Updated on 2022/11/07

写真a

 
ARIMA, Hiroshi
 
Organization
Graduate School of Medicine Program in Integrated Medicine Internal Medicine Professor
Graduate School
Graduate School of Medicine
Undergraduate School
School of Medicine Department of Medicine
Title
Professor
Contact information
メールアドレス

Degree 1

  1. 博士(医学) ( 1997.11   名古屋大学 ) 

Research Interests 2

  1. water balance

  2. water balance

Research Areas 2

  1. Others / Others  / Endocrinology

  2. Others / Others

Current Research Project and SDGs 3

  1. To elucidate the pathogenesis of familial neurohypophysial diabetes insipidus

  2. energy balance

  3. 免疫チェックポイント阻害薬による内分泌障害

Research History 3

  1. Nagoya University   School of Medicine Department of Medicine

    2017.4

  2. Nagoya University   School of Medicine Department of Medicine

    2017.4

  3. Nagoya University   Graduate School of Medicine Program in Integrated Medicine Internal Medicine   Professor

    2015.8

Education 1

  1. Nagoya University   Faculty of Medicine

    1982.4 - 1988.3

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    Country: Japan

Professional Memberships 18

  1. 日本内分泌学会   理事

  2. 日本神経内分泌学会   理事

  3. 日本間脳下垂体腫瘍学会   理事

  4. 日本肥満学会   評議員

  5. 日本肥満症治療学会   評議員

  6. 日本内科学会

  7. 日本糖尿病学会

  8. 日本甲状腺学会

  9. The Eondocrine Society

  10. 日本間脳下垂体腫瘍学会

  11. 日本肥満症治療学会

  12. 日本肥満学会

  13. 日本糖尿病学会

  14. 日本甲状腺学会

  15. 日本内科学会

  16. The Eondocrine Society

  17. 日本神経内分泌学会

  18. 日本内分泌学会

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Papers 217

  1. Changing the name of diabetes insipidus: a position statement of The Working Group for Renaming Diabetes Insipidus.

    Working Group for Renaming Diabetes Insipidus., Arima H, Cheetham T, Christ-Crain M, Cooper D, Gurnell M, Drummond JB, Levy M, McCormack AI, Verbalis J, Newell-Price J, Wass JAH

    Endocrine connections   Vol. 11 ( 11 )   2022.11

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

    DOI: 10.1530/EC-22-0378

    PubMed

  2. Changing the name of diabetes insipidus: a position statement of The Working Group for Renaming Diabetes Insipidus.

    Working Group for Renaming Diabetes Insipidus., Arima H, Cheetham T, Christ-Crain M, Cooper D, Gurnell M, Drummond JB, Levy M, McCormack AI, Verbalis J, Newell-Price J, Wass JAH

    European journal of endocrinology   Vol. 187 ( 5 ) page: P1 - P3   2022.11

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

    DOI: 10.1530/EJE-22-0751

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  3. Differentiation of human induced pluripotent stem cells into hypothalamic vasopressin neurons with minimal exogenous signals and partial conversion to the naive state

    Ozaki Hajime, Suga Hidetaka, Sakakibara Mayu, Soen Mika, Miyake Natsuki, Miwata Tsutomu, Taga Shiori, Nagai Takashi, Kano Mayuko, Mitsumoto Kazuki, Miyata Takashi, Kobayashi Tomoko, Sugiyama Mariko, Onoue Takeshi, Takagi Hiroshi, Hagiwara Daisuke, Iwama Shintaro, Banno Ryoichi, Iguchi Genzo, Takahashi Yutaka, Muguruma Keiko, Inoue Haruhisa, Arima Hiroshi

    SCIENTIFIC REPORTS   Vol. 12 ( 1 ) page: 17381   2022.10

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

    DOI: 10.1038/s41598-022-22405-8

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  4. Changing the name of diabetes insipidus: a position statement of The Working Group for Renaming Diabetes Insipidus

    Arima Hiroshi, Cheetham Timothy, Christ-Crain Mirjam, Cooper Deborah, Gurnell Mark, Drummond Juliana B., Levy Miles, McCormack Ann I, Verbalis Joseph, Newell-Price John, Wass John A. H.

    ENDOCRINE JOURNAL     2022.10

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

    DOI: 10.1507/endocrj.EJ20220831

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  5. Changing the name of diabetes insipidus: a position statement of the working group to consider renaming diabetes insipidus

    Arima Hiroshi, Cheetham Timothy, Christ-Crain Mirjam, Cooper Deborah, Drummond Juliana, Gurnell Mark, Levy Miles, McCormack Ann, Newell-Price John, Verbalis Joseph G., Wass John

    CLINICAL ENDOCRINOLOGY     2022.10

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

    DOI: 10.1111/cen.14819

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  6. Changing the Name of Diabetes Insipidus: A Position Statement of the Working Group to Consider Renaming Diabetes Insipidus

    Arima Hiroshi, Cheetham Timothy, Christ-Crain Mirjam, Cooper Deborah L., Drummond Juliana B., Gurnell Mark, Levy Miles, McCormack Ann, Newell-Price John D., Verbalis Joseph G., Wass John

    HORMONE RESEARCH IN PAEDIATRICS     page: 1 - 3   2022.9

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

    DOI: 10.1159/000527139

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  7. Elevated TSH level, TgAb and prior use of ramucirumab or TKIs as risk factors for thyroid dysfunction in PD-L1 blockade. International journal

    Tomoko Kobayashi, Shintaro Iwama, Ayana Yamagami, Yoshinori Yasuda, Takayuki Okuji, Masaaki Ito, Xin Zhou, Masahiko Ando, Takeshi Onoue, Takashi Miyata, Mariko Sugiyama, Daisuke Hagiwara, Hidetaka Suga, Ryoichi Banno, Tetsunari Hase, Masahiro Morise, Takanori Ito, Toyone Kikumori, Megumi Inoue, Yuichi Ando, Norikazu Masuda, Hiroki Kawashima, Naozumi Hashimoto, Hiroshi Arima

    The Journal of clinical endocrinology and metabolism   Vol. 107 ( 10 ) page: E4115 - E4123   2022.9

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

    BACKGROUND: Thyroid dysfunction is frequently caused by treatment with anti-programmed cell death-1 ligand 1 antibodies (PD-L1-Abs) as well as anti-cancer drugs, including ramucirumab (RAM) and multi-targeted tyrosine kinase inhibitors (multi-TKIs), which are often used prior to PD-L1-Ab treatment in cancer patients. METHODS: A total of 148 patients treated with PD-L1-Abs were evaluated for anti-thyroid antibodies at baseline and for thyroid function every six weeks for 24 weeks after treatment initiation and then were observed until the visits stopped. RESULTS: Of the 148 patients, 15 (10.1%) developed thyroid dysfunction after PD-L1-Ab treatment (destructive thyroiditis in eight and hypothyroidism without preceding thyrotoxicosis in seven). The prevalences of an elevated thyroid-stimulating hormone (TSH) level at baseline (3/15 [20.0%] vs. 4/133 [3.0%], p < 0.05), positive anti-thyroglobulin antibodies (TgAb) at baseline (4/15 [26.7%] vs. 5/133 [3.8%], p < 0.05) and prior treatment with RAM or multi-TKIs (3/15 [20.0%] vs. 5/133 [3.8%], p < 0.05) were significantly higher in patients with versus without thyroid dysfunction. In a multivariate analysis, elevated TSH level at baseline, TgAb positivity at baseline and prior treatment with RAM or multi-TKIs were significantly associated with the development of thyroid dysfunction, with odds ratios of 7.098 (95% confidence interval [CI], 1.154-43.638), 11.927 (95% CI, 2.526-56.316) and 8.476 (95% CI, 1.592-45.115), respectively. CONCLUSIONS: The results of this real-world study suggest that the risk of thyroid dysfunction induced by PD-L1-Abs can be predicted by the TSH level at baseline, TgAb positivity at baseline and prior treatment with RAM or multi-TKIs.

    DOI: 10.1210/clinem/dgac467

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  8. Protein Tyrosine Phosphatase 1B Deficiency Improves Glucose Homeostasis in Insulin-Dependent Diabetes Mellitus Treated with Leptin. International journal

    Yoshihiro Ito, Runan Sun, Hiroshi Yagimuma, Keigo Taki, Akira Mizoguchi, Tomoko Kobayashi, Mariko Sugiyama, Takeshi Onoue, Taku Tsunekawa, Hiroshi Takagi, Daisuke Hagiwara, Shintaro Iwama, Hidetaka Suga, Hiroyuki Konishi, Hiroshi Kiyama, Hiroshi Arima, Ryoichi Banno

    Diabetes   Vol. 71 ( 9 ) page: 1902 - 1914   2022.9

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    Leptin, a hormone secreted by adipocytes, exhibits therapeutic potential for the treatment of insulin-dependent diabetes mellitus (IDDM). Protein tyrosine phosphatase 1B (PTP1B) is a key enzyme that negatively regulates leptin receptor signaling. Here, the role of PTP1B in the treatment of IDDM was investigated using PTP1B deficient (KO) mice and a PTP1B inhibitor. IDDM wild-type (WT) mice induced by streptozotocin showed marked hyperglycemia compared to non-IDDM WT mice. KO mice displayed significantly improved glucose metabolism equivalent to non-IDDM WT mice, whereas peripheral or central administration of leptin partially improved glucose metabolism in IDDM WT mice. Peripheral combination therapy of leptin and a PTP1B inhibitor in IDDM WT mice improved glucose metabolism to the same level as non-IDDM WT mice. Leptin was shown to act on the arcuate nucleus in the hypothalamus to suppress gluconeogenesis in liver and enhance glucose uptake in both brown adipose tissue and soleus muscle via the sympathetic nervous system. These effects were enhanced by PTP1B deficiency. Thus, treatment of IDDM with leptin, PTP1B deficiency or a PTP1B inhibitor was shown to enhance leptin activity in the hypothalamus to improve glucose metabolism. These findings suggest a potential alternative therapy for IDDM.

    DOI: 10.2337/db21-0953

    PubMed

  9. Inflammation in VTA Caused by HFD Induces Activation of Dopaminergic Neurons Accompanied by Binge-like Eating. International journal

    Runan Sun, Mariko Sugiyama, Sixian Wang, Mitsuhiro Kuno, Tomoyuki Sasaki, Tomonori Hirose, Takashi Miyata, Tomoko Kobayashi, Taku Tsunekawa, Takeshi Onoue, Yoshinori Yasuda, Hiroshi Takagi, Daisuke Hagiwara, Shintaro Iwama, Hidetaka Suga, Hiroshi Arima

    Nutrients   Vol. 14 ( 18 )   2022.9

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

    Binge eating is a characteristic symptom observed in obese individuals that is related to dysfunction of dopaminergic neurons (DNs). Intermittent administration of a high-fat diet (HFD) is reported to induce binge-like eating, but the underlying mechanisms remain unclear. We generated dopaminergic neuron specific IKKβ deficient mice (KO) to examine the effects of inflammation in DNs on binge-like eating under inflammatory conditions associated with HFD. After administration of HFD for 4 weeks, mice were fasted for 24 h, and then the consumption of HFD was measured for 2 h. We also evaluated that the mRNA expressions of inflammatory cytokines, glial markers, and dopamine signaling-related genes in the ventral tegmental area (VTA) and striatum. Moreover, insulin was administered intraventricularly to assess downstream signaling. The consumption of HFD was significantly reduced, and the phosphorylation of AKT in the VTA was significantly increased in female KO compared to wild-type (WT) mice. Analyses of mRNA expressions revealed that DNs activity and inflammation in the VTA were significantly decreased in female KO mice. Thus, our data suggest that HFD-induced inflammation with glial cell activation in the VTA affects DNs function and causes abnormal eating behaviors accompanied by insulin resistance in the VTA of female mice.

    DOI: 10.3390/nu14183835

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  10. Disease Modeling of Pituitary Adenoma Using Human Pluripotent Stem Cells

    Matsumoto Ryusaku, Suga Hidetaka, Arima Hiroshi, Yamamoto Takuya

    CANCERS   Vol. 14 ( 15 )   2022.8

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    DOI: 10.3390/cancers14153660

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  11. The multifaceted role of ATF4 in regulating glucose-stimulated insulin secretion

    Sobajima Mitsuaki, Miyake Masato, Hamada Yoshimasa, Tsugawa Kazue, Oyadomari Miho, Inoue Ryota, Shirakawa Jun, Arima Hiroshi, Oyadomari Seiichi

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   Vol. 611   page: 165 - 171   2022.6

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    DOI: 10.1016/j.bbrc.2022.04.038

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  12. Immune checkpoint inhibitor-related thyroid dysfunction.

    Iwama S, Kobayashi T, Yasuda Y, Arima H

    Best practice & research. Clinical endocrinology & metabolism   Vol. 36 ( 3 ) page: 101660   2022.5

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    DOI: 10.1016/j.beem.2022.101660

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  13. イピリムマブ・ニボルマブ併用療法による甲状腺障害の臨床的特徴と高リスクマーカー

    小林 朋子, 岩間 信太郎, 山上 綾菜, 伊藤 雅晃, 奥地 剛之, 安田 康紀, 有馬 寛

    日本内分泌学会雑誌   Vol. 98 ( 1 ) page: 306 - 306   2022.4

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  14. 抗PD-1抗体療法開始前の抗甲状腺抗体の存在は非小細胞肺癌患者の生存期間延長と相関する

    奥地 剛之, 岩間 信太郎, 山上 綾菜, Zhou Xin, 伊藤 雅晃, 小林 朋子, 安田 康紀, 有馬 寛

    日本内分泌学会雑誌   Vol. 98 ( 1 ) page: 305 - 305   2022.4

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  15. ストレプトゾトシン糖尿病マウスにおける抗PD-1抗体の大腸癌細胞株に対する抗腫瘍効果低下とケモカインの関連

    伊藤 雅晃, 岩間 信太郎, 奥地 剛之, 安田 康紀, 山上 綾菜, 周 シン, 小林 朋子, 有馬 寛

    日本内分泌学会雑誌   Vol. 98 ( 1 ) page: 289 - 289   2022.4

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  16. Increased Risk of Thyroid Dysfunction by PD-1 and CTLA-4 Blockade in Patients Without Thyroid Autoantibodies at Baseline. International journal

    Shintaro Iwama, Tomoko Kobayashi, Yoshinori Yasuda, Takayuki Okuji, Masaaki Ito, Masahiko Ando, Xin Zhou, Ayana Yamagami, Takeshi Onoue, Yohei Kawaguchi, Takashi Miyata, Mariko Sugiyama, Hiroshi Takagi, Daisuke Hagiwara, Hidetaka Suga, Ryoichi Banno, Tetsunari Hase, Masahiro Morise, Keiko Wakahara, Kenji Yokota, Masashi Kato, Naoki Nishio, Chie Tanaka, Kazushi Miyata, Atsushi Ogura, Takanori Ito, Tsunaki Sawada, Tomoya Shimokata, Kaoru Niimi, Fumiharu Ohka, Masatoshi Ishigami, Momokazu Gotoh, Naozumi Hashimoto, Ryuta Saito, Hitoshi Kiyoi, Hiroaki Kajiyama, Yuichi Ando, Hideharu Hibi, Michihiko Sone, Masashi Akiyama, Yasuhiro Kodera, Hiroshi Arima

    The Journal of clinical endocrinology and metabolism   Vol. 107 ( 4 ) page: E1620 - E1630   2022.3

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    BACKGROUND: Previous studies showed that although the risk of thyroid dysfunction [thyroid immune-related adverse events (irAEs)] induced by anti-programmed cell death-1 antibodies (PD-1-Ab) was as low as 2% to 7% in patients negative for anti-thyroid antibodies (ATAs) at baseline, it was much higher (30%-50%) in patients positive for ATAs. However, whether a similar increase occurs with combination therapy using PD-1-Ab plus anti-cytotoxic T-lymphocyte antigen-4 antibody (CTLA-4-Ab) is unknown. METHODS: A total of 451 patients with malignancies treated with PD-1-Ab, CTLA-4-Ab, or a combination of PD-1-Ab and CTLA-4-Ab (PD-1/CTLA-4-Abs) were evaluated for ATAs at baseline and for thyroid function every 6 weeks for 24 weeks after treatment initiation and then observed until the last clinical visit. RESULTS: Of the 451 patients, 51 developed thyroid irAEs after immunotherapy [41 of 416 (9.9%) treated with PD-1-Ab, 0 of 8 (0%) treated with CTLA-4-Ab, and 10 of 27 (37.0%) treated with PD-1/CTLA-4-Abs]. The cumulative incidence of thyroid irAEs was significantly higher in patients who were positive vs negative for ATAs at baseline after both PD-1-Ab [28/87 (32.2%) vs 13/329 (4.0%), P < 0.001] and PD-1/CTLA-4-Abs [6/10 (60.0%) vs 4/17 (23.5%), P < 0.05] treatments. The risk of thyroid irAEs induced by PD-1/CTLA-4Abs, which was significantly higher than that induced by PD-1-Ab, in patients negative for ATAs at baseline was not statistically different from that induced by PD-1-Ab in patients positive for ATAs at baseline. CONCLUSIONS: This study showed that the incidence of thyroid irAEs was high and not negligible after PD-1/CTLA-4-Abs treatment even in patients negative for ATAs at baseline.

    DOI: 10.1210/clinem/dgab829

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  17. Functional lactotrophs in induced adenohypophysis differentiated from human iPS cells. International journal

    Natsuki Miyake, Takashi Nagai, Hidetaka Suga, Satoko Osuka, Takatoshi Kasai, Mayu Sakakibara, Mika Soen, Hajime Ozaki, Tsutomu Miwata, Tomoyoshi Asano, Mayuko Kano, Ayako Muraoka, Natsuki Nakanishi, Tomoko Nakamura, Maki Goto, Yoshinori Yasuda, Yohei Kawaguchi, Takashi Miyata, Tomoko Kobayashi, Mariko Sugiyama, Takeshi Onoue, Daisuke Hagiwara, Shintaro Iwama, Akira Iwase, Naoko Inoshita, Hiroshi Arima, Hiroaki Kajiyama

    Endocrinology   Vol. 163 ( 3 )   2022.3

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    Prolactin (PRL), a hormone involved in lactation, is mainly produced and secreted by the lactotrophs of the anterior pituitary (AP) gland. We previously reported a method to generate functional adrenocorticotropic hormone-producing cells by differentiating the AP and hypothalamus simultaneously from human induced pluripotent stem cells (iPSCs). However, PRL-producing cells in the induced AP have not been investigated. Here, we confirmed the presence of PRL-producing cells and evaluated their endocrine functions. We differentiated pituitary cells from human iPSCs using serum-free floating culture of embryoid-like aggregates with quick reaggregation (SFEB-q) method and evaluated the appearance and function of PRL-producing cells. Secretion of PRL from the differentiated aggregates was confirmed, which increased with further culture. Fluorescence immunostaining and immunoelectron microscopy revealed PRL-producing cells and PRL-positive secretory granules, respectively. PRL secretion was promoted by various prolactin secretagogues such as thyrotropin-releasing hormone, vasoactive intestinal peptide, and prolactin-releasing peptide, and inhibited by bromocriptine. Moreover, the presence of tyrosine hydroxylase-positive dopaminergic nerves in the hypothalamic tissue area around the center of the aggregates connecting to PRL-producing cells indicated the possibility of recapitulating PRL regulatory mechanisms through the hypothalamus. In conclusion, we generated pituitary lactotrophs from human iPSCs; these displayed similar secretory responsiveness as human pituitary cells in vivo. In the future, this is expected to be used as a model of human PRL-producing cells for various studies, such as drug discovery, prediction of side effects, and elucidation of tumorigenic mechanisms using disease-specific iPSCs. Furthermore, it may help to develop regenerative medicine for the pituitary gland.

    DOI: 10.1210/endocr/bqac004

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  18. ヒト疾患特異的人工多能性幹細胞(iPS細胞)からのバソプレシン(AVP)神経の分化誘導による家族性中枢性尿崩症(FNDI)のin vitroヒト疾患モデル

    尾崎 創, 須賀 英隆, 三輪田 勤, 井口 元三, 高橋 裕, 有馬 寛

    日本内分泌学会雑誌   Vol. 97 ( 5 ) page: 1243 - 1243   2022.3

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  19. Human Leukocyte Antigens and Biomarkers in Type Diabetes Mellitus Induced by Immune-Checkpoint Inhibitors

    Inaba Hidefumi, Kaido Yosuke, Ito Saya, Hirobata Tomonao, Inoue Gen, Sugita Takakazu, Yamamoto Yuki, Jinnin Masatoshi, Kimura Hiroaki, Kobayashi Tomoko, Iwama Shintaro, Arima Hiroshi, Matsuoka Takaaki

    ENDOCRINOLOGY AND METABOLISM   Vol. 37 ( 1 ) page: 84 - +   2022.2

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    DOI: 10.3803/EnM.2021.1282

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  20. Predicting non-insulin-dependent state in patients with slowly progressive insulin-dependent (type 1) diabetes mellitus or latent autoimmune diabetes in adults. Reply to Sugiyama K and Saisho Y [letter]

    Wada Eri, Onoue Takeshi, Kinoshita Tamaki, Hayase Ayaka, Handa Tomoko, Ito Masaaki, Furukawa Mariko, Okuji Takayuki, Kobayashi Tomoko, Iwama Shintaro, Sugiyama Mariko, Takagi Hiroshi, Hagiwara Daisuke, Suga Hidetaka, Banno Ryoichi, Goto Motomitsu, Arima Hiroshi

    DIABETOLOGIA   Vol. 65 ( 1 ) page: 252 - 253   2022.1

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    DOI: 10.1007/s00125-021-05610-4

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  21. EpCAM Is a Surface Marker for Enriching Anterior Pituitary Cells From Human Hypothalamic-Pituitary Organoids.

    Kodani Y, Kawata M, Suga H, Kasai T, Ozone C, Sakakibara M, Kuwahara A, Taga S, Arima H, Kameyama T, Saito K, Nakashima A, Nagasaki H

    Frontiers in endocrinology   Vol. 13   page: 941166   2022

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    DOI: 10.3389/fendo.2022.941166

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  22. The 100th anniversary is coming: a message from the president

    Arima Hiroshi

    ENDOCRINE JOURNAL   Vol. 69 ( 8 ) page: 877 - 879   2022

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  23. The 100<sup>th</sup> anniversary is coming: a message from the president.

    Arima H

    Endocrine journal   Vol. 69 ( 8 ) page: 877 - 879   2022

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    DOI: 10.1507/endocrj.RMK69-08

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  24. Basigin deficiency prevents anaplerosis and ameliorates insulin resistance and hepatosteatosis Reviewed

    Ryuge Akihiro, Kosugi Tomoki, Maeda Kayaho, Banno Ryoichi, Gou Yang, Zaitsu Kei, Ito Takanori, Sato Yuka, Hirayama Akiyoshi, Tsubota Shoma, Honda Takashi, Nakajima Kazuki, Ozaki Tomoya, Kondoh Kunio, Takahashi Kazuo, Kato Noritoshi, Ishimoto Takuji, Soga Tomoyoshi, Nakagawa Takahiko, Koike Teruhiko, Arima Hiroshi, Yuzawa Yukio, Minokoshi Yasuhiko, Maruyama Shoichi, Kadomatsu Kenji

    JCI INSIGHT   Vol. 6 ( 20 )   2021.10

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    DOI: 10.1172/jci.insight.142464

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  25. Adult-onset autoimmune diabetes identified by glutamic acid decarboxylase autoantibodies: a retrospective cohort study

    Wada Eri, Onoue Takeshi, Kinoshita Tamaki, Hayase Ayaka, Handa Tomoko, Ito Masaaki, Furukawa Mariko, Okuji Takayuki, Kobayashi Tomoko, Iwama Shintaro, Sugiyama Mariko, Takagi Hiroshi, Hagiwara Daisuke, Suga Hidetaka, Banno Ryoichi, Goto Motomitsu, Arima Hiroshi

    DIABETOLOGIA   Vol. 64 ( 10 ) page: 2183 - 2192   2021.10

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    DOI: 10.1007/s00125-021-05516-1

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  26. GABAB receptor signaling in the caudate putamen is involved in binge-like consumption during a high fat diet in mice. International coauthorship International journal

    Runan Sun, Taku Tsunekawa, Tomonori Hirose, Hiroshi Yaginuma, Keigo Taki, Akira Mizoguchi, Takashi Miyata, Tomoko Kobayashi, Mariko Sugiyama, Takeshi Onoue, Hiroshi Takagi, Daisuke Hagiwara, Yoshihiro Ito, Shintaro Iwama, Hidetaka Suga, Ryoichi Banno, Bernhard Bettler, Hiroshi Arima

    Scientific reports   Vol. 11 ( 1 ) page: 19296 - 19296   2021.9

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    Previous studies suggest that signaling by the gamma-aminobutyric acid (GABA) type B receptor (GABABR) is involved in the regulation of binge eating, a disorder which might contribute to the development of obesity. Here, we show that intermittent access to a high fat diet (HFD) induced binge-like eating behavior with activation of dopamine receptor d1 (drd1)-expressing neurons in the caudate putamen (CPu) and nucleus accumbens (NAc) in wild-type (WT) mice. The activation of drd1-expressing neurons during binge-like eating was substantially increased in the CPu, but not in the NAc, in corticostriatal neuron-specific GABABR-deficient knockout (KO) mice compared to WT mice. Treatment with the GABABR agonist, baclofen, suppressed binge-like eating behavior in WT mice, but not in KO mice, as reported previously. Baclofen also suppressed the activation of drd1-expressing neurons in the CPu, but not in the NAc, during binge-like eating in WT mice. Thus, our data suggest that GABABR signaling in CPu neurons expressing drd1 suppresses binge-like consumption during a HFD in mice.

    DOI: 10.1038/s41598-021-98590-9

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  27. Deficiency of WFS1 leads to the impairment of AVP secretion under dehydration in male mice. International journal

    Junki Kurimoto, Hiroshi Takagi, Takashi Miyata, Yuichi Hodai, Yohei Kawaguchi, Daisuke Hagiwara, Hidetaka Suga, Tomoko Kobayashi, Mariko Sugiyama, Takeshi Onoue, Yoshihiro Ito, Shintaro Iwama, Ryoichi Banno, Katsuya Tanabe, Yukio Tanizawa, Hiroshi Arima

    Pituitary   Vol. 24 ( 4 ) page: 582 - 588   2021.8

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    Wolfram syndrome (WS) is mainly caused by mutations in the WFS1 gene and characterized by diabetes mellitus, optic atrophy, hearing loss, and central diabetes insipidus (CDI). WFS1 is an endoplasmic reticulum (ER)-resident transmembrane protein, and Wfs1 knockout (Wfs1-/-) mice, which have been used as a mouse model for WS, reportedly manifested impairment of glucose tolerance due to pancreatic β-cell loss. In the present study, we examined water balance, arginine vasopressin (AVP) secretion, and ER stress in AVP neurons of the hypothalamus in Wfs1-/- mice. There were no differences in urine volumes between Wfs1-/- and wild-type mice with free access to water. Conversely, when mice were subjected to intermittent water deprivation (WD) for 20 weeks, during which water was unavailable for 2 days a week, urine volumes were larger in Wfs1-/- mice, accompanied by lower urine AVP concentrations and urine osmolality, compared to wild-type mice. The mRNA expression of immunoglobulin heavy chain binding protein, a marker of ER stress, was significantly increased in the supraoptic nucleus and paraventricular nuclei in Wfs1-/- mice compared to wild-type mice after WD. Our results thus showed that Wfs1 knockout leads to a decrease in AVP secretion during dehydration, which could explain in part the mechanisms by which Wfs1 mutations cause CDI in humans.

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  28. Prediabetes is associated with proteinuria development but not with glomerular filtration rate decline: A longitudinal observational study

    Furukawa Mariko, Onoue Takeshi, Kato Kiminori, Wada Takashi, Shinohara Yukito, Kinoshita Fumie, Goto Motomitsu, Arima Hiroshi, Tsushita Kazuyo

    DIABETIC MEDICINE   Vol. 38 ( 8 ) page: e14607   2021.8

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    DOI: 10.1111/dme.14607

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  29. Preoperative and long-term efficacy and safety of lanreotide autogel in patients with thyrotropin-secreting pituitary adenoma: a multicenter, single-arm, phase 3 study in Japan. International coauthorship

    Shimatsu A, Nakamura A, Takahashi Y, Fujio S, Satoh F, Tahara S, Nishioka H, Takano K, Yamashita M, Arima H, Tominaga A, Tateishi S, Matsushita Y

    Endocrine journal   Vol. 68 ( 7 ) page: 791 - 805   2021.7

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    DOI: 10.1507/endocrj.EJ20-0707

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  30. Glucocorticoid receptor signaling in ventral tegmental area neurons increases the rewarding value of a high-fat diet in mice International coauthorship

    Mizoguchi Akira, Banno Ryoichi, Sun Runan, Yaginuma Hiroshi, Taki Keigo, Kobayashi Tomoko, Sugiyama Mariko, Tsunekawa Taku, Onoue Takeshi, Takagi Hiroshi, Hagiwara Daisuke, Ito Yoshihiro, Iwama Shintaro, Suga Hidetaka, Nagai Taku, Yamada Kiyofumi, Arima Hiroshi

    SCIENTIFIC REPORTS   Vol. 11 ( 1 ) page: 12873   2021.6

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    DOI: 10.1038/s41598-021-92386-7

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  31. Comparison of High-Resolution Manometry in Patients Complaining of Dysphagia among Patients with or without Diabetes Mellitus. International journal

    Muroi K, Miyahara R, Funasaka K, Furukawa K, Sawada T, Maeda K, Yamamura T, Ishikawa T, Ohno E, Nakamura M, Kawashima H, Onoue T, Arima H, Hirooka Y, Fujishiro M

    Digestion   Vol. 102 ( 4 ) page: 554 - 562   2021.6

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    INTRODUCTION: Dysphagia is a common symptom that occurs in patients with diabetes mellitus (DM). There have been few prospective observational studies on esophageal motility disorders in DM using high-resolution manometry (HRM). This study aimed to clarify the characteristics of esophageal motility disorders using HRM in patients with dysphagia and compare them between DM and non-DM patients. METHODS: Patients with dysphagia were prospectively recruited between October 2018 and July 2019. Patients (n = 89) underwent esophagogastroduodenoscopy and HRM and completed the Gastrointestinal Symptom Rating Scale (GSRS) questionnaire. Manometry parameters and motility disorder classifications were compared between DM and non-DM patients. We also investigated the differences in clinical backgrounds and questionnaire scores among DM patients with normal and abnormal manometry results. RESULTS: A higher prevalence of esophageal motility disorder was observed in DM patients (60%, 21/35) compared to non-DM patients (29.6%, 16/54) (p = 0.001). The prevalence of minor disorders such as ineffective esophageal motor disorder and fragmented peristalsis was significantly higher (45 vs. 11%), and the distal contractile integral, integrated relaxation pressure, and contractile front velocity values were lower in the DM group. Among DM patients, those with abnormal esophageal motility had a significantly higher prevalence of neuropathy, retinopathy, and nephropathy, as well as higher reflux or constipation scores on the GSRS, than those with normal results. CONCLUSIONS: Among patients with dysphagia, the frequency of minor esophageal motility disorders was higher in DM patients than in non-DM patients. Abnormal esophageal motility related to poor esophageal clearance was associated with higher prevalence of diabetic complications.

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  32. Efficacies of programmed cell death 1 ligand 1 blockade in non-small cell lung cancer patients with acquired resistance to prior programmed cell death 1 inhibitor and development of diabetic ketoacidosis caused by two different etiologies: a retrospective case series.

    Ishi A, Tanaka I, Iwama S, Sakakibara T, Mastui T, Kobayashi T, Hase T, Morise M, Sato M, Arima H, Hashimoto N

    Endocrine journal   Vol. 68 ( 5 ) page: 613 - 620   2021.5

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    DOI: 10.1507/endocrj.EJ20-0769

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  33. Macrophages rely on extracellular serine to suppress aberrant cytokine production

    Kurita Kento, Ohta Hiroya, Shirakawa Ibuki, Tanaka Miyako, Kitaura Yasuyuki, Iwasaki Yorihiro, Matsuzaka Takashi, Shimano Hitoshi, Aoe Seiichiro, Arima Hiroshi, Ogawa Yoshihiro, Ito Ayaka, Suganami Takayoshi

    SCIENTIFIC REPORTS   Vol. 11 ( 1 ) page: 11137   2021.5

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    DOI: 10.1038/s41598-021-90086-w

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  34. A new primate model of hypophyseal dysfunction

    Teppei Kawabata, Hidetaka Suga, Kazuhito Takeuchi, Yuichi Nagata, Mayu Sakakibara, Kaori Ushida, Chikafumi Ozone, Atsushi Enomoto, Ikuo Kawamoto, Iori Itagaki, Hideaki Tsuchiya, Hiroshi Arima, Toshihiko Wakabayashi

    Scientific Reports   Vol. 11 ( 1 ) page: 10729   2021.5

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    <title>Abstract</title>For pituitary regenerative medicine, the creation of a hypophyseal model in monkeys is necessary to conduct future preclinical studies; however, previous studies reported that hypophysectomy in monkeys is not always safe or satisfactory. This study aimed to create a hypophyseal dysfunction model in a cynomolgus monkey using a safer surgical technique and establish the protocol of pituitary hormone replacement therapy for this model. Surgical resection of the pituitary gland of a 7.8-year-old healthy adult cynomolgus male monkey weighing 5.45 kg was performed to create a hypophyseal dysfunction model for future regenerative studies. Endoscopic transoral transsphenoidal surgery was used to perform hypophysectomy under navigation support. These procedures were useful for confirming total removal of the pituitary gland without additional bone removal and preventing complications such as cerebrospinal fluid leakage. Total removal was confirmed by pathological examination and computed tomography. Hypopituitarism was verified with endocrinological examinations including stimulation tests. Postoperatively, the monkey’s general condition of hypopituitarism was treated with hormone replacement therapy, resulting in long-term survival. The success of a minimally invasive and safe surgical method and long-term survival indicate the creation of a hypophyseal dysfunction model in a cynomolgus monkey; hence, this protocol can be employed in the future.

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    Other Link: http://www.nature.com/articles/s41598-021-90209-3

  35. CD4+ T cells are essential for the development of destructive thyroiditis induced by anti-PD-1 antibody in thyroglobulin-immunized mice. International journal

    Yoshinori Yasuda, Shintaro Iwama, Daisuke Sugiyama, Takayuki Okuji, Tomoko Kobayashi, Masaaki Ito, Norio Okada, Atsushi Enomoto, Sachiko Ito, Yue Yan, Mariko Sugiyama, Takeshi Onoue, Taku Tsunekawa, Yoshihiro Ito, Hiroshi Takagi, Daisuke Hagiwara, Motomitsu Goto, Hidetaka Suga, Ryoichi Banno, Masahide Takahashi, Hiroyoshi Nishikawa, Hiroshi Arima

    Science translational medicine   Vol. 13 ( 593 )   2021.5

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    Immune-related adverse events induced by anti-programmed cell death-1 antibodies (PD-1-Ab), including destructive thyroiditis (thyroid-irAE), are thought to be caused by activated T cells. However, the T cell subsets that are directly responsible for damaging self-organs remain unclear. To clarify which T cell subsets are involved in the development of thyroid-irAE, a mouse model of thyroid-irAE was analyzed. PD-1-Ab administration 2.5 months after immunization with thyroglobulin caused destructive thyroiditis. Thyroiditis was completely prevented by previous depletion of CD4+ T cells and partially prevented by depleting CD8+ T cells. The frequencies of central and effector memory CD4+ T cell subsets and the secretion of interferon-γ after stimulation with thyroglobulin were increased in the cervical lymph nodes of mice with thyroid-irAE compared with controls. Histopathological analysis revealed infiltration of CD4+ T cells expressing granzyme B in thyroid glands and major histocompatibility complex class II expression on thyrocytes in mice with thyroid-irAE. Adoptive transfer of CD4+ T cells from cervical lymph nodes in mice with thyroid-irAE caused destruction of thyroid follicular architecture in the irradiated recipient mice. Flow cytometric analyses showed that the frequencies of central and effector memory CD4+ T cells expressing the cytotoxic marker CD27 were higher in peripheral blood mononuclear cells collected from patients with thyroid-irAE induced by PD-1-Ab versus those without. These data suggest a critical role for cytotoxic memory CD4+ T cells activated by PD-1-Ab in the pathogenesis of thyroid-irAE.

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  36. High-fat Feeding Causes Inflammation and Insulin Resistance in the Ventral Tegmental Area in Mice. International journal

    Akira Mizoguchi, Ryoichi Banno, Runan Sun, Hiroshi Yaginuma, Keigo Taki, Tomoko Kobayashi, Mariko Sugiyama, Taku Tsunekawa, Takeshi Onoue, Hiroshi Takagi, Daisuke Hagiwara, Yoshihiro Ito, Shintaro Iwama, Hidetaka Suga, Hiroshi Arima

    Neuroscience   Vol. 461   page: 72 - 79   2021.5

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    The reward system plays an important role in the pathogenesis of not only drug addiction, but also diet-induced obesity. Recent studies have shown that insulin and leptin receptor signaling in the ventral tegmental area (VTA) regulate energy homeostasis and that their dysregulation is responsible for obesity and altered food preferences. Although a high-fat diet (HFD) induces inflammation that leads to insulin and leptin resistance in the brain, it remains unclear whether HFD induces inflammation in the VTA. In the present study, we placed male mice on a chow diet or HFD for 3, 7, and 28 days and evaluated the mRNA expression of inflammatory cytokines and microglial activation markers in the VTA. The HFD group showed significantly elevated mRNA expressions of IL1β at 3 days; tumor necrosis factor-alpha (TNFα), IL1β, IL6, Iba1, and CD11b at 7 days; and TNFα, IL1β, Iba1, and CD11b at 28 days. The changes in TNFα were also confirmed in immunohistochemical analysis. Next, after administration of chow or HFD for 7 days, we selected mice with equal weights in both groups. In experiments using these mice, Akt phosphorylation in the VTA was significantly decreased after intracerebroventricular injection of insulin, whereas no change in STAT3 phosphorylation was found with leptin. Taken together, these results suggest that HFD induces inflammation at least partly associated with microglial activation in the VTA leading to insulin resistance, independently of the energy balance. Our data provide new insight into the pathophysiology of obesity caused by a dysfunctional reward system under HFD conditions.

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  37. Anti-pituitary antibodies and susceptible human leukocyte antigen alleles as predictive biomarkers for pituitary dysfunction induced by immune checkpoint inhibitors

    Tomoko Kobayashi, Shintaro Iwama, Daisuke Sugiyama, Yoshinori Yasuda, Takayuki Okuji, Masaaki Ito, Sachiko Ito, Mariko Sugiyama, Takeshi Onoue, Hiroshi Takagi, Daisuke Hagiwara, Yoshihiro Ito, Hidetaka Suga, Ryoichi Banno, Hiroyoshi Nishikawa, Hiroshi Arima

    Journal for ImmunoTherapy of Cancer   Vol. 9 ( 5 ) page: e002493 - e002493   2021.5

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    Background

    Pituitary dysfunction is a life-threatening immune-related adverse event (irAE) induced by immune checkpoint inhibitors (ICIs). To date, it is not possible to identify patients who may develop pituitary irAEs prior to ICI treatment. The aim of this study was to characterize the predisposition for ICI-induced pituitary irAEs by analyzing anti-pituitary antibodies (APAs) and human leukocyte antigens (HLAs).

    Methods

    In this case–control study, APAs and HLA alleles were analyzed in 62 patients (17 who developed ICI-induced isolated adrenocorticotropic hormone deficiency (ICI-IAD), 5 who developed ICI-induced hypophysitis (ICI-H) and 40 who did not develop pituitary irAEs) treated with ICIs between November 2, 2015, and March 31, 2020, at Nagoya University Hospital. The main outcome measures in this study were the association between the development of pituitary irAEs with APAs at baseline and after treatment and HLA alleles.

    Results

    Eleven of 17 (64.7%) patients who developed ICI-IAD had APAs at baseline, whereas APAs were positive only in 1 of 40 (2.5%) control patients. Although APAs were negative at baseline in all patients who developed ICI-H, they had become positive before the onset of ICI-H in 3 of 4 patients several weeks after ipilimumab administration. At the onset of ICI-IAD and ICI-H, APAs were positive in 15 of 17 (88.2%) and 4 of 5 (80%) patients, respectively. The prevalence of HLA-Cw12, HLA-DR15, HLA-DQ7, and HLA-DPw9 was significantly higher in patients with ICI-IAD, whereas that of HLA-Cw12 and HLA-DR15 was significantly higher in patients with ICI-H than in controls.

    Conclusions

    This study showed distinct and overlapped patterns of APAs and HLA alleles between ICI-IAD and ICI-H. Our findings also showed that positive APAs at baseline and after treatment, together with susceptible HLA alleles, could become predictive biomarkers for ICI-IAD and ICI-H, respectively.

    Trial registration number

    UMIN000019024.

    DOI: 10.1136/jitc-2021-002493

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  38. Arginine vasopressin-Venus reporter mice as a tool for studying magnocellular arginine vasopressin neurons. International journal

    Daisuke Hagiwara, Masayoshi Tochiya, Yoshinori Azuma, Tetsuro Tsumura, Yuichi Hodai, Yohei Kawaguchi, Takashi Miyata, Tomoko Kobayashi, Mariko Sugiyama, Takeshi Onoue, Hiroshi Takagi, Yoshihiro Ito, Shintaro Iwama, Hidetaka Suga, Ryoichi Banno, Hiroshi Arima

    Peptides   Vol. 139   page: 170517 - 170517   2021.5

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    Arginine vasopressin (AVP) synthesized in the magnocellular neurons of the hypothalamus is transported through their axons and released from the posterior pituitary into the systemic circulation to act as an antidiuretic hormone. AVP synthesis and release are precisely regulated by changes in plasma osmolality. Magnocellular AVP neurons receive innervation from osmosensory and sodium-sensing neurons, but previous studies showed that AVP neurons per se are osmosensitive as well. In the current study, we made AVP-Venus reporter mice and showed that Venus was expressed exclusively in AVP neurons and was upregulated under water deprivation. In hypothalamic organotypic cultures from the AVP-Venus mice, Venus-labeled AVP neurons in the supraoptic and paraventricular nuclei survived for 1 month, and Venus expression was upregulated by forskolin. Furthermore, in dissociated Venus-labeled magnocellular neurons, treatment with NaCl, but not with mannitol, decreased Venus fluorescence in the soma of the AVP neurons. Thus, Venus expression in AVP-Venus transgenic mice, as well as in primary cultures, faithfully showed the properties of intrinsic AVP expression. These findings indicate that AVP-Venus mice as well as the primary hypothalamic cultures could be useful for studying magnocellular AVP neurons.

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  39. Clinical Characteristics, Management, and Potential Biomarkers of Endocrine Dysfunction Induced by Immune Checkpoint Inhibitors

    Iwama Shintaro, Kobayashi Tomoko, Arima Hiroshi

    ENDOCRINOLOGY AND METABOLISM   Vol. 36 ( 2 ) page: 312 - 321   2021.4

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    DOI: 10.3803/EnM.2021.1007

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  40. イピリムマブ誘発下垂体炎発症者で高抗体価を示す自己抗体の同定 Reviewed

    奥地 剛之, 岩間 信太郎, 周 キン, 伊藤 雅晃, 小林 朋子, 安田 康紀, 有馬 寛

    日本内分泌学会雑誌   Vol. 97 ( 1 ) page: 262 - 262   2021.4

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  41. 抗PD-1抗体誘発甲状腺炎マウスモデルにおける抗サイログロブリン抗体の役割 Reviewed

    安田 康紀, 岩間 信太郎, 伊藤 雅晃, 奥地 剛之, 小林 朋子, 有馬 寛

    日本内分泌学会雑誌   Vol. 97 ( 1 ) page: 267 - 267   2021.4

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  42. Dietary sodium chloride attenuates increased β-cell mass to cause glucose intolerance in mice under a high-fat diet. Reviewed

    Taki K, Takagi H, Hirose T, Sun R, Yaginuma H, Mizoguchi A, Kobayashi T, Sugiyama M, Tsunekawa T, Onoue T, Hagiwara D, Ito Y, Iwama S, Suga H, Banno R, Sakano D, Kume S, Arima H.

    PLos One   Vol. 16 ( 3 ) page: e0248065   2021.3

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  43. Dietary sodium chloride attenuates increased β-cell mass to cause glucose intolerance in mice under a high-fat diet. International journal

    Keigo Taki, Hiroshi Takagi, Tomonori Hirose, Runan Sun, Hiroshi Yaginuma, Akira Mizoguchi, Tomoko Kobayashi, Mariko Sugiyama, Taku Tsunekawa, Takeshi Onoue, Daisuke Hagiwara, Yoshihiro Ito, Shintaro Iwama, Hidetaka Suga, Ryoichi Banno, Daisuke Sakano, Shoen Kume, Hiroshi Arima

    PloS one   Vol. 16 ( 3 ) page: e0248065   2021.3

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    Excessive sodium salt (NaCl) or fat intake is associated with a variety of increased health risks. However, whether excessive NaCl intake accompanied by a high-fat diet (HFD) affects glucose metabolism has not been elucidated. In this study, C57BL/6J male mice were fed a normal chow diet (NCD), a NCD plus high-NaCl diet (NCD plus NaCl), a HFD, or a HFD plus high-NaCl diet (HFD plus NaCl) for 30 weeks. No significant differences in body weight gain, insulin sensitivity, and glucose tolerance were observed between NCD-fed and NCD plus NaCl-fed mice. In contrast, body and liver weights were decreased, but the weight of epididymal white adipose tissue was increased in HFD plus NaCl-fed compared to HFD-fed mice. HFD plus NaCl-fed mice had lower plasma glucose levels in an insulin tolerance test, and showed higher plasma glucose and lower plasma insulin levels in an intraperitoneal glucose tolerance test compared to HFD-fed mice. The β-cell area and number of islets were decreased in HFD plus NaCl-fed compared to HFD-fed mice. Increased Ki67-positive β-cells, and increased expression levels of Ki67, CyclinB1, and CyclinD1 mRNA in islets were observed in HFD-fed but not HFD plus NaCl-fed mice when compared to NCD-fed mice. Our data suggest that excessive NaCl intake accompanied by a HFD exacerbates glucose intolerance, with impairment in insulin secretion caused by the attenuation of expansion of β-cell mass in the pancreas.

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  44. Induction of Functional Hypothalamus and Pituitary Tissues From Pluripotent Stem Cells for Regenerative Medicine. International journal

    Mayuko Kano, Hidetaka Suga, Hiroshi Arima

    Journal of the Endocrine Society   Vol. 5 ( 3 ) page: bvaa188   2021.3

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    The hypothalamus and pituitary have been identified to play essential roles in maintaining homeostasis. Various diseases can disrupt the functions of these systems, which can often result in serious lifelong symptoms. The current treatment for hypopituitarism involves hormone replacement therapy. However, exogenous drug administration cannot mimic the physiological changes that are a result of hormone requirements. Therefore, patients are at a high risk of severe hormone deficiency, including adrenal crisis. Pluripotent stem cells (PSCs) self-proliferate and differentiate into all types of cells. The generation of endocrine tissues from PSCs has been considered as another new treatment for hypopituitarism. Our colleagues established a 3-dimensional (3D) culture method for embryonic stem cells (ESCs). In this culture, the ESC-derived aggregates exhibit self-organization and spontaneous formation of highly ordered patterning. Recent results have shown that strict removal of exogenous patterning factors during early differentiation efficiently induces rostral hypothalamic progenitors from mouse ESCs. These hypothalamic progenitors generate vasopressinergic neurons, which release neuropeptides upon exogenous stimulation. Subsequently, we reported adenohypophysis tissue self-formation in 3D cultures of mouse ESCs. The ESCs were found to differentiate into both nonneural oral ectoderm and hypothalamic neuroectoderm in adjacent layers. Interactions between the 2 tissues appear to be critically important for in vitro induction of a Rathke's pouch-like developing embryo. Various endocrine cells were differentiated from nonneural ectoderm. The induced corticotrophs efficiently secreted adrenocorticotropic hormone when engrafted in vivo, which rescued hypopituitary hosts. For future regenerative medicine, generation of hypothalamic and pituitary tissues from human PSCs is necessary. We and other groups succeeded in establishing a differentiation method with the use of human PSCs. Researchers could use these methods for models of human diseases to elucidate disease pathology or screen potential therapeutics.

    DOI: 10.1210/jendso/bvaa188

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  45. High-fat Feeding Causes Inflammation and Insulin Resistance in the Ventral Tegmental Area in Mice. Reviewed

    Mizoguchi A, Banno R, Sun R, Yaginuma H, Taki K, Kobayashi T, Sugiyama M, Tsunekawa T, Onoue T, Takagi H, Hagiwara D, Ito Y, Iwama S, Suga H, Arima H.

    Neuroscience   Vol. 18 ( 461 ) page: 72 - 79   2021.2

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    DOI: 10.1016/j.neuroscience.2021.02.009.

  46. Hypothalamic-pituitary organoid generation through the recapitulation of organogenesis.

    Hajime Ozaki, Hidetaka Suga, Hiroshi Arima

    Development, growth & differentiation   Vol. 63 ( 2 ) page: 154 - 165   2021.2

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    This paper overviews the development and differentiation of the hypothalamus and pituitary gland from embryonic stem (ES) and induced pluripotent stem (iPS) cells. It is important to replicate the developmental process in vivo to create specific cells/organoids from ES/iPS cells. We also introduce the latest findings and discuss future issues for clinical application. Neuroectodermal progenitors are induced from pluripotent stem cells by strictly removing exogenous patterning factors during the early differentiation period. The induced progenitors differentiate into rostral hypothalamic neurons, in particular magnocellular vasopressin+ neurons. In three-dimensional cultures, the ES/iPS cells differentiate into hypothalamic neuroectoderm as well as non-neural head ectoderm back to back. Rathke's pouch-like structures self-organize at the interface between the two layers and generated various endocrine cells, including corticotrophs and somatotrophs from the Rathke's pouch-like structures. Our next objective is to sophisticate our stepwise methodology to establish the novel transplantation treatment for hypopituitarism and to apply it to developmental disease models.

    DOI: 10.1111/dgd.12719

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  47. Open-label, multicenter, dose-titration study to determine the efficacy and safety of tolvaptan in Japanese patients with hyponatremia secondary to syndrome of inappropriate secretion of antidiuretic hormone.

    Arima H, Goto K, Motozawa T, Mouri M, Watanabe R, Hirano T, Ishikawa SE

    Endocrine journal   Vol. 68 ( 1 ) page: 17 - 29   2021.1

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    DOI: 10.1507/endocrj.EJ20-0216

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  48. イピリムマブとニボルマブの併用療法後に原発性副腎皮質機能低下症と潜在性甲状腺機能低下症を認めた一例 Reviewed

    山田 紗矢加, 岩間 信太郎, 小林 朋子, 伊藤 雅晃, 奥地 剛之, 安田 康紀, 有馬 寛

    日本内分泌学会雑誌   Vol. 96 ( 3 ) page: 720 - 720   2021.1

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  49. Efficacies of programmed cell death 1 ligand 1 blockade in non-small cell lung cancer patients with acquired resistance to prior programmed cell death 1 inhibitor and development of diabetic ketoacidosis caused by two different etiologies: a retrospective case series

    Ishi Azusa, Tanaka Ichidai, Iwama Shintaro, Sakakibara Toshihiro, Mastui Toshinori, Kobayashi Tomoko, Hase Tetsunari, Morise Masahiro, Sato Mitsuo, Arima Hiroshi, Hashimoto Naozumi

    ENDOCRINE JOURNAL   Vol. 68 ( 5 ) page: 613 - 620   2021

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  50. Peripheral combination treatment of leptin and an SGLT2 inhibitor improved glucose metabolism in insulin-dependent diabetes mellitus mice

    Yaginuma Hiroshi, Banno Ryoichi, Sun Runan, Taki Keigo, Mizoguchi Akira, Kobayashi Tomoko, Sugiyama Mariko, Tsunekawa Taku, Onoue Takeshi, Takagi Hiroshi, Hagiwara Daisuke, Ito Yoshihiro, Iwama Shintaro, Suga Hidetaka, Arima Hiroshi

    JOURNAL OF PHARMACOLOGICAL SCIENCES   Vol. 147 ( 4 ) page: 340 - 347   2021

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    DOI: 10.1016/j.jphs.2021.08.010

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  51. Preoperative and long-term efficacy and safety of lanreotide autogel in patients with thyrotropin-secreting pituitary adenoma: a multicenter, single-arm, phase 3 in Japan

    Shimatsu Akira, Nakamura Akinobu, Takahashi Yutaka, Fujio Shingo, Satoh Fumitoshi, Tahara Shigeyuki, Nishioka Hiroshi, Takano Koji, Yamashita Miho, Arima Hiroshi, Tominaga Atsushi, Tateishi Shohei, Matsushita Yusaku

    ENDOCRINE JOURNAL   Vol. 68 ( 7 ) page: 791 - 805   2021

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  52. Open-label, multicenter, dose-titration study to determine the efficacy and safety of tolvaptan in Japanese patients with hyponatremia secondary to syndrome of inappropriate secretion of antidiuretic hormone

    Arima Hiroshi, Goto Koichi, Motozawa Tomohisa, Mouri Makoto, Watanabe Ryo, Hirano Takahiro, Ishikawa San-e

    ENDOCRINE JOURNAL   Vol. 68 ( 1 ) page: 17 - 29   2021

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  53. Induction of Functional Hypothalamus and Pituitary Tissues From Pluripotent Stem Cells for Regenerative Medicine Invited Reviewed

    Kano M, Suga H, Arima H.

    J Endocr Soc   Vol. 5 ( 3 ) page: bvaa188   2020.12

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    DOI: 10.1210/jendso/bvaa188.

  54. Anti-pituitary antibodies as a marker of autoimmunity in pituitary glands.

    Iwama S, Arima H

    Endocrine journal   Vol. 67 ( 11 ) page: 1077 - 1083   2020.11

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    DOI: 10.1507/endocrj.EJ20-0436

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  55. Endoplasmic reticulum chaperone BiP/GRP78 knockdown leads to autophagy and cell death of arginine vasopressin neurons in mice.

    Kawaguchi Y, Hagiwara D, Miyata T, Hodai Y, Kurimoto J, Takagi H, Suga H, Kobayashi T, Sugiyama M, Onoue T, Ito Y, Iwama S, Banno R, Grinevich V, Arima H

    Scientific reports   Vol. 10 ( 1 ) page: 19730   2020.11

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    <title>Abstract</title>The immunoglobulin heavy chain binding protein (BiP), also referred to as 78-kDa glucose-regulated protein (GRP78), is a pivotal endoplasmic reticulum (ER) chaperone which modulates the unfolded protein response under ER stress. Our previous studies showed that BiP is expressed in arginine vasopressin (AVP) neurons under non-stress conditions and that BiP expression is upregulated in proportion to the increased AVP expression under dehydration. To clarify the role of BiP in AVP neurons, we used a viral approach in combination with shRNA interference for BiP knockdown in mouse AVP neurons. Injection of a recombinant adeno-associated virus equipped with a mouse AVP promoter and BiP shRNA cassette provided specific BiP knockdown in AVP neurons of the supraoptic (SON) and paraventricular nuclei (PVN) in mice. AVP neuron-specific BiP knockdown led to ER stress and AVP neuronal loss in the SON and PVN, resulting in increased urine volume due to lack of AVP secretion. Immunoelectron microscopy of AVP neurons revealed that autophagy was activated through the process of AVP neuronal loss, whereas no obvious features characteristic of apoptosis were observed. Pharmacological inhibition of autophagy by chloroquine exacerbated the AVP neuronal loss due to BiP knockdown, indicating a protective role of autophagy in AVP neurons under ER stress. In summary, our results demonstrate that BiP is essential for the AVP neuron system.

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    Other Link: http://www.nature.com/articles/s41598-020-76839-z

  56. Degradation of Mutant Protein Aggregates within the Endoplasmic Reticulum of Vasopressin Neurons. International journal

    Miyata T, Hagiwara D, Hodai Y, Miwata T, Kawaguchi Y, Kurimoto J, Ozaki H, Mitsumoto K, Takagi H, Suga H, Kobayashi T, Sugiyama M, Onoue T, Ito Y, Iwama S, Banno R, Matsumoto M, Kawakami N, Ohno N, Sakamoto H, Arima H

    iScience   Vol. 23 ( 10 ) page: 101648 - 101648   2020.10

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    Misfolded or unfolded proteins in the ER are said to be degraded only after translocation or isolation from the ER. Here, we describe a mechanism by which mutant proteins are degraded within the ER. Aggregates of mutant arginine vasopressin (AVP) precursor were confined to ER-associated compartments (ERACs) connected to the ER in AVP neurons of a mouse model of familial neurohypophysial diabetes insipidus. The ERACs were enclosed by membranes, an ER chaperone and marker protein of phagophores and autophagosomes were expressed around the aggregates, and lysosomes fused with the ERACs. Moreover, lysosome-related molecules were present within the ERACs, and aggregate degradation within the ERACs was dependent on autophagic-lysosomal activity. Thus, we demonstrate that protein aggregates can be degraded by autophagic-lysosomal machinery within specialized compartments of the ER.

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  57. Generation of four induced pluripotent stem cell lines (FHUi003-A, FHUi003-B, FHUi004-A and FHUi004-B) from two affected individuals of a familial neurohypophyseal diabetes insipidus family

    Yoshida Satoru, Okura Hanayuki, Suga Hidetaka, Soen Mika, Kawaguchi Yohei, Kurimoto Junki, Miyata Takashi, Takagi Hiroshi, Arima Hiroshi, Fujikawa Tatsuya, Otsuka Fumio, Matsuyama Akifumi

    STEM CELL RESEARCH   Vol. 48   page: 101960 - 101960   2020.10

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  58. The Smart Life Stay (SLS) program: effects of a lifestyle intervention program in combination with health tourism and health guidance for type 2 diabetes (vol 10, 33, 2020)

    Matsushita Madoka, Muramoto Akiko, Nomura Eri, Eguchi Yukari, Kato Ayako, Sano Yoshiko, Kabayama Mai, Arakawa Masashi, Oguma Yuko, Yabe Daisuke, Matsunaga Masaaki, Yatsuya Hiroshi, Arima Hiroshi, Tsushita Kazuyo

    NUTRITION & DIABETES   Vol. 10 ( 1 ) page: 34   2020.9

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    DOI: 10.1038/s41387-020-00137-w

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  59. Higher level of body mass index (>= 22 kg/m(2)) is a useful predictor of non-insulin requirement in Slowly Progressive Insulin-Dependent (Type 1) Diabetes Mellitus (SPIDDM)

    Onoue T., Wada E., Hayase A., Handa T., Furukawa M., Kobayashi T., Goto M., Arima H.

    DIABETOLOGIA   Vol. 63 ( SUPPL 1 ) page: S176 - S176   2020.9

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  60. The regulation of glucose metabolism by astrocytes in diet induced obesity mice

    Sugiyama M., Banno R., Sun R., Yaginuma H., Taki K., Takagi H., Ito Y., Yamanaka K., Arima H.

    DIABETOLOGIA   Vol. 63 ( SUPPL 1 ) page: S266 - S266   2020.9

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  61. Protein tyrosine phosphatase 1B deficiency enhances leptin action to improve glucose homeostasis in IDDM treatment with leptin

    Ito Y., Banno R., Sun R., Yaginuma H., Taki K., Sugiyama M., Tsunekawa T., Takagi H., Arima H.

    DIABETOLOGIA   Vol. 63 ( SUPPL 1 ) page: S12 - S12   2020.9

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  62. Peripheral combination treatment of leptin and SGLT2 inhibitor improved glucose metabolism in insulin-dependent diabetes mice

    Yaginuma H., Banno R., Sun R., Taki K., Sugiyama M., Tsunekawa T., Takagi H., Ito Y., Arima H.

    DIABETOLOGIA   Vol. 63 ( SUPPL 1 ) page: S259 - S260   2020.9

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  63. The Smart Life Stay (SLS) program: effects of a lifestyle intervention program in combination with health tourism and health guidance for type 2 diabetes International journal

    Matsushita Madoka, Muramoto Akiko, Nomura Eri, Eguchi Yukari, Kato Ayako, Sano Yoshiko, Kabayama Mai, Arakawa Masashi, Oguma Yuko, Yabe Daisuke, Matsunaga Masaaki, Yatsuya Hiroshi, Arima Hiroshi, Tsushita Kazuyo

    NUTRITION & DIABETES   Vol. 10 ( 1 ) page: 33 - 33   2020.8

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    BACKGROUND: The aim of this study was to determine the effectiveness of the Smart Life Stay (SLS) program, which is an experience-oriented stayover program, in combination with health tourism and mandatory health guidance on glucose metabolism after 2 years. METHODS: The participants of the SLS program (n = 792) were recruited from a database of 23 medical insurers. They underwent a mandatory health examination termed Specific Health Checkups in 2014. The participants were included if they had diabetes or were at a high risk of diabetes and if they satisfied the following inclusion criteria: (1) body mass index (BMI; kg/m2) > 25, or (2) waist circumference (WC; cm) > 85 for men and > 90 for women, or (3) hemoglobin A1c (HbA1c; %) > 5.6, or (4) fasting plasma glucose (FPG; mg/dl) > 100. Individuals who corresponded to one or more items were included as study participants. The control subjects (n = 3645) were nonparticipants of the program who were selected from the database and met the inclusion criteria. The lifestyle changes and changes in mean BMI, WC, FPG, and HbA1c in both groups from baseline to 2-year follow-up were compared by inverse probability weighting of a propensity score. RESULTS: The percentage of people who exercised regularly increased significantly in the SLS group compared with the control group. In the SLS group, BW, BMI, and WC significantly decreased by 1.75 kg, 0.60 kg/m2, and 1.45 cm, respectively, whereas in the control group, WC, FPG, and HbA1c increased significantly by 0.38 cm, 3.37 mg/dl, and 0.12%, respectively. The comparison between groups revealed that the BW, BMI, WC, FPG, and HbA1c improved significantly in the SLS group. CONCLUSIONS: The SLS program is suggested to help improve glucose metabolism. This program could be a feasible option as a lifestyle intervention program for diabetes.

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  64. LUBAC accelerates B-cell lymphomagenesis by conferring resistance to genotoxic stress on B cells.

    Jo T, Nishikori M, Kogure Y, Arima H, Sasaki K, Sasaki Y, Nakagawa T, Iwai F, Momose S, Shiraishi A, Kiyonari H, Kagaya N, Onuki T, Shin-Ya K, Yoshida M, Kataoka K, Ogawa S, Iwai K, Takaori-Kondo A

    Blood   Vol. 136 ( 6 ) page: 684 - 697   2020.8

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  65. 免疫チェックポイント阻害薬による下垂体障害に関連する自己抗体の網羅的解析

    奥地 剛之, 岩間 信太郎, 伊藤 雅晃, 岡田 則男, 小林 朋子, 安田 康紀, 有馬 寛

    日本内分泌学会雑誌   Vol. 96 ( 1 ) page: 245 - 245   2020.8

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  66. 甲状腺の内部エコー不均一は甲状腺自己抗体陽性者における抗PD-1抗体関連甲状腺障害の高リスクマーカーとなる

    岡田 則男, 岩間 信太郎, 伊藤 雅晃, 奥地 剛之, 小林 朋子, 安田 康紀, 有馬 寛

    日本内分泌学会雑誌   Vol. 96 ( 1 ) page: 243 - 243   2020.8

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  67. Generation of three induced pluripotent stem cell (iPSC) lines from a multiple endocrine neoplasia type 1 (MEN1) patient and three iPSC lines from an unaffected relative of the patient. Reviewed International journal

    Satoru Yoshida, Hanayuki Okura, Hidetaka Suga, Tomohiko Nishitomi, Akihiro Sakurai, Hiroshi Arima, Akifumi Matsuyama

    Stem cell research   Vol. 46   page: 101846 - 101846   2020.7

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    We generated three disease-specific iPSC lines from a Multiple endocrine neoplasia type 1 (MEN1) patient and three control iPSC lines from an unaffected blood relative of the patient using unutilized lymphoblastoid B cell lines (LCLs) as a cell resource. The expression of pluripotency markers, retaining of normal karyotype of chromosome, absence of episomal vectors used for generating the iPSCs and EBV used for generating LCLs, and the potential to differentiate into three germ layers, were confirmed for each iPSC line. These iPSC lines can be useful for construction of the disease models in vitro, and elucidation of the disease mechanisms.

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  68. Hypothalamic glial cells isolated by MACS reveal that microglia and astrocytes induce hypothalamic inflammation via different processes under high-fat diet conditions Reviewed International journal

    Mariko Sugiyama, Ryoichi Banno, Hiroshi Yaginuma, Keigo Taki, Akira Mizoguchi, Taku Tsunekawa, Takeshi Onoue, Hiroshi Takagi, Yoshihiro Ito, Shintaro Iwama, Motomitsu Goto, Hidetaka Suga, Okiru Komine, Koji Yamanaka, Hiroshi Arima

    Neurochemistry International   Vol. 136   page: 104733 - 104733   2020.6

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    Glial cells can mediate hypothalamic inflammatory processes induced in response to a high-fat diet (HFD). We used magnetic-activated cell sorting (MACS) to isolate microglia and astrocytes from hypothalamus of mice fed HFD and examined changes in expression of inflammation-related cytokines and markers related to glial cell activation status. Hypothalamus from male C57BL6 mice fed a chow diet (chow) or HFD for 1, 3, or 28 days were collected and microglia and astrocytes were isolated by MACS. After confirming cell viability by fluorescence activated cell sorting, mRNA expression levels of inflammation-related cytokines and markers of glial cell activation status were examined by qRT-PCR, which revealed that both glial cell types isolated by MACS retained specificity. On day 3 of HFD, both CD86 and TNFα mRNA expression was significantly increased in microglia relative to the chow group. In astrocytes, TNFα mRNA expression levels were similar between the chow and HFD groups on day 3, but anti-inflammatory cytokine IL-10 levels were significantly increased. On day 7 of HFD, TNFα expression in microglia decreased to levels comparable to the chow group while that in astrocytes remained unchanged. On day 28 of HFD, TNFα levels were significantly increased in both microglia and astrocytes, which had increased mRNA expression of CD86 and MAO-B, respectively. For both glial cell types, results for TNFα expression assessed by RT-PCR and immunohistochemical analysis were similar. These results indicate that the role of microglia and astrocytes in hypothalamic inflammation under HFD conditions changed with time and these changes were accompanied by changes in the activation status of glial cells. Our data suggest that early after initiating HFD, hypothalamic astrocytes suppress diet-induced inflammation at least in part by secreting IL-10, whereas continued HFD feeding impairs this suppressive function such that both microglia and astrocytes promote hypothalamic inflammation.

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  69. Anti-thyroid antibodies and thyroid echo pattern at baseline as risk factors for thyroid dysfunction induced by anti-programmed cell death-1 antibodies: a prospective study. Reviewed International journal

    Norio Okada, Shintaro Iwama, Takayuki Okuji, Tomoko Kobayashi, Yoshinori Yasuda, Eri Wada, Takeshi Onoue, Motomitsu Goto, Mariko Sugiyama, Taku Tsunekawa, Hiroshi Takagi, Daisuke Hagiwara, Yoshihiro Ito, Hidetaka Suga, Ryoichi Banno, Tetsunari Hase, Masahiro Morise, Mitsuro Kanda, Kenji Yokota, Naozumi Hashimoto, Masahiko Ando, Yasushi Fujimoto, Masato Nagino, Yasuhiro Kodera, Mitsuhiro Fujishiro, Hideharu Hibi, Michihiko Sone, Hitoshi Kiyoi, Momokazu Gotoh, Yuichi Ando, Masashi Akiyama, Yoshinori Hasegawa, Hiroshi Arima

    British journal of cancer   Vol. 122 ( 6 ) page: 771 - 777   2020.3

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    BACKGROUND: Anti-programmed cell death-1 (PD-1) antibodies can cause thyroid dysfunction. However, no predictive biomarkers enabling stratification of thyroid dysfunction risk have been identified. METHODS: A total of 209 patients treated with an anti-PD-1 antibody were evaluated for anti-thyroid antibodies at baseline and prospectively for thyroid function every 6 weeks for 24 weeks after treatment initiation, and then observed until the visits stopped. Thyroid ultrasonography was performed if the patient was positive for anti-thyroid antibodies at baseline. RESULTS: Of the 209 patients, 19 (9.1%) developed thyroid dysfunction (destructive thyroiditis or hypothyroidism). The cumulative incidence of thyroid dysfunction was significantly higher in patients who were positive vs. negative for anti-thyroid antibodies (15/44 [34.1%] vs. 4/165 [2.4%], p < 0.001). Forty-two patients positive for anti-thyroid antibodies at baseline were divided into two groups according to the presence of an irregular echo pattern. The cumulative incidence of thyroid dysfunction was significantly higher in those with an irregular vs. a regular echo pattern (13/23 [56.5%] vs. 1/19 [5.3%], p = 0.001). None of the patients developed thyroid dysfunction after the initial 24-week period. CONCLUSIONS: The risk of thyroid dysfunction induced by anti-PD-1 antibodies can be predicted by evaluation of anti-thyroid antibodies and the thyroid echo pattern at baseline. TRIAL REGISTRATION: UMIN000019024.

    DOI: 10.1038/s41416-020-0736-7

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    Other Link: http://www.nature.com/articles/s41416-020-0736-7

  70. 免疫チェックポイント阻害薬による免疫関連有害事象のうち下垂体障害は全生存率延長と関連する

    小林 朋子, 岩間 信太郎, 伊藤 雅晃, 奥地 剛之, 岡田 則男, 安田 康紀, 有馬 寛

    日本内分泌学会雑誌   Vol. 95 ( 4 ) page: 1446 - 1446   2020.2

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  71. 甲状腺自己抗体は抗PD-1抗体による甲状腺機能異常症の高リスク因子となる

    岡田 則男, 岩間 信太郎, 伊藤 雅晃, 奥地 剛之, 小林 朋子, 安田 康紀, 有馬 寛

    日本内分泌学会雑誌   Vol. 95 ( 4 ) page: 1332 - 1332   2020.2

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  72. Dipeptidyl peptidase-4 inhibitor anagliptin reduces fasting apolipoprotein B-48 levels in patients with type 2 diabetes: A randomized controlled trial. Reviewed International journal

    Takeshi Onoue, Motomitsu Goto, Eri Wada, Mariko Furukawa, Takayuki Okuji, Norio Okada, Tomoko Kobayashi, Shintaro Iwama, Mariko Sugiyama, Taku Tsunekawa, Hiroshi Takagi, Daisuke Hagiwara, Yoshihiro Ito, Yoshiaki Morishita, Yusuke Seino, Hidetaka Suga, Ryoichi Banno, Yoji Hamada, Masahiko Ando, Etsuko Yamamori, Hiroshi Arima

    PloS one   Vol. 15 ( 1 ) page: e0228004   2020.1

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    Type 2 diabetes and dyslipidemia are diseases that collectively increase the risk of patients developing cardiovascular complications. Several incretin-based drugs are reported to improve lipid metabolism, and one of these medications, anagliptin, is a dipeptidyl peptidase-4 (DPP-4) inhibitor that has been shown to decrease serum triglyceride and low-density lipoproteins cholesterol. This study aimed to conduct an investigation into the effects of anagliptin on serum lipid profiles. This multicenter, open-label, randomized (1:1), parallel group study was designed to evaluate the effects of anagliptin on serum lipid profiles (triglycerides, lipoproteins, apolipoproteins, and cholesterol fractions). The study involved 24 patients with type 2 diabetes at two participating hospitals for a period of 24 weeks. Patients were randomly assigned to the anagliptin (n = 12) or control (n = 12) groups. Patients in the anagliptin group were treated with 200 mg of the drug twice daily. Patients in the control group did not receive anagliptin, but continued with their previous treatment schedules. Lipid metabolism was examined under fasting conditions at baseline and 24 weeks. Patients treated with anagliptin for 24 weeks exhibited significantly reduced levels of serum apolipoprotein B-48, a marker for lipid transport from the intestine, compared with the control group patients (P < 0.05). After 24 weeks of treatment, serum adiponectin levels were significantly raised, whereas glycated hemoglobin (HbA1c) levels were significantly lower compared with the baseline in the anagliptin group (P < 0.05), but not in the control group. This study showed that the DPP-4 inhibitor anagliptin reduces fasting apolipoprotein B-48 levels, suggesting that this drug may have beneficial effects on lipid metabolism possibly mediated by the inhibition of intestinal lipid transport.

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  73. Dipeptidyl peptidase-4 inhibition prevents nonalcoholic steatohepatitis-associated liver fibrosis and tumor development in mice independently of its anti-diabetic effects International journal

    Kawakubo Mitsuhiro, Tanaka Miyako, Ochi Kozue, Watanabe Akiko, Saka-Tanaka Marie, Kanamori Yohei, Yoshioka Naoki, Yamashita Satoko, Goto Moritaka, Itoh Michiko, Shirakawa Ibuki, Kanai Sayaka, Suzuki Hiromi, Sawada Makoto, Ito Ayaka, Ishigami Masatoshi, Fujishiro Mitsuhiro, Arima Hiroshi, Ogawa Yoshihiro, Suganami Takayoshi

    SCIENTIFIC REPORTS   Vol. 10 ( 1 ) page: 983 - 983   2020.1

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    Nonalcoholic steatohepatitis (NASH) is a hepatic phenotype of the metabolic syndrome, and increases the risk of cirrhosis and hepatocellular carcinoma (HCC). Although increasing evidence points to the therapeutic implications of certain types of anti-diabetic agents in NASH, it remains to be elucidated whether their effects on NASH are independent of their effects on diabetes. Genetically obese melanocortin 4 receptor-deficient (MC4R-KO) mice fed Western diet are a murine model that sequentially develops hepatic steatosis, NASH, and HCC in the presence of obesity and insulin resistance. In this study, we investigated the effect of the dipeptidyl peptidase-4 (DPP-4) inhibitor anagliptin on NASH and HCC development in MC4R-KO mice. Anagliptin treatment effectively prevented inflammation, fibrosis, and carcinogenesis in the liver of MC4R-KO mice. Interestingly, anagliptin only marginally affected body weight, systemic glucose and lipid metabolism, and hepatic steatosis. Histological data and gene expression analysis suggest that anagliptin treatment targets macrophage activation in the liver during the progression from simple steatosis to NASH. As a molecular mechanism underlying anagliptin action, we showed that glucagon-like peptide-1 suppressed proinflammatory and profibrotic phenotypes of macrophages in vitro. This study highlights the glucose metabolism-independent effects of anagliptin on NASH and HCC development.

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  74. Hypothalamic Contribution to Pituitary Functions Is Recapitulated In Vitro Using 3D-Cultured Human iPS Cells. Reviewed International journal

    Takatoshi Kasai, Hidetaka Suga, Mayu Sakakibara, Chikafumi Ozone, Ryusaku Matsumoto, Mayuko Kano, Kazuki Mitsumoto, Koichiro Ogawa, Yu Kodani, Hiroshi Nagasaki, Naoko Inoshita, Mariko Sugiyama, Takeshi Onoue, Taku Tsunekawa, Yoshihiro Ito, Hiroshi Takagi, Daisuke Hagiwara, Shintaro Iwama, Motomitsu Goto, Ryoichi Banno, Jun Takahashi, Hiroshi Arima

    Cell reports   Vol. 30 ( 1 ) page: 18 - +   2020.1

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    The pituitary is a major hormone center that secretes systemic hormones responding to hypothalamus-derived-releasing hormones. Previously, we reported the independent pituitary induction and hypothalamic differentiation of human embryonic stem cells (ESCs). Here, a functional hypothalamic-pituitary unit is generated using human induced pluripotent stem (iPS) cells in vitro. The adrenocorticotropic hormone (ACTH) secretion capacity of the induced pituitary reached a comparable level to that of adult mouse pituitary because of the simultaneous maturation with hypothalamic neurons within the same aggregates. Corticotropin-releasing hormone (CRH) from the hypothalamic area regulates ACTH cells similarly to our hypothalamic-pituitary axis. Our induced hypothalamic-pituitary units respond to environmental hypoglycemic condition in vitro, which mimics a life-threatening situation in vivo, through the CRH-ACTH pathway, and succeed in increasing ACTH secretion. Thus, we generated powerful hybrid organoids by recapitulating hypothalamic-pituitary development, showing autonomous maturation on the basis of interactions between developing tissues.

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  75. Flash glucose monitoring helps achieve better glycemic control than conventional self-monitoring of blood glucose in non-insulin-treated type 2 diabetes: a randomized controlled trial Reviewed

    Wada Eri, Onoue Takeshi, Kobayashi Tomoko, Handa Tomoko, Hayase Ayaka, Ito Masaaki, Furukawa Mariko, Okuji Takayuki, Okada Norio, Iwama Shintaro, Sugiyama Mariko, Tsunekawa Taku, Takagi Hiroshi, Hagiwara Daisuke, Ito Yoshihiro, Suga Hidetaka, Banno Ryoichi, Kuwatsuka Yachiyo, Ando Masahiko, Goto Motomitsu, Arima Hiroshi

    BMJ OPEN DIABETES RESEARCH & CARE   Vol. 8 ( 1 )   2020.1

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    DOI: 10.1136/bmjdrc-2019-001115

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  76. ペムブロリズマブ使用中にバセドウ病が増悪した一例

    岡田 則男, 岩間 信太郎, 伊藤 雅晃, 奥地 剛之, 小林 朋子, 安田 康紀, 恒川 卓, 有馬 寛

    日本内分泌学会雑誌   Vol. 95 ( 3 ) page: 1125 - 1125   2020.1

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  77. Diagnosis and treatment of autoimmune and IgG4-related hypophysitis: clinical guidelines of the Japan Endocrine Society

    Takagi Hiroshi, Iwama Shintaro, Sugimura Yoshihisa, Takahashi Yutaka, Oki Yutaka, Akamizu Takashi, Arima Hiroshi

    ENDOCRINE JOURNAL   Vol. 67 ( 4 ) page: 373 - 378   2020

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    Hypophysitis, which is often accompanied by pituitary dysfunction, is classified into several subtypes based on the cause, histology, and the location of inflammation in the pituitary gland. A definitive diagnosis requires pituitary biopsy, which is invasive, and the process is limited to specialized clinical settings. In this opinion paper, we review the literature associated with hypophysitis, and provide the guidelines of the Japan Endocrine Society for the diagnosis and treatment of autoimmune and IgG4-related hypophysitis.

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  78. Pituitary dysfunction induced by immune checkpoint inhibitors is associated with better overall survival in both malignant melanoma and non-small cell lung carcinoma: a prospective study. Reviewed International journal

    Tomoko Kobayashi, Shintaro Iwama, Yoshinori Yasuda, Norio Okada, Takayuki Okuji, Masaaki Ito, Takeshi Onoue, Motomitsu Goto, Mariko Sugiyama, Taku Tsunekawa, Hiroshi Takagi, Daisuke Hagiwara, Yoshihiro Ito, Hidetaka Suga, Ryoichi Banno, Kenji Yokota, Tetsunari Hase, Masahiro Morise, Naozumi Hashimoto, Masahiko Ando, Yasushi Fujimoto, Hideharu Hibi, Michihiko Sone, Yuichi Ando, Masashi Akiyama, Yoshinori Hasegawa, Hiroshi Arima

    Journal for immunotherapy of cancer   Vol. 8 ( 2 ) page: e000779   2020

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    BACKGROUND: Several immune-related adverse events (irAEs) are reported to be associated with therapeutic efficacy of immune checkpoint inhibitors, yet whether pituitary dysfunction, a life-threatening irAE, affects overall survival (OS) in patients with malignancies is unclear. This prospective study examined the association of pituitary dysfunction (pituitary-irAE) with OS of patients with non-small cell lung carcinoma (NSCLC) or malignant melanoma (MM). METHODS: A total of 174 patients (NSCLC, 108; MM, 66) treated with ipilimumab, nivolumab, pembrolizumab, or atezolizumab at Nagoya University Hospital were evaluated for OS and the development of pituitary-irAE. Kaplan-Meier curves of OS as a function of the development of pituitary-irAE were produced with the log-rank test as a primary endpoint. RESULTS: Pituitary-irAE was observed in 16 patients (4 (3.7%) with NSCLC, 12 (18.2%) with MM) having two different disease types: hypophysitis with deficiency of multiple anterior pituitary hormones accompanied by pituitary enlargement, and isolated adrenocorticotropic hormone (ACTH) deficiency without pituitary enlargement. Among these patients, 6 developed pituitary-irAE while being treated with ipilimumab (6/25 patients (24.0%) treated with ipilimumab) and 10 developed pituitary-irAE during treatment with nivolumab or pembrolizumab (10/167 (6.0%)). All 16 patients had ACTH deficiency and were treated with physiological doses of hydrocortisone. The development of pituitary-irAE was associated with better OS in patients with NSCLC (not reached vs 441 (95% CI not calculated) days, p<0.05) and MM (885 (95% CI 434 to 1336) vs 298 (95% CI 84 to 512) days, p<0.05). CONCLUSIONS: In our study cohort, the incidence of pituitary-irAE was higher than previously reported and the development of pituitary-irAE predicted better prognosis for both NSCLC and MM when patients were treated with physiological doses of hydrocortisone. CLINICAL TRIALS REGISTRATION: UMIN000019024.

    DOI: 10.1136/jitc-2020-000779

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  79. Diagnosis of central diabetes insipidus using a vasopressin radioimmunoassay during hypertonic saline infusion Reviewed International journal

    Hiroshi Takagi, Daisuke Hagiwara, Tomoko Handa, Mariko Sugiyama, Takeshi Onoue, Taku Tsunekawa, Yoshihiro Ito, Shintaro Iwama, Motomitsu Goto, Hidetaka Suga, Ryoichi Banno, Kunihiko Takahashi, Shigeyuki Matsui, Hiroshi Arima

    Endocrine Journal   Vol. 67 ( 3 ) page: 267 - 274   2020

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    DOI: 10.1507/endocrj.EJ19-0224

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  80. Anti-pituitary antibodies as a marker of autoimmunity in pituitary glands

    Iwama Shintaro, Arima Hiroshi

    ENDOCRINE JOURNAL   Vol. 67 ( 11 ) page: 1077 - 1083   2020

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  81. GABAB Receptor Signaling in the Mesolimbic System Suppresses Binge-like Consumption of a High-Fat Diet. International journal

    Tsunekawa T, Banno R, Yaginuma H, Taki K, Mizoguchi A, Sugiyama M, Onoue T, Takagi H, Hagiwara D, Ito Y, Iwama S, Goto M, Suga H, Bettler B, Arima H

    iScience   Vol. 20   page: 337 - +   2019.10

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    Binge eating could contribute to the development of obesity, and previous studies suggest that gamma-aminobutyric acid (GABA) type B receptor (GABABR) signaling is involved in the regulation of binge eating. Here, we show that time-restricted access to a high-fat diet (HFD) induces binge-like eating behavior in wild-type mice. HFD consumption during restricted time was significantly increased in corticostriatal neuron-specific GABABR-deficient mice compared with wild-type mice. Furthermore, the GABABR agonist baclofen suppressed HFD intake during restricted time in wild-type mice but not in corticostriatal or dopaminergic neuron-specific GABABR-deficient mice. In contrast, there were no significant differences in food consumption among genotypes under ad libitum access to HFD. Thus, our data show that the mesolimbic system regulates food consumption under time-restricted but not ad libitum access to HFD and have identified a mechanism by which GABABR signaling suppresses binge-like eating of HFD.

    DOI: 10.1016/j.isci.2019.09.032

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  82. 臨床研究への取り組み方 IoTを用いた生活習慣病へのアプローチ Reviewed

    尾上 剛史, 津下 一代, 有馬 寛

    肥満研究   Vol. 25 ( Suppl. ) page: 146 - 146   2019.10

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  83. Improved methods for the differentiation of hypothalamic vasopressin neurons using mouse induced pluripotent stem cells.

    Mitsumoto K, Suga H, Sakakibara M, Soen M, Yamada T, Ozaki H, Nagai T, Kano M, Kasai T, Ozone C, Ogawa K, Sugiyama M, Onoue T, Tsunekawa T, Takagi H, Hagiwara D, Ito Y, Iwama S, Goto M, Banno R, Arima H

    Stem cell research   Vol. 40   page: 101572   2019.9

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    DOI: 10.1016/j.scr.2019.101572

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  84. TDP-43 regulates early-phase insulin secretion via CaV1.2-mediated exocytosis in islets. International journal

    Kunihiko Araki, Amane Araki, Daiyu Honda, Takako Izumoto, Atsushi Hashizume, Yasuhiro Hijikata, Shinichiro Yamada, Yohei Iguchi, Akitoshi Hara, Kazuhiro Ikumi, Kaori Kawai, Shinsuke Ishigaki, Yoko Nakamichi, Shin Tsunekawa, Yusuke Seino, Akiko Yamamoto, Yasunori Takayama, Shihomi Hidaka, Makoto Tominaga, Mica Ohara-Imaizumi, Atsushi Suzuki, Hiroshi Ishiguro, Atsushi Enomoto, Mari Yoshida, Hiroshi Arima, Shin-Ichi Muramatsu, Gen Sobue, Masahisa Katsuno

    The Journal of clinical investigation   Vol. 129 ( 9 ) page: 3578 - 3593   2019.9

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    TAR DNA-binding protein 43 kDa (TDP-43), encoded by TARDBP, is an RNA-binding protein, the nuclear depletion of which is the histopathological hallmark of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder affecting both upper and lower motor neurons. Besides motor symptoms, patients with ALS often develop nonneuronal signs including glucose intolerance, but the underlying pathomechanism is still controversial, i.e., whether it is impaired insulin secretion and/or insulin resistance. Here, we showed that ALS subjects reduced early-phase insulin secretion and that the nuclear localization of TDP-43 was lost in the islets of autopsied ALS pancreas. Loss of TDP-43 inhibited exocytosis by downregulating CaV1.2 calcium channels, thereby reducing early-phase insulin secretion in a cultured β cell line (MIN6) and β cell-specific Tardbp knockout mice. Overexpression of CaV1.2 restored early-phase insulin secretion in Tardbp knocked-down MIN6 cells. Our findings suggest that TDP-43 regulates cellular exocytosis mediated by L-type voltage-dependent calcium channels and thus plays an important role in the early phase of insulin secretion by pancreatic islets. Thus, nuclear loss of TDP-43 is implicated in not only the selective loss of motor neurons but also in glucose intolerance due to impaired insulin secretion at an early stage of ALS.

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  85. Automated Feedback Messages With Shichifukujin Characters Using IoT System-Improved Glycemic Control in People With Diabetes: A Prospective, Multicenter Randomized Controlled Trial. International journal

    Tomoko Kobayashi, Kazuyo Tsushita, Eri Nomura, Akiko Muramoto, Ayako Kato, Yukari Eguchi, Takeshi Onoue, Motomitsu Goto, Shigeki Muto, Hiroshi Yatsuya, Hiroshi Arima

    Journal of diabetes science and technology   Vol. 13 ( 4 ) page: 796 - 798   2019.7

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    DOI: 10.1177/1932296819851785

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  86. Tanycyte-Like Cells Derived From Mouse Embryonic Stem Culture Show Hypothalamic Neural Stem/Progenitor Cell Functions International journal

    Kano Mayuko, Suga Hidetaka, Ishihara Takeshi, Sakakibara Mayu, Soen Mika, Yamada Tomiko, Ozaki Hajime, Mitsumoto Kazuki, Kasai Takatoshi, Sugiyama Mariko, Onoue Takeshi, Tsunekawa Taku, Takagi Hiroshi, Hagiwara Daisuke, Ito Yoshihiro, Iwama Shintaro, Goto Motomitsu, Banno Ryoichi, Arima Hiroshi

    ENDOCRINOLOGY   Vol. 160 ( 7 ) page: 1701 - 1718   2019.7

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    Tanycytes have recently been accepted as neural stem/progenitor cells in the postnatal hypothalamus. Persistent retina and anterior neural fold homeobox (Rax) expression is characteristic of tanycytes in contrast to its transient expression of whole hypothalamic precursors. In this study, we found that Rax+ residual cells in the maturation phase of hypothalamic differentiation in mouse embryonic stem cell (mESC) cultures had similar characteristics to ventral tanycytes. They expressed typical neural stem/progenitor cell markers, including Sox2, vimentin, and nestin, and differentiated into mature neurons and glial cells. Quantitative RT-PCR analysis showed that Rax+ residual cells expressed Fgf-10, Fgf-18, and Lhx2, which are expressed by ventral tanycytes. They highly expressed tanycyte-specific genes Dio2 and Gpr50 compared with Rax+ early hypothalamic progenitor cells. Therefore, Rax+ residual cells in the maturation phase of hypothalamic differentiation were considered to be more differentiated and similar to late progenitor cells and tanycytes. They self-renewed and formed neurospheres when cultured with exogenous FGF-2. Additionally, these Rax+ neurospheres differentiated into three neuronal lineages (neurons, astrocytes, and oligodendrocytes), including neuropeptide Y+ neuron, that are reported to be differentiated from ventral tanycytes toward the arcuate nuclei. Thus, Rax+ residual cells were multipotent neural stem/progenitor cells. Rax+ neurospheres were stably passaged and retained high Sox2 expression even after multiple passages. These results suggest the successful induction of Rax+ tanycyte-like cells from mESCs [induced tanycyte-like (iTan) cells]. These hypothalamic neural stem/progenitor cells may have potential in regenerative medicine and as a research tool.

    DOI: 10.1210/en.2019-00105

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  87. Improved water dispersibility and photostability in folic acid nanoparticles with transglycosylated naringin using combined processes of wet-milling and freeze-drying.

    Semba K, Kadota K, Arima H, Nakanishi A, Tandia M, Uchiyama H, Sugiyama K, Tozuka Y

    Food research international (Ottawa, Ont.)   Vol. 121   page: 108 - 116   2019.7

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    DOI: 10.1016/j.foodres.2019.03.034

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  88. 免疫チェックポイント阻害薬関連下垂体障害発症例では全生存率が延長する

    小林 朋子, 岩間 信太郎, 奥地 剛之, 岡田 則男, 安田 康紀, 有馬 寛

    日本内分泌学会雑誌   Vol. 95 ( 1 ) page: 332 - 332   2019.4

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  89. 甲状腺自己抗体陽性例はペムブロリズマブによる甲状腺機能異常症の発症率が高い

    岡田 則男, 岩間 信太郎, 奥地 剛之, 小林 朋子, 安田 康紀, 有馬 寛

    日本内分泌学会雑誌   Vol. 95 ( 1 ) page: 494 - 494   2019.4

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  90. 糖尿病腎症重症化予防のための戦略 全国自治体における糖尿病性腎症重症化予防プログラムの実証支援と事業評価

    古川 麻里子, 栄口 由香里, 村本 あき子, 岩竹 麻希, 野村 恵里, 安西 慶三, 植木 浩二郎, 岡村 智教, 樺山 舞, 後藤 資実, 有馬 寛, 佐野 喜子, 平田 匠, 福田 敬, 三浦 克之, 森山 美知子, 安田 宜成, 矢部 大介, 和田 隆志, 津下 一代

    糖尿病   Vol. 62 ( Suppl.1 ) page: S - 54   2019.4

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  91. 抗PD-1抗体誘発甲状腺炎マウスモデルの開発とリンパ球動態の解析

    岩間 信太郎, 安田 康紀, 奥地 剛之, 杉山 大介, 岡田 則男, 小林 朋子, 西川 博嘉, 有馬 寛

    日本内分泌学会雑誌   Vol. 95 ( 1 ) page: 398 - 398   2019.4

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  92. 免疫チェックポイント阻害薬(ICIs)関連内分泌障害発症例では全生存率が延長する

    小林 朋子, 岩間 信太郎, 奥地 剛之, 岡田 則男, 安田 康紀, 有馬 寛

    日本内科学会雑誌   Vol. 108 ( Suppl. ) page: 226 - 226   2019.2

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  93. Short-Term Steroid Regimen for Adult Steroid-Sensitive Minimal Change Disease International journal

    Ozeki Takaya, Katsuno Takayuki, Hayashi Hiroki, Kato Sawako, Yasuda Yoshinari, Ando Masahiko, Tsuboi Naotake, Hagiwara Daisuke, Arima Hiroshi, Maruyama Shoichi

    AMERICAN JOURNAL OF NEPHROLOGY   Vol. 49 ( 1 ) page: 54 - 63   2019

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    BACKGROUND: In pediatric patients with steroid-sensitive nephrotic syndrome, recent trials have revealed that a 2-month, short-term steroid regimen is not inferior to an extended steroid course. However, the optimal duration of initial steroid therapy for adult steroid-sensitive minimal change disease (MCD) remains unclear. OBJECTIVES: The aim of present study was to evaluate the effectiveness of a 2-month, short-term steroid regimen in the treatment of adult steroid-sensitive MCD patients. METHOD: This was a prospective observational study. Adult patients with steroid-sensitive MCD (n = 35) who were initiated on a short-term steroid regimen between January 2015 and June 2016 were included. The details of the regimen are as follows: (1) prednisolone was administered at an initial dose of 0.8-1.0 mg/kg/day and continued for 4-6 weeks and (2) dosage was reduced to 0.5-0.6 mg/kg/alternate day and continued for 4 weeks. Control patients (n = 140), who were treated using conventional steroid administration, were selected from our previous adult MCD cohort. All patients fulfilled the following criteria: biopsy-proven MCD, age ≥20 years, first episode of nephrotic syndrome, and attainment of complete remission within 4 weeks. The following parameters of patients who received short-term treatment regimen and control patients were compared: any relapse and frequent relapse, adverse events caused by steroid treatment and cumulative steroid dose. RESULTS: Throughout the observation period (median: 17.3 months), 24 (68.6%) patients in the short-term group developed at least one relapse. The short-term regimen showed earlier occurrence of any relapse than the conventional regimen (adjusted hazard ratio [aHR] 2.45; 95% CI 1.51-3.97; p < 0.001), but there was no difference in frequent relapse (aHR 1.31; 95% CI 0.43-3.99; p = 0.63). None of the patients showed any symptoms of adrenal insufficiency after discontinuation of corticosteroids. The cumulative steroid dose during the observational period was significantly lower in the short-term group than in the conventional group. CONCLUSIONS: The short-term steroid regimen may represent an effective treatment option that ensures lower steroid exposure when treating adult steroid-sensitive MCD patients.

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  94. Severe hypocalcemia following denosumab treatment in a patient with secondary osteoporosis associated with primary sclerosing cholangitis

    Yasuda Yoshinori, Iwama Shintaro, Arima Hiroshi

    ENDOCRINE JOURNAL   Vol. 66 ( 3 ) page: 271 - 275   2019

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    Primary sclerosing cholangitis (PSC) has been known as a cause of secondary osteoporosis, which often requires medication. Herein, we give the first report of a case of a 38-year-old man with fatigue and paralysis in both upper limbs who had been treated with denosumab for secondary osteoporosis associated with PSC. Since bisphosphonate (alendronate) was ineffective in our patient, the treatment was changed from alendronate to denosumab. Despite replacements with calcium and active vitamin D (alfacalcidol; 1-hydroxycholecalciferol), he developed severe hypocalcemia (albumin-adjusted serum calcium: 5.2 mg/dL) 2 weeks after the second administration of denosumab, which required immediate correction. After that, the corrected serum calcium levels were controlled within the normal range with 0.75 μg of eldecalcitol (1α,25-dihydroxy-2β-(3-hydroxypropyloxy)vitamin D3) and increased doses of calcium (1,500 mg daily) and phosphate (900 mg daily) without denosumab. Even though denosumab treatment had been terminated, the T score of the lumbar spine improved from -4.4 to -2.6 by 1 year after the second administration, possibly due to the amelioration of osteomalacia through the treatment with eldecalcitol and the higher doses of calcium and phosphate. This report indicates that denosumab can cause severe hypocalcemia in patients with osteoporosis associated with chronic diseases of the hepatobiliary system including PSC, in turn suggesting that the possibility of vitamin D deficiency or osteomalacia should be considered before administering treatments and that serum calcium levels should be closely monitored to detect life-threatening hypocalcemia in patients who have high risk factors for hypocalcemia.

    DOI: 10.1507/endocrj.EJ18-0545

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  95. Management of immune-related adverse events in endocrine organs induced by immune checkpoint inhibitors: clinical guidelines of the Japan Endocrine Society.

    Hiroshi Arima, Shintaro Iwama, Hidefumi Inaba, Hiroyuki Ariyasu, Noriko Makita, Michio Otsuki, Kazunori Kageyama, Akihisa Imagawa, Takashi Akamizu

    Endocrine journal   Vol. 66 ( 7 ) page: 581 - 586   2019

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    Immune checkpoint inhibitors (ICIs) have become a promising treatment for advanced malignancies. However, these drugs can induce immune-related adverse events (irAEs) in several organs, including skin, gastrointestinal tract, liver, muscle, nerve, and endocrine organs. Endocrine irAEs comprise hypopituitarism, primary adrenal insufficiency, thyroid dysfunction, hypoparathyroidism, and type 1 diabetes mellitus. These conditions have the potential to lead to life-threatening consequences, such as adrenal crisis, thyroid storm, severe hypocalcemia, and diabetic ketoacidosis. It is therefore important that both endocrinologists and oncologists understand the clinical features of each endocrine irAE to manage them appropriately. This opinion paper provides the guidelines of the Japan Endocrine Society and in part the Japan Diabetes Society for the management of endocrine irAEs induced by ICIs.

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  96. ペムブロリズマブ使用中止2ヵ月後に1型糖尿病を発症した一例

    岡田 則男, 岩間 信太郎, 半田 朋子, 奥地 剛之, 小林 朋子, 安田 康紀, 恒川 卓, 有馬 寛

    日本内分泌学会雑誌   Vol. 94 ( 3 ) page: 976 - 976   2018.12

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  97. Association of antithyroglobulin antibodies with the development of thyroid dysfunction induced by nivolumab. Reviewed

    Kimbara S, Fujiwara Y, Iwama S, Ohashi K, Kuchiba A, Arima H, Yamazaki N, Kitano S, Yamamoto N, Ohe Y

    Cancer science     2018.9

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    DOI: 10.1111/cas.13800

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  98. 高脂肪食の継続投与はグリア細胞の極性変化を伴い視床下部炎症が増悪する

    杉山 摩利子, 坂野 僚一, 柳沼 裕史, 滝 啓吾, 溝口 暁, 恒川 卓, 高木 博史, 伊藤 禎浩, 小峯 起, 山中 宏二, 有馬 寛

    肥満研究   Vol. 24 ( Suppl. ) page: 185 - 185   2018.9

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  99. Chemical chaperone 4-phenylbutylate reduces mutant protein accumulation in the endoplasmic reticulum of arginine vasopressin neurons in a mouse model for familial neurohypophysial diabetes insipidus International journal

    Masayoshi Tochiya, Daisuke Hagiwara, Yoshinori Azuma, Takashi Miyata, Yoshiaki Morishita, Hidetaka Suga, Takeshi Onoue, Taku Tsunekawa, Hiroshi Takagi, Yoshihiro Ito, Shintaro Iwama, Motomitsu Goto, Ryoichi Banno, Hiroshi Arima

    Neuroscience Letters   Vol. 682   page: 50 - 55   2018.8

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    Familial neurohypophysial diabetes insipidus (FNDI), characterized by progressive polyuria and loss of arginine vasopressin (AVP) neurons, is an autosomal dominant disorder caused by AVP gene mutations. Our previous studies with FNDI model mice demonstrated that mutant proteins accumulated in the endoplasmic reticulum (ER) of AVP neurons. Here, we examined therapeutic effects of the chemical chaperone 4-phenylbutylate (4-PBA) in FNDI mice. Treatment with 4-PBA reduced mutant protein accumulation in the ER of FNDI mice and increased AVP release, leading to reduced urine volumes. Furthermore, AVP neuron loss under salt loading was attenuated by 4-PBA treatment. These data suggest that 4-PBA ameliorated mutant protein accumulation in the ER of AVP neurons and thereby prevented FNDI phenotype progression.

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  100. Functional adenosine triphosphate-sensitive potassium channel is required in high-carbohydrate diet-induced increase in β-cell mass. Reviewed

        2018.8

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    DOI: 10.1111/jdi.12907

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  101. A novel mechanism of autophagy-associated cell death of vasopressin neurons in familial neurohypophysial diabetes insipidus. Invited Reviewed

    Hagiwara D, Grinevich V, Arima H

    Cell and tissue research     2018.6

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    DOI: 10.1007/s00441-018-2872-4

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  102. Dipeptidyl peptidase-4 inhibitors-associated bullous pemphigoid: A retrospective study of 168 pemphigoid and 9,304 diabetes mellitus patients. Reviewed

    Kawaguchi Y, Shimauchi R, Nishibori N, Kawashima K, Oshitani S, Fujiya A, Shibata T, Ohashi N, Izumi K, Nishie W, Shimizu H, Arima H, Sobajima H

    Journal of diabetes investigation     2018.6

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    DOI: 10.1111/jdi.12877

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  103. Association of pre-existing thyroid autoimmunity with the development of thyroid dysfunction induced by nivolumab.

    Kimbara Shiro, Fujiwara Yutaka, Iwama Shintaro, Ohashi Ken, Kuchiba Aya, Arima Hiroshi, Yamazaki Naoya, Kitano Shigehisa, Yamamoto Noboru, Ohe Yuichiro

    JOURNAL OF CLINICAL ONCOLOGY   Vol. 36 ( 15 )   2018.5

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  104. Functional Pituitary Tissue Generation from Human Embryonic Stem Cells. Reviewed International journal

    Kano M, Suga H, Kasai T, Ozone C, Arima H

    Current protocols in neuroscience   Vol. 83 ( 1 ) page: e48   2018.4

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    The anterior pituitary gland produces several hormones essential for regulation of the somatic endocrine system. Deficiency of these hormones can cause life-threatening diseases, including adrenal crisis. Pituitary tissue generated from human pluripotent stem cells is expected to provide better treatment than current hormone replacement therapy. During early mammalian development, the pituitary anlage (Rathke's pouch) develops from non-neural ectoderm adjacent to the developing ventral hypothalamus. The close interaction between these two tissues is crucial for Rathke's pouch development and involves several signaling molecules. Early exposure of human embryonic stem cells in 3D floating culture to sonic hedgehog and bone morphogenetic protein 4 promoted the cells' differentiation into oral ectoderm and, subsequently, hormone-producing cells such as corticotrophs (adrenocorticotropic hormone-producing cells). The differentiation approach described herein, which induces the formation of pituitary tissue in contact with hypothalamic neural tissue, mimics mammalian pituitary development. The differentiated corticotrophs are functional, responding normally to both release and feedback signals. © 2018 by John Wiley & Sons, Inc.

    DOI: 10.1002/cpns.48

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  105. ニボルマブ誘発破壊性甲状腺炎の発症率は甲状腺自己抗体陽性者で有意に高い

    小林 朋子, 岩間 信太郎, 岡田 則男, 安田 康紀, 有馬 寛

    日本内分泌学会雑誌   Vol. 94 ( 1 ) page: 420 - 420   2018.4

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  106. 小胞体内凝集体形成機序の解明 家族性中枢性尿崩症モデルマウスを用いた検討

    宮田 崇, 萩原 大輔, 橡谷 昌佳, 森下 啓明, 坂本 浩隆, 有馬 寛

    日本内分泌学会雑誌   Vol. 94 ( 1 ) page: 385 - 385   2018.4

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  107. ペムブロリズマブによる内分泌障害の臨床的特徴(中間報告)

    岡田 則男, 岩間 信太郎, 小林 朋子, 安田 康紀, 有馬 寛

    日本内分泌学会雑誌   Vol. 94 ( 1 ) page: 345 - 345   2018.4

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  108. Patients With Antithyroid Antibodies Are Prone To Develop Destructive Thyroiditis by Nivolumab: A Prospective Study International journal

    Kobayashi Tomoko, Iwama Shintaro, Yasuda Yoshinori, Okada Norio, Tsunekawa Taku, Onoue Takeshi, Takagi Hiroshi, Hagiwara Daisuke, Ito Yoshihiro, Morishita Yoshiaki, Goto Motomitsu, Suga Hidetaka, Banno Ryoichi, Yokota Kenji, Hase Tetsunari, Morise Masahiro, Hashimoto Naozumi, Ando Masahiko, Kiyoi Hitoshi, Gotoh Momokazu, Ando Yuichi, Akiyama Masashi, Hasegawa Yoshinori, Arima Hiroshi

    JOURNAL OF THE ENDOCRINE SOCIETY   Vol. 2 ( 3 ) page: 241 - 251   2018.3

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    Context: Immune checkpoint inhibitors, including anti-programmed cell death-1 (PD-1) antibodies, have become promising treatments for a variety of advanced malignancies. However, these medicines can cause immune-related adverse events (irAEs), including endocrinopathies. Objective: This study examined the incidence of endocrine irAEs induced by nivolumab. Patients and Main Outcome Measured: Sixty-six patients treated with nivolumab at Nagoya University Hospital were prospectively evaluated for pituitary hormones, thyroid function, antithyroid antibodies (Abs), and glucose levels every 6 weeks after the initiation of nivolumab for 24 weeks. Results: Four out of 66 patients developed destructive thyroiditis, and three patients developed hypothyroidism requiring levothyroxine replacement. The prevalence of positive anti-thyroglobulin Abs (TgAbs) and/or anti-thyroid peroxidase Abs (TPOAbs) at baseline was significantly higher in the group that developed destructive thyroiditis (3/4) compared with the group that did not develop thyroiditis (3/62; P = 0.002). There were no significant differences in other clinical variables between the groups. There were no endocrine irAEs other than destructive thyroiditis during the 24 weeks. The prevalence of TgAbs and/or TPOAbs at baseline was not associated with the development of other irAEs, including pneumonitis, colitis, or skin reactions. Conclusions: Our real-world data showed that destructive thyroiditis was an endocrine irAE that was frequently induced by nivolumab and was significantly associated with positive TgAbs and/or TPOAbs before treatment. Our findings indicate that evaluating these Abs before treatment may help identify patients with a high risk of thyroidal irAEs and may have important clinical benefit.

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  109. Vasopressin-secreting neurons derived from human embryonic stem cells through specific induction of dorsal hypothalamic progenitors. Reviewed

    Ogawa K, Suga H, Ozone C, Sakakibara M, Yamada T, Kano M, Mitsumoto K, Kasai T, Kodani Y, Nagasaki H, Yamamoto N, Hagiwara D, Goto M, Banno R, Sugimura Y, Arima H

    Scientific reports   Vol. 8 ( 1 ) page: 3615   2018.2

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    DOI: 10.1038/s41598-018-22053-x

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  110. Glucose-dependent insulinotropic polypeptide is required for moderate high fat diet, but not high carbohydrate diet-induced weight gain. Reviewed

    Maekawa R, Ogata H, Murase M, Harada N, Suzuki K, Joo E, Sankoda A, Iida A, Izumoto T, Tsunekawa S, Hamada Y, Oiso Y, Inagaki N, Arima H, Hayashi Y, Seino Y

    American journal of physiology. Endocrinology and metabolism     2018.2

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    DOI: 10.1152/ajpendo.00352.2017

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  111. Critical role of rabphilin-3A in the pathophysiology of experimental lymphocytic neurohypophysitis. Reviewed

    Yasuda Y, Iwama S, Kiyota A, Izumida H, Nakashima K, Iwata N, Ito Y, Morishita Y, Goto M, Suga H, Banno R, Enomoto A, Takahashi M, Arima H, Sugimura Y

    The Journal of pathology     2018.1

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    DOI: 10.1002/path.5046

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  112. Cullin-associated NEDD8-dissociated protein 1, a novel interactor of rabphilin-3A, deubiquitylates rabphilin-3A and regulates arginine vasopressin secretion in PC12 cells.

    Nakashima K, Takeuchi S, Iwama S, Kiyota A, Yasuda Y, Iwata N, Enomoto A, Arima H, Sugimura Y

    Endocrine journal     2018.1

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    DOI: 10.1507/endocrj.EJ17-0399

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  113. Glucose-dependent insulinotropic polypeptide is required for moderate high fat diet, but not high carbohydrate diet-induced weight gain. Reviewed

    Maekawa R, Ogata H, Murase M, Harada N, Suzuki K, Joo E, Sankoda A, Iida A, Izumoto T, Tsunekawa S, Hamada Y, Oiso Y, Inagaki N, Arima H, Hayashi Y, Seino Y

    Am J Physiol Endocrinol Metab.   Vol. 1 ( 314 ) page: 572 - 583   2018.1

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  114. 抗カルジオリピン抗体陽性であった両側副腎梗塞の1例

    高田 和尚, 尾上 剛史, 大屋 有夏, 福井 彩子, 恒川 卓, 岩間 信太郎, 森下 啓明, 有馬 寛

    日本内分泌学会雑誌   Vol. 93 ( 3 ) page: 899 - 899   2017.12

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  115. Chronic high-sucrose diet increases fibroblast growth factor 21 production and energy expenditure in mice International journal

    Ryuya Maekawa, Yusuke Seino, Hidetada Ogata, Masatoshi Murase, Atsushi Iida, Kaori Hosokawa, Erina Joo, Norio Harada, Shin Tsunekawa, Yoji Hamada, Yutaka Oiso, Nobuya Inagaki, Yoshitaka Hayashi, Hiroshi Arima

    JOURNAL OF NUTRITIONAL BIOCHEMISTRY   Vol. 49   page: 71 - 79   2017.11

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    Excess carbohydrate intake causes obesity in humans. On the other hand, acute administration of fructose, glucose or sucrose in experimental animals has been shown to increase the plasma concentration of anti-obesity hormones such as glucagon-like peptide 1 (GLP-1) and Fibroblast growth factor 21 (FGF21), which contribute to reducing body weight. However, the secretion and action of GLP-1 and FGF21 in mice chronically fed a high-sucrose diet has not been investigated. To address the role of anti-obesity hormones in response to increased sucrose intake, we analyzed mice fed a high-sucrose diet, a high-starch diet or a normal diet for 15 weeks. Mice fed a high-sucrose diet showed resistance to body weight gain, in comparison with mice fed a high-starch diet or control diet, due to increased energy expenditure. Plasma FGF21 levels were highest among the three groups in mice fed a high-sucrose diet, whereas no significant difference in GLP-1 levels was observed. Expression levels of uncoupling protein 1 (UCP-1), FGF receptor 1c (FGFR1c) and beta-klotho (KLB) mRNA in brown adipose tissue were significantly increased in high sucrose-fed mice, suggesting increases in FGF21 sensitivity and energy expenditure. Expression of carbohydrate responsive element binding protein (ChREBP) mRNA in liver and brown adipose tissue was also increased in high sucrose-fed mice. These results indicate that FGF21 production in liver and brown adipose tissue is increased in high-sucrose diet and participates in resistance to weight gain. (C) 2017 The Authors. Published by Elsevier Inc.

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  116. メトトレキサート治療中に両側副腎腫大を来した一例

    半田 朋子, 森下 啓明, 伊藤 崇浩, 有馬 寛

    日本内分泌学会雑誌   Vol. 93 ( 2 ) page: 642 - 642   2017.10

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  117. Sequestosome 1 (SQSTMI/p62) maintains protein folding capacity under endoplasmic reticulum stress in mouse hypothalamic organotypic culture International journal

    Takashi Tominaga, Motomitsu Goto, Takeshi Onoue, Akira Mizoguchi, Mariko Sugiyama, Taku Tsunekawa, Daisuke Hagiwara, Yoshiaki Morishita, Yoshihiro Ito, Shintaro Iwama, Hidetaka Suga, Ryoichi Banno, Hiroshi Arima

    NEUROSCIENCE LETTERS   Vol. 656   page: 103 - 107   2017.8

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    Sequestosome 1 (SQSTM1) also known as ubiquitin-binding protein p62 (p62) is a cargo protein involved in the degradation of misfolded proteins via selective autophagy. Disruption of autophagy and resulting accumulation of misfolded proteins in the endoplasmic reticulum (ER) leads to ER stress. ER stress is implicated in several neurodegenerative diseases and obesity. As knockout of p62 (p62KO) reportedly induces obesity in mice, we examined how p62 contributes to ER stress and the ensuing unfolded protein response (UPR) in hypothalamus using mouse organotypic cultures in the present study. Cultures from p62KO mice showed significantly reduced formation of LC3-GFP puncta, an index of autophagosome formation, in response to the chemical ER stressor thapsigargin compared to wild-type (WT) cultures. Hypothalamic cultures from p62KO mice exhibited higher basal expression of the UPR/ER stress markers CHOP mRNA and ATF4 mRNA than WT cultures. Thapsigargin enhanced CHOP, ATF4, and BiP mRNA as well as p-elF2 alpha protein expression in both NWT and p62KO cultures, but all peak values were greater in p621(0 cultures. A proteasome inhibitor increased p62 expression in WT cultures and upregulated the UPR/ER stress markers CHOP mRNA and ATF4 mRNA in both genotypes, but to a greater extent in p62KO cultures. Therefore, p62 deficiency disturbed autophagosome formation and enhanced both basal and chemically induced ER stress, suggesting that p62 serves to prevent ER stress in mouse hypothalamus by maintaining protein folding capacity. (C) 2017 Elsevier B.V. All rights reserved.

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  118. Randomized controlled trial for assessment of Internet of Things system to guide intensive glucose control in diabetes outpatients: Nagoya Health Navigator Study protocol International journal

    Takeshi Onoue, Motomitsu Goto, Tomoko Kobayashi, Takashi Tominaga, Masahiko Ando, Hiroyuki Honda, Yasuko Yoshida, Takahiro Tosaki, Hisashi Yokoi, Sawako Kato, Shoichi Maruyama, Hiroshi Arima

    NAGOYA JOURNAL OF MEDICAL SCIENCE   Vol. 79 ( 3 ) page: 323 - 329   2017.8

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    The Internet of Things (IoT) allows collecting vast amounts of health-relevant data such as daily activity, body weight (BW), and blood pressure (BP) automatically. The use of IoT devices to monitor diabetic patients has been studied, but could not evaluate IoT-dependent effects because health data were not measured in control groups. This multicenter, open-label, randomized, parallel group study will compare the impact of intensive health guidance using IoT and conventional medical guidance on glucose control. It will be conducted in outpatients with type 2 diabetes for a period of 6 months. IoT devices to measure amount of daily activity, BW, and BP will be provided to IoT group patients. Healthcare professionals (HCPs) will provide appropriate feedback according to the data. Non-IoT control, patients will be given measurement devices that do not have a feedback function. The primary outcome is glycated hemoglobin at 6 months. The study has already enrolled 101 patients, 50 in the IoT group and 51 in the non-IoT group, at the two participating outpatient clinics. The baseline characteristics of two groups did not differ, except for triglycerides. This will be the first randomized, controlled study to evaluate IoT-dependent effects of intensive feedback from HCPs. The results will validate a new method of health-data collection and provision of feedback suitable for diabetes support with increased effectiveness and low cost.

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  119. PTP1B deficiency improves hypothalamic insulin sensitivity resulting in the attenuation of AgRP mRNA expression under high-fat diet conditions International journal

    Mariko Sugiyama, Ryoichi Banno, Akira Mizoguchi, Takashi Tominaga, Taku Tsunekawa, Takeshi Onoue, Daisuke Hagiwara, Yoshihiro Ito, Yoshiaki Morishita, Shintaro Iwama, Motomitsu Goto, Hidetaka Suga, Hiroshi Arima

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   Vol. 488 ( 1 ) page: 116 - 121   2017.6

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    Hypothalamic insulin receptor signaling regulates energy balance and glucose homeostasis via agouti related protein (AgRP). While protein tyrosine phosphatase 1B (PTP1B) is classically known to be a negative regulator of peripheral insulin signaling by dephosphorylating both insulin receptor beta (IR beta) and insulin receptor substrate, the role of PTP1B in hypothalamic insulin signaling remains to be fully elucidated. In the present study, we investigated the role of PTP1B in hypothalamic insulin signaling using PTP1B deficient (KO) mice in vivo and ex vivo. For the in vivo study, hypothalamic insulin resistance induced by a high-fat diet (HFD) improved in KO mice compared to wild-type (WT) mice. Hypothalamic AgRP mRNA expression levels were also significantly decreased in KO mice independent of body weight changes. In an ex vivo study using hypothalamic organotypic cultures, insulin treatment significantly increased the phosphorylation of both IR beta and Akt in the hypothalamus of KO mice compared to WT mice, and also significantly decreased AgRP mRNA expression levels in KO mice. While incubation with inhibitors of phosphatidylinositol-3 kinase (PI3K) had no effect on basal levels of Akt phosphorylation, these suppressed insulin induction of Akt phosphorylation to almost basal levels in WT and KO mice. The inhibition of the PI3K-Akt pathway blocked the downregulation of AgRP mRNA expression in KO mice treated with insulin. These data suggest that PTP1B acts on the hypothalamic insulin signaling via the PI3K-Akt pathway. Together, our results suggest a deficiency of PTP1B improves hypothalamic insulin sensitivity resulting in the attenuation of AgRP mRNA expression under HFD conditions. (C) 2017 Elsevier Inc. All rights reserved.

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  120. S100B impairs glycolysis via enhanced poly(ADP-ribosyl) ation of glyceraldehyde-3-phosphate dehydrogenase in rodent muscle cells International journal

    Kaori Hosokawa, Yoji Hamada, Atsushi Fujiya, Masatoshi Murase, Ryuya Maekawa, Yasuhiro Niwa, Takako Izumoto, Yusuke Seino, Shin Tsunekawa, Hiroshi Arima

    AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM   Vol. 312 ( 6 ) page: E471 - E481   2017.6

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    S100 calcium-binding protein B (S100B), a multifunctional macromolecule mainly expressed in nerve tissues and adipocytes, has been suggested to contribute to the pathogenesis of obesity. To clarify the role of S100B in insulin action and glucose metabolism in peripheral tissues, we investigated the effect of S100B on glycolysis in myoblast and myotube cells. Rat myoblast L6 cells were treated with recombinant mouse S100B to examine glucose consumption, lactate production, glycogen accumulation, glycolytic metabolites and enzyme activity, insulin signaling, and poly(ADP-ribosyl)ation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Glycolytic metabolites were investigated by enzyme assays or metabolome analysis, and insulin signaling was assessed by Western blot analysis. Enzyme activity and poly(ADP-ribosyl) ation of GAPDH was evaluated by an enzyme assay and immunoprecipitation followed by dot blot with an anti-poly(ADP-ribose) antibody, respectively. S100B significantly decreased glucose consumption, glucose analog uptake, and lactate production in L6 cells, in either the presence or absence of insulin. In contrast, S100B had no effect on glycogen accumulation and insulin signaling. Metabolome analysis revealed that S100B increased the concentration of glycolytic intermediates upstream of GAPDH. S100B impaired GAPDH activity and increased poly(ADP-ribosyl) ated GAPDH proteins. The effects of S100B on glucose metabolism were mostly canceled by a poly(ADP-ribose) polymerase inhibitor. Similar results were obtained in C2C12 myotube cells. We conclude that S100B as a humoral factor may impair glycolysis in muscle cells independent of insulin action, and the effect may be attributed to the inhibition of GAPDH activity from enhanced poly(ADP-ribosyl) ation of the enzyme.

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  121. Anti-pituitary antibodies against corticotrophs in IgG4-related hypophysitis International journal

    Naoko Iwata, Shintaro Iwama, Yoshihisa Sugimura, Yoshinori Yasuda, Kohtaro Nakashima, Seiji Takeuchi, Daisuke Hagiwara, Yoshihiro Ito, Hidetaka Suga, Motomitsu Goto, Ryoichi Banno, Patrizio Caturegli, Teruhiko Koike, Yoshiharu Oshida, Hiroshi Arima

    PITUITARY   Vol. 20 ( 3 ) page: 301 - 310   2017.6

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    Purpose IgG4-related disease is a systemic inflammatory disease characterized by infiltration of IgG4-positive plasma cells into multiple organs, including the pituitary gland. Autoimmunity is thought to be involved in the pathogenesis of IgG4-related disease. The diagnosis of IgG4-related hypophysitis (IgG4-RH) is difficult because its clinical features, such as pituitary swelling and hypopituitarism, are similar to those of other pituitary diseases, including lymphocytic hypophysitis and sellar/suprasellar tumors. The presence and significance of anti-pituitary antibodies (APA) in IgG4-RH is unclear.
    Methods In this case-control study, we used single indirect immunofluorescence on human pituitary substrates to assess the prevalence of serum APA in 17 patients with IgG4-RH, 8 control patients with other pituitary diseases (lymphocytic infundibulo-neurohypophysitis, 3; craniopharyngioma, 2; germinoma, 3), and 9 healthy subjects.We further analyzed the endocrine cells targeted by the antibodies using double indirect immunofluorescence.
    Results APA were found in 5 of 17 patients with IgG4-RH (29%), and in none of the pituitary controls or healthy subjects. The endocrine cells targeted by the antibodies in the 5 IgG4-RH cases were exclusively corticotrophs. Antibodies were of the IgG1 subclass, rather than IgG4, in all 5 cases, suggesting that IgG4 is not directly involved in the pathogenesis. Finally, antibodies recognized pro-opiomelanocortin in 2 of the cases.
    Conclusions Our study suggests that autoimmunity is involved in the pathogenesis of IgG4-RH and that corticotrophs are the main antigenic target, highlighting a possible new diagnostic marker for this condition.

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  122. 免疫チェックポイント阻害薬による内分泌障害(臨床研究第一報)

    小林 朋子, 岩間 信太郎, 安田 康紀, 岩田 尚子, 椙村 益久, 安藤 雄一, 秋山 真志, 長谷川 好規, 有馬 寛

    日本内分泌学会雑誌   Vol. 93 ( Suppl.Update ) page: 70 - 72   2017.6

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    2016年6月時点において、当院で免疫チェックポイント阻害薬として抗CTLA-4抗体イピリムマブ(Ipi)が投与された12例および抗PD-1抗体ニボルマブ(Niv)が投与された23例を対象に、内分泌学的評価を行った。その結果、Ipi投与中の内分泌有害事象は下垂体炎が2件(16.7%)、低Na血症が2件(16.7%)、副腎炎が1件(8.3%)、TSH値異常が4件(33.3%)に認められた。Niv投与中の内分泌有害事象はTSH値異常が7件(35.0%)、破壊性甲状腺炎が1件(4.3%)、甲状腺自己抗体陽転化が1件(4.3%)に認められた。Ipi投与中に発生した下垂体炎は、2件とも前治療としてNivが投与されており、Niv治療歴のある場合にはIpiによる下垂体炎を特に注意する必要があると考えられた。また、当院で経験した重篤な破壊性甲状腺炎の経過から、Niv投与前に甲状腺自己抗体が陽性の場合には甲状腺障害の発症に注意が必要であると示唆された。

    Other Link: https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2017&ichushi_jid=J01160&link_issn=&doc_id=20170718400022&doc_link_id=10.1507%2Fendocrine.93.S.Update_70&url=https%3A%2F%2Fdoi.org%2F10.1507%2Fendocrine.93.S.Update_70&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

  123. 4-PBAは家族性中枢性尿崩症モデルマウスにおいて多尿の進行およびバソプレシンニューロンの細胞死を抑制する

    橡谷 昌佳, 萩原 大輔, 宮田 崇, 森下 啓明, 有馬 寛

    日本内分泌学会雑誌   Vol. 93 ( 1 ) page: 263 - 263   2017.4

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  124. 抗ラブフィリン3A抗体の小児期発症リンパ球性漏斗下垂体後葉炎における診断的有用性に関する検討

    岩田 尚子, 岩間 信太郎, 安田 康紀, 椙村 益久, 有馬 寛

    日本内分泌学会雑誌   Vol. 93 ( 1 ) page: 317 - 317   2017.4

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  125. ラブフィリン3A免疫マウスにおける視床下部下垂体後葉炎び病態の解析

    安田 康紀, 岩間 信太郎, 岩田 尚子, 椙村 益久, 有馬 寛

    日本内分泌学会雑誌   Vol. 93 ( 1 ) page: 276 - 276   2017.4

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  126. ニボルマブによる甲状腺障害の臨床的特徴

    小林 朋子, 岩間 信太郎, 安田 康紀, 岩田 尚子, 横田 憲二, 椙村 益久, 近藤 征史, 安藤 雄一, 秋山 真志, 長谷川 好規, 有馬 寛

    日本内分泌学会雑誌   Vol. 93 ( 1 ) page: 360 - 360   2017.4

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  127. AVPニューロンのin vitro実験系の確立 AVP-Venusマウスを用いた検討

    萩原 大輔, 宮田 崇, 橡谷 昌佳, 森下 啓明, 有馬 寛

    日本内分泌学会雑誌   Vol. 93 ( 1 ) page: 276 - 276   2017.4

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  128. Effects of clozapine on adipokine secretions/productions and lipid droplets in 3T3-L1 adipocytes.

    Tomomi Tsubai, Akira Yoshimi, Yoji Hamada, Makoto Nakao, Hiroshi Arima, Yutaka Oiso, Yukihiro Noda

    Journal of pharmacological sciences   Vol. 133 ( 2 ) page: 79 - 87   2017.2

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    Clozapine, a second-generation antipsychotic (SGA), is a cause of side effects related to metabolic syndrome. The participation of serotonin 5-HT2C and histamine H1 receptors in the central nervous system has been reported as a mechanism of the weight gain caused by clozapine. In the present study, we investigated the direct pharmacological action of clozapine on the 3T3-L1 adipocytes and compared it to that of blonanserin, an SGA with low affinity for both receptors. Short-term exposure to clozapine decreased secretion and mRNA expression of leptin. Long-term exposure decreased leptin as well as adiponectin secretion, and further increased lipid droplets accumulation. However, short- and long-term exposures to blonanserin did not affect these parameters. A selective serotonin 5-HT2C, but not a histamine H1, receptor antagonist enhanced the decreased secretion of leptin induced by short-term exposure to clozapine, but did not affect the increased accumulation of lipid droplets. Our findings indicate that clozapine, but not blonanserin, strongly and directly affected the secretion of adipokines, such as leptin, in adipocytes and caused adipocyte enlargement.

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  129. Deficiency of PTP1B Attenuates Hypothalamic Inflammation via Activation of the JAK2-STAT3 Pathway in Microglia

    Taku Tsunekawa, Ryoichi Banno, Akira Mizoguchi, Mariko Sugiyama, Takashi Tominaga, Takeshi Onoue, Daisuke Hagiwara, Yoshihiro Ito, Shintaro Iwama, Motomitsu Goto, Hidetaka Suga, Yoshihisa Sugimura, Hiroshi Arima

    EBIOMEDICINE   Vol. 16   page: 172 - 183   2017.2

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    Protein tyrosine phosphatase 1B (PTP1B) regulates leptin signaling in hypothalamic neurons via the JAK2-STAT3 pathway. PTP1B has also been implicated in the regulation of inflammation in the periphery. However, the role of PTP1B in hypothalamic inflammation, which is induced by a high-fat diet (HFD), remains to be elucidated. Here, we showed that STAT3 phosphorylation (p-STAT3) was increased in microglia in the hypothalamic arcuate nucleus of PTP1B knock-out mice (KO) on a HFD, accompanied by decreased Tnf and increased Il10 mRNA expression in the hypothalamus compared to wild-type mice (WT). In hypothalamic organotypic cultures, incubation with TNF alpha led to increased p-STAT3, accompanied by decreased Tnf and increased Il10 mRNA expression, in KO compared to WT. Incubation with p-STAT3 inhibitors or microglial depletion eliminated the differences in inflammation between genotypes. These data indicate an important role of JAK2-STAT3 signaling negatively regulated by PTP1B in microglia, which attenuates hypothalamic inflammation under HFD conditions. (C) 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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  130. NMDA receptor antagonist prevents cell death in the hippocampal dentate gyrus induced by hyponatremia accompanying adrenal insufficiency in rats

    Hisakazu Izumida, Hiroshi Takagi, Haruki Fujisawa, Naoko Iwata, Kohtaro Nakashima, Seiji Takeuchi, Shintaro Iwama, Takashi Namba, Yukio Komatu, Kozo Kaibuchi, Yutaka Oiso, Hiroshi Arima, Yoshihisa Sugimura

    EXPERIMENTAL NEUROLOGY   Vol. 287 ( Pt 1 ) page: 65 - 74   2017.1

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    Selective apoptosis of granule cells in the hippocampal dentate gyrus (DG) of rats with bilateral adrenalectomy (ADX) and in patients who died of adrenal insufficiency has been reported. Although adrenal insufficiency is a common disease and is usually associated with hyponatremia, its effect on the central nervous system and in apoptosis in the hippocampus remain to be elucidated. Using rat models to represent clinical hyponatremia accompanying adrenal insufficiency, we show that reduced serum [Na+] was associated with selective apoptosis in the DG. Nine days after ADX, apoptotic cells were observed in the DG of rats whose serum [Na+] was &lt;125 mEq/L (moderate hyponatremia), but rarely in those whose serum [Na+] was 125 mEq/L or in normonatremic rats. Although all hyponatremic ADX rats survived following treatment with corticosterone and saline started 7 days after ADX when apoptosis had not yet occurred, selective apoptosis on day 9 was not prevented in moderately hyponatremic rats. Interestingly, treatment with memantine, a noncompetitive NMDAR antagonist, prevented the selective apoptosis in the DG in moderately hyponatremic, ADX rats, and improved electrophysiological dysfunction, including impaired basal synaptic transmission and long-term potentiation at the entorhinal cortex-DG synapses. These results demonstrated that in adrenal insufficient rats, hyponatremia was associated with apoptosis in the DG, and that memantine prevented the apoptosis and improved cell function. Our data imply the importance of assessing the possibility of neurological impairments after treatment with CORT in patients with moderate or severe hyponatremia accompanying adrenal insufficiency and that memantine may represent a beneficial therapeutic strategy to prevent neurological impairments in such patients. (C) 2016 Elsevier Inc. All rights reserved.

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  131. IgG4関連下垂体炎における抗下垂体抗体の解析

    岩田 尚子, 岩間 信太郎, 安田 康紀, 椙村 益久, 有馬 寛

    日本内分泌学会雑誌   Vol. 92 ( 3 ) page: 731 - 731   2017.1

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  132. 水バランスの調節 バソプレシンニューロンと小胞体ストレス

    萩原 大輔, 宮田 崇, 橡谷 昌佳, 東 慶成, 森下 啓明, 有馬 寛

    日本内分泌学会雑誌   Vol. 92 ( 3 ) page: 717 - 717   2017.1

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  133. 家族性中枢性尿崩症モデルマウスに対するケミカルシャペロン4-Phenylbutyric acidの治療効果の検討

    橡谷 昌佳, 萩原 大輔, 宮田 崇, 東 慶成, 森下 啓明, 有馬 寛

    日本内分泌学会雑誌   Vol. 92 ( 3 ) page: 734 - 734   2017.1

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  134. ニボルマブに伴う甲状腺障害に関する前向き臨床研究(中間報告)

    岩間 信太郎, 小林 朋子, 安田 康紀, 岩田 尚子, 椙村 益久, 安藤 雄一, 秋山 真志, 長谷川 好規, 有馬 寛

    日本内分泌学会雑誌   Vol. 92 ( 3 ) page: 612 - 612   2017.1

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  135. イピリムマブ誘発下垂体炎2例の下垂体機能検査およびMRI画像変化に関する検討

    岩間 信太郎, 小林 朋子, 安田 康紀, 岩田 尚子, 横田 憲二, 椙村 益久, 安藤 雄一, 秋山 真志, 有馬 寛

    日本内分泌学会雑誌   Vol. 92 ( 3 ) page: 731 - 731   2017.1

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  136. RPH3A蛋白による下垂体後葉炎モデルマウスの開発

    安田 康紀, 岩間 信太郎, 岩田 尚子, 椙村 益久, 有馬 寛

    日本内分泌学会雑誌   Vol. 92 ( 3 ) page: 729 - 729   2017.1

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  137. Normalization of Bilateral Adrenal Gland Enlargement after Treatment for Cryptococcosis

    Muraoka Yuka, Iwama Shintaro, Arima Hiroshi

    CASE REPORTS IN ENDOCRINOLOGY   Vol. 2017   page: 1543149   2017

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    DOI: 10.1155/2017/1543149

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    PubMed

  138. Clinical practice and mechanism of endocrinological adverse events associated with immune checkpoint inhibitors

    Shintaro Iwama, Hiroshi Arima

    Japanese Journal of Clinical Immunology   Vol. 40 ( 2 ) page: 90 - 94   2017

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    Immune checkpoint inhibitors, used for cancer immunotherapy, show anti-tumor effects through T cell activations. Monoclonal antibodies against cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed cell death (PD)-1, or PD-ligand 1 which is a ligand of PD-1 have been shown to be effective in the treatments of advanced cancers including malignant melanoma, non-small cell lung cancer, and renal cell carcinoma. However, these drugs also have immune-related adverse events (irAEs). The irAEs, which have unique characteristics different from those seen in conventional cytotoxic anti-tumor medicines, are observed in the several tissues such as skin, gastrointestinal tract, liver, lung, muscle, nerve and endocrine systems. To safely use immune checkpoint inhibitors, it is quite important to understand the characteristics of irAEs and to manage them in clinical practice. In this review, we focus on clinical characteristics and pathogenesis of adverse events in the pituitary gland.

    DOI: 10.2177/jsci.40.90

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    PubMed

  139. Identification of the novel autoantigen candidate Rab GDP dissociation inhibitor alpha in isolated adenocorticotropin deficiency Reviewed

    Kiyota A, Iwama S, Sugimura Y, Takeuchi S, Takagi H, Iwata N, Nakashima K, Suzuki H, Nishioka T, Kato T, Enomoto A, Arima H, Kaibuchi K, Oiso Y

    Endocr J   Vol. 62 ( 2 ) page: 153-160   2015

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  140. Comparison of incidence of hyponatremia between intranasal and oral desmopressin in patients with central diabetes insipidus Reviewed

    Kataoka Y, Nishida S, Hirakawa A, Oiso Y, Arima H

    Endocr J   Vol. 62 ( 2 ) page: 195-200   2015

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  141. Glutamate input in the dorsal raphe nucleus as a determinant of escalated aggression in male mice Reviewed

    Takahashi A, Lee R, Iwasato T, Itohara S, Arima H, Bettler B, Miczek K, Koide T

    J Neurosci   Vol. 35 ( 16 ) page: 6452-6463   2015

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  142. Rabphilin-3A as a targeted autoantigen in lymphocytic infundibulo-neurohypophysitis Reviewed

    Iwama S, Sugimura Y, Kiyota A, Kato T, Enomoto A, Suzuki H, Iwata N, Takeuchi S, Nakashima K, Takagi H, Izumida H, Ochiai H, Fujisawa H, Suga H, Arima H, Shimoyama Y, Takahashi M, Nishioka H, Ishikawa SE, Shimatsu A, Caturegli P, Oiso Y

    J Clin Endocrinol Metab   Vol. 100 ( 7 ) page: E946-54   2015

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  143. Effect of hyperglycemia on hepatocellular carcinoma development in diabetes

    Niwa Y, Ishikawa K, Ishigami M, Honda T, Achiwa K, Izumoto T, Maekawa R, Hosokawa K, Iida A, Seino Y, Hamada Y, Goto H, Oiso Y, Arima H, Tsunekawa S

    Biochem Biophys Res Commun   Vol. 463 ( 3 ) page: 344-350   2015

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  144. BMP4 and FGF strongly induce differentiation of mouse ES cells into oral ectoderm. Reviewed

      Vol. 15 ( 2 ) page: 290-298   2015

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  145. Activating transcription factor 6a is required for the vasopressin neuron system to maintain water balance under dehydration in male mice

    Azuma Y, Hagimoto D, Lu W, Morishita Y, Suga H, Goto M, Banno R, Sugimura Y, Oyadomari S, Mori K, Shiota A, Asai N, Takahashi M, OisoY, Arima H

    Endocrinology   Vol. 155   page: 4905-4914   2014

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  146. Minocycline prevents osmotic demyelination associated with aquaresis

    Takagi H, Sugimura Y, Suzuki H, Iwama S, Izumida H, Fujisawa H, Ogawa K, Nakashima K, Ochiai H, Takeuchi S, Kiyota A, Suga H, Goto M, Banno R, Arima H, Oiso Y

    Kidney Int   Vol. 86 ( 5 ) page: 964-964   2014

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  147. Mitogen-activated protein kinase phosphatase 1 negatively regulates MAPK signaling in mouse hypothalamus

    Adachi K, Goto M, Onoue T, Tsunekawa T, Shibata M, Hagimoto S, Ito Y, Banno R, Suga H, Sugimura Y, Oiso Y, Arima H

    Neurosci Lett   Vol. 569   page: 49-54   2014

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  148. Arginine vasopressin neuronal loss results from autophagy-associated cell death in a mouse model for familial neurohypophysial diabetes insipidus Reviewed

    Hagiwara D, Arima H, Morishita Y, Wenjun L, Azuma Y, Ito Y, Suga H, Goto M, Banno R, Sugimura Y, Shiota A, Asai N, Takahashi M, Oiso Y

    Cell Death Dis   Vol. 5   page: e1148   2014

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  149. Adipsia increases risk of death in patients with central diabetes insipidus Reviewed

    Arima H, Wakabayashi T, Nagatani T, Fujii M, Hirakawa A, Murase T, Yambe Y, Yamada T, Yamakawa F, Yamamori I, Yamauchi M, Oiso Y

    Endocr J   Vol. 61 ( 2 ) page: 143-148   2014

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  150. Efficacy and safety of desmopressin orally disintegrating tablet in patients with central diabetes insipidus: results of a multicenter open-label dose-titration study Reviewed

    Arima H, Oiso Y, Juul KV, Nørgaard JP

    Endocr J   Vol. 60 ( 9 ) page: 1085-1094   2013.9

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  151. GABA Type B Receptor Signaling in Proopiomelanocortin Neurons Protects Against Obesity, Insulin Resistance and Hypothalamic Inflammation in Male Mice on a High Fat Diet. Reviewed

    Ito Y, Banno R, Shibata M, Adachi K, Hagimoto S, Hagiwara D, Ozawa Y, Goto M, Suga H, Sugimura Y, Bettler B, Oiso Y, and Arima H.

    J Neurosci   Vol. 33 ( 43 ) page: 17166-17173   2013

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  152. Expression of neuropeptide Y and agouti-related protein mRNA stimulated by glucocorticoids is attenuated via NF-κB p65 under ER stress in mouse hypothalamic cultures

    Hagimoto S, Arima H, Adachi K, Ito Y, Suga H, Sugimura Y, Goto M, Banno R, and Oiso Y.

    Neurosci Lett   Vol. 553   page: 165-169   2013

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  153. Lesion of area postrema attenuated hyperphagic responses to glucoprivation but not transcriptional activation of neuropeptide Y gene in rats

    Ozawa Y, Arima H, Banno R, Ito Y, Goto M, Morishita Y, Sugimura Y, Ozaki N, Nagasaki H, Oiso Y

    Neuroreport   Vol. 23 ( 11 ) page: 673-5   2012

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  154. Inflammatory changes in adipose tissue enhance expression of GPR84, a medium-chain fatty acid receptor TNFα enhances GPR84 expression in adipocytes Reviewed

    Nagasaki H, Kondo T, Fuchigami M, Hashimoto H, Sugimura Y, Ozaki N, Arima H, Ota A, Hamada Y, Oiso Y

    FEBS Lett   Vol. 586 ( 4 ) page: 368-72   2012

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  155. BiP mRNA expression is upregulated by dehydration in vasopressin neurons in the hypothalamus in mice

    Hagiwara D, Arima H, Morishita Y, Goto M, Banno R, Sugimura Y, Oiso Y

    Peptides   Vol. 33 ( 2 ) page: 346-50   2012

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  156. TNFα increases hypothalamic PTP1B activity via the NFκB pathway in rat hypothalamic organotypic cultures Reviewed

    Ito Y, Banno R, Hagimoto S, Ozawa Y, Arima H, Oiso Y

    Regul Pept   Vol. 174 ( 1-3 ) page: 58-64   2012

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  157. Reduction of Insulin Signaling Upregulates Angiopoietin-like Protein 4 Through Elevated Free Fatty Acids in Diabetic Mice Reviewed

    Mizutani N, Ozaki N, Seino Y, Fukami A, Sakamoto E, Fukuyama T, Sugimura Y, Nagasaki H, Arima H, Oiso Y.

    Exp Clin Endocrinol Diabetes   Vol. 120 ( 3 ) page: 139-44   2012

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  158. Repeated glucoprivation delayed hyperphagic responses while activating neuropeptide Y neurons in rats Reviewed

    Peptides   Vol. 32 ( 4 ) page: 763-769   2011.4

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  159. Time-dependent changes in proinflammatory and neurotrophic responses of microglia and astrocytes in a rat model of osmotic demyelination syndrome Reviewed

    Glia   Vol. 59 ( 3 ) page: 452-462   2011.3

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  160. Poly(A) Tail length of neurohypophysial hormones is shortened under endoplasmic reticulum stress Reviewed

    Morishita Y, Arima H, Hiroi M, Hayashi M, Hagiwara D, Asai N, Ozaki N, Sugimura Y, Nagasaki H, Shiota A, Takahashi M, Oiso Y

    Endocrinology   Vol. 152 ( 12 ) page: 4846-55   2011

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  161. Minocycline prevents osmotic demyelination syndrome by inhibiting the activation of microglia Reviewed

    Suzuki H, Sugimura Y, Iwama S, Suzuki H, Ozaki N, Nagasaki H, Arima H, Sawada M, Oiso Y

    J Am Soc Nephrol   Vol. 21 ( 12 ) page: 2090-2098   2010.12

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  162. Baclofen reduced body weight in obese subjects: a pilot study. Reviewed

    Inter Med   Vol. 49   page: 2043-2047   2010.10

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  163. Protective effect of hedgehog signaling on cytokine-induced cytotoxicity in pancreatic beta-cells Reviewed

    Umeda H, Ozaki N, Mizutani N, Fukuyama T, Nagasaki H, Arima H, Oiso Y

    Exp Clin Endocrinol Diabetes   Vol. 118 ( 10 ) page: 692-698   2010.10

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  164. Mechanisms underlying progressive polyuria in familiar neurohypophysial diabetes insipidus. Invited Reviewed

    Arima H, Oiso Y

    J Neuroendocrinol   Vol. 22 ( 7 ) page: 754-757   2010.7

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  165. The feasibility study of docetaxel in patients with anaplastic thyroid cancer. Reviewed

    Kawada K, Kitagawa K, Kamei S, Inada M, Mitsuma A, Sawaki M, Kikumori T, Fujimoto Y, Arima H, Imai T, Ando Y

    Jpn J Clin Oncol   Vol. 40 ( 6 ) page: 596-599   2010.6

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  166. Activation of vasopressin neurons leads to phenotype progression in a mouse model for familial neurohypophysial diabetes insipidus. Reviewed

    Hiroi M, Morishita Y, Hayashi M, Ozaki N, Sugimura Y, Nagasaki H, Shiota A Oiso Y, Arima H.

    Am J Physiol Regul Integr Comp Physiol   Vol. 298 ( 2 ) page: R486-93   2010.2

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  167. Glucocorticoids increase NPY gene expression in the arcuate nucleus by inhibiting mTOR signaling in rat hypothalamic organotypic cultures Reviewed

    Shimizu H, Arima H, Ozawa Y, Watanabe M, Banno R, Sugimura Y, Ozaki N, Nagasaki H, Oiso Y

    Peptides   Vol. 31 ( 1 ) page: 145-149   2010.1

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  168. Fos proteins are not prerequisite for osmotic induction of vasopressin transcription in supraoptic nucleus of rats Reviewed

    Arima H, Baler R, Aguilera G

    Neurosci Lett   Vol. 486 ( 1 ) page: 5-9   2010

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  169. Improvement of respiratory failure by growth hormone replacement in a male patient with panhypopituitarism Reviewed

    Sato I, Yokoyama Y, Misaki R, Taniguchi H, Arima H, Yoshioka S

    BMJ Case Reports     2010

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    DOI: 10.1136/bcr.02.2010.2742

  170. Genetic analysis of two Japanese patients with nonclassical 21-hydroxylase deficiency Reviewed

    Imamine R, Arima H, Kusakabe M, Umeda H, Sato I, Homma K, Usui T, Oiso Y

    Intern Med   Vol. 48 ( 9 ) page: 705-709   2009.9

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  171. Central adiponectin functions to inhibit arginine vasopressin release in conscious rats. Reviewed

    Iwama S, Sugimura Y, Murase T, Hiroi M, Goto M, Hayashi M, Arima H, Oiso Y

    J Neuroendocrinol   Vol. 21 ( 9 ) page: 753-759   2009.9

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  172. *Progressive Polyuria without Vasopressin Neuron Loss in a Mouse Model for Familial Neurohypophysial Diabetes Insipidus. Reviewed

    Hayashi M, Arima H, Ozaki N, Morishita Y, Hiroi M, Ozaki N, Nagasaki H, Kinoshita N, Ueda M, Shiota A, Oiso Y

    Am J Physiol Regul Integr Comp Physiol   Vol. 296 ( 5 ) page: R1641-9   2009.5

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  173. Inflammatory cytokines regulate glycoprotein subunit beta5 of thyrostimulin through nuclear factor-kappaB. Reviewed

    Suzuki C, Nagasaki H, Okajima Y, Suga H, Ozaki N, Arima H, Iwasaki Y, Oiso Y

    Endocrinology   Vol. 150 ( 5 ) page: 2237-2243   2009.5

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  174. Normalization of plasma growth hormone levels improved cardiac dysfunction due to acromegalic cardiomyopathy with severe fibrosis Reviewed

    Yokota F, Arima H, Hirano M, Uchikawa T, Inden Y, Nagatani, T, Oiso Y

    BMJ Case Reports     2009

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    DOI: 10.1136/bcr.12.2009.2559

  175. The medial hypothalamus is required for the feeding response to glucoprivation but not to food deprivation Reviewed

    Watanabe M, Arima H, Ozawa Y, Goto M, Shimizu H, Banno R, Sugimura Y, Ozaki N, Nagasaki H, Oiso Y

    Neurosci Lett   Vol. 464 ( 1 ) page: 6-9   2009

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  176. Direct and indirect modulation of neuropeptide Y gene expression in response to hypoglycemia in rat arcuate nucleus. Reviewed

    Watanabe M, Arima H, Kuriko Fukushima K, Goto M, Shimizu H, Hayashi M, Banno R, Sato I, Ozaki N, Nagasaki H, Oiso Y

    FEBS Lett   Vol. 582 ( 25-26 ) page: 3632-3638   2008.10

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  177. *Increase Neuropeptide Y and Agouti-Related Peptide Gene Expression via AMP-Activated Protein Kinase Signaling in the Arcuate Nucleus of Rats. Reviewed

    Shimizu H, Arima H, Watanabe M, Goto M, Banno R, Sato I, Ozaki N, Nagasaki H, Oiso Y.

    Endocrinology   Vol. 149 ( 9 ) page: 4544-4553   2008.9

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  178. Novel treatment for lithium-induced nephrogenic diabetes insipidus rat model using the Sendai-virus vector carrying aquaporin 2 gene. Reviewed

    Suga H, Nagasaki H, Kondo TA, Okajima Y, Suzuki C, Ozaki N, Arima H, Yamamoto T, Ozaki N, Akai M, Sato A, Uozumi N, Inoue M, Hasegawa M, Oiso Y

    Endocrinology   Vol. 149 ( 9 ) page: 4544-4553   2008.9

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  179. Ping-pong champion with adrenal insufficiency Reviewed

    Arima H, Imamine R, Oiso Y

    BMJ Case Reports     2008

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    DOI: 10.1136/bcr.10.2008.1172

  180. Biochemical roles of the oligosaccharide chains in thyrostimulin, a heterodimeric hormone of glycoprotein hormone subunits alpha 2 (GPA2) and beta 5 (GPB5) Reviewed

    Okajima Y, Nagasaki H, Suzuki C, Suga H, Ozaki N, Arima H, Hamada Y, Civelli O, Oiso Y

    Regul Pept   Vol. 148 ( 1-3 ) page: 62-67   2008

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  181. Immunological insulin resistance due to insulin antibodies developed after cessation of insulin therapy in a patient with type 2 diabetes Reviewed

    Hirano M, Arima H, Oiso Y

    Diabetes Care   Vol. 31 ( 11 ) page: e84   2008

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  182. Peripherally administered baclofen reduced food intake and body weight in db/db as well as diet-induced obese mice, FEBS Letters in press. Reviewed

    Sato I, Arima H, Ozaki N, Ozaki N, Watanabe M, Goto M, Shimizu H, Hayashi M, Banno R, Nagasaki H, Oiso Y.

    FEBS Lett   Vol. 581   page: 4857-4864   2007.9

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  183. Insulin is not a prerequisite for rapid regulation of neuropeptide Y gene transcription in the arcuate nucleus in food-restricted rats. Reviewed

    Goto M, Arima H, Hiroi M, Shimizu H, Watanabe M, Hayashi M, Banno R, Sato I, Ozaki N, Nagasaki H, Oiso Y

    Neurosci Lett   Vol. 420   page: 61-65   2007

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  184. Thel LIM domain homobox gene isl-1 is a positive regulator of glycoprotein alpha 2 (GPA2), a subunit of thyrostimulin. Reviewed

    Suzuki C, Nagasaki H, Okajima Y, Suga H, Arima H, Iwasaki H, Oiso Y

    Regul Pept   Vol. 142 ( 1-2 ) page: 60-7   2007

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  185. Central administration of melanocortin agonist increased insulin sensitivity in diet-induced obese rats Reviewed

    Banno R, Arima H, Hayashi M, Goto M, Watanabe M, Sato I, Ozaki N, Nagasaki H, Ozaki N, Oiso Y

    FEBS Letters   Vol. 581   page: 1131-6   2007

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  186. Vasopressin gene transcription increases in response to decreases in plasma volume, but not to increases in plasma osmolality, in chronically dehydrated rats. Reviewed

    Hayashi M, Arima H, Goto M, Banno R, Watanabe M, Sato I, Nagasaki H, Oiso Y

    Am J Physiol Endocrinol Metab   Vol. 290   page: E213-7   2006

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  187. Ghrelin increases neuropeptide Y and agouti-related peptide gene expression in the arcuate nucleus in rat hypothalamic organotypic cultures. Reviewed

    Goto M, Arima H, Watanabe M, Hayashi M, Banno R, Sato I, Nagasaki H, Oiso Y

    Endocrinology   Vol. 147   page: 5102-5109   2006

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  188. Insulin inhibits neuropeptide Y gene expression in the arcuate nucleus through GABAergic systems. Reviewed

    Sato I, Arima H, Ozaki N, Watanabe M, Goto M, Hayashi M, Banno R, Nagasaki H, Oiso Y

    J Neurosci   Vol. 25 ( 38 ) page: 8657-8664   2005

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  189. Leukemia inhibitory factor stimulates vasopressin release in rats. Reviewed

    Ishizaki S, Murase T, Sugimura Y, Banno R, Arima H, Miura Y, Oiso Y

    Neurosci Lett   Vol. 359   page: 77-80   2004

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  190. The melanocortin agonist melanotan II increases insulin sensitivity in OLETF rats. Reviewed

    Banno R, Arima H, Sato I, Hayashi M, Goto M, Sugimura Y, Murase T, Oiso Y

    Peptides   Vol. 25   page: 1279-1286   2004

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  191. NFAT Is Involved in the Depolarization-Induced Activation of Growth Hormone Releasing Hormone Gene Transcription In Vitro. Reviewed

    Asai M, Iwasaki Y, Yoshida M, Mutsuga-Nakayama N, Arima H, Ito M, Takano K, Oiso Y

    Mol Endocrinol   Vol. 18   page: 3011-3019   2004

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  192. Osmoregulation of vasopressin release and gene transcription under acute and chronic hypovolemia in rats. Reviewed

    Kondo N, Arima H, Banno R, Kuwahara S, Sato I, Oiso Y

    Am J Physiol Endocrinol Metab   Vol. 286 ( 3 ) page: E337-346   2004

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  193. Centrally administered tuberinfundibular peptide of 39 residues inhibits arginine vasopressin release in conscious rats Reviewed

    Sugimura Y, Murase T, Ishizaki S, Tachikawa K, Arima H, Miura U, Usdin TB, Oiso Y

    Endocrinology   Vol. 144 ( 7 ) page: 2791-2796   2003.7

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  194. Altered cardiovascular regulation in arginine vasopressin-overexpressing transgenic rat. Reviewed

    Tachikawa K, Yokoi H, Nagasaki H, Arima H, Murase T, Sugimura Y, Miura Y, Hirabayashi M, Oiso Y

    Am J Physiol Endocrinol Metab   Vol. 285 ( 6 ) page: E1161-1166   2003.6

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  195. Regulation of vasopressin gene expression by cAMP and glucocorticoids in the parvocellualr neurons of the paraventricular nucleus in rat hypothalamic organotypidc cultures. Reviewed

    Kuwahara S, Arima H, Banno R, Sato I, Kondo N, Oiso Y

    J Neurosci   Vol. 23 ( 32 ) page: 10231-10237   2003

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  196. Role of ghrelin in the regulation of vasopressin release in conscious rats. Reviewed

    Ishizaki S, Murase T, Sugimura Y, Kakiya S, Yokoi H, Tachikawa K, Arima H, Miura Y, Oiso Y

    Endocrinology   Vol. 143 ( 5 ) page: 1589-1593   2002.5

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  197. Ciliary neurotrophic factor increases the survival of magnocellular vasopressin and oxytocin neurons in rat supraoptic nucleus in organotypic cultures Reviewed

    Rusnak M, House SB, Arima H, Gainer H

    Microsc Res Tech   Vol. 56 ( 2 ) page: 101-112   2002.2

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  198. Overexpression of vasopressin in the rat transgenic for the metallothionein-vasopressin fugion gene Reviewed

    Nagasaki H, Yokoi H, Arima H, Hirabayashi M, Ishizaki S, Tachikawa K, Murase T, Miura Y, Oiso Y

    J Endocrinol   Vol. 173 ( 1 ) page: 35-44   2002.1

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  199. Adaptation to sustained high plasma vasopressin in water and electrolyte homeostasis in the rat transgenic for the metallothinonein-vasopressin fusion gene Reviewed

    Yokoi H, Nagasaki H, Tachikawa K, Arima H, Murase T, Miura Y, Hirabayashi M, Oiso Y

    J Endocrinol   Vol. 173 ( 1 ) page: 23-33   2002.1

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  200. Neuronal activity is required for the circadian rhythm of vasopressin gene transcription in the suprachiasmatic nucleus in vivo. Reviewed

    Arima H, House SB, Gainer H, Aguilera G

    Endocrinology   Vol. 143   page: 4165-4171   2002

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  201. Diurnal changes in arginine vasopressin gene transcription in the rat suprachiasmatic nucleus. Reviewed

    Yambe Y, Arima H, Kakiya S, Murase T, Oiso Y

    Mol Brain Res   Vol. 104   page: 132-136   2002

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  202. Sulfonylurea receptor transgenic mice resist seizure induction and exonitoxic neuron death Reviewed

    Hernandez-Sanches C, Basile AS, Fedorova I, Arima H, Stannard B, Fernandez A, LeRoith D

      Vol. 98 ( 6 ) page: 3549-3554   2001.6

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  203. Direct stimulation of arginine vasopressin gene transcription by cAMP in parvocellular neurons of the paraventricular nucleus in organotypic cultures. Reviewed

    Arima H, House SB, Gainer H, Aguilera G

    Endocrinology   Vol. 142   page: 5027-5030   2001

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  204. Role of endogenous nociception in the regulation of arginine vasopressin release in conscious rats Reviewed

    Kakiya S, Murase T, Arima H, Yokoi H, Iwasaki Y, Miura Y, Oiso Y

    Endocrinology   Vol. 141 ( 12 ) page: 4466-4471   2000.12

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  205. Analysis of the vasopressin system and water regulation in genetically polydipsic mice. Reviewed

    Yambe Y, Watanabe-Tomita Y, Kakiya S, Yokoi H, Nagasaki H, Arima H, Murase T, Yuasa H, Kondo K, Yamashita H, Oiso Y

    Am J Physiol Endocrinol Metab   Vol. 278 ( 2 ) page: E189-194   2000.2

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  206. Vasopressinergic and Oxytocinergic neurons of Hypothalamic Supraoptic and Paraventricular Nuclei Co-express mRNA for Type-1 and Type-2 Corticotropin-Releasing Hormone Receptors. Reviewed

    Arima H, Aguilera G

    J Neuroendocrinol   Vol. 12   page: 833-842   2000

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  207. Effects of acute hypotensive stimulli on arginine vasopressin gene transcription in the rat hypothalamus. Reviewed

    Kakiya S, Arima H, Yokoi H, Murase T, Yambe Y, Oiso Y

    Am J Physiol Endocrinol Metab   Vol. 279 ( 4 ) page: E886-E892   2000

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  208. Rapid and sensitive vasopressin heteronuclear RNA response to change in plasma osmolality. Reviewed

    Arima H, Kondo K, Kakiya S, Nagasaki H, Yokoi H, Yambe Y, Murase T, Iwasaki Y, and Oiso Y

    J Neurondocrinology   Vol. 11   page: 337-341   1999

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  209. Age-associated decrease in response of rat aquaporin-2 gene expression to dehydration Reviewed

    Terashima Y, Kondo K, Inagaki A, Yokoi H, Arima H, Murase T, Iwasaki Y, Oiso Y

    Life Sci   Vol. 62 ( 10 ) page: 873-882   1998.10

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  210. Anoretic effect of pituitary adenylate cyclase activating polypeptide (PACAP) in rats:lack of evidence for involvement of hypothalamic neuropeptide gene expression. Reviewed

    Mizuno Y, Kondo K, Terashima Y, Arima H, Murase T, Oiso Y

    J Neuroendocrinol   Vol. 10 ( 8 ) page: 611-616   1998.8

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  211. Central administration of urocortin inhibits vasopressin release in conscious rats. Reviewed

    Kakiya S, Yokoi H, Arima H, Iwasaki Y, Oki Y, Oiso Y.

    Neurosci Lett   Vol. 248 ( 2 ) page: 144-146   1998.2

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  212. Antiserum against neuropeptide FF augments vasopressin release in conscious rats Reviewed

    Yokoi H, Arima H, Kondo K, Murase T, Iwasaki Y, Yang HY, Oiso Y

    Peptides   Vol. 19 ( 2 ) page: 393-395   1998.2

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  213. Regulation of vasopressin synthesis and release by area postrema in rats. Reviewed

    Arima H, Kondo K, Murase T, Yokoi H, Iwasaki Y, Saito H, Oiso Y

    Endocrinology   Vol. 139   page: 1481-1486   1998

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  214. Neuropeptide FF reduces food intake in rats Reviewed

    Murase T, Arima H, Kondo K, Oiso Y

    Peptidfes   Vol. 17 ( 2 ) page: 353-354   1996

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  215. Centrally administered neuropeptide FF inhibits arginine vasopressin release in conscious rats. Reviewed

    Arima H, Murase T, Kondo K, Iwasaki Y, and Oiso Y.

    Endocrinology   Vol. 137   page: 1523-1529   1996

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  216. Intracerebroventricular injection of adrenomedullin inhibits vasopressin release in conscious rats. Reviewed

    Yokoi H, Arima H, Murase T, Kondo K, Iwasaki Y, Oiso Y

    Neurosci Lett   Vol. 216 ( 1 ) page: 65-67   1996

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  217. The expression of pituitary adenylate cyclase-activating polypeptide (PACAP) mRNA in rat brain: possible role of endogenous PACAP in vasopressin release Reviewed

    Murase T, Kondo K, Arima H, Iwasaki Y, Ito M, Miura Y, Oiso Y

    Neurosci Lett   Vol. 185 ( 2 ) page: 103-106   1995

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Books 20

  1. 下垂体の免疫関連有害事象

    岩間信太郎、有馬寛

    医学のあゆみ/医歯薬出版株式会社  2021.2 

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    Language:Japanese

  2. 下垂体オルガノイドによるマイ・メディシン

    須賀英隆、有馬寛

    医学のあゆみ  2021.2 

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    Total pages:8   Responsible for pages:8   Language:Japanese

  3. インスリンを使用していない2型糖尿病患者におけるflash glucose monitoring(FGM)による血糖コントロール

    尾上剛史 有馬寛、他( Role: Joint author)

    Calm, 先端医学社  2021.1 

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    Total pages:5   Responsible for pages:5   Language:Japanese Book type:Scholarly book

  4. 高齢社会における人と自動車

    青木 宏文 尾上剛史 有馬寛、他

    コロナ社  2021.1 

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    Language:Japanese Book type:Scholarly book

  5. 抗利尿ホルモン不適切分泌症候群(SIADH)

    萩原大輔、有馬寛

    救急・集中治療 ER・ICUでの薬の使い方・考え方-エキスパートが実践する秘訣(コツ)- 2021-22'/総合医学社  2020.10 

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    Total pages:4   Responsible for pages:4  

  6. 特集:夜間頻尿と睡眠障害 夜間頻尿に対する薬物療法(治療後のQOL・メリットを含む) 内科の立場から(多尿・夜間多尿)

    萩原大輔、有馬寛

    PROGRESS IN MEDICINE/ライフ・サイエンス  2020.10 

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    Language:Japanese Book type:Scholarly book

  7. iPS細胞由来の下垂体オルガノイドを用いたホルモン補充療法

    多賀詩織、須賀英隆、木村徹、有馬寛

    Drug Delivery System  2020.9 

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    Total pages:8   Responsible for pages:8   Language:Japanese

  8. 免疫チェックポイント阻害薬による内分泌障害

    小林朋子, 岩間信太郎, 有馬寛( Role: Joint author)

    臨床消化器内科  2020.5 

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    Total pages:5   Responsible for pages:5   Language:Japanese Book type:Dictionary, encyclopedia

  9. 尿崩症

    萩原大輔、有馬寛( Role: Joint author)

    薬局2020年3月増刊号「病気と薬2000」/南山堂  2020.3 

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    Total pages:3   Responsible for pages:3   Language:Japanese

  10. 中枢性尿崩症

    有馬寛( Role: Sole author)

    新臨床内科学/医学書院  2020.3 

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    Total pages:3   Responsible for pages:3   Language:Japanese

  11. 内分泌疾患の最近の動向

    有馬寛( Role: Sole author)

    今日の診断指針/医学書院  2020.3 

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    Total pages:1   Responsible for pages:1   Language:Japanese

  12. 高Na血症

    有馬寛( Role: Sole author)

    ライフメディコム  2009.7 

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  13. 下垂体腫瘍のすべて

    有馬寛、大磯ユタカ( Role: Joint author)

    医学書院  2009 

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  14. 総合臨床 新版処方計画法 尿崩症(中枢性・腎性)

    有馬寛、大磯ユタカ( Role: Joint author)

    永井書院  2008 

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  15. 内分泌・糖尿病科・視床下部弓状核を介したエネルギー調節

    有馬寛( Role: Sole author)

    科学評論社  2007.6 

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  16. ホルモンと臨床・バゾプレシンの産生・分泌機構

    有馬寛、大磯ユタカ( Role: Joint author)

    医学の世界社  2006.5 

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  17. 日本臨床・バゾプレシン関連遺伝子改変動物

    林正幸、有馬寛、大磯ユタカ( Role: Joint author)

    日本臨床社  2005 

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  18. 最新医学・尿崩症治療の展望

    有馬寛、大磯ユタカ( Role: Joint author)

    最新医学社  2002 

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  19. ホルモンと臨床・尿崩症-最近の話題-

    有馬寛、大磯ユタカ( Role: Joint author)

    医学の世界社  2002 

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  20. 内分泌・糖尿病科・Vasopressin ニューロンシステム

    有馬寛( Role: Sole author)

    医学の世界社  1998 

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MISC 36

  1. The elucidation of functions of iPS cell-derived regenerative brain organoid by quantum-nano sensor

    徳永真登, 湯川博, 三輪田勤, 須賀英隆, 有馬寛, 西村勇姿, 馬場嘉信

    日本化学会春季年会講演予稿集(Web)   Vol. 14 ( 2 ) page: 143 - 143   2021.5

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    J-GLOBAL

  2. 細胞傷害性CD4陽性T細胞は抗PD-1抗体誘発破壊性甲状腺炎の発症に関与する

    安田康紀, 岩間信太郎, 奥地剛之, 伊藤雅晃, 小林朋子, 周きん, 山上綾菜, 有馬寛

    日本内分泌学会雑誌   Vol. 97 ( 3 (Web) )   2021

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  3. ナノ量子センサーを用いたiPS細胞由来再生脳オルガノイド機能解明

    徳永真登, 湯川博, 三輪田勤, 須賀英隆, 有馬寛, 西村勇姿, 馬場嘉信

    日本再生医療学会総会(Web)   Vol. 20th ( 3 ) page: 100 - 100   2021

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    Language:Japanese   Publisher:(一社)日本臓器保存生物医学会  

    J-GLOBAL

  4. ストレプトゾトシン糖尿病マウスにおいて抗PD-1抗体の大腸癌細胞株に対する抗腫瘍効果は低下する

    伊藤雅晃, 岩間信太郎, 奥地剛之, 安田康紀, 小林朋子, 周きん, 山上綾菜, 有馬寛

    日本内分泌学会雑誌   Vol. 97 ( 3 (Web) )   2021

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  5. 日本人間ドック学会大規模データベースを用いた境界型糖尿病と慢性腎臓病(CKD)の関連についての検討

    古川 麻里子, 津下 一代, 加藤 公則, 和田 高士, 篠原 幸人, 尾上 剛史, 後藤 資実, 有馬 寛

    糖尿病   Vol. 63 ( Suppl.1 ) page: S - 134   2020.8

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  6. 中枢性尿崩症

    須賀英隆, 髙木博史, 有馬寛

    内科(特集:内分泌Up To Date)   Vol. 124 ( 6 ) page: 2441 - 2444   2019.11

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  7. 視床下部と下垂体とのハイブリッド Invited

    須賀英隆, 有馬寛

    月刊細胞   Vol. 51 ( 4 ) page: 20 - 24   2019.3

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  8. Chemical chaperone 4-phenylbutylate reduces mutant protein accumulation in the endoplasmic reticulum of arginine vasopressin neurons in a mouse model for familial neurohypophysial diabetes insipidus Reviewed International journal

    Masayoshi Tochiya, Daisuke Hagiwara, Yoshinori Azuma, Takashi Miyata, Yoshiaki Morishita, Hidetaka Suga, Takeshi Onoue, Taku Tsunekawa, Hiroshi Takagi, Yoshihiro Ito, Shintaro Iwama, Motomitsu Goto, Ryoichi Banno, Hiroshi Arima

    Neuroscience Letters   Vol. 682   page: 50 - 55   2018.8

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    Language:English   Publishing type:Rapid communication, short report, research note, etc. (scientific journal)   Publisher:Elsevier Ireland Ltd  

    Familial neurohypophysial diabetes insipidus (FNDI), characterized by progressive polyuria and loss of arginine vasopressin (AVP) neurons, is an autosomal dominant disorder caused by AVP gene mutations. Our previous studies with FNDI model mice demonstrated that mutant proteins accumulated in the endoplasmic reticulum (ER) of AVP neurons. Here, we examined therapeutic effects of the chemical chaperone 4-phenylbutylate (4-PBA) in FNDI mice. Treatment with 4-PBA reduced mutant protein accumulation in the ER of FNDI mice and increased AVP release, leading to reduced urine volumes. Furthermore, AVP neuron loss under salt loading was attenuated by 4-PBA treatment. These data suggest that 4-PBA ameliorated mutant protein accumulation in the ER of AVP neurons and thereby prevented FNDI phenotype progression.

    DOI: 10.1016/j.neulet.2018.06.013

    Scopus

    PubMed

  9. Functional Pituitary Tissue Generation from Human Embryonic Stem Cells. Reviewed International journal

    Kano M, Suga H, Kasai T, Ozone C, Arima H

    Current protocols in neuroscience   Vol. 83 ( 1 ) page: e48   2018.4

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    The anterior pituitary gland produces several hormones essential for regulation of the somatic endocrine system. Deficiency of these hormones can cause life-threatening diseases, including adrenal crisis. Pituitary tissue generated from human pluripotent stem cells is expected to provide better treatment than current hormone replacement therapy. During early mammalian development, the pituitary anlage (Rathke's pouch) develops from non-neural ectoderm adjacent to the developing ventral hypothalamus. The close interaction between these two tissues is crucial for Rathke's pouch development and involves several signaling molecules. Early exposure of human embryonic stem cells in 3D floating culture to sonic hedgehog and bone morphogenetic protein 4 promoted the cells' differentiation into oral ectoderm and, subsequently, hormone-producing cells such as corticotrophs (adrenocorticotropic hormone-producing cells). The differentiation approach described herein, which induces the formation of pituitary tissue in contact with hypothalamic neural tissue, mimics mammalian pituitary development. The differentiated corticotrophs are functional, responding normally to both release and feedback signals. © 2018 by John Wiley & Sons, Inc.

    DOI: 10.1002/cpns.48

    PubMed

  10. 炭水化物と脂肪ではGIPによる体重増加作用やインスリン分泌促進作用は異なる

    前川 龍也, 清野 祐介, 村瀬 正敏, 尾方 秀忠, 林 良敬, 有馬 寛

    糖尿病   Vol. 61 ( Suppl.1 ) page: S - 251   2018.4

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  11. IoT(Internet of Things)システムの糖尿病療養指導への応用

    小林 朋子, 後藤 資実, 尾上 剛史, 村本 あき子, 加藤 綾子, 栄口 由香里, 野村 恵里, 武藤 繁貴, 八谷 寛, 津下 一代, 有馬 寛

    糖尿病   Vol. 61 ( Suppl.1 ) page: S - 440   2018.4

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  12. Patients With Antithyroid Antibodies Are Prone To Develop Destructive Thyroiditis by Nivolumab: A Prospective Study Reviewed International journal

    Kobayashi Tomoko, Iwama Shintaro, Yasuda Yoshinori, Okada Norio, Tsunekawa Taku, Onoue Takeshi, Takagi Hiroshi, Hagiwara Daisuke, Ito Yoshihiro, Morishita Yoshiaki, Goto Motomitsu, Suga Hidetaka, Banno Ryoichi, Yokota Kenji, Hase Tetsunari, Morise Masahiro, Hashimoto Naozumi, Ando Masahiko, Kiyoi Hitoshi, Gotoh Momokazu, Ando Yuichi, Akiyama Masashi, Hasegawa Yoshinori, Arima Hiroshi

    JOURNAL OF THE ENDOCRINE SOCIETY   Vol. 2 ( 3 ) page: 241-251 - 251   2018.3

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    Context: Immune checkpoint inhibitors, including anti-programmed cell death-1 (PD-1) antibodies, have become promising treatments for a variety of advanced malignancies. However, these medicines can cause immune-related adverse events (irAEs), including endocrinopathies. Objective: This study examined the incidence of endocrine irAEs induced by nivolumab. Patients and Main Outcome Measured: Sixty-six patients treated with nivolumab at Nagoya University Hospital were prospectively evaluated for pituitary hormones, thyroid function, antithyroid antibodies (Abs), and glucose levels every 6 weeks after the initiation of nivolumab for 24 weeks. Results: Four out of 66 patients developed destructive thyroiditis, and three patients developed hypothyroidism requiring levothyroxine replacement. The prevalence of positive anti-thyroglobulin Abs (TgAbs) and/or anti-thyroid peroxidase Abs (TPOAbs) at baseline was significantly higher in the group that developed destructive thyroiditis (3/4) compared with the group that did not develop thyroiditis (3/62; P = 0.002). There were no significant differences in other clinical variables between the groups. There were no endocrine irAEs other than destructive thyroiditis during the 24 weeks. The prevalence of TgAbs and/or TPOAbs at baseline was not associated with the development of other irAEs, including pneumonitis, colitis, or skin reactions. Conclusions: Our real-world data showed that destructive thyroiditis was an endocrine irAE that was frequently induced by nivolumab and was significantly associated with positive TgAbs and/or TPOAbs before treatment. Our findings indicate that evaluating these Abs before treatment may help identify patients with a high risk of thyroidal irAEs and may have important clinical benefit.

    DOI: 10.1210/js.2017-00432

    PubMed

  13. 耐糖能障害の合併を認めたインスリノーマの1症例

    半田 朋子, 恒川 卓, 清野 祐介, 有馬 寛

    糖尿病   Vol. 61 ( 2 ) page: 79 - 79   2018.2

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  14. 高スターチ食によるインスリン分泌増加は、KATPチャンネル依存性の系と非依存性の系により制御されている

    村瀬 正敏, 清野 祐介, 前川 龍也, 丹羽 靖浩, 尾方 秀忠, 飯田 淳史, 細川 香里, 林 良敬, 有馬 寛

    日本病態栄養学会誌   Vol. 21 ( Suppl. ) page: S - 70   2018.1

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    Language:Japanese   Publishing type:Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)   Publisher:(一社)日本病態栄養学会  

  15. Chronic high-sucrose diet increases fibroblast growth factor 21 production and energy expenditure in mice International journal

    Ryuya Maekawa, Yusuke Seino, Hidetada Ogata, Masatoshi Murase, Atsushi Iida, Kaori Hosokawa, Erina Joo, Norio Harada, Shin Tsunekawa, Yoji Hamada, Yutaka Oiso, Nobuya Inagaki, Yoshitaka Hayashi, Hiroshi Arima

    JOURNAL OF NUTRITIONAL BIOCHEMISTRY   Vol. 49   page: 71 - 79   2017.11

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    Language:English   Publishing type:Rapid communication, short report, research note, etc. (scientific journal)   Publisher:ELSEVIER SCIENCE INC  

    Excess carbohydrate intake causes obesity in humans. On the other hand, acute administration of fructose, glucose or sucrose in experimental animals has been shown to increase the plasma concentration of anti-obesity hormones such as glucagon-like peptide 1 (GLP-1) and Fibroblast growth factor 21 (FGF21), which contribute to reducing body weight. However, the secretion and action of GLP-1 and FGF21 in mice chronically fed a high-sucrose diet has not been investigated. To address the role of anti-obesity hormones in response to increased sucrose intake, we analyzed mice fed a high-sucrose diet, a high-starch diet or a normal diet for 15 weeks. Mice fed a high-sucrose diet showed resistance to body weight gain, in comparison with mice fed a high-starch diet or control diet, due to increased energy expenditure. Plasma FGF21 levels were highest among the three groups in mice fed a high-sucrose diet, whereas no significant difference in GLP-1 levels was observed. Expression levels of uncoupling protein 1 (UCP-1), FGF receptor 1c (FGFR1c) and beta-klotho (KLB) mRNA in brown adipose tissue were significantly increased in high sucrose-fed mice, suggesting increases in FGF21 sensitivity and energy expenditure. Expression of carbohydrate responsive element binding protein (ChREBP) mRNA in liver and brown adipose tissue was also increased in high sucrose-fed mice. These results indicate that FGF21 production in liver and brown adipose tissue is increased in high-sucrose diet and participates in resistance to weight gain. (C) 2017 The Authors. Published by Elsevier Inc.

    DOI: 10.1016/j.jnutbio.2017.07.010

    Web of Science

    PubMed

  16. Adverse events induced by immune checkpoint inhibitors in pituitary gland

      Vol. 263 ( 1 ) page: 109 - 113   2017.10

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  17. Randomized controlled trial for assessment of Internet of Things system to guide intensive glucose control in diabetes outpatients: Nagoya Health Navigator Study protocol Reviewed International journal

    Takeshi Onoue, Motomitsu Goto, Tomoko Kobayashi, Takashi Tominaga, Masahiko Ando, Hiroyuki Honda, Yasuko Yoshida, Takahiro Tosaki, Hisashi Yokoi, Sawako Kato, Shoichi Maruyama, Hiroshi Arima

    Nagoya Journal of Medical Science   Vol. 79 ( 3 ) page: 323 - 329   2017.8

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    Language:English   Publishing type:Rapid communication, short report, research note, etc. (scientific journal)   Publisher:Nagoya University  

    The Internet of Things (IoT) allows collecting vast amounts of health-relevant data such as daily activity, body weight (BW), and blood pressure (BP) automatically. The use of IoT devices to monitor diabetic patients has been studied, but could not evaluate IoT-dependent effects because health data were not measured in control groups. This multicenter, open-label, randomized, parallel group study will compare the impact of intensive health guidance using IoT and conventional medical guidance on glucose control. It will be conducted in outpatients with type 2 diabetes for a period of 6 months. IoT devices to measure amount of daily activity, BW, and BP will be provided to IoT group patients. Healthcare professionals (HCPs) will provide appropriate feedback according to the data. Non-IoT control, patients will be given measurement devices that do not have a feedback function. The primary outcome is glycated hemoglobin at 6 months. The study has already enrolled 101 patients, 50 in the IoT group and 51 in the non-IoT group, at the two participating outpatient clinics. The baseline characteristics of two groups did not differ, except for triglycerides. This will be the first randomized, controlled study to evaluate IoT-dependent effects of intensive feedback from HCPs. The results will validate a new method of health-data collection and provision of feedback suitable for diabetes support with increased effectiveness and low cost.

    DOI: 10.18999/nagjms.79.3.323

    Scopus

    PubMed

  18. Randomized controlled trial for assessment of Internet of Things system to guide intensive glucose control in diabetes outpatients: Nagoya Health Navigator Study protocol International journal

    Takeshi Onoue, Motomitsu Goto, Tomoko Kobayashi, Takashi Tominaga, Masahiko Ando, Hiroyuki Honda, Yasuko Yoshida, Takahiro Tosaki, Hisashi Yokoi, Sawako Kato, Shoichi Maruyama, Hiroshi Arima

    NAGOYA JOURNAL OF MEDICAL SCIENCE   Vol. 79 ( 3 ) page: 323 - 329   2017.8

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    The Internet of Things (IoT) allows collecting vast amounts of health-relevant data such as daily activity, body weight (BW), and blood pressure (BP) automatically. The use of IoT devices to monitor diabetic patients has been studied, but could not evaluate IoT-dependent effects because health data were not measured in control groups. This multicenter, open-label, randomized, parallel group study will compare the impact of intensive health guidance using IoT and conventional medical guidance on glucose control. It will be conducted in outpatients with type 2 diabetes for a period of 6 months. IoT devices to measure amount of daily activity, BW, and BP will be provided to IoT group patients. Healthcare professionals (HCPs) will provide appropriate feedback according to the data. Non-IoT control, patients will be given measurement devices that do not have a feedback function. The primary outcome is glycated hemoglobin at 6 months. The study has already enrolled 101 patients, 50 in the IoT group and 51 in the non-IoT group, at the two participating outpatient clinics. The baseline characteristics of two groups did not differ, except for triglycerides. This will be the first randomized, controlled study to evaluate IoT-dependent effects of intensive feedback from HCPs. The results will validate a new method of health-data collection and provision of feedback suitable for diabetes support with increased effectiveness and low cost.

    DOI: 10.18999/nagjms.79.3.323

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  19. Sequestosome 1 (SQSTMI/p62) maintains protein folding capacity under endoplasmic reticulum stress in mouse hypothalamic organotypic culture International journal

    Takashi Tominaga, Motomitsu Goto, Takeshi Onoue, Akira Mizoguchi, Mariko Sugiyama, Taku Tsunekawa, Daisuke Hagiwara, Yoshiaki Morishita, Yoshihiro Ito, Shintaro Iwama, Hidetaka Suga, Ryoichi Banno, Hiroshi Arima

    NEUROSCIENCE LETTERS   Vol. 656   page: 103 - 107   2017.8

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    Sequestosome 1 (SQSTM1) also known as ubiquitin-binding protein p62 (p62) is a cargo protein involved in the degradation of misfolded proteins via selective autophagy. Disruption of autophagy and resulting accumulation of misfolded proteins in the endoplasmic reticulum (ER) leads to ER stress. ER stress is implicated in several neurodegenerative diseases and obesity. As knockout of p62 (p62KO) reportedly induces obesity in mice, we examined how p62 contributes to ER stress and the ensuing unfolded protein response (UPR) in hypothalamus using mouse organotypic cultures in the present study. Cultures from p62KO mice showed significantly reduced formation of LC3-GFP puncta, an index of autophagosome formation, in response to the chemical ER stressor thapsigargin compared to wild-type (WT) cultures. Hypothalamic cultures from p62KO mice exhibited higher basal expression of the UPR/ER stress markers CHOP mRNA and ATF4 mRNA than WT cultures. Thapsigargin enhanced CHOP, ATF4, and BiP mRNA as well as p-elF2 alpha protein expression in both NWT and p62KO cultures, but all peak values were greater in p621(0 cultures. A proteasome inhibitor increased p62 expression in WT cultures and upregulated the UPR/ER stress markers CHOP mRNA and ATF4 mRNA in both genotypes, but to a greater extent in p62KO cultures. Therefore, p62 deficiency disturbed autophagosome formation and enhanced both basal and chemically induced ER stress, suggesting that p62 serves to prevent ER stress in mouse hypothalamus by maintaining protein folding capacity. (C) 2017 Elsevier B.V. All rights reserved.

    DOI: 10.1016/j.neulet.2017.06.014

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  20. Involvement of pituitary gland associated with the treatment of CTLA-4 antibodies

      Vol. 261 ( 12 ) page: 1137 - 1141   2017.6

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  21. Anti-pituitary antibodies against corticotrophs in IgG4-related hypophysitis International journal

    Naoko Iwata, Shintaro Iwama, Yoshihisa Sugimura, Yoshinori Yasuda, Kohtaro Nakashima, Seiji Takeuchi, Daisuke Hagiwara, Yoshihiro Ito, Hidetaka Suga, Motomitsu Goto, Ryoichi Banno, Patrizio Caturegli, Teruhiko Koike, Yoshiharu Oshida, Hiroshi Arima

    PITUITARY   Vol. 20 ( 3 ) page: 301 - 310   2017.6

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    Purpose IgG4-related disease is a systemic inflammatory disease characterized by infiltration of IgG4-positive plasma cells into multiple organs, including the pituitary gland. Autoimmunity is thought to be involved in the pathogenesis of IgG4-related disease. The diagnosis of IgG4-related hypophysitis (IgG4-RH) is difficult because its clinical features, such as pituitary swelling and hypopituitarism, are similar to those of other pituitary diseases, including lymphocytic hypophysitis and sellar/suprasellar tumors. The presence and significance of anti-pituitary antibodies (APA) in IgG4-RH is unclear.
    Methods In this case-control study, we used single indirect immunofluorescence on human pituitary substrates to assess the prevalence of serum APA in 17 patients with IgG4-RH, 8 control patients with other pituitary diseases (lymphocytic infundibulo-neurohypophysitis, 3; craniopharyngioma, 2; germinoma, 3), and 9 healthy subjects.We further analyzed the endocrine cells targeted by the antibodies using double indirect immunofluorescence.
    Results APA were found in 5 of 17 patients with IgG4-RH (29%), and in none of the pituitary controls or healthy subjects. The endocrine cells targeted by the antibodies in the 5 IgG4-RH cases were exclusively corticotrophs. Antibodies were of the IgG1 subclass, rather than IgG4, in all 5 cases, suggesting that IgG4 is not directly involved in the pathogenesis. Finally, antibodies recognized pro-opiomelanocortin in 2 of the cases.
    Conclusions Our study suggests that autoimmunity is involved in the pathogenesis of IgG4-RH and that corticotrophs are the main antigenic target, highlighting a possible new diagnostic marker for this condition.

    DOI: 10.1007/s11102-016-0780-8

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  22. S100B impairs glycolysis via enhanced poly(ADP-ribosyl) ation of glyceraldehyde-3-phosphate dehydrogenase in rodent muscle cells International journal

    Kaori Hosokawa, Yoji Hamada, Atsushi Fujiya, Masatoshi Murase, Ryuya Maekawa, Yasuhiro Niwa, Takako Izumoto, Yusuke Seino, Shin Tsunekawa, Hiroshi Arima

    AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM   Vol. 312 ( 6 ) page: E471 - E481   2017.6

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    S100 calcium-binding protein B (S100B), a multifunctional macromolecule mainly expressed in nerve tissues and adipocytes, has been suggested to contribute to the pathogenesis of obesity. To clarify the role of S100B in insulin action and glucose metabolism in peripheral tissues, we investigated the effect of S100B on glycolysis in myoblast and myotube cells. Rat myoblast L6 cells were treated with recombinant mouse S100B to examine glucose consumption, lactate production, glycogen accumulation, glycolytic metabolites and enzyme activity, insulin signaling, and poly(ADP-ribosyl)ation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Glycolytic metabolites were investigated by enzyme assays or metabolome analysis, and insulin signaling was assessed by Western blot analysis. Enzyme activity and poly(ADP-ribosyl) ation of GAPDH was evaluated by an enzyme assay and immunoprecipitation followed by dot blot with an anti-poly(ADP-ribose) antibody, respectively. S100B significantly decreased glucose consumption, glucose analog uptake, and lactate production in L6 cells, in either the presence or absence of insulin. In contrast, S100B had no effect on glycogen accumulation and insulin signaling. Metabolome analysis revealed that S100B increased the concentration of glycolytic intermediates upstream of GAPDH. S100B impaired GAPDH activity and increased poly(ADP-ribosyl) ated GAPDH proteins. The effects of S100B on glucose metabolism were mostly canceled by a poly(ADP-ribose) polymerase inhibitor. Similar results were obtained in C2C12 myotube cells. We conclude that S100B as a humoral factor may impair glycolysis in muscle cells independent of insulin action, and the effect may be attributed to the inhibition of GAPDH activity from enhanced poly(ADP-ribosyl) ation of the enzyme.

    DOI: 10.1152/ajpendo.00328.2016

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  23. PTP1B deficiency improves hypothalamic insulin sensitivity resulting in the attenuation of AgRP mRNA expression under high-fat diet conditions International journal

    Mariko Sugiyama, Ryoichi Banno, Akira Mizoguchi, Takashi Tominaga, Taku Tsunekawa, Takeshi Onoue, Daisuke Hagiwara, Yoshihiro Ito, Yoshiaki Morishita, Shintaro Iwama, Motomitsu Goto, Hidetaka Suga, Hiroshi Arima

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   Vol. 488 ( 1 ) page: 116 - 121   2017.6

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    Hypothalamic insulin receptor signaling regulates energy balance and glucose homeostasis via agouti related protein (AgRP). While protein tyrosine phosphatase 1B (PTP1B) is classically known to be a negative regulator of peripheral insulin signaling by dephosphorylating both insulin receptor beta (IR beta) and insulin receptor substrate, the role of PTP1B in hypothalamic insulin signaling remains to be fully elucidated. In the present study, we investigated the role of PTP1B in hypothalamic insulin signaling using PTP1B deficient (KO) mice in vivo and ex vivo. For the in vivo study, hypothalamic insulin resistance induced by a high-fat diet (HFD) improved in KO mice compared to wild-type (WT) mice. Hypothalamic AgRP mRNA expression levels were also significantly decreased in KO mice independent of body weight changes. In an ex vivo study using hypothalamic organotypic cultures, insulin treatment significantly increased the phosphorylation of both IR beta and Akt in the hypothalamus of KO mice compared to WT mice, and also significantly decreased AgRP mRNA expression levels in KO mice. While incubation with inhibitors of phosphatidylinositol-3 kinase (PI3K) had no effect on basal levels of Akt phosphorylation, these suppressed insulin induction of Akt phosphorylation to almost basal levels in WT and KO mice. The inhibition of the PI3K-Akt pathway blocked the downregulation of AgRP mRNA expression in KO mice treated with insulin. These data suggest that PTP1B acts on the hypothalamic insulin signaling via the PI3K-Akt pathway. Together, our results suggest a deficiency of PTP1B improves hypothalamic insulin sensitivity resulting in the attenuation of AgRP mRNA expression under HFD conditions. (C) 2017 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.bbrc.2017.05.019

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  24. 慢性的な高スクロース負荷はFGF21分泌と基礎代謝を亢進させる

    前川 龍也, 清野 祐介, 村瀬 正敏, 細川 香里, 林 良敬, 有馬 寛

    日本内分泌学会雑誌   Vol. 93 ( 1 ) page: 331 - 331   2017.4

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  25. 高蛋白質食負荷は、グルカゴン分泌増加を介して肝臓のアミノ酸代謝を規定する

    前川 龍也, 高野 悠子, 清野 祐介, 村瀬 正敏, 有馬 寛, 林 良敬

    糖尿病   Vol. 60 ( Suppl.1 ) page: S - 262   2017.4

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  26. 高スターチ食によるインスリン分泌増加の機序の検討

    村瀬 正敏, 清野 祐介, 前川 龍也, 林 良敬, 有馬 寛

    糖尿病   Vol. 60 ( Suppl.1 ) page: S - 469   2017.4

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  27. 運動療法に対する2型糖尿病教育入院患者の行動変容ステージと自己効力感の関係性

    栢本 あずさ, 眞鍋 朋誉, 佐藤 克成, 鄭 よ廷, 高木 大地, 柴田 篤志, 森 友洋, 門野 泉, 清野 祐介, 後藤 資実, 有馬 寛

    糖尿病   Vol. 60 ( Suppl.1 ) page: S - 222   2017.4

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  28. 2型糖尿病患者に対する握力とSPPB評価の特徴

    眞鍋 朋誉, 栢本 あずさ, 佐藤 克成, 鄭 よ廷, 高木 大地, 柴田 篤志, 森 友洋, 門野 泉, 清野 祐介, 後藤 資実, 有馬 寛

    糖尿病   Vol. 60 ( Suppl.1 ) page: S - 221   2017.4

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  29. IoT(Internet of Things)システムを用いた療養指導強化による糖代謝改善についての検討 教育入院患者を対象とした前向き研究

    小林 朋子, 後藤 資実, 尾上 剛史, 村本 あき子, 加藤 綾子, 栄口 由香里, 野村 恵里, 武藤 繁貴, 八谷 寛, 津下 一代, 有馬 寛

    糖尿病   Vol. 60 ( Suppl.1 ) page: S - 376   2017.4

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  30. 血清CA19-9高値が血糖コントロール改善により低下した両側内膜症性嚢胞、子宮筋腫合併2型糖尿病の1例

    山口 麻里子, 福井 彩子, 清野 祐介, 有馬 寛

    糖尿病   Vol. 60 ( Suppl.1 ) page: S - 226   2017.4

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  31. Deficiency of PTP1B Attenuates Hypothalamic Inflammation via Activation of the JAK2-STAT3 Pathway in Microglia

    Taku Tsunekawa, Ryoichi Banno, Akira Mizoguchi, Mariko Sugiyama, Takashi Tominaga, Takeshi Onoue, Daisuke Hagiwara, Yoshihiro Ito, Shintaro Iwama, Motomitsu Goto, Hidetaka Suga, Yoshihisa Sugimura, Hiroshi Arima

    EBIOMEDICINE   Vol. 16   page: 172 - 183   2017.2

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    Protein tyrosine phosphatase 1B (PTP1B) regulates leptin signaling in hypothalamic neurons via the JAK2-STAT3 pathway. PTP1B has also been implicated in the regulation of inflammation in the periphery. However, the role of PTP1B in hypothalamic inflammation, which is induced by a high-fat diet (HFD), remains to be elucidated. Here, we showed that STAT3 phosphorylation (p-STAT3) was increased in microglia in the hypothalamic arcuate nucleus of PTP1B knock-out mice (KO) on a HFD, accompanied by decreased Tnf and increased Il10 mRNA expression in the hypothalamus compared to wild-type mice (WT). In hypothalamic organotypic cultures, incubation with TNF alpha led to increased p-STAT3, accompanied by decreased Tnf and increased Il10 mRNA expression, in KO compared to WT. Incubation with p-STAT3 inhibitors or microglial depletion eliminated the differences in inflammation between genotypes. These data indicate an important role of JAK2-STAT3 signaling negatively regulated by PTP1B in microglia, which attenuates hypothalamic inflammation under HFD conditions. (C) 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

    DOI: 10.1016/j.ebiom.2017.01.007

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  32. Effects of clozapine on adipokine secretions/productions and lipid droplets in 3T3-L1 adipocytes.

    Tomomi Tsubai, Akira Yoshimi, Yoji Hamada, Makoto Nakao, Hiroshi Arima, Yutaka Oiso, Yukihiro Noda

    Journal of pharmacological sciences   Vol. 133 ( 2 ) page: 79 - 87   2017.2

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    Clozapine, a second-generation antipsychotic (SGA), is a cause of side effects related to metabolic syndrome. The participation of serotonin 5-HT2C and histamine H1 receptors in the central nervous system has been reported as a mechanism of the weight gain caused by clozapine. In the present study, we investigated the direct pharmacological action of clozapine on the 3T3-L1 adipocytes and compared it to that of blonanserin, an SGA with low affinity for both receptors. Short-term exposure to clozapine decreased secretion and mRNA expression of leptin. Long-term exposure decreased leptin as well as adiponectin secretion, and further increased lipid droplets accumulation. However, short- and long-term exposures to blonanserin did not affect these parameters. A selective serotonin 5-HT2C, but not a histamine H1, receptor antagonist enhanced the decreased secretion of leptin induced by short-term exposure to clozapine, but did not affect the increased accumulation of lipid droplets. Our findings indicate that clozapine, but not blonanserin, strongly and directly affected the secretion of adipokines, such as leptin, in adipocytes and caused adipocyte enlargement.

    DOI: 10.1016/j.jphs.2017.01.004

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  33. NMDA receptor antagonist prevents cell death in the hippocampal dentate gyrus induced by hyponatremia accompanying adrenal insufficiency in rats

    Hisakazu Izumida, Hiroshi Takagi, Haruki Fujisawa, Naoko Iwata, Kohtaro Nakashima, Seiji Takeuchi, Shintaro Iwama, Takashi Namba, Yukio Komatu, Kozo Kaibuchi, Yutaka Oiso, Hiroshi Arima, Yoshihisa Sugimura

    EXPERIMENTAL NEUROLOGY   Vol. 287 ( Pt 1 ) page: 65 - 74   2017.1

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    Selective apoptosis of granule cells in the hippocampal dentate gyrus (DG) of rats with bilateral adrenalectomy (ADX) and in patients who died of adrenal insufficiency has been reported. Although adrenal insufficiency is a common disease and is usually associated with hyponatremia, its effect on the central nervous system and in apoptosis in the hippocampus remain to be elucidated. Using rat models to represent clinical hyponatremia accompanying adrenal insufficiency, we show that reduced serum [Na+] was associated with selective apoptosis in the DG. Nine days after ADX, apoptotic cells were observed in the DG of rats whose serum [Na+] was &lt;125 mEq/L (moderate hyponatremia), but rarely in those whose serum [Na+] was 125 mEq/L or in normonatremic rats. Although all hyponatremic ADX rats survived following treatment with corticosterone and saline started 7 days after ADX when apoptosis had not yet occurred, selective apoptosis on day 9 was not prevented in moderately hyponatremic rats. Interestingly, treatment with memantine, a noncompetitive NMDAR antagonist, prevented the selective apoptosis in the DG in moderately hyponatremic, ADX rats, and improved electrophysiological dysfunction, including impaired basal synaptic transmission and long-term potentiation at the entorhinal cortex-DG synapses. These results demonstrated that in adrenal insufficient rats, hyponatremia was associated with apoptosis in the DG, and that memantine prevented the apoptosis and improved cell function. Our data imply the importance of assessing the possibility of neurological impairments after treatment with CORT in patients with moderate or severe hyponatremia accompanying adrenal insufficiency and that memantine may represent a beneficial therapeutic strategy to prevent neurological impairments in such patients. (C) 2016 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.expneurol.2016.08.007

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  34. 発症30年以上経過して、緩徐進行1型糖尿病と診断された1例

    真野 頌子, 水野 裕子, 清野 祐介, 有馬 寛

    糖尿病   Vol. 60 ( 1 ) page: 50 - 50   2017.1

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  35. Clinical practice and mechanism of endocrinological adverse events associated with immune checkpoint inhibitors.

    Iwama S, Arima H

    Nihon Rinsho Men'eki Gakkai kaishi = Japanese journal of clinical immunology   Vol. 40 ( 2 ) page: 90-94   2017

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    DOI: 10.2177/jsci.40.90

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  36. Normalization of Bilateral Adrenal Gland Enlargement after Treatment for Cryptococcosis

    Muraoka Yuka, Iwama Shintaro, Arima Hiroshi

    CASE REPORTS IN ENDOCRINOLOGY   Vol. 2017   page: 1543149   2017

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    DOI: 10.1155/2017/1543149

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▼display all

Presentations 82

  1. 新専門医制度 Invited

    有馬寛

    第31回臨床内分泌代謝Update  2021.11.26  日本内分泌学会

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    Event date: 2021.11

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Venue:大阪   Country:Japan  

  2. バソプレシンニューロンと小胞体ストレス Invited

    有馬寛

    第35回日本下垂体研究会学術集会  2021.8.20  日本下垂体研究会

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    Event date: 2021.8

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Venue:福岡  

  3. ナトリウム代謝異常 Invited

    有馬寛

    第94回日本内分泌学会学術総会  2021.4.22  日本内分泌学会

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    Event date: 2021.4

    Language:Japanese   Presentation type:Symposium, workshop panel (nominated)  

    Venue:群馬  

  4. 中枢神経によるエネルギーバランスの調節 Invited

    有馬寛

    第41回日本肥満学会  2021.3.20  日本肥満学会

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    Event date: 2021.3

    Language:Japanese   Presentation type:Symposium, workshop panel (nominated)  

  5. 免疫チェックポイント阻害薬による内分泌障害の診断と治療 Invited

    有馬寛

    第21回日本内分泌学会近畿支部学術集会  2020.11.7  日本内分泌学会

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    Event date: 2020.11

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Venue:大阪  

  6. Management of immune-related adverse events in endocrine organs induced by immune checkpoint inhibitors Invited International conference

    Arima Hiroshi

    AOCE-SICEM 2020 (The 17th Asia-Oceania Congress of Endocrinology and the 8th Seoul International Congress of Endocrinology and Metabolism)  2020.10  Korean Endocrine Society

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    Event date: 2020.10

    Language:English  

  7. 糖代謝異常を呈する内分泌疾患の診断と治療 Invited International coauthorship

    有馬寛

    第54回糖尿病学の進歩  2020.9.2  日本糖尿病学会

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    Event date: 2020.9

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

  8. 間脳下垂体機能障害に関する調査研究班の取り組み Invited International coauthorship

    有馬寛

    第93回日本内分泌学会学術総会  2020.7  日本内分泌学会

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    Event date: 2020.7

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

  9. 免疫チェックポイント阻害薬による内分泌障害 Invited

    有馬寛

    第93回日本内分泌学会学術総会  2020.7  日本内分泌学会

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    Event date: 2020.7

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

  10. Diagnosis and treatment of central diabetes insipidus Invited

    Arima Hiroshi

    Online Symposium of the Korean Endocrine Society  Korean Endocrine Society

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    Event date: 2020.5

    Language:English   Presentation type:Symposium, workshop panel (nominated)  

  11. AVPの最近の進歩 Invited

    有馬寛

    日本内分泌学会 

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    Event date: 2019.6

    Language:Japanese   Presentation type:Oral presentation (keynote)  

    Venue:仙台   Country:Japan  

  12. 免疫チェックポイント阻害薬による内分泌関連の副作用と対策 Invited

    有馬寛

    日本内科学会 

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    Event date: 2019.4

    Language:Japanese   Presentation type:Symposium, workshop panel (nominated)  

    Venue:名古屋   Country:Japan  

  13. Novel approach to rescue vasopressin neuron functioning in familial diabetes insipidus Invited International conference

    Hiroshi Arima

    WCNH2019 

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    Event date: 2019.4

    Language:English   Presentation type:Symposium, workshop panel (nominated)  

    Venue:Israel   Country:Israel  

  14. 体重コントロールを目指した糖尿病治療 Invited

    有馬寛

    日 第7回日本くすりと糖尿病学会学術集会 

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    Event date: 2018.10

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Venue:名古屋   Country:Japan  

  15. バソプレシンからのアプローチ Invited

    有馬寛

    第91回日本内分泌学会学術総会 

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    Event date: 2018.4

    Language:Japanese   Presentation type:Oral presentation (keynote)  

    Venue:宮崎   Country:Japan  

  16. 術後の水バランスの管理 Invited

    有馬寛

    第28回日本間脳下垂体腫瘍学会 

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    Event date: 2018.2

    Language:Japanese   Presentation type:Symposium, workshop panel (nominated)  

    Venue:浜松   Country:Japan  

  17. 中枢性尿崩症の診断と治療 Invited

    有馬寛

    第27回臨床内分泌代謝Update 

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    Event date: 2017.11

    Language:Japanese   Presentation type:Oral presentation (keynote)  

    Venue:神戸   Country:Japan  

  18. 低ナトリウム血症 Invited

    有馬寛

    第27回臨床内分泌代謝Update 

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    Event date: 2017.11

    Language:Japanese   Presentation type:Oral presentation (keynote)  

    Venue:神戸   Country:Japan  

  19. 体液調節の臨床 Invited

    有馬寛

    第35回内分泌代謝学サマーセミナー 

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    Event date: 2017.7

    Language:Japanese   Presentation type:Oral presentation (keynote)  

    Venue:群馬   Country:Japan  

  20. 免疫チェックポイント阻害薬による下垂体機能障害 Invited

    有馬寛

    第90回日本内分泌学会学術総会 

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    Event date: 2017.4

    Language:Japanese   Presentation type:Symposium, workshop panel (nominated)  

    Venue:京都   Country:Japan  

  21. A new in vitro model using mouse iPS cells to study endoplasmic reticulum stress in vasopressin neurons Invited

    Hiroshi Arima

     More details

    Event date: 2017.3

    Language:English   Presentation type:Symposium, workshop panel (nominated)  

    Country:Japan  

  22. 間脳下垂体(後葉) Invited

    有馬寛

    日本内分泌学会 第3回生涯教育講習会 

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    Event date: 2016.11

    Language:English   Presentation type:Oral presentation (keynote)  

    Venue:大宮   Country:Japan  

  23. 低ナトリウム血症 Invited

    有馬寛

    第26回臨床内分泌代謝Update 

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    Event date: 2016.11

    Language:Japanese   Presentation type:Oral presentation (keynote)  

    Venue:大宮   Country:Japan  

  24. バソプレシンニューロンにおけるER-associated compartment (ERAC)の形成 Invited

    有馬寛

    BMB 2015  

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    Event date: 2015.12

    Language:Japanese   Presentation type:Symposium, workshop panel (nominated)  

    Venue:神戸   Country:Japan  

  25. 肥満とストレス Invited

    有馬寛

    第36回日本肥満学会 

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    Event date: 2015.10

    Language:Japanese   Presentation type:Symposium, workshop panel (nominated)  

    Venue:名古屋   Country:Japan  

  26. Formation of Endoplasmic Reticulum-Associated Compartment (ERAC) in Vasopressin Neurons: A Mechanism by Which ER Stress Is Reduced International conference

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    Event date: 2015.9

    Language:English   Presentation type:Symposium, workshop panel (nominated)  

    Venue:仙台   Country:Japan  

  27. 中枢性尿崩症の治療の新展開 Invited

    有馬寛

    第41回日本神経内分泌学会学術集会 

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    Event date: 2014.10 - 2014.11

    Language:Japanese   Presentation type:Symposium, workshop panel (nominated)  

    Country:Japan  

  28. バゾプレシンニューロンと小胞体ストレス Invited

    有馬寛

    第87回日本内分泌学会学術総会 

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    Event date: 2014.4

    Language:Japanese   Presentation type:Symposium, workshop panel (nominated)  

    Venue:福岡   Country:Japan  

  29. 中枢性尿崩症 Invited

    有馬寛

    第23回 臨床内分泌代謝Update 

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    Event date: 2014.1

    Language:Japanese   Presentation type:Symposium, workshop panel (nominated)  

    Venue:名古屋   Country:Japan  

  30. Mechanisms underlying glucocorticoid-induced changes in feeding behavior Invited

    Hiroshi Arima

    THE 36th Naito Conference 

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    Event date: 2013.10

    Language:English   Presentation type:Symposium, workshop panel (nominated)  

    Country:Japan  

  31. Aggregate formation in endoplasmic reticulum of vasopressin neurons in familial diabetes insipidus model mice Invited International conference

    Hiroshi Arima

    WCNH2013 

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    Event date: 2013.7

    Language:English   Presentation type:Symposium, workshop panel (nominated)  

    Venue:Bristol   Country:United Kingdom  

  32. 中枢性尿崩症の診断と治療 Invited

    有馬寛

    第85回日本内分泌学会学術総会 

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    Event date: 2012.4

    Language:Japanese   Presentation type:Symposium, workshop panel (nominated)  

    Country:Japan  

  33. バゾプレシンニューロンにおける 小胞体ストレスと中枢性尿崩症 Invited International conference

    有馬寛

    第85回日本内分泌学会学術総会 

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    Event date: 2012.4

    Language:Japanese   Presentation type:Symposium, workshop panel (nominated)  

    Venue:名古屋   Country:Japan  

  34. 視床下部GABABシステムによる エネルギーバランスの調節 Invited

    有馬寛

    第32回日本肥満学会 

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    Event date: 2011.9

    Language:Japanese   Presentation type:Symposium, workshop panel (nominated)  

    Venue:淡路島   Country:Japan  

  35. バゾプレシン分泌異常症 Invited

    有馬寛 椙村益久 石川三衛 大磯ユタカ

    第84回日本内分泌学会学術総会 

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    Event date: 2011.4

    Language:Japanese   Presentation type:Symposium, workshop panel (nominated)  

    Venue:神戸   Country:Japan  

  36. Polyuria progressed in the absence of vasopressin neuron loss in a mouse model for familial neurohypophysial diabetes insipidus Invited International conference

    Hiroshi Arima

    WCNH2009 

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    Event date: 2009.9

    Language:English   Presentation type:Symposium, workshop panel (nominated)  

    Country:Japan  

  37. バゾプレシン分泌障害の分子メカニズム

    第81回日本内分泌学会学術総会 

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    Event date: 2008.5

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

  38. Regulation of neuropeptide Y gene expression in arcuate nucleus by glucocorticoids

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    Event date: 2008.3

    Language:English   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

  39. エネルギー調節におけるグルココルチコイドとAMPキナーゼの関係

    第26回内分泌代謝学サマーセミナー 

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    Event date: 2008.7

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

  40. Regulation of neuropeptide Y gene expression in the arcuate nucleus

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    Event date: 2007.7

    Language:English   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

  41. Mechanisms underlying progressive polyuria in a mouse model for familial neurohypophysial diabetes insipidus International conference

    Arima H, Oiso Y

    The 7th International Congress NEUROENDOCRINOLOGY 

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    Event date: 2010.7

    Language:English   Presentation type:Symposium, workshop panel (nominated)  

    Country:France  

  42. 多尿が明らかでない中枢性尿崩症

    有馬寛、大磯ユタカ

     More details

    Event date: 2007.6

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

  43. 末梢シグナルによる視床下部弓状核ニューロペプタイドY遺伝子発現の調節

    有馬寛、大磯ユタカ

    第50回日本糖尿病学会年次学術集会 

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    Event date: 2007.5

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

  44. グルココルチコイドによるバゾプレシン分泌調節

    第17回臨床内分泌代謝Update 

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    Event date: 2007.3

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

  45. Rapid increases in neuropeptide Y gene transcription in the arcuate nucleus in response to hypoglycemia in rats International conference

    Society for Neuroscience 36th anual meeting 

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    Event date: 2006.10

    Language:English   Presentation type:Poster presentation  

  46. Estrogen accelerated progressive polyuria in female knock-in mice for familial neurohypopheseal diabetes insipidus. International conference

    Society for Neuroscience 36th anual meeting 

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    Event date: 2006.10

    Language:English   Presentation type:Poster presentation  

  47. 視床下部を介したエネルギー調節

    有馬寛、大磯ユタカ

    第79回日本内分泌学会学術総会 

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    Event date: 2006.5

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

  48. 家族性中枢性尿崩症

    有馬寛、林正幸、大磯ユタカ

    第79回日本内分泌学会学術総会 

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    Event date: 2006.5

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

  49. メラノコルチン4型受容体アゴニストの中枢投与が白色脂肪の分化増殖を誘導し、adiponectinおよびleptinの発現を促進する

    坂野僚一、有馬寛、後藤資実、林正幸、渡邉峰守、佐藤郁子、大磯ユタカ

    第49回日本糖尿病学会総会 

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    Event date: 2006.5

    Language:Japanese   Presentation type:Poster presentation  

  50. 水電解質バランスのコントロールに苦慮する症例

    有馬寛、大磯ユタカ

    第16回臨床内分泌代謝Update 

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    Event date: 2006.3

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

  51. Changes in neuropeptide Y gene transcription in the arcuate nucleus in schedule-fed rats. International conference

    Society for Neuroscience 35th annual meeting 

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    Event date: 2005.11

    Language:English   Presentation type:Poster presentation  

  52. Insulin inhibits neuropeptide Y gene expression in the arcuate nucleus through GABAergic systems. International conference

    Society for Neuroscience 35th annual meeting 

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    Event date: 2005.11

    Language:English   Presentation type:Poster presentation  

  53. Central administration of melanotan II, a melanocortin agonist, decreased the size of adipocyte and increased the serum levels of adiponectin and leptin in diet-induced obesity rats. International conference

    Society for Neuroscience 35th annual meeting 

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    Event date: 2005.11

    Language:English   Presentation type:Poster presentation  

  54. インスリンは視床下部弓状核におけるGlutamic Acid Decarboxylase (GAD) 遺伝子発現を増強する-視床下部器官培養における検討-

    佐藤郁子、有馬寛、後藤資実、林正幸、坂野僚一、大磯ユタカ

    第78回日本内分泌学会学術総会 

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    Event date: 2005.7

    Language:Japanese   Presentation type:Oral presentation (general)  

    Country:Japan  

  55. グレリンがprotein kinase Cを介して弓状核neuropeptide Yの遺伝子発現を増強する

    後藤資実、有馬寛、佐藤郁子、坂野僚一、林正幸、大磯ユタカ

    第32回日本神経内分泌学会/第20回日本下垂体研究会 合同大会 

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    Event date: 2005.7

    Language:Japanese   Presentation type:Poster presentation  

    Country:Japan  

  56. 絶食後のrefeedingにより視床下部弓状核におけるGABAシステムが活性化される

    佐藤郁子、有馬寛、後藤資実、林正幸、坂野僚一、大磯ユタカ

    第32回日本神経内分泌学会/第20回日本下垂体研究会 合同大会 

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    Event date: 2005.7

    Language:Japanese   Presentation type:Poster presentation  

    Country:Japan  

  57. 慢性脱水下におけるvasopressin(AVP)転写調節機構の検討

    有馬寛、林正幸、後藤資実、坂野僚一、佐藤郁子、大磯ユタカ

    第78回日本内分泌学会学術総会 

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    Event date: 2005.7

    Language:Japanese   Presentation type:Poster presentation  

    Country:Japan  

  58. 変異遺伝子導入マウスを用いた家族性中枢性尿崩症の病因の検討

    林正幸、有馬寛、後藤資実、坂野僚一、佐藤郁子、大磯ユタカ

    第78回日本内分泌学会学術総会 

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    Event date: 2005.7

    Language:Japanese   Presentation type:Poster presentation  

  59. Acute hypovolemia, but not osmotic stimuli, increased vasopressin gene transcription in water-deprived rats. International conference

    2005 World Congress of Neurohypophysial Hormones 

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    Event date: 2005.7

    Language:English   Presentation type:Poster presentation  

  60. メラノコルチン4型受容体(MC4R)アゴニストであるMTIIの中枢投与が白色脂肪細胞を小型化しアディポネクチン分泌を促進する

    坂野僚一、有馬寛、後藤資実、林正幸、佐藤郁子、尾崎紀之、大磯ユタカ

    第48回日本糖尿病学会年次学術集会 

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    Event date: 2005.5

    Language:Japanese   Presentation type:Oral presentation (general)  

    Country:Japan  

  61. 時間制限給餌下におけるインスリン分泌と弓状核Neuropeptide Y 遺伝子転写活性の変化

    後藤資実、有馬寛、佐藤郁子、坂野僚一、林正幸、大磯ユタカ

    第48回日本糖尿病学会総会 

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    Event date: 2005.5

    Language:Japanese   Presentation type:Poster presentation  

    Country:Japan  

  62. 遺伝子組換えマウスによる家族性中枢性尿崩症の病因の検討(第2報)

    林正幸、有馬寛、尾崎紀之、塩田明、木下憲明、中嶋光代、長崎弘、上田正次、杉浦康夫、大磯ユタカ

    第15回バソプレシン研究会 

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    Event date: 2005.1

    Language:Japanese   Presentation type:Oral presentation (general)  

    Country:Japan  

  63. グレリンによる弓状核neuropeptide Y 遺伝子発現調節―視床下部器官培養を用いた検討―

    後藤資実、有馬寛、佐藤郁子、坂野僚一、林正幸、大磯ユタカ

    第31回日本神経内分泌学会総会学術集会 

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    Event date: 2004.10

    Language:Japanese   Presentation type:Oral presentation (general)  

    Country:Japan  

  64. インスリンはGABAを介して弓状核におけるneuropeptide Yの遺伝子発現を抑制する

    佐藤郁子、有馬寛、後藤資実、林正幸、坂野僚一、大磯ユタカ

    第77回日本内分泌学会学術総会 

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    Event date: 2004.6

    Language:Japanese   Presentation type:Oral presentation (general)  

    Country:Japan  

  65. 家族性中枢性尿崩症の変異遺伝子を導入したノックインマウスの作製

    林正幸、有馬寛、尾崎紀之、塩田明、木下憲明、中嶋光代、長崎弘、上田正次、杉浦康夫、大磯ユタカ

    第77回日本内分泌学会学術総会 

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    Event date: 2004.6

    Language:Japanese   Presentation type:Oral presentation (general)  

    Country:Japan  

  66. Melanocortin agonist中枢投与が高脂肪食によるインスリン抵抗性を改善する

    坂野僚一、有馬寛、後藤資実、林正幸、佐藤郁子、大磯ユタカ

    第47回日本糖尿病学会年次学術集会 

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    Event date: 2004.5

    Language:Japanese   Presentation type:Oral presentation (general)  

    Country:Japan  

  67. バゾプレシン遺伝子の発現調節

    有馬寛

    第14回バゾプレシン研究会 

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    Event date: 2004.1

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

  68. 遺伝子組換えマウスによる家族性中枢性尿崩症の病因の検討

    林正幸、有馬寛、尾崎紀之、塩田明、木下憲明、中嶋光代、長崎弘、上田正次、杉浦康夫、大磯ユタカ

    第14回バゾプレシン研究会 

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    Event date: 2004.1

    Language:Japanese   Presentation type:Oral presentation (general)  

    Country:Japan  

  69. Insulin inhibits neuropeptide Y expression in the arcuate nucleus through GABAergic neurons in the hypothalamic organotypic cultures. International conference

    The Endocrine Society s 86th Annual Meeting 

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    Event date: 2004

    Language:English   Presentation type:Poster presentation  

  70. Central administration of melanocortin agonist improves insulin resistance caused by high fat diet in rats. International conference

    The Endocrine Society s 86th Annual Meeting 

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    Event date: 2004

    Language:English   Presentation type:Poster presentation  

  71. 術後の水バランスの管理 Invited International conference

    有馬寛

    第28回日本間脳下垂体腫瘍学会  2018.2.10 

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    Language:Japanese   Presentation type:Symposium, workshop panel (nominated)  

    Venue:浜松  

  72. 免疫チェックポイント阻害薬による内分泌関連の副作用と対策 Invited International conference

    有馬寛

    日本内科学会  2019.4.26 

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    Language:Japanese   Presentation type:Symposium, workshop panel (nominated)  

    Venue:名古屋  

  73. 免疫チェックポイント阻害薬による下垂体機能障害 Invited International conference

    有馬寛

    第90回日本内分泌学会学術総会  2017.4.20 

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    Language:Japanese   Presentation type:Symposium, workshop panel (nominated)  

    Venue:京都  

  74. 体重コントロールを目指した糖尿病治療 Invited International conference

    有馬寛

    日 第7回日本くすりと糖尿病学会学術集会  2018.10.13 

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    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Venue:名古屋  

  75. 体液調節の臨床 Invited International conference

    有馬寛

    第35回内分泌代謝学サマーセミナー  2017.7.13 

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    Language:Japanese   Presentation type:Oral presentation (keynote)  

    Venue:群馬  

  76. 低ナトリウム血症 Invited International conference

    有馬寛

    第27回臨床内分泌代謝Update  2017.11.24 

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    Language:Japanese   Presentation type:Oral presentation (keynote)  

    Venue:神戸  

  77. 中枢性尿崩症の診断と治療 Invited International conference

    有馬寛

    第27回臨床内分泌代謝Update  2017.11.24 

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    Language:Japanese   Presentation type:Oral presentation (keynote)  

    Venue:神戸  

  78. バソプレシンからのアプローチ Invited International conference

    有馬寛

    第91回日本内分泌学会学術総会  2018.4.26 

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    Language:Japanese   Presentation type:Oral presentation (keynote)  

    Venue:宮崎  

  79. Novel approach to rescue vasopressin neuron functioning in familial diabetes insipidus Invited

    Hiroshi Arima

    WCNH2019  2019.4.8 

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    Language:English   Presentation type:Symposium, workshop panel (nominated)  

    Venue:Israel  

  80. AVPの最近の進歩 Invited International conference

    有馬寛

    日本内分泌学会  2019.6.9 

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    Language:Japanese   Presentation type:Oral presentation (keynote)  

    Venue:仙台  

  81. A new in vitro model using mouse iPS cells to study endoplasmic reticulum stress in vasopressin neurons Invited International conference

    Hiroshi Arima

    2017.3.28 

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    Language:English   Presentation type:Symposium, workshop panel (nominated)  

  82. Changing the name of diabetes insipidus: a position statement of the working group to consider renaming diabetes insipidus.

    Arima H, Cheetham T, Christ-Crain M, Cooper DL, Drummond JB, Gurnell M, Levy M, McCormack A, Newell-Price JD, Verbalis JG, Wass J

    Archives of endocrinology and metabolism  2022.10.11 

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    Language:English   Presentation type:Oral presentation (general)  

    DOI: 10.20945/2359-3997000000528

    PubMed

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Research Project for Joint Research, Competitive Funding, etc. 9

  1. 糖尿病患者における自己血糖測定記録電子化およびクラウドを介した主治医との共有による糖代謝改善効果の検討

    2019.7

  2. ヒト多能性幹細胞を用いた下垂体機能低下症に対する再生医療の技術開発

    2018.4

    日本医療研究開発機構 再生医療実現拠点ネットワーク事業技術開発個別課題 

    須賀英隆

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    Grant type:Competitive

  3. 間脳下垂体機能障害に関する調査研究

    2017.4

    科学技術振興調整費 

    有馬寛

      More details

    Grant type:Competitive

  4. IoT活用による糖尿病重症化予防法の開発を目指した研究

    2017.4 - 2020.3

    日本医療研究開発機構 IoT等活用生活習慣病行動変容研究事業 

    植木浩二郎

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    Grant type:Competitive

  5. 疾患モデル高度化による視床下部・下垂体難病研究

    2017.4 - 2020.3

    日本医療研究開発機構 再生医療実現拠点ネットワークプログラム・疾患特異的iPS細胞の利活用促進・難病研究加速プログラム 

    須賀英隆

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    Grant type:Competitive

  6. AVPキット「ヤマサ」のRIAキットを用いた血漿バソプレシン濃度の解析

    2016.9

  7. 免疫チェックポイント阻害薬に伴う内分泌障害に関する研究

    2016.7

  8. 2型糖尿病患者の血中脂質に対するDPP4阻害薬スイニー(アナグリプチン)の効果に関する研究

    2014.1

    受託研究 

  9. GABAB agonists as a new therapeutic reagent for obesity

    2010

      More details

    Grant type:Competitive

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KAKENHI (Grants-in-Aid for Scientific Research) 22

  1. Establishment of the system for predicting pituitary dysfunction induced by immune checkpoint inhibitors

    Grant number:22H03127  2022.4 - 2025.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

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    Authorship:Principal investigator 

    Grant amount:\17550000 ( Direct Cost: \13500000 、 Indirect Cost:\4050000 )

  2. Study of identification for autoantigens in a mouse model of pituitary dysfunction induced by CTLA-4 or PD-1 blockade

    Grant number:22K08648  2022.4 - 2025.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

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    Authorship:Coinvestigator(s) 

  3. グルココルチコイドによるバソプレシン分泌調節機構ー仮面尿崩症の病態解明に向けてー

    Grant number:21K08552  2021.4 - 2024.3

    科学研究費助成事業  科学研究費助成事業

    萩原 大輔

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    Authorship:Coinvestigator(s)  Grant type:Competitive

    仮面尿崩症とは,中枢性尿崩症に副腎皮質機能低下症を合併した場合に,グルココルチコイド(GC)の分泌不全に伴い多尿が不顕性化する病態である.GCがバソプレシン(AVP)分泌を抑制することは知られているが,体循環へのAVP分泌を担う大細胞性AVPニューロン(magnAVP)にはGC受容体(GR)は発現しない.一方で,副腎皮質刺激ホルモンの放出を刺激する小細胞性AVPニューロンはGRを発現し,GCのネガティブフィードバックを受ける.本研究では,AVPニューロン特異的GRノックアウトマウスやmagnAVPへの投射ニューロンでGRをノックアウトしたマウスを用い,GCがAVP分泌を制御する機序を検討する.

  4. ヒトES細胞・iPS細胞を用いた視床下部神経幹細胞の創出

    Grant number:20K08859  2020.4 - 2023.3

    科学研究費助成事業  基盤研究(C)

    須賀 英隆, 有馬 寛

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    ヒト多能性幹細胞(ES細胞、iPS細胞)から視床下部神経幹細胞への分化誘導法を確立し、誘導した細胞が神経幹細胞として機能を果たすことを示す。
    視床下部神経組織は再生能力が低く、一旦傷つくと回復は難しい。我々はマウスES細胞から視床下部神経を分化させ、その中に増殖能と分化能とを併せ持った細胞、すなわち神経幹細胞が存在することを証明し、単離することに成功した。一方、ヒトでは生体から視床下部組織を採取することが難しく、神経幹細胞の研究は進んでいない。本研究ではヒトES細胞・iPS細胞を利用し、vitroでの分化技術と合わせ、ヒトの視床下部における神経幹細胞の存在に迫る。
    本研究では、ヒトES細胞・iPS細胞から視床下部神経幹細胞への分化誘導法を確立し、誘導した細胞が神経幹細胞として機能を果たすことを証明するのが最終目的である。
    当研究チームでは、マウスES細胞を用いた視床下部神経幹細胞同定と抽出の先行研究を世界初で報告しており、また、ヒトES細胞・iPS細胞を用いた視床下部神経への分化法を確立し基盤技術として維持している。いずれも当研究チームの独自技術であり、これらを組み合わせることでヒト視床下部神経幹細胞の分化・同定の検討を進めた。具体的には以下の3項目を並行して3年間進めている。
    項目A. ヒトES細胞のRax::Venusノックイン株を用いて視床下部神経幹細胞を単離、同定:マウス胎児の脳発生過程で視床下部幹細胞が出現することが報告されており、その特徴的なマーカーのひとつにRaxがある。ヒトのES細胞・iPS細胞から視床下部神経への分化誘導方法を応用し、ヒトES細胞から視床下部神経幹細胞の誘導を行った。ヒトES細胞を用いた視床下部神経への分化法を基礎に、神経成熟過程の分化プロトコールを見直し、Rax持続陽性細胞を10%程度まで増やした。Venusを目印にRax長期発現残存細胞をcell sorterで分離採取し、視床下部幹細胞としての性質を持つかどうか検討を進めた。
    項目B. 表面抗原を検索し、ノックイン細胞でなくとも視床下部神経幹細胞を単離可能にする:Rax持続陽性細胞の表面抗原を網羅的に解析することで、特異的な表面抗原を検索する。ヒトES細胞から視床下部分化には長期間を要するため、マウスES細胞で検索方法の検討を先んじて実施した。
    項目C. 動物移植により、生着と視床下部神経への分化を証明する:短期間で繰り返し実験の行いやすいマウスES細胞を利用して、移植の基本技術を予め確立しておく作業を遂行中である。
    項目Aについては以下である。2020年度はヒトES細胞を用いた視床下部神経への分化法を基礎に、分化プロトコールを見直し、Rax持続陽性細胞を増やす工夫をした。ヒトES細胞のRax::Venusノックイン株を用いて、神経成熟が得られるday100の時期であってもRax持続陽性細胞を10%程度まで増やすことに成功した。ポイントはBMP4シグナルの強さ調節にあった。次に、神経成熟が得られる時期(day100)でもなおRax発現を続ける細胞を、Venusを目印にcell sorterで分離採取した。採取したRax持続陽性細胞に、神経幹細胞としてのマーカーすなわちSox2、Nestin、Vimentinが発現していることを免疫染色で確認した。また、sortした細胞を接着培養することにより視床下部神経(特にNPY神経やPOMC神経へ多く分化した)やグリア細胞へ分化することを確認した。更に、分取したヒトES細胞由来Rax持続陽性細胞を用いてneurosphereを形成する培養条件を見出した。幹細胞としての多分化能を維持するにはFGF2やEGFシグナルが必須であった。このようにして形成させたneurophereは継代可能であった。以上、in vitroで視床下部神経幹細胞の性質を備えているデータをほぼ取得することができたと言える。加えて、neurosphereの凍結保存法にも挑戦し、端緒を得た。
    項目Bは以下の進捗である。ヒトES細胞から視床下部分化には約100日と長期間を要するため、実験上、小回りが効かない。マウスES細胞Rax::eGFP株では約30日間で済ますことが出来るため、2020年度はマウスES細胞で検索方法検討を先に実施した。Rax持続陽性細胞の表面抗原を網羅的に解析し、特異的な表面抗原を検索、マウスES細胞で候補Xを見出した。
    項目Cは、移植の基本技術を予め検討開始した。
    項目Aについては、引き続き視床下部神経幹細胞としての性質検討を行い、データを揃える。ヒトES細胞由来Rax発現残存細胞を単離、神経への分化能について検討を続け、視床下部神経の中でもどの種類が分化しやすいか、その条件などの性質を追究する。Neurosphereについてもその方法を一層洗練させる。
    項目Bについては、前年度にマウスES細胞で確立した表面抗原検索の方法論をヒトES細胞へ適応し、ヒトES細胞由来Rax持続陽性細胞の表面抗原を検索する。
    項目Cの動物移植では、視床下部障害モデルマウスを用いて移植方法を確立し、移植細胞の生着や神経の分化、更には機能回復を検討する。

  5. 糖尿病患者における自己血糖測定記録電子化およびクラウドを介した主治医との共有による糖代謝改善効果の検討

    2019.7

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    Grant type:Competitive

  6. 抗PD-1抗体誘発甲状腺炎マウスモデルを用いた免疫関連有害事象の発症機序の解明

    Grant number:19K08976  2019.4 - 2022.3

    科学研究費助成事業  基盤研究(C)

    岩間 信太郎, 有馬 寛

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    免疫チェックポイント阻害薬を用いたがん免疫療法では、自己免疫機序が想定される免疫関連有害事象(irAEs)の発生が課題であるが、発症機序は不明で、有用な動物モデルもないのが現状である。最も広く使用されている抗PD-1抗体では、irAEsとして甲状腺機能異常症の頻度が高い。
    本課題では、抗PD-1抗体誘発甲状腺炎マウスモデルを開発し、甲状腺irAEs発症に関与する特異的リンパ球を同定する。甲状腺およびその他のirAEs患者検体においてマウスモデルの結果を検証し、ヒトのirAEsに共通する炎症発症機構を解明する。
    irAEsの発症機序を解明し、がん免疫療法の発展および自己免疫疾患の病態解明へ繋げる。
    免疫チェックポイント阻害薬を用いたがん免疫療法では、自己免疫機序が想定される免疫関連有害事象(irAEs)の発生が課題であるが、発症機序は不明で、有用な動物モデルもないのが現状である。最も広く使用されている抗PD-1抗体では、irAEsとして甲状腺機能異常症の頻度が高い。
    本課題では、抗PD-1抗体誘発甲状腺炎マウスモデルを開発し、甲状腺irAEs発症に関与する特異的リンパ球を同定することを目的としている。
    これまでの検討から、サイログロブリンを予め皮下投与した後に抗PD-1抗体を投与した結果、破壊性甲状腺炎を呈するマウスモデルが確立された。破壊性甲状腺炎を発症したマウスにおいて、CD4陽性のエフェクターメモリーT細胞およびセントラルメモリーT細胞の増加が認められ、CD4陽性T細胞では細胞障害作用を示唆する蛋白(グランザイムB)の発現が認められた。次に、本マウスモデルにおいて、予めCD4陽性T細胞、CD8陽性T細胞またはCD20陽性B細胞を除去して検討した結果、CD4陽性T細胞を除去した際に抗PD-1抗体による破壊性甲状腺炎の発症が完全に抑制された。
    以上の結果より、抗PD-1抗体による破壊性甲状腺炎において、細胞傷害作用を有するCD4陽性T細胞が発症に必須の役割を果たしていることが示唆された。
    免疫チェックポイント阻害薬は細胞傷害作用を有するCD8陽性T細胞の活性化を介して抗腫瘍作用を発揮すると考えられていたが、irAEsの一つである破壊性甲状腺炎では細胞傷害性CD4陽性T細胞が重要な役割を果たしていることが示された。本研究成果はirAEsの新たな治療法および予防法の確立に繋がることが期待される。
    甲状腺特異的な蛋白であるサイログロブリンをマウスに皮下投与し、2ヶ月半後に抗PD-1抗体を投与することで著明な炎症細胞浸潤を伴う破壊性甲状腺炎を呈するマウスモデルを確立した。本モデルにおいて、CD4陽性T細胞はサイログロブリンに特異的に反応することおよび細胞傷害作用を示す蛋白(グランザイムB)の発現が認められることが明らかとなった。さらに、抗PD-1抗体による破壊性甲状腺炎の発症は、予めCD4陽性T細胞を除去することで完全に抑制されたのに対し、CD8陽性T細胞の除去では部分的に抑制された。
    以上の結果より、抗PD-1抗体による破壊性甲状腺炎の発症には細胞傷害作用を有するCD4陽性T細胞が必須の役割を果たしていることが明らかとなり、抗PD-1抗体による副作用の病態解明に繋がる知見が得られたから。
    これまでの検討により、抗PD-1抗体による破壊性甲状腺炎マウスモデルにおいて、その発症には細胞傷害性CD4陽性T細胞が必須の役割を果たしていることが明らかとなった。これまで、免疫チェックポイント阻害薬は細胞傷害作用を有するCD8陽性T細胞の活性化を介して抗腫瘍作用を発揮すると考えられていたが、irAEsの一つである破壊性甲状腺炎では細胞傷害性CD4陽性T細胞が重要な役割を果たしていることが示唆されるため、ヒトの検体において、抗PD-1抗体による破壊性甲状腺炎を発症した患者の末梢血リンパ球の解析、さらには甲状腺炎以外のirAEsを発症した患者の末梢血リンパ球を解析し、抗PD-1抗体によるirAEsに共通した免疫学的機序の解明へ展開する。

  7. ヒト多能性幹細胞を用いた下垂体機能低下症に対する再生医療の技術開発

    2018.4

    日本医療研究開発機構  日本医療研究開発機構 再生医療実現拠点ネットワーク事業技術開発個別課題 

    須賀英隆

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  8. The role of Protein Tyrosine Phosphatase 1B in the reward system under a high fat diet condition

    Grant number:18K08473  2018.4 - 2021.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Banno Ryoichi

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    The brain reward system plays an important role in hedonic values of food.The neurons in reward system are regulated by leptin, insulin and inflammation.
    We investigated the effect of protein tyrosine phosphatase-1B (PTP1B), which regulates these three factors, on palatability for a high-fat diet.
    Our data suggested that PTP1B in the dopaminergic neurons in the ventral tegmental area of the midbrain in the reward system contributes to the formation of preference for a high-fat diet.

  9. 間脳下垂体機能障害に関する調査研究

    2017.4

    厚生労働省  厚生労働科学研究費補助金 

    有馬寛

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  10. Developing the method for induction of hypothalamic and pituitary unit

    Grant number:17K09878  2017.4 - 2020.3

    Suga Hidetaka

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    The pituitary gland plays an important role in maintaining homeostasis in the living body. It functions under the control of the hypothalamus. In the current hormone replacement therapy for clinical hypopituitarism, it may not be possible to reproduce the blood hormone changes that should be finely tuned, because the function of the hypothalamus cannot be compensated. To solve this problem in regenerative medicine using human ES / iPS cells, we have developed a technique for simultaneous generation of the pituitary gland and the hypothalamus, which is the upper control organ to pituitary. In the induced cell-aggregate, hypothalamic tissue and pituitary tissue coexist and linked functionally.

  11. IoT活用による糖尿病重症化予防法の開発を目指した研究

    2017.4 - 2020.3

    日本医療研究開発機構  日本医療研究開発機構 IoT等活用生活習慣病行動変容研究事業 

    植木浩二郎

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  12. 疾患モデル高度化による視床下部・下垂体難病研究

    2017.4 - 2020.3

    日本医療研究開発機構  日本医療研究開発機構 再生医療実現拠点ネットワークプログラム・疾患特異的iPS細胞の利活用促進・難病研究加速プログラム 

    須賀英隆

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    Grant type:Competitive

  13. AVPキット「ヤマサ」のRIAキットを用いた血漿バソプレシン濃度の解析

    2016.9

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  14. 免疫チェックポイント阻害薬に伴う内分泌障害に関する研究

    2016.7

    小野薬品工業株式会社 

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  15. The role of protein tyrosine phosphatase-1B in the hypothalamic inflammation induced by a high fat diet

    Grant number:15K09381  2015.4 - 2018.3

    Banno Ryoichi

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    Hypothalamus plays an important role in the regulation of energy balance. A high fat diet induces hypothalamic inflammation, which is known to play a causal role in obesity. We investigated the role of protein tyrosine phosphatase-1B(PTP1B), a regulator of leptin, insulin and inflammatory signaling, in the hypothalamic inflammation induced by a high fat diet. Our results suggest that PTP1B in the microglia enhances hypothalamic inflammation, and PTP1B in the astrocye increases body weight under a high fat diet conditions.

  16. Analysis of the rewards GABAB system in energy balance

    Grant number:15K09426  2015.4 - 2018.3

    Arima Hiroshi

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    Grant amount:\4680000 ( Direct Cost: \3600000 、 Indirect Cost:\1080000 )

    Knockout mouse of GABAB receptors in the reward system consumed a more high fat diet than wild-type mice when they were given the food intermittently. There were no significant differences in body weight or glucose tolerance between genotypes, suggesting that GABAB receptors in the reward system is not involved in the regulation of energy homeostasis, Baclofen, a GABAB agonist, decreased the consumption of the high fat diet when given just before the high fat diet was presented in wild-type, but not in the knockout mice in the intermittent high fat die protocol. These data indicate that the GABAB neurons in the reward system plays an inhibitory role in the binge eating of a high fat diet.

  17. マウス疾患特異的iPS細胞を用いた遺伝性中枢性尿崩症in vitro実験系の確立

    2014.4 - 2017.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    須賀英隆

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  18. 2型糖尿病患者の血中脂質に対するDPP4阻害薬スイニー(アナグリプチン)の効果に関する研究

    2014.1

    三和化学株式会社  受託研究 

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    Grant type:Competitive

  19. NPYニューロンに発現するグルココルチコイドレセプターの機能解析

    2011.4 - 2014.3

    科学研究費補助金  基盤研究(C)

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  20. 視床下部におけるプロテインタイロシンフォスファターゼ1B発現調節機構の解析

    2011.4 - 2014.3

    科学研究費補助金  基盤研究(C)

    坂野僚一

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  21. 疾患モデル動物における小胞体ストレスから細胞死に至るプロセスの解析

    2011.4 - 2014.3

    科学研究費補助金 

    大磯ユタカ

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  22. NPYニューロンに発現するグルココルチコイドレセプターの機能解析

    Grant number: 23591350  2011.4 - 2013.3

    科学研究費助成事業  基盤(C)

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Industrial property rights 1

  1. 抗肥満薬及びその利用

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    Applicant:有馬寛、佐藤郁子、大磯ユタカ

    Application no:PCT/JP2007/064225  Date applied:2007.7

    Country of applicant:Foreign country  

    GABABアゴニストは摂食を抑え、熱消費を増加させることで肥満および糖代謝を改善する。

 

Teaching Experience (On-campus) 3

  1. 医学入門

    2019

  2. 特別講義:生活習慣病

    2019

  3. 内分泌学講義

    2019

Teaching Experience (Off-campus) 3

  1. 特別講義:生活習慣病

    Nagoya University)

  2. 医学入門

    Nagoya University)

  3. 内分泌学講義

    Nagoya University)