Papers - ITOH Hiroshi

NNMT activation can contribute to the development of fatty liver disease by modulating the NAD ⁺ metabolism

Komatsu M., Kanda T., Urai H., Kurokochi A., Kitahama R., Shigaki S., Ono T., Yukioka H., Hasegawa K., Tokuyama H., Kawabe H., Wakino S., Itoh H.

Scientific Reports (Scientific Reports)  8 ( 1 )  2018.12

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© 2018 The Author(s). Nicotinamide N-methyltransferase (NNMT) catalyses the reaction between nicotinamide (NAM) and S-adenosylmethionine to produce 1-methylnicotinamide and S-adenosylhomocysteine. Recently, this enzyme has also been reported to modulate hepatic nutrient metabolism, but its role in the liver has not been fully elucidated. We developed transgenic mice overexpressing NNMT to elucidate its role in hepatic nutrient metabolism. When fed a high fat diet containing NAM, a precursor for nicotinamide adenine dinucleotide (NAD)+, these NNMT-overexpressing mice exhibit fatty liver deterioration following increased expression of the genes mediating fatty acid uptake and decreased very low-density lipoprotein secretion. NNMT overactivation decreased the NAD+ content in the liver and also decreased gene activity related to fatty acid oxidation by inhibiting NAD+-dependent deacetylase Sirt3 function. Moreover, the transgenic mice showed liver fibrosis, with the induction of inflammatory and fibrosis genes. Induced NNMT expression decreased the tissue methylation capacity, thereby reducing methylation of the connective tissue growth factor (CTGF) gene promoter, resulting in increased CTGF expression. These data indicate that NNMT links the NAD+ and methionine metabolic pathways and promotes liver steatosis and fibrosis. Therefore, targeting NNMT may serve as a therapeutic strategy for treating fatty liver and fibrosis.

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High Basolateral Glucose Increases Sodium-Glucose Cotransporter 2 and Reduces Sirtuin-1 in Renal Tubules through Glucose Transporter-2 Detection

Umino H., Hasegawa K., Minakuchi H., Muraoka H., Kawaguchi T., Kanda T., Tokuyama H., Wakino S., Itoh H.

Scientific Reports (Scientific Reports)  8 ( 1 )  2018.12

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© 2018 The Author(s). Under diabetic conditions, sodium-glucose cotransporter 2 (SGLT2) for glucose uptake in proximal tubules (PTs) increases, whereas NAD+-dependent protein deacetylase silent mating type information regulation 2 homolog 1 (Sirtuin-1; SIRT1) for PT survival decreases. Therefore, we hypothesized that increased glucose influx by SGLT2 reduces SIRT1 expression. To test this hypothesis, db/db mice with diabetes and high-glucose (HG)-cultured porcine PT LLC-PK1 cells in a two-chamber system were treated with the SGLT2 inhibitor canagliflozin. We also examined SIRT1 and SGLT2 expression in human kidney biopsies. In db/db mice, SGLT2 expression increased with concomitant decreases in SIRT1, but was inhibited by canagliflozin. For determination of the polarity of SGLT2 and SIRT1 expression, LLC-PK1 cells were seeded into Transwell chambers (pore size, 0.4 μm; Becton Dickinson, Oxford, UK). HG medium was added to either or to both of the upper and lower chambers, which corresponded to the apical and basolateral sides of the cells, respectively. In this system, the lower chamber with HG showed increased SGLT2 and decreased SIRT1 expression. Canagliflozin reversed HG-induced SIRT1 downregulation. Gene silencing and inhibitors for glucose transporter 2 (GLUT2) blocked HG-induced SGLT2 expression upregulation. Gene silencing for the hepatic nuclear factor-1α (HNF-1α), whose nuclear translocation was enhanced by HG, blocked HG-induced SGLT2 expression upregulation. Similarly, gene silencing for importin-α1, a chaperone protein bound to GLUT2, blocked HG-induced HNF-1α nuclear translocation and SGLT2 expression upregulation. In human kidney, SIRT1 immunostaining was negatively correlated with SGLT2 immunostaining. Thus, under diabetic conditions, SIRT1 expression in PTs was downregulated by an increase in SGLT2 expression, which was stimulated by basolateral HG through activation of the GLUT2/importin-α1/HNF-1α pathway.

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非糖尿病慢性腎不全モデルラットへのSGLT2阻害薬投与による腸内環境の変化とその影響

松井 歩, 吉藤 歩, 入江 潤一郎, 田島 敬也, 内山 清貴, 伊藤 智章, 脇野 修, 伊藤 裕

日本内分泌学会雑誌 ((一社)日本内分泌学会)  94 ( 4 ) 1574 - 1574 2018.12

Accepted,  ISSN  0029-0661

認知症周辺症状管理で処方のリスペリドンにて高血糖高浸透圧症候群を発症した2型糖尿病の1例

宇都 飛鳥, 税所 芳史, 田中 正巳, 遠藤 翔, 入江 潤一郎, 目黒 周, 伊藤 裕

日本内分泌学会雑誌 ((一社)日本内分泌学会)  94 ( 4 ) 1584 - 1584 2018.12

Accepted,  ISSN  0029-0661

2型糖尿病患者におけるweekly DPP4阻害薬トレラグリプチンの有効性・安全性の検討

田中 正巳, 西村 健志, 目黒 周, 入江 潤一郎, 税所 芳史, 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 ( 4 ) 1577 - 1577 2018.12

Accepted,  ISSN  0029-0661

2型糖尿病患者における収縮期血圧、総ビリルビン濃度と網膜症との関連

田中 正巳, 西村 健志, 目黒 周, 入江 潤一郎, 税所 芳史, 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 ( 4 ) 1577 - 1577 2018.12

Accepted,  ISSN  0029-0661

GLP-1受容体作動薬は抗CD3抗体誘導マウス非アルコール性脂肪肝を抑制する

入江 潤一郎, 伊藤 新, 加藤 まり, 田中 久美子, 菊地 理恵子, 藤田 真隆, 中島 裕也, 山田 悟, 河合 俊英, 伊藤 裕

日本内分泌学会雑誌 ((一社)日本内分泌学会)  94 ( 4 ) 1575 - 1575 2018.12

Accepted,  ISSN  0029-0661

副腎発生の血管筋脂肪腫の一例

内藤 真規子, 栗原 勲, 宮下 和季, 小林 佐紀子, 横田 健一, 篠島 利明, 大家 基嗣, 亀山 香織, 伊藤 裕

日本内分泌学会雑誌 ((一社)日本内分泌学会)  94 ( 3 ) 858 - 858 2018.12

ISSN  0029-0661

高血圧合併2型糖尿病患者における血清アルブミン濃度と細小血管障害との関連

田中 正巳, 西村 健志, 目黒 周, 入江 潤一郎, 税所 芳史, 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 ( 4 ) 1578 - 1578 2018.12

Accepted,  ISSN  0029-0661

甲状腺中毒症発症後3年半でTRAb陽性となり、バセドウ病と診断した1例

三石 正憲, 宮下 和季, 三石 木綿子, 菊地 徹洋, 川野 義長, 税所 芳史, 入江 潤一郎, 田中 正巳, 目黒 周, 伊藤 裕

日本内分泌学会雑誌 ((一社)日本内分泌学会)  94 ( 4 ) 1583 - 1583 2018.12

Accepted,  ISSN  0029-0661

肥満糖尿病患者におけるbariatric surgeryの腸内細菌叢と代謝指標への影響

菊地 理恵子, 入江 潤一郎, 後藤 伸子, 吉川 絵梨, 関 洋介, 笠間 和典, 伊藤 裕

日本内分泌学会雑誌 ((一社)日本内分泌学会)  94 ( 4 ) 1576 - 1576 2018.12

Accepted,  ISSN  0029-0661

Penile calciphylaxis in a patient on combined peritoneal dialysis and hemodialysis

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

CEN case reports (CEN case reports)  7 ( 2 ) 204 - 207 2018.11

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Calciphylaxis presents with painful purpura and intractable skin ulcers on the trunk and particularly the distal extremities, and it mainly occurs in patients on chronic dialysis. A 66-year-old man with renal failure due to diabetic nephropathy was on peritoneal dialysis alone for 1 year, followed by peritoneal dialysis combined with hemodialysis for 3 years. He developed calciphylaxis of the penis, which was diagnosed from the skin biopsy findings and clinical observation. To treat this condition, PD was stopped and HD was performed three times a week. In addition, warfarin therapy was discontinued and infusion of sodium thiosulfate was performed. The penile ulcers decreased in size and pain was markedly improved, so the patient was discharged from hospital. Following discharge, PD was resumed after changing the peritoneal dialysis fluid to bicarbonate-buffered dialysate. The penile ulcers eventually resolved completely. There have been very few reports about calciphylaxis in patients on combined dialysis modalities. In our patient, penile calciphylaxis progressed when lactate-buffered peritoneal dialysis fluid was used and resolved after switching to bicarbonate-buffered fluid together with cessation of warfarin therapy and infusion of sodium thiosulfate.

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The impact of a remote monitoring system of healthcare resource consumption in patients on automated peritoneal dialysis (APD): A simulation study

Uchiyama K., Washida N., Yube N., Kasai T., Shinozuka K., Morimoto K., Hishikawa A., Inoue H., Urai H., Hagiwara A., Fujii K., Wakino S., Deenitchina S., Itoh H.

Clinical Nephrology (Clinical Nephrology)  90 ( 5 ) 334 - 340 2018.11

ISSN  03010430

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©2018 Dustri-Verlag Dr. K. Feistle Aims: Remote monitoring (RM) can improve management of chronic diseases. We evaluated the impact of RM in automated peritoneal dialysis (APD) in a simulation study. Materials and methods: We simulated 12 patient scenarios with common clinical problems and estimated the likely healthcare resource consumption with and without the availability of RM (RM+ and RM- groups, respectively). Scenarios were evaluated 4 times by randomly allocated nephrologist-nurse teams or nephrologist-alone assessors. Results: The RM+ group was assessed as having significantly lower total healthcare resource consumption compared with the RM- group (36.8 vs. 107.5 total episodes of resource consumption, p = 0.002). The RM+ group showed significantly lower “unplanned hospital visits” (2.3 vs. 11.3, p = 0.005), “emergency room visits” (0.5 vs. 5.3, p = 0.003), “home visits” (0.5 vs. 5.8, p = 0.016), “exchanges over the telephone” (18.5 vs. 57.8, p = 0.002), and “change to hemodialysis” (0.5 vs. 2.5, p = 0.003). Evaluations did not differ between nephrologist-nurse teams vs. nephrologist-alone assessors. Conclusion: RM can be expected to reduce healthcare resource consumption in APD patients.

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Achieving LDL-C target levels less than 70 mg/dL may provide extra cardiovascular protection in high-risk patients: exploratory analysis of the Standard Versus Intensive Statin Therapy for Patients With Hypercholesterolemia and Diabetic Retinopathy Study

Itoh H, Komuro I, Takeuchi M, Akasaka T, Daida H, Egashira Y, Fujita H, Higaki J, Hirata KI, 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, EMPATHY Investigators

Diabetes Obes Metab  2018.11

Accepted

Clinical characteristics and postoperative outcomes of primary aldosteronism in the elderly

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

Journal of Clinical Endocrinology and Metabolism (Journal of Clinical Endocrinology and Metabolism)  103 ( 10 ) 3620 - 3629 2018.10

ISSN  0021972X

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© 2018 Oxford University Press. All rights reserved. Context: Primary aldosteronism (PA) in the elderly has increased in importance in association with population aging. Objective: To investigate the characteristics and outcomes of elderly patients with PA undergoing adrenalectomy. Patients and Methods: Using a database of patients with PA who underwent adrenal venous sampling (AVS),wecompared elderly patients (65 years old)with nonelderly patients (,65 years old) in terms of characteristics, subtype classification in ACTH-stimulated AVS, and outcomes after adrenalectomy. Results: The elderly group had a higher prevalence of comorbidities than the nonelderly group. The proportion of the unilateral subtype [defined as a lateralization index (LI) .4] was comparable between the age groups. In patients who received adrenalectomy, biochemical cure was comparable between the groups, whereas persistent hypertension was more common in the elderly group. The prevalences of hyperkalemia and renal impairment (chronic kidney disease stage 3b or higher) were higher in the elderly group. Multiple regression analysis showed that the duration of hypertension predicted persistent hypertension and hyperkalemia and that preoperative estimated glomerular filtration rate predicted renal impairment in the elderly group. LI .4 in AVS was an independent predictor of biochemical cure after adrenalectomy in the elderly group but not in the nonelderly group. Age was negatively associated with biochemical cure in patients with LI #4. Conclusion: Adrenalectomy contributes to biochemical improvement in elderly patients if determined in accordance with AVS. The treatment strategy should be determined considering the high postoperative incidence of persistent hypertension and hyperkalemia in elderly patients with a long history of hypertension or renal impairment in those with reduced renal function.

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Organ memory: a key principle for understanding the pathophysiology of hypertension and other non-communicable diseases

Itoh H., Kurihara I., Miyashita K.

Hypertension Research (Hypertension Research)  41 ( 10 ) 771 - 779 2018.10

ISSN  09169636

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© 2018, The Japanese Society of Hypertension. In recent years, several post-interventional analyses of large-scale randomized controlled clinical trials have given us a new concept regarding the risk management of hypertension and cardiovascular diseases. The beneficial effects of intensive treatments were extended even after the interventions ended. This phenomenon is known as “metabolic memory” or “legacy effect”, and we recognized its clinical significance. A certain level of evidence in human and animal studies employing organ transplantation techniques has indicated that this type of “memory” resides in each organ and could be transferrable, erasable, and rewritable, which is similar to neuronal and immune “memory”. In this review, we define this memory as “organ memory” and summarize the current picture and future direction of this concept. “Organ memory” can be observed in many clinical settings, including in the control of hypertension, diabetes mellitus, and dyslipidemia. Several intensive treatments were demonstrated to have the potential to rewrite “organ memory”, leading to the curability of targeted diseases. “Organ memory” is the engraved phenotype of altered organ responsiveness acquired by a time-dependent accumulation of organ stress responses. Not only is the epigenetic change of key genes involved in the formation of “organ memory” but the alteration of multiple factors, including low molecular weight energy metabolites, immune mediators, and tissue structures, is involved as well. These factors intercommunicate during every stress response and carry out incessant remodeling in a certain direction in a spiral fashion through positive feedback mechanisms. Future studies should be directed toward the identification of the core unit of “organ memory” and its manipulation.

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Oral adsorbent AST-120 ameliorates gut environment and protects against the progression of renal impairment in CKD rats

Yoshifuji A., Wakino S., Irie J., Matsui A., Hasegawa K., Tokuyama H., Hayashi K., Itoh H.

Clinical and Experimental Nephrology (Clinical and Experimental Nephrology)  22 ( 5 ) 1069 - 1078 2018.10

ISSN  13421751

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© 2018, The Author(s). Background: Oral charcoal adsorbent AST-120 (AST) is reported to ameliorate renal dysfunction by the absorption of toxic substance in the gut. Recent study revealed that, in CKD, gut environment is disturbed including the decrease in tight junctions and Lactobacillus (Lact). In this study, we examined whether AST improves the renal dysfunction through gut environment. Method: Six-week-old spontaneously hypertensive rats (SHR) were rendered CKD by 5/6th nephrectomy (Nx). SHRs were divided into SHR (Sham), SHR with Nx (Nx), and Nx given AST (Nx + AST) (n = 10, each). After 12 weeks, rats were killed and biochemical parameters were explored. The gut flora was analyzed. Furthermore, gut molecular changes in tight junctions and toll-like receptors were examined. We also investigated the effects of the combination therapy with AST and Lact. Results: The increase in serum urea nitrogen and urinary protein excretion in Nx was restored in Nx + AST. The increased renal glomerulosclerosis in Nx was ameliorated in Nx + AST. Increases in serum uremic toxins and IL-6 in Nx were ameliorated in Nx + AST. The gut flora analysis revealed that the decrease in Lact in Nx was restored in Nx + AST. The downregulation in the tight junction and TLR2 in Nx was mitigated by AST. However, combination therapy failed to exhibit additional effects. Conclusion: AST ameliorated renal function with the restoration of Lact and tight junction through TLR pathway, which would mitigate systemic inflammation and contributed to their renoprotective effects. Our study provides a novel mechanism of the renoprotective effects by AST.

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重症低血糖を繰り返す60歳女性のSAP療法の導入 エンパワメント向上を目指して

平島 麻衣子, 芦田 真由美, 相川 加代子, 小倉 由美子, 小谷 紀子, 入江 潤一郎, 目黒 周, 伊藤 裕

糖尿病 ((一社)日本糖尿病学会)  61 ( 10 ) 718 - 718 2018.10

Accepted,  ISSN  0021-437X

がん、糖尿病の合併症 腸内細菌と糖尿病・がん

入江 潤一郎, 伊藤 裕

糖尿病合併症 ((一社)日本糖尿病合併症学会)  32 ( Suppl.1 ) 158 - 158 2018.10

Accepted

繰り返す低血糖による意識障害をSAPにより回避しえた1型糖尿病患者の1例

佐々木 裕伸, 小谷 紀子, 川野 義長, 三石 正憲, 税所 芳史, 入江 潤一郎, 目黒 周, 田中 正巳, 伊藤 裕

糖尿病 ((一社)日本糖尿病学会)  61 ( 10 ) 735 - 735 2018.10

Accepted,  ISSN  0021-437X