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Papers - ITOH Hiroshi

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The Impact of Laparoscopic Sleeve Gastrectomy with Duodenojejunal Bypass on Intestinal Microbiota Differs from that of Laparoscopic Sleeve Gastrectomy in Japanese Patients with Obesity

Kikuchi R., Irie J., Yamada-Goto N., Kikkawa E., Seki Y., Kasama K., Itoh H.

Clinical Drug Investigation (Clinical Drug Investigation) 38 ( 6 ) 545 - 552 2018.06

ISSN 11732563

© 2018, Springer International Publishing AG, part of Springer Nature. Background and Objectives: Bariatric surgery improves metabolic diseases and alters the intestinal microbiota in animals and humans, but different procedures reportedly have different impacts on the intestinal microbiota. We developed laparoscopic sleeve gastrectomy with duodenojejunal bypass (LSG-DJB) as an alternative to laparoscopic Roux-en-Y gastric bypass (LRYGB) in addition to laparoscopic sleeve gastrectomy (LSG) for Japanese patients with obesity. We investigated the precise change in the intestinal microbiota induced by these procedures in the present study. Methods: A prospective observational study of 44 Japanese patients with obesity was conducted [22 patients underwent LSG, 18 underwent LSG-DJB, and 4 underwent laparoscopic adjustable gastric banding (LAGB)]. The patients’ clinical parameters and intestinal microbiota were investigated before and for 6 months after surgery. The microbiota was analyzed by a 16S rDNA method. Results: LSG and LSG-DJB significantly improved the metabolic disorders in the patients with obesity. The proportion of the phylum Bacteroidetes and order Lactobacillales increased significantly in the LSG group, and that of the order Enterobacteriales increased significantly in the LSG-DJB group. Conclusions: LSG and LSG-DJB improved obesity and type 2 diabetes in Japanese patients with obesity, but the impact of LSG-DJB on the intestinal microbiota differed from that of LSG. This difference in the impact on the intestinal environment could explain the different efficacies of LSG and LSG-DJB in terms of their ability to resolve metabolic disorders in the clinical setting.

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Intensive treat-to-target statin therapy in high-risk Japanese patients with hypercholesterolemia and diabetic retinopathy: Report of a randomized study

Itoh H., Komuro I., Takeuchi M., Akasaka T., Daida H., Egashira Y., Fujita H., Higaki J., Hirata K., Ishibashi S., Isshiki T., Ito S., Kashiwagi A., Kato S., Kitagawa K., Kitakaze M., Kitazono T., Kurabayashi M., Miyauchi K., Murakami T., Murohara T., Node K., Ogawa S., Saito Y., Seino Y., Shigeeda T., Shindo S., Sugawara M., Sugiyama S., Terauchi Y., Tsutsui H., Ueshima K., Utsunomiya K., Yamagishi M., Yamazaki T., Yo S., Yokote K., Yoshida K., Yoshimura M., Yoshimura N., Nakao K., Nagai R.

Diabetes Care (Diabetes Care) 41 ( 6 ) 1275 - 1284 2018.06

ISSN 01495992

© 2018 by the American Diabetes Association. OBJECTIVE Diabetes is associated with high risk of cardiovascular (CV) events, particularly in patients with dyslipidemia and diabetic complications. We investigated the incidence of CV events with intensive or standard lipid-lowering therapy in patients with hypercholesterolemia, diabetic retinopathy, and no history of coronary artery disease (treat-to-target approach). RESEARCH DESIGN AND METHODS In this multicenter, prospective, randomized, open-label, blinded end point study, eligible patients were randomly assigned (1:1) to intensive statin therapy targeting LDL cholesterol (LDL-C) <70 mg/dL (n = 2,518) or standard statin therapy targeting LDL-C 100-120 mg/dL (n = 2,524). RESULTS Mean follow-up was 37± 13months. LDL-C at 36 months was 76.5± 21.6mg/dL in the intensive group and 104.1 ± 22.1 mg/dL in the standard group (P < 0.001). The primary end point events occurred in 129 intensive group patients and 153 standard group patients (hazard ratio [HR] 0.84 [95% CI 0.67-1.07]; P = 0.15). The relationship between the LDL-C difference in the two groups and the event reduction rate was consistent with primary prevention studies in patients with diabetes. Exploratory findings showed significantly fewer cerebral events in the intensive group (HR 0.52 [95% CI 0.31-0.88]; P = 0.01). Safety did not differ significantly between the two groups. CONCLUSIONS We found no significant decrease in CV events or CV-associated deaths with intensive therapy, possibly because our between-group difference of LDL-C was lower than expected (27.7 mg/dL at 36 months of treatment). The potential benefit of achieving LDL-C <70 mg/dL in a treat-to-target strategy in high-risk patients deserves further investigation.

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Nanogel-based nasal vaccines for infectious and lifestyle-related diseases

Azegami T., Yuki Y., Nakahashi R., Itoh H., Kiyono H.

Molecular Immunology (Molecular Immunology) 98 19 - 24 2018.06

ISSN 01615890

© 2017 Because the mucosa is the major entry route for most pathogens, the development of mucosal vaccines is a rational approach for protecting against these undesired agents. Mucosal administration of vaccine antigen is useful for non-infectious chronic diseases as well, because of its advantages over injection routes, including comparable efficacy in the induction of systemic immune responses, less pain, and no risk of adverse events at the injection site. However, because it is difficult to effectively induce and regulate antigen-specific mucosal and systemic immune responses when antigen alone is mucosally administered, an appropriate form of mucosal delivery vehicle must be used. Antigen delivery systems involving nanogels, which act as artificial chaperones and mucosal adhesives, are a promising approach to overcoming this problem. Here, we introduce current perspectives regarding the development of nanogel-based nasal vaccines for both infectious and lifestyle-related diseases.

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2型糖尿病患者において低ビリルビン血症は網膜症と大血管障害の高い合併率と関連する

田中正巳, 西村健志, 目黒周, 入江潤一郎, 税所芳文, 三石正憲, 川野義長, 伊藤裕

日本内分泌学会雑誌 ((一社)日本内分泌学会) 94 ( Suppl.Update ) 69 - 71 2018.06

Accepted, ISSN 0029-0661

2型糖尿病644名を対象に、血清ビリルビン濃度、糖尿病性網膜症、大血管障害(脳卒中、虚血性心疾患、末梢動脈性疾患)の関連について検討した。網膜症の合併は42%、大血管障害の合併は34%にみられ、非合併例と比較して網膜症合併例では大血管障害の合併率が有意に高く、網膜症合併症例、大血管障害合併例では総ビリルビン濃度が有意に低かった。また、ロジスティック回帰分析では網膜症合併が大血管障害のリスク因子である可能性、低ビリルビン血症が網膜症、大血管障害の共通したリスク因子である可能性が示唆された。2型糖尿病患者において低ビリルビン血症は細小血管障害、大血管障害を有する患者を発見するためのバイオマーカーとして有用である可能性があること、ビリルビンは網膜症と大血管障害の両者に対して保護的な作用を発揮している可能性があることが示された。

Serum total bilirubin concentration in patients with type 2 diabetes as a possible biomarker of polyvascular disease

Nishimura T., Tanaka M., Sekioka R., Itoh H.

Diabetology International (Diabetology International) 9 ( 2 ) 129 - 135 2018.05

ISSN 21901678

© 2017, The Japan Diabetes Society. Aims: The aim of this study was to investigate the association between serum total bilirubin concentration and complicated macrovascular diseases, such as cerebrovascular disease (CBVD), cardiovascular disease (CAD), and peripheral arterial disease (PAD), in patients with type 2 diabetes. Methods: We performed a retrospective cross-sectional study in 674 patients with type 2 diabetes. Serum total bilirubin concentration was compared between patients with and without CBVD, CAD, and PAD. Logistic regression analyses were performed to identify risk factors for CBVD, CAD, and PAD. Associations between total bilirubin concentration and the number of complicated macrovascular diseases were analyzed. Results: Patients with CBVD and PAD showed significantly lower serum total bilirubin concentrations than did those patients without those diseases. However, the bilirubin concentration did not differ between patients with and without CAD. Total bilirubin concentration was an independent predictor of CBVD, but not of CAD or PAD. There was a statistically significant trend for a decrease in bilirubin concentration in the presence of an increasing number of macrovascular diseases. Conclusion: The presence of more than one macrovascular disease, called polyvascular disease, carries a high risk for cardiovascular mortality. Serum total bilirubin concentration may be useful as a clinical biomarker of polyvascular disease.

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Accuracy of adrenal computed tomography in predicting the unilateral subtype in young patients with hypokalaemia and elevation of aldosterone in primary aldosteronism

Umakoshi H., Ogasawara T., Takeda Y., Kurihara I., Itoh H., Katabami T., Ichijo T., Wada N., Shibayama Y., Yoshimoto T., Ogawa Y., Kawashima J., Sone M., Inagaki N., Takahashi K., Watanabe M., Matsuda Y., Kobayashi H., Shibata H., Kamemura K., Otsuki M., Fujii Y., Yamamto K., Ogo A., Yanase T., Okamura S., Miyauchi S., Suzuki T., Tsuiki M., Naruse M.

Clinical Endocrinology (Clinical Endocrinology) 88 ( 5 ) 645 - 651 2018.05

ISSN 03000664

© 2018 John Wiley & Sons Ltd Context: The current Endocrine Society Guideline suggests that patients aged <35 years with marked primary aldosteronism (PA) and unilateral adrenal lesions on adrenal computed tomography (CT) scan may not need adrenal vein sampling (AVS) before proceeding to unilateral adrenalectomy. This suggestion is, however, based on the data from only one report in the literature. Objective: We sought to determine the accuracy of CT findings in young PA patients who had unilateral adrenal disease on CT with hypokalaemia and elevation of aldosterone. Design and patients: We retrospectively studied 358 PA patients (n = 30, aged <35 years; n = 39, aged 35-40 years; n = 289, aged ≥40 years) with hypokalaemia and elevation of aldosterone and unilateral disease on CT who had successful AVS. Main outcome measure: Accuracy of CT findings is determined by AVS findings and/or surgical outcomes in patients aged <35 years. Results: Concordance of the diagnosis between CT and AVS was 90% (27/30) in patients aged <35 years, 79% (31/39) in patients aged 35-40 years and 69% (198/289) in those aged ≥40 years (trend for P <.01). Surgical benefit was confirmed in three patients aged <35 years and in three patients aged 35-40 years with the available surgical data who had discordance between CT and AVS findings. Collectively, the diagnostic accuracy of CT findings was 100% (30/30) if aged <35 years and 87% (34/39) if aged 35-40 years. Conclusion: Primary aldosteronism patients aged <35 years with hypokalaemia and elevation of aldosterone and unilateral disease on adrenal CT could be spared AVS.

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Aldosterone and Insulin Resistance: Vicious Combination in Patients on Maintenance Hemodialysis

Wakino S., Minakuchi H., Miya K., Takamatsu N., Tada H., Tani E., Inamoto H., Minakuchi J., Kawashima S., Itoh H.

Therapeutic Apheresis and Dialysis (Therapeutic Apheresis and Dialysis) 22 ( 2 ) 142 - 151 2018.04

ISSN 17449979

© 2017 International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy Recently, we demonstrated that plasma aldosterone contributed to insulin resistance in chronic kidney disease. The aim of this study is the clinical impact of this relationship in hemodialysis patients. In a cross section study using a total of 128 hemodialysis patients, multiple regression analysis revealed that plasma aldosterone levels were independently associated with HOMA-IR, insulin resistance index. This association was found to be more stringent in diabetic patients than in non-diabetic patients. Aldosterone levels were associated with cardiac hypertrophy and carotid artery stenosis. HOMA-IR was associated with cardiac hypertrophy. The patients whose aldosterone and HOMA-IR were above the top tertile of each parameter in this cohort showed more severe cardiac hypertrophy and lower contractile function as compared with the patients whose aldosterone levels and HOMA-IR are below the lowest tertile of each parameter. In conclusion, in hemodialysis patients, aldosterone levels and insulin resistance are closely interrelated and the constellation of the two is related to severe cardiovascular tissue damages.

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Barley β-glucan improves metabolic condition via short-chain fatty acids produced by gut microbial fermentation in high fat diet fed mice

Miyamoto J., Watanabe K., Taira S., Kasubuchi M., Li X., Irie J., Itoh H., Kimura I.

PLoS ONE (PLoS ONE) 13 ( 4 ) 2018.04

© 2018 Miyamoto 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. Dietary intake of barley β-glucan (BG) is known to affect energy metabolism. However, its underlying mechanism remains poorly understood because studies have presented inconsistent results, with both positive and negative effects reported in terms of satiety, energy intake, weight loss, and glycemic control. The objective of this study was to clarify the physiological role underlying the metabolic benefits of barley BG using a mouse model of high fat diet (HFD)-induced obesity. Male 4-wk-old C57BL/6J mice were fed an HFD with 20% barley flour containing either high BG (HBG; 2% BG) or low BG (LBG; 0.6% BG) levels under conventional and germ-free (GF) conditions for 12 wks. In addition, mice were fed either an HFD with 5% cellulose (HFC; high fiber cellulose) or 5% barley BG (HFB; high fiber β-glucan) for 12 wks. Then, metabolic parameters, gut microbial compositions, and the production of fecal short-chain fatty acids (SCFAs) were analyzed. The weight gain and fat mass of HBG-fed mice were lower than those of control mice at 16-wk-old. Moreover, the secretion of the gut hormones PYY and GLP-1 increased in HBG-fed mice, thereby reducing food intake and improving insulin sensitivity by changing the gut microbiota and increasing SCFAs (especially, butyrate) under conventional condition. These effects in HBG-fed mice were abolished under GF conditions. Moreover, the HFB diets also increased PYY and GLP-1 secretion, and decreased food intake compared with that in HFC-fed mice. These results suggest that the beneficial metabolic effects of barley BG are primary due to the suppression of appetite and improvement of insulin sensitivity, which are induced by gut hormone secretion promoted via gut microbiota-produced SCFAs.

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Non-tuberculous mycobacterial infections related to peritoneal dialysis

Inoue H., Washida N., Morimoto K., Shinozuka K., Kasai T., Uchiyama K., Tokuyama H., Wakino S., Itoh H.

Peritoneal Dialysis International (Peritoneal Dialysis International) 38 ( 2 ) 147 - 149 2018.03

ISSN 08968608

© 2018 International Society for Peritoneal Dialysis. Most infections related to peritoneal dialysis (PD) are caused by common bacteria, and non-tuberculous mycobacteria are rare. The clinical characteristics and prognosis of PD patients with non-tuberculous mycobacterial infections were investigated at our hospital. Non-tuberculous mycobacteria were detected in 11 patients (exit-site infection, tunnel infection, and peritonitis in 3, 5, and 3 patients, respectively). Mycobacterium fortuitum, Mycobacterium chelonae, and Mycobacterium abscessus were identified in 4, 2, and 2 patients, respectively. Most patients with peritonitis or tunnel infection required catheter removal. During the study period (2007 – 2017), peritonitis occurred in 44 patients, including 3 patients (6.8%) with non-tuberculous mycobacterial peritonitis. When non-tuberculous mycobacterial infection occurs, multi-agent antibiotic therapy, unroofing surgery, and/or catheter replacement should be performed to prevent peritonitis.

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Association of Maternal Factors with Perinatal Complications in Pregnancies Complicated with Diabetes: A Single-Center Retrospective Analysis.

Endo S, Saisho Y, Miyakoshi K, Ochiai D, Matsumoto T, Kawano Y, Mitsuishi M, Irie J, Tanaka M, Meguro S, Tanaka M, Itoh H

Journal of clinical medicine 7 ( 1 ) 2018.01

ISSN 2077-0383

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Serum triglycerides predict first cardiovascular events in diabetic patients with hypercholesterolemia and retinopathy

Tada H., Kawashiri M., Nomura A., Yoshimura K., Itoh H., Komuro I., Yamagishi M.

European Journal of Preventive Cardiology (European Journal of Preventive Cardiology) 25 ( 17 ) 1852 - 1860 2018.01

ISSN 20474873

© The European Society of Cardiology 2018. Aims: Low-density lipoprotein cholesterol predicts cardiovascular events in patients with diabetes. However, it is uncertain whether serum triglycerides level is also associated with an occurrence of future cardiovascular events in diabetic patients. We aimed to test whether serum triglycerides is associated with first cardiovascular events in diabetic patients. Methods and results: We recruited 5042 participants with diabetes mellitus from the standard versus intEnsive statin therapy for hypercholesteroleMic Patients with diAbetic retinopaTHY (EMPATHY), multicenter, prospective, randomized, open-label, blinded-endpoint study. Median follow-up was three years. We evaluated an association of serum triglycerides with first cardiovascular events in cox-regression hazard models adjusted by age, sex, hypertension, current smoking, low-density lipoprotein cholesterol, and body mass index. Cardiovascular events were defined as (a) major adverse cardiac events including myocardial infarction, stroke, or cardiac death; and (b) cardiovascular diseases including myocardial infarction, unstable angina, ischemic stroke, or large artery disease or peripheral arterial disease. Serum triglycerides were associated with major adverse cardiac events (adjusted hazard ratio: 1.021 per 10 mg/dl; 95% confidence interval: 1.007-1.035; p=0.0025) and cardiovascular diseases (adjusted hazard ratio: 1.023 per 10 mg/dl; 95% confidence interval: 1.013-1.034; p=0.0000077). Comparing the top quintile (>185 mg/dl) with the bottom quintile (<79 mg/dl), the adjusted hazard ratio increased 1.89 (95% confidence interval: 1.03-2.80, p=0.04) for major adverse cardiac events, and 1.90 (95% confidence interval: 1.18-3.07, p=0.007) for cardiovascular diseases. There were no overall interactions of triglycerides and treatment assignment (standard/intensive statins) on both outcomes (p-trend=0.33 for major adverse cardiac events, p-trend=0.62 for cardiovascular diseases). Conclusions: Serum triglycerides were associated with first cardiovascular events among high-risk diabetes patients with hypercholesterolemia and retinopathy.

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Effectiveness of nationwide screening and lifestyle intervention for abdominal obesity and cardiometabolic risks in Japan: The metabolic syndrome and comprehensive lifestyle intervention study on nationwide database in Japan (MetS ACTION-J study)

Nakao Y., Miyamoto Y., Ueshima K., Nakao K., Nakai M., Nishimura K., Yasuno S., Hosoda K., Ogawa Y., Itoh H., Ogawa H., Kangawa K., Nakao K.

PLoS ONE (PLoS ONE) 13 ( 1 ) 2018.01

© 2018 Nakao 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 Lifestyle interventions can substantially improve obesity and cardiometabolic risks. However, evidence of long-term benefits of national intervention is sparse. We aimed to evaluate the long-term effectiveness of a nationwide program for abdominal obesity. Methods A retrospective cohort study was performed using a longitudinal nationwide individual data in subjects aged 40–74 years who underwent checkups in fiscal year (FY) 2008. Lifestyle interventions were provided via interview in subjects with abdominal obesity and at least one cardiometabolic risk factor. Subjects who attended the lifestyle intervention (participants) were compared to those who did not attend (non-participants). Outcomes were waist circumferences (WC) and body mass index (BMI) reduction, reversal of metabolic syndrome (MetS), and changes in cardiometabolic risks. We used a three-step process with robust analytic approaches to account for selection bias that included traditional multivariate analysis, propensity-score matching and instrumental variable (IV) analyses. Results Of 19,969,722 subjects, 4,370,042 were eligible for analyses; 111,779 participants and 907,909 non-participants. A higher percentage of participants had 5% reductions in obesity profiles at year 3, compared to non-participants (WC, 21.4% vs 16.1%; BMI, 17.6% vs 13.6%; p<0.001 each). Participants also had higher reversal for MetS (adjusted odds ratio 1.31; 95% confidence interval: 1.29–1.33; p<0.001). Greater reductions in cardiometabolic risks were observed in participants. Those results were confirmed in analyses using a propensity score-matched cohort (n = 75,777, each) and IV analyses. Limitations of this work include the use of non-randomized national data in Japan to assess the effectiveness of the nationwide preventive program. Conclusions In the nationwide lifestyle intervention for abdominal obesity, the at-risk population achieved significant reductions in WC, BMI, and cardiometabolic risks in 3 years. This study provides evidence that the nationwide program effectively achieved long-term improvement in abdominal obesity and cardiometabolic risks.

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Transcription factors as therapeutic targets in chronic kidney disease

Hishikawa A., Hayashi K., Itoh H.

Molecules (Molecules) 23 ( 5 ) 2018

© 2018 by the authors. The growing number of patients with chronic kidney disease (CKD) is recognized as an emerging problem worldwide. Recent studies have indicated that deregulation of transcription factors is associated with the onset or progression of kidney disease. Several clinical trials indicated that regression of CKD may be feasible via activation of the transcription factor nuclear factor erythroid-2 related factor 2 (Nrf2), which suggests that transcription factors may be potential drug targets for CKD. Agents stabilizing hypoxia-inducible factor (HIF), which may be beneficial for renal anemia and renal protection, are also now under clinical trial. Recently, we have reported that the transcription factor Kruppel-like factor 4 (KLF4) regulates the glomerular podocyte epigenome, and that the antiproteinuric effect of the renin–angiotensin system blockade may be partially mediated by KLF4. KLF4 is one of the Yamanaka factors that induces iPS cells and is reported to be involved in epigenetic remodeling. In this article, we summarize the transcription factors associated with CKD and particularly focus on the possibility of transcription factors being novel drug targets for CKD through epigenetic modulation.

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The Role of Non-Tuberculous Mycobacteria in Peritoneal Dialysis-Related Infections: A Literature Review

Washida N., Itoh H.

Contributions to Nephrology (Contributions to Nephrology) 196 155 - 161 2018

ISSN 03025144

© 2018 S. Karger AG, Basel. Background: Peritonitis is one of the most frequent reasons for withdrawal of peritoneal dialysis (PD). Although most cases of PD-related peritonitis can be treated with antibiotics, it is occasionally refractory and culture-negative. Summary: The causes of refractory PD-related peritonitis include antibiotic-resistant bacteria, fungal peritonitis, biofilm formation in PD catheters, bacterial translocation from the gastrointestinal tract, and encapsulating peritoneal sclerosis. Among them, culture-negative peritonitis is notable, and non-tuberculous mycobacteria (NTM) can be a cause of culture-negative peritonitis. In the present study, the treatment and outcomes of NTM peritonitis and exit site infections were investigated by collecting data from relevant reviews published during the last 10 years. Catheter removal was required in 92.2% of the patients with NTM peritonitis, and withdrawal of PD was performed in 91.9%. The overall mortality rate (including unrelated deaths) was 12.4% in patients with NTM peritonitis. Among patients with NTM exit site infections, 33.3% developed peritonitis, and catheter removal was required in 50.0%. A lower percentage of patients stopped PD when the catheter was removed without developing peritonitis (37.5%) than when it was removed after the onset of peritonitis (91.9%). Changing the exit site or unroofing was performed in 12.5% of the patients with NTM exit site infections. In addition, these infections resolved with antibiotics alone or without antibiotics in 18.8 and 12.5% of the patients, respectively, while 6.25% of the patients died.

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Significance of computed tomography and serum potassium in predicting subtype diagnosis of primary aldosteronism

Umakoshi H., Tsuiki M., Takeda Y., Kurihara I., Itoh H., Katabami T., Ichijo T., Wada N., Yoshimoto T., Ogawa Y., Kawashima J., Sone M., Inagaki N., Takahashi K., Watanabe M., Matsuda Y., Kobayashi H., Shibata H., Kamemura K., Otsuki M., Fujii Y., Yamamto K., Ogo A., Yanase T., Suzuki T., Naruse M., JPAS Study Group

Journal of Clinical Endocrinology and Metabolism (Journal of Clinical Endocrinology and Metabolism) 103 ( 3 ) 900 - 908 2018

ISSN 0021972X

Copyright © 2018 Endocrine Society. Context: The number of centers with established adrenal venous sampling (AVS) programs for the subtype diagnosis of primary aldosteronism (PA) is limited. Objective: Aim was to develop an algorithm for AVS based on subtype prediction by computed tomography (CT) and serum potassium. Design: A multi-institutional retrospective cohort study in Japan. Patients: A total of 1591 patients with PA were classified into four groups according to CT findings and potassium status. Subtype diagnosis of PA was determined by AVS. Main Outcome Measure: Prediction value of the combination of CT findings and potassium status for subtype diagnosis. Results: The percentages of unilateral hyperaldosteronism on AVS were higher in patients with unilateral disease on CT than those with bilateral normal results on CT (50.8% vs 14.6%, P, 0.01), and these percentages were higher in those with hypokalemia than those with normokalemia (58.4% vs 11.5%, P, 0.01). The prevalence and odds ratio for unilateral hyperaldosteronism on AVS were as follows: bilateral normal on CT with normokalemia, 6.2% (reference); unilateral disease on CT with normokalemia, 23.8% and 4.8 [95% confidence interval (CI), 3.1 to 7.2]; bilateral normal on CT with hypokalemia, 38.1% and 9.4 (95% CI, 6.2 to 14.1), and unilateral disease on CT with hypokalemia, 70.6% and 36.4 (95% CI, 24.7 to 53.5). Conclusions: Patients with PA with bilateral normal results on CT and normokalemia likely have a low prior probability of a lateralized form of AVS and could be treated medically, whereas those with unilateral disease on CT and hypokalemia have a high probability of a lateralized form of AVS.

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Prevalence of Cardiovascular Disease and Its Risk Factors in Primary Aldosteronism A Multicenter Study in Japan

Ohno Y., Sone M., Inagaki N., Yamasaki T., Ogawa O., Takeda Y., Kurihara I., Itoh H., Umakoshi H., Tsuiki M., Ichijo T., Katabami T., Tanaka Y., Wada N., Shibayama Y., Yoshimoto T., Ogawa Y., Kawashima J., Takahashi K., Fujita M., Watanabe M., Matsuda Y., Kobayashi H., Shibata H., Kamemura K., Otsuki M., Fujii Y., Yamamoto K., Ogo A., Okamura S., Miyauchi S., Fukuoka T., Izawa S., Yoneda T., Hashimoto S., Yanase T., Suzuki T., Kawamura T., Tabara Y., Matsuda F., Naruse M.

Hypertension (Hypertension) 71 ( 3 ) 530 - 537 2018

ISSN 0194911X

© 2018 American Heart Association, Inc. There have been several clinical studies examining the factors associated with cardiovascular disease (CVD) in patients with primary aldosteronism (PA); however, their results have left it unclear whether CVD is affected by the plasma aldosterone concentration or hypokalemia. We assessed the PA database established by the multicenter JPAS (Japan Primary Aldosteronism Study) and compared the prevalence of CVD among patients with PA with that among age-, sex-, and blood pressure-matched essential hypertension patients and participants with hypertension in a general population cohort. We also performed binary logistic regression analysis to determine which parameters significantly increased the odds ratio for CVD. Of the 2582 patients with PA studied, the prevalence of CVD, including stroke (cerebral infarction, cerebral hemorrhage, or subarachnoid hemorrhage), ischemic heart disease (myocardial infarction or angina pectoris), and heart failure, was 9.4% (stroke, 7.4%; ischemic heart disease, 2.1%; and heart failure, 0.6%). The prevalence of CVD, especially stroke, was higher among the patients with PA than those with essential hypertension/ hypertension. Hypokalemia (K+ ≤3.5 mEq/L) and the unilateral subtype significantly increased adjusted odds ratios for CVD. Although aldosterone levels were not linearly related to the adjusted odds ratio for CVD, patients with plasma aldosterone concentrations ≥125 pg/mL had significantly higher adjusted odds ratios for CVD than those with plasma aldosterone concentrations <125 pg/mL. Thus, patients with PA seem to be at a higher risk of developing CVD than patients with essential hypertension. Moreover, patients with PA presenting with hypokalemia, the unilateral subtype, or plasma aldosterone concentration ≥125 pg/mL are at a greater risk of CVD and have a greater need for PA-specific treatments than others.

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Lower serum total bilirubin concentration is associated with higher prevalence of gestational diabetes mellitus in Japanese pregnant women

Nishimura T., Tanaka M., Saisho Y., Miyakoshi K., Tanaka M., Itoh H.

Endocrine Journal (Endocrine Journal) 65 ( 12 ) 1199 - 1208 2018

ISSN 09188959

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

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Development and validation of subtype prediction scores for the workup of primary aldosteronism

Kobayashi H., Abe M., Soma M., Takeda Y., Kurihara I., Itoh H., Umakoshi H., Tsuiki M., Katabami T., Ichijo T., Wada N., Yoshimoto T., Ogawa Y., Kawashima J., Sone M., Inagaki N., Takahashi K., Watanabe M., Matsuda Y., Shibata H., Kamemura K., Yanase T., Otsuki M., Fujii Y., Yamamoto K., Ogo A., Nanba K., Tanabe A., Suzuki T., Naruse M.

Journal of Hypertension (Journal of Hypertension) 36 ( 11 ) 2269 - 2276 2018

ISSN 02636352

Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. Objectives: A subtype prediction score for primary aldosteronism has not yet been developed and validated using a large dataset. This study aimed to develop and validate a new subtype prediction score and to compare it with existing scores using a large multicenter database. Methods: In total, 1936 patients with primary aldosteronism were randomly assigned to the development and validation datasets, constituting 1290 and 646 patients, respectively. Three prediction scores were generated with or without confirmatory tests, using logistic regression analysis. In the validation dataset, new and existing prediction scores were compared using receiver operating characteristic curve, net reclassification improvement, and integrated discrimination improvement analyses. Results: The new prediction score is simply calculated using serum potassium levels [>3.9 mmol/l (four points); 3.5-3.9 mmol/l (three points)], the absence of adrenal nodules during computed tomography (three points), a baseline plasma aldosterone concentration of <210.0 pg/ ml (two points), a baseline aldosterone/renin ratio of less than 620 (two points), and female sex (one point). Using the validation dataset, we found that a new subtype prediction score of at least 8 had a positive predictive value of 93.5% for bilateral hyperaldosteronism. The new prediction score for bilateral hyperaldosteronism was better than the existing prediction scores in the receiver operating characteristic curve and net reclassification improvement analyses. Conclusion: The new prediction score has clear advantages over the existing prediction scores in terms of diagnostic accuracy, feasibility, and the potential for generalization in a large population. These data will help healthcare professionals to better select patients who require adrenal venous sampling.

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High Glucose Stimulates Mineralocorticoid Receptor Transcriptional Activity Through the Protein Kinase C beta Signaling

Hayashi, T., Shibata, H., Kurihara, I., Yokota, K., Mitsuishi, Y., Ohashi, K., Murai-Takeda, A., Jo, R., Ohyama, T., Sakamoto, M., Tojo, K., Tajima, N., Utsunomiya, K. and Itoh, H.

Int Heart J 2017.09

ISSN 1349-2365

Activation of mineralocorticoid receptor (MR) is shown in resistant hypertension including diabetes mellitus. Although protein kinase C (PKC) signaling is involved in the pathogenesis of diabetic complications, an association between PKC and MR is not known. Activation of PKCalpha and PKCbeta by TPA (12-O-Tetradecanoylphorbol 13-acetate) increased MR proteins and its transcriptional activities in HEK293-MR cells. In contrast, a high glucose condition resulted in PKCbeta but not PKCalpha activation, which is associated with elevation of MR protein levels and MR transcriptional activities. Reduction of endogenous PKCbeta by siRNA decreased those levels. Interestingly, high glucose did not affect MR mRNA levels, but rather decreased ubiquitination of MR proteins. In db/db mice kidneys, levels of phosphorylated PKCbeta2, MR and Sgk-1 proteins were elevated, and the administration of PKC inhibitor reversed these changes compared to db/+ mice. These data suggest that high glucose stimulates PKCbeta signaling, which leads to MR stabilization and its transcriptional activities.

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Association between severity of obstructive sleep apnea and glycated hemoglobin level in Japanese individuals with and without diabetes

Kurosawa, H., Saisho, Y., Fukunaga, K., Haraguchi, M., Yamasawa, W., Kurihara, I., Betsuyaku, T. and Itoh, H.

Endocr J 2017.09

ISSN 0918-8959

Aim of this study was to examine the association between the severity of obstructive sleep apnea (OSA) and dysglycemia in Japanese individuals with and without type 2 diabetes (T2DM). We enrolled 115 individuals diagnosed with OSA with an apnea hypopnea-index (AHI) >/= 20 in whom continuous positive airway pressure (CPAP) therapy was introduced (N = 115, 44 with T2DM, age 62 +/- 11 years, BMI 27.0 +/- 4.4 kg/m2 and AHI median 36.1; interquartile range 27.2-48.1). During admission, the severity of OSA was evaluated by polysomnography, and its association with glycated hemoglobin (HbA1c) level was examined. Continuous glucose monitoring (CGM) was also conducted during the admission in 94 individuals. Apnea-hypopnea index (AHI), non-rapid eye movement (REM) AHI, minimum peripheral capillary oxygen saturation (SpO2) and percentage of sleep time (%TST) with SpO2 < 90% were significantly associated with HbA1c level in total and non-diabetic individuals (all p < 0.05) but not in those with T2DM, the majority of whom were treated with anti-diabetic medications. The associations of the non-REM AHI and %TST with SpO2 < 90% with HbA1c level remained significant after adjustment for age, sex and BMI in non-diabetic and T2DM subjects treated with dietary therapy only. Mean glucose level, but not SD or coefficient of variation of glucose, assessed by CGM was significantly associated with AHI and non-REM AHI in non-diabetic subjects after adjustment for age, sex and BMI. In conclusion, the severity of OSA was associated with increased HbA1c level independently of BMI in Japanese individuals, especially in those without diabetes.

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