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Papers - Ito, Hiroshi

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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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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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Pancreas Fat and beta Cell Mass in Humans With and Without Diabetes: An Analysis in the Japanese Population

Murakami, R., Saisho, Y., Watanabe, Y., Inaishi, J., Tsuchiya, T., Kou, K., Sato, S., Kitago, M., Kitagawa, Y., Yamada, T. and Itoh, H.

J Clin Endocrinol Metab 102 ( 9 ) 3251 - 3260 2017.09

ISSN 0021-972

Context: The mechanisms by which beta cell mass is reduced in patients with type 2 diabetes remain unclear. It has been postulated that ectopic fat deposits in the pancreas induce beta cell apoptosis, leading to the development of diabetes. Objective: The aim of this study was to clarify the effects of intrapancreatic fat on beta and alpha cell mass in humans with and without diabetes. Design and Subjects: Using our tissue database, pancreas sections of 72 Japanese nondiabetic (NDM) autopsy cases and 50 diabetic and 49 age- and body mass index (BMI)-matched NDM patients who underwent pancreatic surgery were analyzed. In addition to histological grading, intrapancreatic fat area (IPFA) was quantified as fractional intralobular, but not interlobular, fat area to the whole pancreas area. Results: Although IPFA was positively correlated with age and BMI, there was no significant difference in IPFA between cases with and without diabetes. Moreover, no association was found between IPFA and either beta or alpha cell area, or glycated hemoglobin. Conclusion: These findings suggest that pancreatic fat deposits have little effect on beta cell mass and the development of diabetes in humans.

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GLP-1 receptor agonist, liraglutide, ameliorates hepatosteatosis induced by anti-CD3 antibody in female mice

Itoh, A., Irie, J., Tagawa, H., Kusumoto, Y., Kato, M., Kobayashi, N., Tanaka, K., Kikuchi, R., Fujita, M., Nakajima, Y., Wu, Y., Yamada, S., Kawai, T., Ridgway, W. M. and Itoh, H.

J Diabetes Complications 31 ( 9 ) 1370 - 1375 2017.09

ISSN 1056-8727

AIMS: Hepatosteatosis is mainly induced by obesity and metabolic disorders, but various medications also induce hepatosteatosis. The administration of anti-CD3 antibody was shown to induce hepatosteatosis, but changes in lipid and glucose metabolism remain unclear. We investigated the mechanism of hepatosteatosis induced by anti-CD3 antibody and the effects of glucagon-like peptide-1 (GLP-1) receptor agonist that was recently shown to affect immune function in metabolic disorders. METHODS: Anti-CD3 antibody was administered to female BALB/c and C.B-17-scid mice with or without reconstitution by naive CD4-positive splenocytes. Hepatic lipid content, serum lipid profile and glucose tolerance were evaluated. Splenic CD4-positive T lymphocytes were stimulated with the GLP-1R agonist, liraglutide, and cytokine production was measured. The effect of liraglutide on metabolic parameters in vivo was investigated in a T-cell activation-induced hepatosteatosis model. RESULTS: The administration of anti-CD3 antibody induced hepatosteatosis, hyperlipidemia, and glucose intolerance. C.B-17-scid mice reconstituted with CD4-positive T lymphocytes developed hepatosteatosis induced by anti-CD3 antibody. Liraglutide suppressed CD4-positive T lymphocyte cytokine expression in vitro and in vivo, and improved hepatosteatosis, glucose tolerance, and insulin sensitivity. CONCLUSIONS: Liraglutide suppressed the activation of CD4-positive T lymphocytes, and improved hepatosteatosis and metabolic disorders induced by T-cell activation in female mice.

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Intranasal vaccination against angiotensin II type 1 receptor and pneumococcal surface protein A attenuates hypertension and pneumococcal infection in rodents

Azegami, T., Yuki, Y., Hayashi, K., Hishikawa, A., Sawada, S. I., Ishige, K., Akiyoshi, K., Kiyono, H. and Itoh, H.

J Hypertens (Journal of Hypertension) 36 ( 2 ) 387 - 394 2017.08

ISSN 0263-6352

OBJECTIVES: To combat global increases in the prevalence of lifestyle-related diseases and concomitant infectious diseases, we aimed to develop an innovative intranasal vaccine that simultaneously targets both hypertension and pneumonia, is not given by invasive injection, and offers prolonged therapeutic effect and reduced frequency of administration. METHODS: Angiotensin II type 1 receptor-pneumococcal surface protein A (AT1R-PspA) vaccine, consisting of a cationic nanometer-sized hydrogel incorporating AT1R partial peptide conjugated with PspA and cyclic diguanylate monophosphate adjuvant, was created and given intranasally to spontaneously hypertensive rats (SHRs). Antigen-specific antibodies and blood pressure were examined to evaluate immune responses and the antihypertensive effect of the vaccine. To examine the protective effect of antibodies induced by vaccination on pneumococcal infection, sera obtained from immunized SHRs were incubated with a lethal dose of Streptococcus pneumoniae and then administered to mice. RESULTS: Five doses of AT1R-PspA nasal-vaccine-induced AT1R-specific serum IgG antibody production and attenuated the development of hypertension in SHRs in the long term. Both in-vitro and in-vivo studies revealed that responses to angiotensin II were suppressed in vaccinated rats. Mice passively immunized with sera obtained from AT1R-PspA-vaccinated SHRs were protected from lethal pneumococcal infection. CONCLUSION: Intranasal immunization with AT1R-PspA vaccine has the potential to simultaneously attenuate the development of hypertension and protect from lethal pneumococcal infection.

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Investigation of Metabolic Factors Associated with eGFR Decline Over 1 Year in a Japanese Population without CKD

Hayashi, K., Takayama, M., Abe, T., Kanda, T., Hirose, H., Shimizu-Hirota, R., Shiomi, E., Iwao, Y. and Itoh, H.

J Atheroscler Thromb 24 ( 8 ) 863 - 875 2017.08

ISSN 1340-3478

AIM: Early intervention before the progression of chronic kidney disease (CKD) is essential to prevent end-stage renal disease (ESRD) and cardiovascular complications. This study evaluated the correlation between metabolic and lifestyle-related factors and the decline of estimated glomerular filtration rate (eGFR) over 1 year in a Japanese population without CKD. METHODS: Subjects who received two consecutive annual health checkups from 2013 to 2015 were involved. Factors associated with eGFR decline were identified using multiple regression models. RESULTS: A total of 2531 subjects aged 58.9+/-11.7 years old were included in this study. Baseline levels of HDL-C and ApoA1 correlated with the eGFR decline over 1 year defined as eGFR reduction rate of 15% or more and/or eGFR at the next year 60 ml/min/m2 (odds ratio (OR) 0.87 (per 10 mg/dl); 95% CI, 0.80-0.94; p=0.0012, 0.90 (per 10 mg/dl); 0.86-0.96; p=0.0004, respectively). A U-shaped relationship between the eGFR decline and HDL-C or ApoA1 levels was not observed in non-CKD population of this study. Metabolic syndrome was significantly associated with eGFR decline (OR 1.32; 1.04-1.67; p=0.0205), although obesity-related factors did not show a significant correlation with eGFR decline over 1 year. CONCLUSION: Low HDL-C and ApoA1 levels significantly correlated with eGFR decline in a short period of 1 year. Metabolic syndrome also showed a significant association with eGFR decline. This study suggests the importance of hypertension and low HDL-C in the metabolic syndrome effect on eGFR decline rather than obesity in non-CKD population.

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Association of Kidney Dysfunction With Asymptomatic Cerebrovascular Abnormalities in a Japanese Population With Health Checkups

Hayashi, K., Takayama, M., Kanda, T., Kashiwagi, K., Hishikawa, A., Iwao, Y. and Itoh, H.

Circ J 81 ( 8 ) 1191 - 1197 2017.07

ISSN 1346-9843

BACKGROUND: Cerebrovascular disease is a major cause of mortality and morbidity. Chronic kidney disease (CKD) is prevalent in stroke patients. This study evaluated the correlation between kidney dysfunction and asymptomatic findings on carotid ultrasonography (US) and brain magnetic resonance imaging (MRI) in a Japanese population with health checkups.Methods and Results:In total, 1,716 subjects aged 40-80 years, who received health checkups from January 1 to December 31, 2015, were included. Common carotid artery intima-media thickness (CCA-IMT) and carotid plaques by US, and the presence of old non-lacunar infarctions, lacunar infarctions, white matter lesions (WMLs), cerebral microbleeds (CMBs), and atrophy by brain MRI were evaluated. After adjusting for cardiovascular risk factors, multiple regression analyses revealed that an eGFR ranging from 15 to 44 mL/min/1.73 m2was independently associated with CCA plaques and hypoechoic or heterogeneous plaques. Proteinuria was associated with CCA or internal carotid artery plaques, the number of carotid plaques, and the presence of old non-lacunar infarctions and CMBs. CONCLUSIONS: Decreased eGFR and proteinuria were independent risk factors for asymptomatic abnormalities on carotid US and brain MRI, which are surrogate markers for cerebrovascular diseases. Evaluation of these abnormalities may be useful for prevention of symptomatic cerebrovascular events in CKD patients.

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Treatment of sarcopenia and glucose intolerance through mitochondrial activation by 5-aminolevulinic acid

Fujii, C., Miyashita, K., Mitsuishi, M., Sato, M., Fujii, K., Inoue, H., Hagiwara, A., Endo, S., Uto, A., Ryuzaki, M., Nakajima, M., Tanaka, T., Tamaki, M., Muraki, A., Kawai, T. and Itoh, H.

Sci Rep 7 ( 1 ) 4013 2017.06

ISSN 2045-2322

Recently, sarcopenia has attracted attention as therapeutic target because it constitutes a risk factor for metabolic and cardiovascular diseases. We focused 5-aminolevulinic acid (ALA) which act as electron carriers in the mitochondrial electron transport system. The mice that received ALA for 8 weeks gained muscle strength and endurance, and exhibited increased muscle mass and mitochondrial amount. Administration of ALA to sarcopenia mice aged 100 weeks and chronic kidney disease (CKD) model mice also increased muscle mass and improved physical performance. Metabolome analysis revealed increased branched-chain amino acids (BCAAs) levels in the skeletal muscle of ALA-treated mice. Quantitative PCR analysis revealed decreased expression levels in branched-chain amino acid transaminases (BCATs) that degrade BCAAs and other muscle-degrading factors, and increased levels of mitochondria-activating factors. We also studied in cultured myocytes and obtained compatible results. ALA-treated mice tended to increase body weight, but reduced blood glucose level. These suggested that ALA treatment not only activated muscle mitochondria but also enhanced muscle mass through an increase in BCAAs contents, as to improve muscle strength, endurance and glucose tolerance in mice. In these ways, muscle mitochondrial activation with ALA is suggested to be useful for the treatment of sarcopenia and glucose intolerance.

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