not surgery is appropriate.

DOI： 10.2169/internalmedicine.53.2133

Language：English   Publishing type：Research paper (scientific journal)  

The patient presented in this case was an 83-year-old female who was referred to our department for a detailed examination and treatment of a diabetic foot. She had history of treatment with continuous oral steroid therapy (8 mg/day) for polymyalgia rheumatica (PMR), insulin therapy (NovoRapid 30 Mix: 8 units in the morning and 2 units in the evening), and oral treatment with acarbose (100 mg, 3T) for diabetes. Although she did not complain of abdominal fullness or pain, a routine abdominal X-ray revealed free air below the diaphragm and noticeable gaseous distention in the ascending and transverse colon. Abdominal CT demonstrated dilatation, mesenteric edema, and diffuse pneumatosis intestinalis throughout the ascending and transverse colon. A diagnosis of pneumatosis cystoides intestinalis (PCI) was made based on these findings. As the α-glucosidase inhibitor (α-GI) was suspected to be the cause of the PCI, we administered conservative treatment, discontinuing acarbose with fasting and fluid supplementation. The patient progressed well, and 3 weeks later, an abdominal X-ray and CT scan confirmed the disappearance of the pneumocystis lesions in the colon. With the recent rise in the number of elderly individuals and increased awareness of PMR, the number of reported patients with PMR receiving steroid therapy in Japan has increased. Therefore, the incidence of PMR among elderly patients with diabetes mellitus receiving α-GI and steroid therapy is anticipated to increase in the future. Hence, PCI should be carefully assessed as a possible complication and the gastrointestinal tract should be investigated in such patients.

DOI： 10.1007/s13340-014-0158-y

Language：English   Publishing type：Research paper (scientific journal)  

Objective Expression of corticotropin-releasing factor type 1 receptor (CRFR1) has been shown on pancreatic β cells, and its activation potentiates glucose-stimulated insulin secretion (GSIS). However, the roles of CRFR1 in energy metabolism beyond insulin release remain elusive. Materials/Methods We characterized the metabolic phenotypes of mice lacking CRFR1 (CRFR1KO mice) under conditions of energy excess. Results When fed a normal diet, the glucose profile of CRFR1KO mice in response to a glucose tolerance test was similar to that of wild-type (WT) mice, while serum insulin levels were significantly lower in CRFR1KO mice, reflecting high insulin sensitivity in part due to very low glucocorticoid levels. Histology of the pancreas revealed islet hypoplasia in CRFR1KO mice, suggesting a role of CRFR1 in maintaining the β cell mass in a manner similar to incretins. In response to a high-fat diet, CRFR1KO mice showed insulin resistance, but serum insulin levels during glucose challenge remained at a low level, indicating defective GSIS. In addition, CRFR1KO mice showed resistance to diet-induced obesity and hepatic steatosis. Although total food intake was not different between CRFR1KO and WT mice, oxygen consumption was significantly increased in CRFR1KO mice. The increased energy expenditure may explain the lean phenotype of CRFR1KO mice under conditions of energy excess. Conclusions Our results suggest that CRFR1 plays important roles in whole body energy homeostasis, providing compelling evidence of the close relationship between energy homeostasis and the function of the hypothalamic-pituitary-adrenal axis.

DOI： 10.1016/j.metabol.2013.08.005

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Activin, a transforming growth factor β family member, has a wide range of physiological roles during embryonic development and organogenesis. In the ovary, activin, secreted from ovarian granulosa cells, not only acts on the pituitary gland to regulate the gonadotropin secretion from the pituitary gland in an endocrine manner but also acts on granulosa cells in a paracrine/autocrine manner to regulate folliculogenesis. Previously, we showed that activin signals through activin type IB receptor (ActRIB) and up-regulates follicle-stimulating hormone receptor expression and P450 aromatase activity in human ovarian granulose cell-like KGN cells. In the current study, we demonstrate the direct involvement of Smad2 as a downstream signal mediator of ActRIB in the transcriptional regulation of the P450 aromatase gene (CYP19A) in KGN cells. Upon activin stimulation, Smad2 activation and an increase in P450 aromatase messenger RNA (mRNA) were observed in KGN cells. Interestingly, Smad2 phosphorylation correlated well with the increase in P450 aromatase mRNA. Reciprocally, knockdown of Smad2 mRNA in KGN cells led to a decrease in the P450 aromatase mRNA expression, suggesting that Smad2 regulates CYP19A gene expression. Further analysis of CYP19A promoter activity revealed that the 5' upstream region between -2069 and -1271. bp is required for the activation by Smad2. Finally, we provide compelling evidence that Smad2 shows follicular stage-specific expression, which is high in granulosa cells of preantral or early antral follicles in mice. Our results suggest that activin signaling through the ActRIB-Smad2 pathway plays a pivotal role in CYP19A expression and thus in follicular development.

DOI： 10.1016/j.bbrc.2013.05.124

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In patients with acromegaly, cardiovascular diseases are the most common cause of death. Arterial stiffness is increasingly recognized as a valuable surrogate marker for predicting cardiovascular events. To evaluate the vascular status of acromegalic patients, we used the cardio-ankle vascular index (CAVI) to reflect the arterial stiffness from the heart to the ankles. We analyzed 21 acromegalic patients, comprising five patients with untreated active acromegaly, one patient treated with medication and 15 patients who underwent transsphenoidal surgery. Among the 15 patients with surgery, 10 received additional therapies with dopamine agonists and/or somatostatin analogs. All patients with acromegaly unexpectedly showed significant reductions in the CAVI, indicating reduced arterial stiffness, compared with age- and sex-matchedcontrols, regardless of whether they underwent surgery. There was a significant negative correlation between the CAVI and the serum insulin-like growth factor (IGF)-I level in these patients. Active acromegalic patients were associated with lower CAVI than controlled patients. Sequential measurements of the CAVI and serum IGF-I before and after treatment with octreotide and transsphenoidal surgery revealed that a reduced IGF-I level after treatment was accompanied by CAVI elevation. The present findings indicate that the CAVI is negatively correlated with the serum IGF-I level in acromegaly. These findings are consistent with previous reports indicating that the GH/IGF-I axis reduces peripheral vascular resistance. This non-invasive assessment can reflect the present vascular status and would be a useful marker for evaluation of therapeutic effects in patients with acromegaly.

DOI： 10.1507/endocrj.EJ12-0189

Language：English   Publishing type：Research paper (scientific journal)  

Smad2 is a critical mediator of TGF-β signals that are known to play an important role in a wide range of biological processes in various cell types. Its role in the development of the CNS, however, is largely unknown. Mice lacking Smad2 in the CNS (Smad2-CNS-KO) were generated by a Cre-loxP approach. These mice exhibited behavioral abnormalities in motor coordination from an early postnatal stage and mortality at approximately 3 weeks of age, suggestive of severe cerebellar dysfunction. Gross observation of Smad2-CNS-KO cerebella demonstrated aberrant foliations in lobule IX and X. Further analyses revealed increased apoptotic cell death, delayed migration and maturation of granule cells, and retardation of dendritic arborization of Purkinje cells. These findings indicate that Smad2 plays a key role in cerebellar development and motor function control.

DOI： 10.1074/jbc.M111.223271

Language：Japanese  

Language：English   Publishing type：Research paper (scientific journal)  

Sonic hedgehog (SHH) signaling, acting in a combinatorial manner with androgen signaling, is essential for prostate patterning and development. Recently, elevated activation of SHH signaling has been shown to play important roles in proliferation, progression and metastasis of prostate cancer. In this report, we demonstrate for the first time, that GLI1, which has been shown to play a central role in SHH signaling in prostate cancer, can act as a co-repressor to substantially block androgen receptor (AR)-mediated transactivation, at least in part, by directly interacting with AR. Our observations suggest that the SHH-GLI pathway might be one of determinants governing the transition of prostate cancer from an. androgen-dependent to an androgen-independent state by compensating, or even superseding androgen signaling.

DOI： 10.1016/j.bbrc.2010.12.065

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1097/TP.0b013e3181fc4b55

Language：English   Publishing type：Research paper (scientific journal)  

Sonic hedgehog (SHH) signaling, acting in a combinatorial manner with androgen signaling, is essential for prostate patterning and development. Recently, elevated activation of SHH signaling has been shown to play important roles in proliferation, progression and metastasis of prostate cancer. In this report, we demonstrate for the first time, that GLI1, which has been shown to play a central role in SHH signaling in prostate cancer, can act as a co-repressor to substantially block androgen receptor (AR)-mediated transactivation, at least in part, by directly interacting with AR. Our observations suggest that the SHH-GLI pathway might be one of determinants governing the transition of prostate cancer from anandrogen-dependent to an androgen-independent state by compensating, or even superseding androgen signaling.

DOI： 10.1016/j.bbrc.2010.12.065

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1097/TP.0b013e3181fc4b55

Language：Japanese  

Language：English   Publishing type：Research paper (other academic)  

Language：Japanese  

Language：Japanese  

股関節痛を主訴とする36歳女性症例について検討した。恥骨骨折、胸椎圧迫骨折を指摘された。副腎皮質刺激ホルモン(ACTH):83.7pg/ml・コルチゾール値:30.4μg/dlで、ACTH放出ホルモン(CRH)負荷試験・バソプレッシン負荷試験に反応した。下垂体MRIでは下垂体右側に径7mm大の腫瘍を認め、クッシング病の診断で経蝶骨洞腫瘍摘出術(TSS)を行った。しかし、ACTH・コルチゾール値の改善はみられず、また、術後1ヵ月で下垂体左側に径5mm大の腫瘍を認め、2回目のTSSを行った。再手術後、ACTH:40.8pg/ml・コルチゾール値:18.6μg/dlとなり、骨粗鬆症に対してアレンドロネート製剤の投与を開始した。経過中、大きな変化はみられなかったが、再手術から3年後、副腎不全症状や倦怠感が悪化した。下垂体MRIでは下垂体左側に径3mm大の腫瘍を認めた。クッシング病の再燃と診断し、放射線治療を行った。難治性クッシング病に伴う骨粗鬆症にアレンドロネート製剤が有効であることが示された。

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コルチゾールのコントロール目的で両側副腎摘除を選択したクッシング病の2症例について検討した。症例1は46歳女性で、高コルチゾール血症が原因と考えられる精神症状・多発骨折を認めた。症例2は63歳女性で、難治性高血圧・脳血管障害を認めた。2例とも、両側副腎摘除により、臨床症状、およびQOLの劇的な改善を認めた。しかし、症例1は、術約3年後、ネルソン症候群を発症した。難治性クッシング病の症例には両側副腎摘除術も治療選択肢の1つとして考慮することが必要だと考えられた。また、術後、ネルソン症候群の発症に十分に留意した経過観察を行う必要があると思われた。

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A 62-year-old man presented with clinical signs of acute abdominal pain and adrenal insufficiency. Computerized tomographic scans revealed bilateral adrenal tumors and the left adrenal tumor was surgically resected. The patient was found to have retroperitoneal mesothelioma presenting as bilateral metastatic adrenal tumors, which were well controlled by systemic chemotherapy with CDDP and 5-FU. This case appears to be the first reported case in the literature of adrenal failure due to bilateral adrenal infiltration caused by retroperitoneal malignant mesothelioma.

DOI： 10.2169/internalmedicine.48.2438

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58歳男性。患者は腹痛および嘔吐を主訴に近医を受診、腹部CTにて両側副腎腫大を指摘され、精査目的で著者らの施設へ紹介となった。所見では抗核抗体陽性、抗Sm抗体陽性、関節痛、胸膜炎が認められ、更にループスアンチコアグラント陽性で、全身性エリテマトーデス(SLE)および抗リン脂質抗体症候群(APS)と診断された。また、腹部CT所見、内分泌学的検査所見より、両側副腎梗塞後出血による急性副腎機能不全を来したものと診断された。以上、これらのことより、SLEに対してはプレドニゾロンの投与を行い、APSおよび心房細動による血栓傾向に対してはワーファリンの内服を開始した。その結果、関節痛ならびに胸膜炎所見、副腎不全の症状は改善し、両側副腎腫大も縮小傾向を認めた。

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DOI： 10.2169/naika.96.994

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MEN type I presenting hypokalemia and hypertension, complicated with acromegaly, adrenal cortical tumor and rectal carcinoid tumor

DOI： 10.2169/naika.95.2298

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.2169/naika.95.2298

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A case of mediastinal pancreatic pseudocysts conservatively treated with somatostatin analogue

DOI： 10.11405/nisshoshi1964.100.713

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67歳男性.糖尿病歴なし.腎癌肺転移に対しニボルマブとイピリムマブ併用療法開始し14日後に免疫関連副作用(immune-related Adverse Events:irAE)による破壊性甲状腺炎を発症し,65日後に糖尿病性ケトアシドーシスを発症し,救急搬送後の随時血糖1234mg/dL,HbA1c 9.1%,グルカゴン負荷後の血中CPR測定感度未満,膵島関連自己抗体は陰性であり,またヒト白血球抗原(HLA)検査でDRB1*04:05-DQB1*04:01のヘテロ接合を認めた.本症例を含めたirAEでの1型糖尿病発症自験例4例を比較したところ,全症例において日本人における1型糖尿病発症との関連が示されているDRB1*0405もしくはDRB1*0901のHLAハプロタイプを示し,抗PD-1抗体と抗CTLA-4抗体併用療法では抗PD-1抗体単独治療と比較し発症までの期間は明らかに短縮していた.(著者抄録)

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術後再発を認めたSilent subtype 3 pituitary adenomaが疑われた下垂体腺腫の一例

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原発性アルドステロン症の機能確認検査を用いた片側性病変の診断に関する多施設共同研究(WAVES-J)

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骨粗鬆症の早期診断法を開発するため、骨量正常にもかかわらず脆弱性骨折を引き起こす骨質劣化型骨粗鬆症に着目し、副腎由来ホルモンにおける骨粗鬆症への病態生理学的意義を検討した。副腎由来ホルモン過剰モデルであるヒト副腎腫瘍を対象とした観察研究、健常人を対象としたゲノムワイド関連研究を用いたメンデルランダム化研究、健常人の血液検体を対象とした網羅的ステロイドミクス解析を行った。その結果、副腎由来ホルモンは骨質制御に重要な役割を担っていることが明らかになった。さらに、生理的濃度の副腎由来ホルモンの変動も骨粗鬆症の進展に影響すること、健常人において副腎由来ホルモンに個人差を認めることも明らかになった。副腎由来ホルモンは有用な骨質サロゲート指標になり得ると考えられた。

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MEN type I presenting hypokalemia and hypertension, complicated with acromegaly, adrenal cortical tumor and rectal carcinoid tumor

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20歳女性。患者は体重増加、多毛、赤色皮膚線条、創傷治癒遅延、月経不順を主訴に、精査目的で著者らの施設へ入院となった。所見では高血圧、中心性肥満、満月様顔貌、四肢の浮腫がみられ、更に左乳腺に小指頭大結節、および一般検査で耐糖能障害を認めた。一方、内分泌検査では尿中17-OHCS、尿中遊離コルチゾールの高値、血漿ACTH低値、血中コルチゾール高値を認め、血中コルチゾールは日内変動の消失とデキサメタゾンに対する抑制の欠如を認めた。また、腹部CTでは両側副腎に結節が確認された。以上、これらのことより、本症例は両副腎腫瘍によるクッシング症候群と診断され、二期的に両側副腎摘出を施行したところ、病理組織学的にはPPNADで、術後はクッシング徴候や上記症状の改善を認めた。尚、乳房超音波では左乳腺C領域に低エコー結節が認められ、細胞診により乳腺線維腫であった。

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当院では肥満外科手術(腹腔鏡下スリーブ胃切除術)における理学療法介入として、入院中は術前運動機能評価と退院前運動・生活指導を行い、退院後の外来では運動機能評価と運動・生活指導を行っている。今回、2016年5月～2018年3月に肥満外科手術を受けた高度肥満患者20例を対象とし、術前と術後1年時における「握力」「膝伸展筋力」「体重比膝伸展筋力」「10m歩行時間」「BMI」「SMI」の変化について調査した。「握力」は平均12%低下し、「膝伸展筋力」は6%低下していたが、「体重比膝伸展筋力」は28%向上していた。「10m歩行時間」は7%短縮し、「BMI」は26%低下、「SMI」は12%低下しており、「膝伸展筋力」を除く全ての項目で有意差が認められた。「膝伸展筋力」が向上した群(8例)と低下した群(12例)に分けて検討した結果、向上群のみ「10m歩行時間」が有意に短縮していた。

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副腎皮質腫瘍を対象として、液体クロマトグラフィータンデム質量分析(LC/MS/MS)によるメタボロミクスを基盤とした腫瘍組織の統合解析から、副腎皮質腫瘍における代謝特性の多様性の成因を明らかにすることを目的とした。アルドステロン産生腫瘍、顕性コルチゾール産生腫瘍、不顕性コルチゾール産生腫瘍、非副腎皮質腫瘍を対象として、LC/MS/MSを用いて組織中のアルドステロン、コルチゾールの定量を行った。アルドステロンについては、アルドステロン産生腫瘍においてのみ有意な上昇がみられたが、コルチゾールにおいては、興味深いことにアルドステロン産生腫瘍は不顕性コルチゾール産生腫瘍と同定度のコルチゾール過剰分泌がみられた。アルドステロン産生腫瘍における、腫瘍内コルチゾール合成の局在を評価する目的で、代謝産物の可視化法として、最新技術であるイメージング質量顕微鏡を用いた解析を行った。免疫組織学染色のコルチゾール合成酵素(CYP11B1)の局在と一致して、コルチゾール合成が腫瘍内で均一的に行われることを同定した。アルドステロン産生腫瘍およびコルチゾール分泌が緩徐である、不顕性コルチゾール産生腫瘍を対象として、RNA-seqを施行した。315遺伝子に発現変動が確認され、予想通りAPAにおいてアルドステロン合成に関連するパスウェイがエンリッチされた。一方で、steroid metabolic processパスウェイ(27遺伝子)もエンリッチされていたが、コルチゾール合成に関連する遺伝子発現は両腫瘍において差異は検出されなかった。

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Publisher：PloS one  

[This corrects the article DOI: 10.1371/journal.pone.0296006.].

DOI： 10.1371/journal.pone.0303862

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J-GLOBAL

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

67歳男性.糖尿病歴なし.腎癌肺転移に対しニボルマブとイピリムマブ併用療法開始し14日後に免疫関連副作用(immune-related Adverse Events:irAE)による破壊性甲状腺炎を発症し,65日後に糖尿病性ケトアシドーシスを発症し,救急搬送後の随時血糖1234mg/dL,HbA1c 9.1%,グルカゴン負荷後の血中CPR測定感度未満,膵島関連自己抗体は陰性であり,またヒト白血球抗原(HLA)検査でDRB1*04:05-DQB1*04:01のヘテロ接合を認めた.本症例を含めたirAEでの1型糖尿病発症自験例4例を比較したところ,全症例において日本人における1型糖尿病発症との関連が示されているDRB1*0405もしくはDRB1*0901のHLAハプロタイプを示し,抗PD-1抗体と抗CTLA-4抗体併用療法では抗PD-1抗体単独治療と比較し発症までの期間は明らかに短縮していた.(著者抄録)

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BACKGROUND: Diabetes is associated with an increased risk of deleterious changes in muscle mass and function or sarcopenia, leading to physical inactivity and worsening glycaemic control. Given the negative energy balance during sodium-glucose cotransporter-2 (SGLT2) inhibition, whether SGLT2 inhibitors affect skeletal muscle mass and function is a matter of concern. However, how SGLT2 inhibition affects the skeletal muscle function in patients with diabetes remains insufficiently explored. We aimed to explore the effects of canagliflozin (CANA), an SGLT2 inhibitor, on skeletal muscles in genetically diabetic db/db mice focusing on the differential responses of oxidative and glycolytic muscles. METHODS: Db/db mice were treated with CANA for 4 weeks. We measured running distance and handgrip strength to assess skeletal muscle function during CANA treatment. At the end of the experiment, we performed a targeted metabolome analysis of the skeletal muscles. RESULTS: CANA treatment improved the reduced endurance capacity, as revealed by running distance in db/db mice (414.9 ± 52.8 vs. 88.7 ± 22.7 m, P < 0.05). Targeted metabolome analysis revealed that 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranosyl 5'-monophosphate (AICARP), a naturally occurring AMP-activated protein kinase (AMPK) activator, increased in the oxidative soleus muscle (P < 0.05), but not in the glycolytic extensor digitorum longus muscle (P = 0.4376), with increased levels of AMPK phosphorylation (P < 0.01). CONCLUSIONS: This study highlights the potential role of the AICARP/AMPK pathway in oxidative rather than glycolytic skeletal muscles during SGLT2 inhibition, providing novel insights into the mechanism by which SGLT2 inhibitors improve endurance capacity in patients with type 2 diabetes.

DOI： 10.1002/jcsm.13350

Language：Japanese   Publisher：(一社)日本肥満学会  

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