Faculty Profiles - ARIMA, Hiroshi

Compensatory mechanisms underlying arginine vasopressin regulation in transient polyuria during pregnancy

Combined PD-1 and CTLA-4 Blockade Increases the Risks of Multiple Pituitary Hormone Deficiency and Isolated Adrenocorticotropic Deficiency: A Prospective Study.

Iwama S, Kobayashi T, Izuchi T, Suzuki K, Murase T, Ando M, Handa T, Onoue T, Miyata T, Sugiyama M, Hagiwara D, Suga H, Banno R, Hase T, Mori S, Sano T, Akamatsu S, Akiyama M, Ishii M, Arima H

Endocrinology and metabolism (Seoul, Korea) 2025.2

Tsumura, T; Hagiwara, D; Naito, S; Kondo, Y; Kawaguchi, Y; Miyata, T; Kobayashi, T; Sugiyama, M; Onoue, T; Iwama, S; Suga, H; Banno, R; Arima, H

PEPTIDES Vol. 184 page： 171352 2025.2

Management, biomarkers and prognosis in people developing endocrinopathies associated with immune checkpoint inhibitors

Iwama, S; Kobayashi, T; Arima, H

NATURE REVIEWS ENDOCRINOLOGY 2025.1

Guidance on Energy Intake Based on Resting Energy Expenditure and Physical Activity: Effective for Reducing Body Weight in Patients with Obesity

Handa, T; Onoue, T; Maeda, R; Mizutani, K; Suzuki, K; Kobayashi, T; Miyata, T; Sugiyama, M; Hagiwara, D; Iwama, S; Suga, H; Banno, R; Arima, H

NUTRIENTS Vol. 17 ( 2 ) 2025.1

A deep learning approach to predict differentiation outcomes in hypothalamic-pituitary organoids

Tomoyoshi Asano, Hidetaka Suga, Hirohiko Niioka, Hiroshi Yukawa, Mayu Sakakibara, Shiori Taga, Mika Soen, Tsutomu Miwata, Hiroo Sasaki, Tomomi Seki, Saki Hasegawa, Sou Murakami, Masatoshi Abe, Yoshinori Yasuda, Takashi Miyata, Tomoko Kobayashi, Mariko Sugiyama, Takeshi Onoue, Daisuke Hagiwara, Shintaro Iwama, Yoshinobu Baba, Hiroshi Arima

Communications Biology Vol. 7 ( 1 ) page： 1468 2024.12

Voluntary exercise suppresses inflammation and improves insulin resistance in the arcuate nucleus and ventral tegmental area in mice on a high-fat diet. International journal

Tomoyuki Sasaki, Mariko Sugiyama, Mitsuhiro Kuno, Takashi Miyata, Tomoko Kobayashi, Yoshinori Yasuda, Takeshi Onoue, Hiroshi Takagi, Daisuke Hagiwara, Shintaro Iwama, Hidetaka Suga, Ryoichi Banno, Hiroshi Arima

Physiology & behavior Vol. 287 page： 114703 - 114703 2024.12

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

A high-fat diet (HFD) causes inflammation with an increase in microglial activity in the hypothalamic arcuate nucleus (ARC) and ventral tegmental area (VTA), resulting in insulin resistance in both regions. This leads to a deterioration in glucose and energy metabolism. The effect of voluntary exercise on HFD-induced inflammation in the central nervous system (CNS) remains unclear. To clarify the effects of voluntary exercise on the CNS, 8-week-old male C57BL6 mice were fed a chow diet (CHD) or HFD for 4 weeks; each group was further divided into running exercise (EX+) on a wheel and no exercise (EX-) groups. The expression of the inflammatory cytokine, tumor necrosis factor alpha (TNFα), in the ARC and VTA was significantly increased in the HFD/EX- group, with an increase of microglial activity noted, compared to the CHD/EX- group. The expression of TNFα was significantly suppressed, with a decrease of microglial activity, in the HFD/EX+ compared to HFD/EX- group. Insulin resistance in the ARC and VTA was improved with the suppression of TNFα expression. The HFD/EX- group showed significant weight gain and impaired glucose metabolism compared to the CHD/EX- group. The HFD/EX+ group showed an improvement in glucose and energy metabolism compared to the HFD/EX- group. In addition, voluntary wheel running suppressed HFD-induced inflammation in the ARC, with a decrease in microglial activity observed independently of weight changes. Our data suggest that voluntary exercise prevents obesity and improves glucose metabolism by suppressing inflammation in the ARC and VTA under HFD conditions.

DOI： 10.1016/j.physbeh.2024.114703

Development of pituitary dysfunction and destructive thyroiditis is associated with better survival in non-small cell lung cancer patients treated with programmed cell death-1 inhibitors: a prospective study with immortal time bias correction. International journal

Koji Suzuki, Tomoko Kobayashi, Tetsushi Izuchi, Koki Otake, Masahiko Ando, Tomoko Handa, Takashi Miyata, Mariko Sugiyama, Takeshi Onoue, Daisuke Hagiwara, Hidetaka Suga, Ryoichi Banno, Tetsunari Hase, Megumi Inoue, Makoto Ishii, Hiroshi Arima, Shintaro Iwama

Frontiers in endocrinology Vol. 15 page： 1490042 - 1490042 2024.11

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

BACKGROUND: Immune-related adverse events (irAEs) are reported to be associated with better overall survival (OS) in non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors. However, there may be a bias in that patients who develop irAEs must survive long enough to experience the irAEs, and no prospective studies adjusting for immortal time bias (ITB) have examined the relationship between OS and pituitary dysfunction or the two different types of thyroid dysfunction: destructive thyroiditis and hypothyroidism without prior thyrotoxicosis (isolated hypothyroidism). METHODS: Patients with NSCLC who received nivolumab or pembrolizumab at Nagoya University Hospital between November 2, 2015 and February 1, 2023 were enrolled. Endocrine irAEs were prospectively assessed during scheduled evaluations of hormone levels. The association between irAE development and survival when considering ITB was examined by time-dependent Cox regression analysis. RESULTS: Of the 194 patients included, 11 (5.7%), 10 (5.2%), and 5 (2.6%) developed pituitary dysfunction, destructive thyroiditis, and isolated hypothyroidism, respectively. The development of pituitary dysfunction (HR 0.36, 95% CI 0.13-0.98, p = 0.045) and destructive thyroiditis (HR 0.31, 95% CI 0.10-0.97, p = 0.044), but not isolated hypothyroidism (HR 1.15, 95% CI 0.42-3.20, p = 0.786), was significantly associated with longer OS. CONCLUSION: NSCLC patients developing pituitary dysfunction and destructive thyroiditis showed better OS even after adjusting for ITB, suggesting that these irAEs indicate a better prognosis.

DOI： 10.3389/fendo.2024.1490042

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, D; Drummond, J; Gurnell, M; Levy, M; McCormack, A; Newell-Price, J; Verbalis, JG; Wass, J

CLINICAL ENDOCRINOLOGY Vol. 101 ( 5 ) page： 443 - 445 2024.11

Internet of things-based approach for glycemic control in people with type 2 diabetes: A randomized controlled trial Invited Reviewed

Bouchi, R; Izumi, K; Ishizuka, N; Uemura, Y; Ohtsu, H; Miyo, K; Tanaka, S; Satoh-Asahara, N; Hara, K; Odawara, M; Kusunoki, Y; Koyama, H; Onoue, T; Arima, H; Tsushita, K; Watada, H; Kadowaki, T; Ueki, K

JOURNAL OF DIABETES INVESTIGATION Vol. 15 ( 9 ) page： 1287 - 1296 2024.9

Thyroid autoantibodies at baseline predict longer survival in non-small cell lung cancer patients treated with anti-programmed cell death-1 blockade: a prospective study. Reviewed

Takayuki Okuji, Shintaro Iwama, Tomoko Kobayashi, Yoshinori Yasuda, Masaaki Ito, Ayana Yamagami, Masahiko Ando, Tetsunari Hase, Hirofumi Shibata, Takahiro Hatta, Xin Zhou, Takeshi Onoue, Yohei Kawaguchi, Takashi Miyata, Mariko Sugiyama, Daisuke Hagiwara, Hidetaka Suga, Ryoichi Banno, Yuichi Ando, Naozumi Hashimoto, Hiroshi Arima

Nagoya journal of medical science Vol. 86 ( 3 ) page： 452 - 463 2024.8

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

The presence of anti-thyroid antibodies (ATAs) is a biomarker for the development of thyroid dysfunction induced by anti-programmed cell death-1 antibodies (PD-1-Abs). While patients with thyroid dysfunction reportedly showed better overall survival (OS), it remains unknown if ATAs at baseline can predict OS. Therefore, in this study, we examined the association of ATAs at baseline with OS in non-small cell lung cancer (NSCLC) patients with different levels of programmed cell death-1 ligand 1 (PD-L1) positivity associated with PD-1-Ab treatment efficacy. A total of 81 NSCLC patients treated with PD-1-Abs were evaluated for ATAs at baseline and prospectively for OS. Among the 81 patients, 49 and 32 patients had ≥50% (group A) and <50% (group B) PD-L1 positivity, respectively. Median OS did not differ significantly between patients with (n = 13) and without (n = 36) ATAs at baseline in group A. In contrast, median OS was significantly longer in patients with (n = 10) versus without (n = 22) ATAs at baseline in group B (not reached vs 378 days, respectively; 95% CI, 182 to 574 days, p = 0.049). These findings suggest that the presence of ATAs at baseline is a biomarker to predict better treatment efficacy of PD-1-Abs in NSCLC patients with low PD-L1 positivity, while the difference in OS in those with high PD-L1 positivity may be masked by increased tumor expression of PD-L1.

DOI： 10.18999/nagjms.86.3.452

Combined use of tyrosine kinase inhibitors with PD-(L)1 blockade increased the risk of thyroid dysfunction in PD-(L)1 blockade: a prospective study Reviewed

Hyperthyroidism Due to Functioning Metastatic Bone Lesions of Follicular Thyroid Carcinoma Treated With Lenvatinib. Reviewed

Kobayashi T, Iwama S, Suzuki K, Arima H

JCEM case reports Vol. 2 ( 7 ) page： luae139 2024.7

Kobayashi, T; Iwama, S; Yamagami, A; Izuchi, T; Suzuki, K; Otake, K; Yasuda, Y; Ando, M; Onoue, T; Miyata, T; Sugiyama, M; Hagiwara, D; Suga, H; Banno, R; Hase, T; Nishio, N; Mori, S; Shimokata, T; Sano, T; Niimi, K; Yoshikawa, N; Akamatsu, S; Ando, Y; Akiyama, M; Sone, M; Ishii, M; Arima, H

CANCER IMMUNOLOGY IMMUNOTHERAPY Vol. 73 ( 8 ) page： 146 2024.6

Rapidly progressive interstitial lung disease with positive anti-MDA5 antibody as an immune-related complication of nivolumab: A case report

Kato, S; Sakamoto, K; Sato, T; Kobayashi, T; Shindo, Y; Morise, M; Iwama, S; Arima, H; Ishii, M

RESPIRATORY INVESTIGATION Vol. 62 ( 2 ) page： 313 - 316 2024.3

Simplified drug efficacy evaluation system for vasopressin neurodegenerative disease using mouse disease-specific induced pluripotent stem cells Reviewed

Tsutomu Miwata, Hidetaka Suga, Kazuki Mitsumoto, Jun Zhang, Yoshimasa Hamada, Mayu Sakakibara, Mika Soen, Hajime Ozaki, Tomoyoshi Asano, Takashi Miyata, Yohei Kawaguchi, Yoshinori Yasuda, Tomoko Kobayashi, Mariko Sugiyama, Takeshi Onoue, Daisuke Hagiwara, Shintaro Iwama, Seiichi Oyadomari, Hiroshi Arima

Peptides Vol. 173 page： 171151 - 171151 2024.3

【オルガノイドがもたらすライフサイエンス革命あなたの研究に、どう使う?進化と深化を生む未来型研究30選】(第1章)オルガノイド創出技術の最新動向組織幹細胞から多能性幹細胞,正常から疾患まで内分泌系オルガノイド下垂体オルガノイドを中心に

須賀英隆, 有馬寛

実験医学 Vol. 42 ( 5 ) page： 700 - 707 2024.3

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：(株)羊土社

内分泌組織のオルガノイドといえば膵β細胞が激戦区であるが,それ以外にも甲状腺,副甲状腺,副腎,生殖腺,腎臓など種々存在する.そのなかで視床下部-下垂体オルガノイドを例にとり,胎児発生を試験管内で再現する考え方を概説する.その結果,視床下部と下垂体とが1つのオルガノイド内で相互作用して発生し,成熟し,そして機能連携する.これを利用すれば直ちに疾患モデルとできるし,技術を磨けばいずれ再生医療に到達するだろう.将来的には,より広範な部位を含み多様性に富む視床下部-下垂体オルガノイドとし,生体の恒常性を司るしくみをこの一塊に凝縮させたい.(著者抄録)

The multifaceted role of ATF4 in regulating glucose-stimulated insulin secretion (vol 611, pg 165, 2022) Reviewed

Sobajima, M; Miyake, M; Hamada, Y; Tsugawa, K; Oyadomari, M; Inoue, R; Shirakawa, J; Arima, H; Oyadomari, S

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS Vol. 692 page： 149412 2024.1

A machine learning approach for predicting treatment response of hyponatremia Reviewed

Kinoshita, T; Oyama, S; Hagiwara, D; Azuma, Y; Arima, H

ENDOCRINE JOURNAL Vol. 71 ( 4 ) page： 345 - 355 2024

Impact of coronavirus disease 2019 on medical practice in endocrine and metabolic diseases in Japan: a nationwide surveillance study conducted by the Japan Endocrine Society Reviewed

Manaka, K; Kato, S; Sakamoto, R; Yamakage, H; Uema, T; Kawai, S; Shibata, M; Hiratsuka, I; Nakachi, S; Onoue, T; Tsuchiya, T; Fukui, M; Hashimoto, K; Suzuki, A; Makita, N; Ogawa, Y; Arima, H; Satoh-Asahara, N; Masuzaki, H

ENDOCRINE JOURNAL Vol. 71 ( 5 ) page： 499 - 514 2024

Effects of Digitization of Self-Monitoring of Blood Glucose Records Using a Mobile App and the Cloud System on Outpatient Management of Diabetes: Single-Armed Prospective Study. International journal

Tomoko Handa, Takeshi Onoue, Tomoko Kobayashi, Ryutaro Maeda, Keigo Mizutani, Ayana Yamagami, Tamaki Kinoshita, Yoshinori Yasuda, Shintaro Iwama, Takashi Miyata, Mariko Sugiyama, Hiroshi Takagi, Daisuke Hagiwara, Hidetaka Suga, Ryoichi Banno, Yoshinori Azuma, Takatoshi Kasai, Shuko Yoshioka, Yachiyo Kuwatsuka, Hiroshi Arima

JMIR diabetes Vol. 9 page： e48019 2024

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

BACKGROUND: In recent years, technologies promoting the digitization of self-monitoring of blood glucose (SMBG) records including app-cloud cooperation systems have emerged. Studies combining these technological interventions with support from remote health care professionals have reported improvements in glycemic control. OBJECTIVE: To assess the use of an app-cloud cooperation system linked with SMBG devices in clinical settings, we evaluated its effects on outpatient management of diabetes without remote health care professional support. METHODS: In this multicenter, open-label, and single-armed prospective study, 48 patients with diabetes (including type 1 and type 2) at 3 hospitals in Japan treated with insulin or glucagon-like peptide 1 receptor agonists and performing SMBG used the app-cloud cooperation system for 24 weeks. The SMBG data were automatically uploaded to the cloud via the app. The patients could check their data, and their attending physicians reviewed the data through the cloud prior to the patients' regular visits. The primary outcome was changes in glycated hemoglobin (HbA1c) levels. RESULTS: Although HbA1c levels did not significantly change in all patients, the frequency of daily SMBG following applying the system was significantly increased before induction at 12 (0.60 per day, 95% CI 0.19-1.00; P=.002) and 24 weeks (0.43 per day, 95% CI 0.02-0.84; P=.04). In the subset of 21 patients whose antidiabetic medication had not been adjusted during the intervention period, a decrease in HbA1c level was observed at 12 weeks (P=.02); however, this significant change disappeared at 24 weeks (P=.49). The Diabetes Treatment Satisfaction Questionnaire total score and "Q4: convenience" and "Q5: flexibility" scores significantly improved after using the system (all P<.05), and 72% (33/46) patients and 76% (35/46) physicians reported that the app-cloud cooperation system helped them adjust insulin doses. CONCLUSIONS: The digitization of SMBG records and sharing of the data by patients and attending physicians during face-to-face visits improved self-management in patients with diabetes. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCT) jRCTs042190057; https://jrct.niph.go.jp/en-latest-detail/jRCTs042190057.

DOI： 10.2196/48019

Clinical characteristics and potential biomarkers of thyroid and pituitary immune-related adverse events Reviewed

Kobayashi, T; Iwama, S; Arima, H

ENDOCRINE JOURNAL Vol. 71 ( 1 ) page： 23 - 29 2024

A case of hypophysitis after COVID-19 vaccination with a detection of anti-pituitary antibody, with review of literature Reviewed

Kyo, C; Kobayashi, T; Iwama, S; Kosugi, R; Sawabe, F; Hayafusa, R; Sakai, Y; Ogawa, T; Kotani, M; Inoue, T; Arima, H; Ariyasu, H

ENDOCRINE JOURNAL Vol. 71 ( 8 ) page： 799 - 807 2024

Changes in TgAb and TPOAb titers are greater in thyrotoxicosis than isolated hypothyroidism induced by PD-1 blockade Reviewed

Ayana Yamagami, Shintaro Iwama, Tomoko Kobayashi, Xin Zhou, Yoshinori Yasuda, Takayuki Okuji, Masaaki Ito, Tetsushi Izuchi, Masahiko Ando, Takeshi Onoue, Takashi Miyata, Mariko Sugiyama, Daisuke Hagiwara, Hidetaka Suga, Ryoichi Banno, Hiroshi Arima

Endocrine Journal Vol. 71 ( 5 ) page： 515 - 526 2024

Improved glycemic control after the use of flash glucose monitoring accompanied by improved treatment satisfaction in patients with non-insulin-treated type 2 diabetes: A post-hoc analysis of a randomized controlled trial. Reviewed International journal

Ayaka Hayase, Takeshi Onoue, Tomoko Kobayashi, Eri Wada, Tomoko Handa, Tamaki Kinoshita, Ayana Yamagami, Yoshinori Yasuda, Shintaro Iwama, Yohei Kawaguchi, Takashi Miyata, Mariko Sugiyama, Hiroshi Takagi, Daisuke Hagiwara, Hidetaka Suga, Ryoichi Banno, Yachiyo Kuwatsuka, Masahiko Ando, Motomitsu Goto, Hiroshi Arima

Primary care diabetes Vol. 17 ( 6 ) page： 575 - 580 2023.12

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

AIMS: In our previously reported randomized controlled trial in patients with noninsulin-treated type 2 diabetes, the use of flash glucose monitoring (FGM) improved glycated hemoglobin (HbA1c), and the improvement was sustained after the cessation of glucose monitoring. In this post-hoc analysis, we examined data from our trial to identify the factors that influenced FGM efficacy. METHODS: We analyzed data for 48 of 49 participants of the FGM group who completed the trial to clarify the changes in various parameters and factors related to HbA1c improvement with the use of FGM. RESULTS: Analyses of the FGM data during the 12-week FGM provision period showed that the weekly mean blood glucose levels considerably decreased as early as at 1 week compared with the baseline values, and this decline continued for 12 weeks. An enhancement in the Diabetes Treatment Satisfaction Questionnaire regarding "willingness to continue the current treatment" score was significantly associated with the improvement in HbA1c at 12 (p = 0.009) and 24 weeks (p = 0.012). CONCLUSIONS: Glycemic control was improved soon after FGM initiation, accompanied by improved satisfaction with continuation of the current treatment in patients with noninsulin-treated type 2 diabetes.

DOI： 10.1016/j.pcd.2023.09.009

肥満症診療の未来とAI活用生活習慣病診療において患者への介入・支援をどこまで機械・アプリケーションに任せられるのか

尾上剛史, 津下一代, 有馬寛

肥満研究 Vol. 29 ( 合同学術集会抄録集 ) page： 211 - 211 2023.11

Risk of Thyroid Dysfunction in PD-1 Blockade Is Stratified by the Pattern of TgAb and TPOAb Positivity at Baseline. Reviewed International journal

Xin Zhou, Shintaro Iwama, Tomoko Kobayashi, Masahiko Ando, Hiroshi Arima

The Journal of clinical endocrinology and metabolism Vol. 108 ( 10 ) page： E1056 - E1062 2023.9

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

CONTEXT: Positive antithyroglobulin (TgAb) and/or antithyroid peroxidase antibodies (TPOAb) at baseline indicate a high risk of thyroid immune-related adverse events (irAEs) induced by antiprogrammed cell death-1 antibodies (anti-PD-1-Ab). However, whether the positivity patterns of both antibodies are associated with the risk of thyroid irAEs is unknown. OBJECTIVE: The aim of the present study was to clarify the association of the pattern of TgAb and TPOAb positivity at baseline with the risk of thyroid irAEs induced by anti-PD-1-Ab. METHODS: Patients (n = 516) were evaluated for TgAb and TPOAb at baseline and prospectively for thyroid function every 6 weeks for 24 weeks after initiating anti-PD-1-Ab. RESULTS: Fifty-one (9.9%) patients developed thyroid irAEs (thyrotoxicosis in 34, hypothyroidism without prior thyrotoxicosis in 17). Twenty-five patients subsequently developed hypothyroidism following thyrotoxicosis. The cumulative incidence of thyroid irAEs differed among 4 groups classified by the presence of TgAb/TPOAb at baseline (group 1: TgAb-(-)/TPOAb-(-), 4.6% [19/415]; group 2: TgAb-(-)/TPOAb-(+), 15.8% [9/57]; group 3: TgAb-(+)/TPOAb-(-), 42.1% [8/19]; group 4: TgAb-(+)/TPOAb-(+), 60.0% [15/25]) as follows: groups 1 vs 2-4 (P ≤ .001) and groups 2 vs 3 (P = .008) and 4 (P < .001). There were different incidences of thyrotoxicosis (groups 1-4, 3.1%, 5.3%, 31.6%, 48.0%, respectively; P < .001) in groups 1 vs 3 and 4, and groups 2 vs 3 and 4, and of hypothyroidism (groups 1-4: 2.9%, 15.8%, 31.6%, 60.0%, respectively; P < .001) in groups 1 vs 2 to 4, and groups 2 vs 4. CONCLUSION: The risk of thyroid irAEs was affected by the pattern of TgAb and TPOAb positivity at baseline; there were high risks of thyrotoxicosis in patients with TgAb-(+) and of hypothyroidism in patients with TgAb-(+) and those with TPOAb-(+).

DOI： 10.1210/clinem/dgad231

Generation and purification of ACTH-secreting hPSC-derived pituitary cells for effective transplantation. International journal

Shiori Taga, Hidetaka Suga, Tokushige Nakano, Atsushi Kuwahara, Naoko Inoshita, Yu Kodani, Hiroshi Nagasaki, Yoshitaka Sato, Yusuke Tsumura, Mayu Sakakibara, Mika Soen, Tsutomu Miwata, Hajime Ozaki, Mayuko Kano, Kenji Watari, Atsushi Ikeda, Mitsugu Yamanaka, Yasuhiko Takahashi, Sachiko Kitamoto, Yohei Kawaguchi, Takashi Miyata, Tomoko Kobayashi, Mariko Sugiyama, Takeshi Onoue, Yoshinori Yasuda, Daisuke Hagiwara, Shintaro Iwama, Yoshitaka Tomigahara, Toru Kimura, Hiroshi Arima

Stem cell reports Vol. 18 ( 8 ) page： 1657 - 1671 2023.8

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

Pituitary organoids are promising graft sources for transplantation in treatment of hypopituitarism. Building on development of self-organizing culture to generate pituitary-hypothalamic organoids (PHOs) using human pluripotent stem cells (hPSCs), we established techniques to generate PHOs using feeder-free hPSCs and to purify pituitary cells. The PHOs were uniformly and reliably generated through preconditioning of undifferentiated hPSCs and modulation of Wnt and TGF-β signaling after differentiation. Cell sorting using EpCAM, a pituitary cell-surface marker, successfully purified pituitary cells, reducing off-target cell numbers. EpCAM-expressing purified pituitary cells reaggregated to form three-dimensional pituitary spheres (3D-pituitaries). These exhibited high adrenocorticotropic hormone (ACTH) secretory capacity and responded to both positive and negative regulators. When transplanted into hypopituitary mice, the 3D-pituitaries engrafted, improved ACTH levels, and responded to in vivo stimuli. This method of generating purified pituitary tissue opens new avenues of research for pituitary regenerative medicine.

DOI： 10.1016/j.stemcr.2023.05.002

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, 安田康紀, 井土哲志, 奥地剛之, 山上綾菜, Xin Zhou, 小林朋子, 有馬寛

日本内分泌学会雑誌 Vol. 99 ( 3 ) page： 721 - 721 2023.7

線条体ニューロンにおけるPTP1Bは高脂肪食に対する報酬効果を増強する

久納光皓, 坂野僚一, 王思嫻, 佐々木智之, 孫汝楠, 廣瀬友矩, 杉山摩利子, 高木博史, 有馬寛

日本内分泌学会雑誌 Vol. 99 ( 1 ) page： 321 - 321 2023.5

高脂肪食摂取により生じる視床下部弓状核と中脳腹側被蓋野の炎症は自発運動により抑制される

佐々木智之, 杉山摩利子, 久納光皓, 孫汝楠, 廣瀬友矩, 高木博史, 坂野僚一, 有馬寛

日本内分泌学会雑誌 Vol. 99 ( 1 ) page： 322 - 322 2023.5

重症低ナトリウム血症の治療における血清ナトリウム濃度予測システムの精度検証

木下珠希, 萩原大輔, 東慶成, 大山慎太郎, 有馬寛

日本内分泌学会雑誌 Vol. 99 ( 1 ) page： 293 - 293 2023.5

PD-1遮断における甲状腺機能障害のリスクはベースライン時の抗甲状腺抗体陽性数によって層別化される(The risk of thyroid dysfunction in PD-1 blockade is stratified by the number of positive anti-thyroid antibodies at baseline.)

Zhou Xin, 岩間信太郎, 小林朋子, 山上綾菜, 井土哲志, 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. 99 ( 1 ) page： 314 - 314 2023.5

抗PD-1抗体関連甲状腺機能異常症の臨床的特徴と抗甲状腺抗体価との関連

山上綾菜, 岩間信太郎, 小林朋子, Zhou Xin, 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. 99 ( 1 ) page： 306 - 306 2023.5

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メモリーT細胞分画、PD-1発現およびPD-L1発現の検討

伊藤雅晃, 岩間信太郎, 安田康紀, 井土哲志, 奥地剛之, 山上綾菜, Zhou Xin, 小林朋子, 有馬寛

日本内分泌学会雑誌 Vol. 99 ( 1 ) page： 305 - 305 2023.5

【甲状腺疾患アップデート:明日から役立つ最新知見】薬剤性甲状腺機能異常症抗PD-1抗体による甲状腺障害の基礎と臨床

安田康紀, 岩間信太郎, 有馬寛

診断と治療 Vol. 111 ( 5 ) page： 665 - 668 2023.5

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：(株)診断と治療社

＜文献概要＞Headline 1 免疫チェックポイント阻害薬(ICI)による免疫関連有害事象(irAE)の発症が問題となっており,内分泌irAEでは抗PD-1抗体による甲状腺障害の発症頻度が高い.2 抗PD-1抗体による甲状腺障害の発症には抗PD-1抗体治療開始前の甲状腺自己抗体の存在が発症リスク因子であり,発症機序として細胞傷害性CD4陽性T細胞から放出されるグランザイムBによる直接的な甲状腺組織傷害の関与が示唆されている.3 ICI治療を安全に継続するためには,ICI治療開始前での甲状腺自己抗体を含む甲状腺機能のフォローと内分泌専門医との連携が重要である.

Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J00697&link_issn=&doc_id=20230518020024&doc_link_id=10.34433%2Fdt.0000000264&url=https%3A%2F%2Fdoi.org%2F10.34433%2Fdt.0000000264&type=%E5%8C%BB%E6%9B%B8.jp_%E3%82%AA%E3%83%BC%E3%83%AB%E3%82%A2%E3%82%AF%E3%82%BB%E3%82%B9&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Anti-tumor effects of anti-programmed cell death-1 antibody treatment are attenuated in streptozotocin-induced diabetic mice. Reviewed International journal

Masaaki Ito, Shintaro Iwama, Daisuke Sugiyama, Yoshinori Yasuda, Takayuki Okuji, Tomoko Kobayashi, Xin Zhou, Ayana Yamagami, Takeshi Onoue, Takashi Miyata, Mariko Sugiyama, Daisuke Hagiwara, Hidetaka Suga, Ryoichi Banno, Hiroyoshi Nishikawa, Hiroshi Arima

Scientific reports Vol. 13 ( 1 ) page： 5939 - 5939 2023.4

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

Hyperglycemia impairs immune response; however, it remains unknown whether the anti-tumor effects of anti-programmed cell death-1 antibody (PD-1-Ab) treatment are changed in hyperglycemic conditions. We analyzed the effect of PD-1-Ab on tumor growth in streptozotocin-induced diabetic mice (STZ-mice) subcutaneously inoculated with MC38 (a colon carcinoma cell line). Furthermore, we assessed the expression of chemokines by polymerase chain reaction (PCR) array in tumor-draining lymph nodes (dLNs) of these mice and MC38 cells cultured in different glucose concentrations. The suppressive effect of PD-1-Ab on tumor growth was attenuated. This was accompanied by fewer tumor-infiltrating CD8+ T cells, and STZ-mice had fewer tumor-infiltrating CD11c+ dendritic cells (DCs) than normoglycemic mice. mRNA expression levels of CXCL9, a chemokine recruiting CD8+ T cells, were lower in dLNs of STZ-mice than in normoglycemic mice after PD-1-Ab treatment, and its protein was expressed in DCs. In MC38 cells cultured with 25 mM glucose, mRNA expression of CCL7, a chemokine recruiting DCs, was decreased compared to cells cultured with 5 mM glucose. These results suggest that the STZ-induced hyperglycemia impairs the effect of PD-1-Ab treatment on MC38 tumor growth, and is accompanied by reduced infiltration of DCs and CD8+ T cells and decreased expression of CCL7 and CXCL9.

DOI： 10.1038/s41598-023-33049-7

Generation of hypothalamic neural stem cell-like cells in vitro from human pluripotent stem cells. Reviewed International journal

Tsutomu Miwata, Hidetaka Suga, Yohei Kawaguchi, Mayu Sakakibara, Mayuko Kano, Shiori Taga, Mika Soen, Hajime Ozaki, Tomoyoshi Asano, Hiroo Sasaki, Takashi Miyata, Yoshinori Yasuda, Tomoko Kobayashi, Mariko Sugiyama, Takeshi Onoue, Hiroshi Takagi, Daisuke Hagiwara, Shintaro Iwama, Hiroshi Arima

Stem cell reports Vol. 18 ( 4 ) page： 869 - 883 2023.4

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

When damaged, restoring the function of the hypothalamus is currently impossible. It is unclear whether neural stem cells exist in the hypothalamus. Studies have reported that adult rodent tanycytes around the third ventricle function as hypothalamic neural stem cell-like cells. However, it is currently impossible to collect periventricular cells from humans. We attempted to generate hypothalamic neural stem cell-like cells from human embryonic stem cells (ESCs). We focused on retina and anterior neural fold homeobox (RAX) because its expression is gradually restricted to tanycytes during the late embryonic stage. We differentiated RAX::VENUS knockin human ESCs (hESCs) into hypothalamic organoids and sorted RAX+ cells from mature organoids. The isolated RAX+ cells formed neurospheres and exhibited self-renewal and multipotency. Neurogenesis was observed when neurospheres were transplanted into the mouse hypothalamus. We isolated RAX+ hypothalamic neural stem cell-like cells from wild-type human ES organoids. This is the first study to differentiate human hypothalamic neural stem cell-like cells from pluripotent stem cells.

DOI： 10.1016/j.stemcr.2023.02.006

Amino acid polymorphisms in human histocompatibility leukocyte antigen class II and proinsulin epitope have impacts on type 1 diabetes mellitus induced by immune-checkpoint inhibitors Reviewed

Inaba, H; Morita, S; Kosugi, D; Asai, Y; Kaido, Y; Ito, S; Hirobata, T; Inoue, G; Yamamoto, Y; Jinnin, M; Kimura, H; Ota, M; Okudaira, Y; Nakatani, H; Kobayashi, T; Iwama, S; Arima, H; Matsuoka, T

FRONTIERS IN IMMUNOLOGY Vol. 14 page： 1165004 2023.4

Dapagliflozinは脂質と食塩の過剰摂取によって生じる耐糖能異常を改善する

廣瀬友矩, 高木博史, 久納光皓, 佐々木智之, 孫汝楠, 杉山摩利子, 坂野僚一, 有馬寛

糖尿病 Vol. 66 ( Suppl.1 ) page： S - 232 2023.4

Subcutaneous transplantation of human embryonic stem cells-derived pituitary organoids

Sasaki, H; Suga, H; Takeuchi, K; Nagata, Y; Harada, H; Kondo, T; Ito, E; Maeda, S; Sakakibara, M; Soen, M; Miwata, T; Asano, T; Ozaki, H; Taga, S; Kuwahara, A; Nakano, T; Arima, H; Saito, R

FRONTIERS IN ENDOCRINOLOGY Vol. 14 page： 1130465 2023.3

Resting energy expenditure depends on energy intake during weight loss in people with obesity: a retrospective cohort study. Reviewed International journal

Tomoko Handa, Takeshi Onoue, Tomoko Kobayashi, Eri Wada, Ayaka Hayase, Tamaki Kinoshita, Ayana Yamagami, Yoshinori Yasuda, Shintaro Iwama, Yohei Kawaguchi, Takashi Miyata, Mariko Sugiyama, Hiroshi Takagi, Daisuke Hagiwara, Hidetaka Suga, Ryoichi Banno, Motomitsu Goto, Hiroshi Arima

Archives of endocrinology and metabolism Vol. 67 ( 2 ) page： 233 - 241 2023.3

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: Resting energy expenditure (REE) decreases if there is reduced energy intake and body weight (BW). The decrease in REE could make it difficult for patients with obesity to maintain decreased BW. This study aimed to investigate the correlation among changes in REE, energy intake, and BW during the weight loss process in patients with obesity. MATERIALS AND METHODS: We conducted a retrospective cohort study of patients hospitalized for the treatment of obesity in Japan. Patients received fully controlled diet during hospitalization and performed exercises if able. REE was measured once a week using a hand-held indirect calorimetry. Energy intake was determined by actual dietary intake. RESULTS: Of 44 inpatients with obesity, 17 were included in the analysis. Their BW decreased significantly after 1 week (-4.7 ± 2.0 kg, P < 0.001) and 2 weeks (-5.7 ± 2.2 kg, P < 0.001). The change in REE after 1 and 2 weeks was positively correlated with the energy intake/energy expenditure ratio (r = 0.66, P = 0.004 at 1 week, r = 0.71, P = 0.002 at 2 weeks). Using a regression equation (y = 0.5257x - 43.579), if the energy intake/energy expenditure ratio within the second week was 82.9%, the REE after 2 weeks was similar to the baseline level. There was no significant correlation between the change in REE and BW. CONCLUSION: Our data suggest that changes in REE depend on energy intake/energy expenditure ratio and that the decrease in REE can be minimized by matching energy intake to energy expenditure, even during the weight loss process.

DOI： 10.20945/2359-3997000000532

抗PD-L1抗体による甲状腺障害の発症リスク因子の検討

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

日本内分泌学会雑誌 Vol. 98 ( 5 ) page： 1294 - 1294 2023.3

放射線治療とパシレオチドの併用が奏功したクッシング病の1例

村瀬萌絵, 安田康紀, 杉山摩利子, 永田雄一, 竹内和人, 井下尚子, 有馬寛

日本内分泌学会雑誌 Vol. 98 ( 5 ) page： 1401 - 1401 2023.3

Pyogenic spondylitis due to <i>Streptococcus agalactiae</i> with paraspinal abscess and vertebral destruction in a diabetic patient: time course of imagings Reviewed

Kobayashi, T; Iwata, T; Handa, K; Arima, H

ENDOCRINOLOGY DIABETES AND METABOLISM CASE REPORTS Vol. 2023 ( 1 ) 2023.1

Knockdown of endoplasmic reticulum chaperone BiP leads to the death of parvocellular AVP/CRH neurons in mice. Reviewed International journal

Yohei Kawaguchi, Daisuke Hagiwara, Tetsuro Tsumura, Takashi Miyata, Tomoko Kobayashi, Mariko Sugiyama, Takeshi Onoue, Yoshinori Yasuda, Shintaro Iwama, Hidetaka Suga, Ryoichi Banno, Valery Grinevich, Hiroshi Arima

Journal of neuroendocrinology Vol. 35 ( 1 ) page： e13223 2023.1

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

Arginine vasopressin (AVP) is expressed in both magnocellular (magnAVP) and parvocellular AVP (parvAVP) neurons of the paraventricular nucleus, and AVP colocalizes with corticotropin-releasing hormone (CRH) only in the parvocellular neurons. The immunoglobulin heavy chain binding protein (BiP) is a major endoplasmic reticulum (ER) chaperone which regulates the unfolded protein response under ER stress. We previously demonstrated that knockdown of BiP in magnAVP neurons exacerbated ER stress, which resulted in the autophagy-associated cell death of magnAVP neurons. Using the same approach, in the present study we examined the role of BiP in mouse parvAVP/CRH neurons. Our data demonstrate that BiP is expressed in mouse parvAVP/CRH neurons under nonstress conditions and is upregulated in proportion to the increase in CRH expression after adrenalectomy. For BiP knockdown in parvAVP/CRH neurons, we utilized a viral approach in combination with shRNA interference. Knockdown of BiP expression induced ER stress in parvAVP/CRH neurons, as reflected by the expression of C/EBP homologous protein. Furthermore, BiP knockdown led to the loss of parvAVP/CRH neurons after 4 weeks. In summary, our results demonstrate that BiP plays a pivotal role in parvAVP/CRH neurons, which function as neuroendocrine cells producing a large number of secretory proteins.

DOI： 10.1111/jne.13223

Mineralocorticoids induce polyuria by reducing apical aquaporin-2 expression of the kidney in partial vasopressin deficiency. Open Access

Junki Kurimoto, Hiroshi Takagi, Takashi Miyata, Yohei Kawaguchi, Yuichi Hodai, Tetsuro Tsumura, Daisuke Hagiwara, Tomoko Kobayashi, Yoshinori Yasuda, Mariko Sugiyama, Takeshi Onoue, Shintaro Iwama, Hidetaka Suga, Ryoichi Banno, Takeshi Katsuki, Fumiaki Ando, Shinichi Uchida, Hiroshi Arima

Endocrine journal Vol. 70 ( 3 ) page： 295 - 304 2023

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

The symptoms of diabetes insipidus may be masked by the concurrence of adrenal insufficiency and emerge after the administration of hydrocortisone, occasionally at high doses. To elucidate the mechanism underlying polyuria induced by the administration of high-dose corticosteroids in the deficiency of arginine vasopressin (AVP), we first examined the secretion of AVP in three patients in whom polyuria was observed only after the administration of high-dose corticosteroids. Next, we examined the effects of dexamethasone or aldosterone on water balance in wild-type and familial neurohypophysial diabetes insipidus (FNDI) model mice. A hypertonic saline test showed that AVP secretion was partially impaired in all patients. In one patient, there were no apparent changes in AVP secretion before and after the administration of high-dose corticosteroids. In FNDI mice, unlike dexamethasone, the administration of aldosterone increased urine volumes and decreased urine osmolality. Immunohistochemical analyses showed that, after the administration of aldosterone in FNDI mice, aquaporin-2 expression was decreased in the apical membrane and increased in the basolateral membrane in the collecting duct. These changes were not observed in wild-type mice. The present data suggest that treatment with mineralocorticoids induces polyuria by reducing aquaporin-2 expression in the apical membrane of the kidney in partial AVP deficiency.

DOI： 10.1507/endocrj.EJ22-0339

Response to endoplasmic reticulum stress in arginine vasopressin neurons. Invited

Daisuke Hagiwara, Yoshinori Azuma, Yohei Kawaguchi, Takashi Miyata, Hiroshi Arima

Endocrine journal Vol. 70 ( 6 ) page： 567 - 572 2023

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

Arginine vasopressin (AVP) is an antidiuretic hormone synthesized principally in the hypothalamic supraoptic and paraventricular nuclei. The immunoglobulin heavy chain binding protein (BiP), one of the most abundant endoplasmic reticulum (ER) chaperones, is highly expressed in AVP neurons, even under basal conditions. Moreover, its expression is upregulated in proportion to the increase in AVP expression under dehydration. These data suggest that AVP neurons are constantly exposed to ER stress. BiP knockdown in AVP neurons induces ER stress and autophagy, resulting in AVP neuronal loss, indicating that BiP is pivotal in maintaining the AVP neuron system. Furthermore, inhibition of autophagy after BiP knockdown exacerbates AVP neuronal loss, suggesting that autophagy induced under ER stress is a protective cellular mechanism by which AVP neurons cope with ER stress. Familial neurohypophysial diabetes insipidus (FNDI) is an autosomal dominant disorder caused by mutations in the AVP gene. It is characterized by delayed-onset progressive polyuria and eventual AVP neuronal loss. In AVP neurons of FNDI model mice, mutant protein aggregates are confined to a specific compartment of the ER, called the ER-associated compartment (ERAC). The formation of ERACs contributes to maintaining the function of the remaining intact ER, and mutant protein aggregates in ERACs undergo autophagic-lysosomal degradation without isolation or translocation from the ER, representing a novel protein degradation system in the ER.

DOI： 10.1507/endocrj.EJ23-0193

A retrospective study on tolvaptan prescription in clinical practice in patients with syndrome of inappropriate secretion of antidiuretic hormone (SIADH) using the Japanese claims database Reviewed

Hagiwara, D; Matsukawa, M; Tasaki, J; Nakamura, Y; Arima, H

ENDOCRINE JOURNAL Vol. 70 ( 12 ) page： 1195 - 1205 2023

Changing the Name of Diabetes Insipidus: A Position Statement of the Working Group for Renaming Diabetes Insipidus. Reviewed

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

The Journal of clinical endocrinology and metabolism Vol. 108 ( 1 ) page： 1 - 3 2022.12

Changing the name of diabetes insipidus

Arima, H; Bichet, DG; Cheetham, T; Christ-Crain, M; Drummond, J; Gurnell, M; Levy, M; McCormack, A; Newell-Price, J; Verbalis, JG; Wass, J; Cooper, D

PITUITARY Vol. 25 ( 6 ) page： 777 - 779 2022.12

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 journal Vol. 69 ( 11 ) page： 1281 - 1284 2022.11

Changing the name of diabetes insipidus: a position statement of The 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

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

Arima, H; Cheetham, T; Christ-Crain, M; Cooper, D; Gurnell, M; Drummond, JB; Levy, M; McCormack, A; Verbalis, J; Newell-Price, J; Wass, JAH

EUROPEAN JOURNAL OF ENDOCRINOLOGY Vol. 187 ( 5 ) page： P1 - P3 2022.11

Changing the name of diabetes insipidus: a position statement of the working group to consider renaming diabetes insipidus Open Access

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 METABOLISM Vol. 66 ( 6 ) page： 868 - 870 2022.11

実臨床データに基づいた機械学習による低ナトリウム血症治療における血清ナトリウム濃度予測

木下珠希, 大山慎太郎, 萩原大輔, 有馬寛

医療情報学連合大会論文集 Vol. 42回 page： 1195 - 1200 2022.11

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

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

Scientific reports Vol. 12 ( 1 ) page： 17381 - 17381 2022.10

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

Familial neurohypophyseal diabetes insipidus (FNDI) is a degenerative disease of vasopressin (AVP) neurons. Studies in mouse in vivo models indicate that accumulation of mutant AVP prehormone is associated with FNDI pathology. However, studying human FNDI pathology in vivo is technically challenging. Therefore, an in vitro human model needs to be developed. When exogenous signals are minimized in the early phase of differentiation in vitro, mouse embryonic stem cells (ESCs)/induced pluripotent stem cells (iPSCs) differentiate into AVP neurons, whereas human ESCs/iPSCs die. Human ESCs/iPSCs are generally more similar to mouse epiblast stem cells (mEpiSCs) compared to mouse ESCs. In this study, we converted human FNDI-specific iPSCs by the naive conversion kit. Although the conversion was partial, we found improved cell survival under minimal exogenous signals and differentiation into rostral hypothalamic organoids. Overall, this method provides a simple and straightforward differentiation direction, which may improve the efficiency of hypothalamic differentiation.

DOI： 10.1038/s41598-022-22405-8

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

機械学習を用いた重症低ナトリウム血症の治療予測システムの構築

木下珠希, 萩原大輔, 大山慎太郎, 有馬寛

日本内分泌学会雑誌 Vol. 98 ( 2 ) page： 554 - 554 2022.10

Arima, H; Cheetham, T; Christ-Crain, M; Cooper, DL; Drummond, JB; Gurnell, M; Levy, M; McCormack, A; Newell-Price, JD; Verbalis, JG; Wass, J

HORMONE RESEARCH IN PAEDIATRICS Vol. 96 ( 4 ) page： 423 - 425 2022.9

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

Authorship：Last author Language：English 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

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

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

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

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

Authorship：Last author Language：English 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

Disease Modeling of Pituitary Adenoma Using Human Pluripotent Stem Cells Reviewed

Ryusaku Matsumoto, Hidetaka Suga, Hiroshi Arima, Takuya Yamamoto

Cancers Vol. 14 ( 15 ) page： 3660 2022.8

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

Pituitary adenomas are characterized by abnormal growth in the pituitary gland. Surgical excision is the first-line treatment for functional (hormone-producing) pituitary adenomas, except for prolactin-producing adenomas; however, complete excision is technically challenging, and many patients require long-term medication after the treatment. In addition, the pathophysiology of pituitary adenomas, such as tumorigenesis, has not been fully understood. Pituitary adenoma pathophysiology has mainly been studied using animal models and animal tumor-derived cell lines. Nevertheless, experimental studies on human pituitary adenomas are difficult because of the significant differences among species and the lack of reliable cell lines. Recently, several methods have been established to differentiate pituitary cells from human pluripotent stem cells (hPSCs). The induced pituitary hormone-producing cells retain the physiological properties already lost in tumor-derived cell lines. Moreover, CRISPR/Cas9 systems have expedited the introduction of causative gene mutations in various malignant tumors into hPSCs. Therefore, hPSC-derived pituitary cells have great potential as a novel platform for studying the pathophysiology of human-specific pituitary adenomas and developing novel drugs. This review presents an overview of the recent progresses in hPSC applications for pituitary research, functional pituitary adenoma pathogenesis, and genome-editing techniques for introducing causative mutations. We also discuss future applications of hPSCs for studying pituitary adenomas.

DOI： 10.3390/cancers14153660

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

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 2022.7

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

Sobajima, M; Miyake, M; Hamada, Y; Tsugawa, K; Oyadomari, M; Inoue, R; Shirakawa, J; Arima, H; Oyadomari, S

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

Immune checkpoint inhibitor-related thyroid dysfunction Invited Reviewed

Shintaro Iwama, Tomoko Kobayashi, Yoshinori Yasuda, Hiroshi Arima

Best Practice & Research Clinical Endocrinology & Metabolism Vol. 36 ( 3 ) page： 101660 - 101660 2022.5

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

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

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

部分的なバソプレシン分泌不全状態ではミネラルコルチコイドの作用により多尿が顕在化する

栗本隼樹, 高木博史, 津村哲郎, 蓬臺優一, 川口頌平, 宮田崇, 萩原大輔, 須賀英隆, 安藤史顕, 内田信一, 有馬寛

日本内分泌学会雑誌 Vol. 98 ( 1 ) page： 278 - 278 2022.4

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

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

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

Functional lactotrophs in induced adenohypophysis differentiated from human iPS cells. Reviewed 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

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

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

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

高脂肪食摂取に伴う中脳腹側被蓋野の炎症は絶食後の摂餌量を増加させる

孫汝楠, 杉山摩利子, 佐々木智之, 廣瀬友矩, 恒川卓, 高木博史, 坂野僚一, 有馬寛

肥満研究 Vol. 27 ( Suppl. ) page： 342 - 342 2022.3

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

Inaba, H; Kaido, Y; Ito, S; Hirobata, T; Inoue, G; Sugita, T; Yamamoto, Y; Jinnin, M; Kimura, H; Kobayashi, T; Iwama, S; Arima, H; Matsuoka, T

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

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]. Reviewed International journal

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

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

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

Arima H

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

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

Arima Hiroshi

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

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 Vol. 69 ( 11 ) page： 1281 - 1284 2022

Basigin deficiency prevents anaplerosis and ameliorates insulin resistance and hepatosteatosis Reviewed

Ryuge, A; Kosugi, T; Maeda, K; Banno, R; Gou, Y; Zaitsu, K; Ito, T; Sato, Y; Hirayama, A; Tsubota, S; Honda, T; Nakajima, K; Ozaki, T; Kondoh, K; Takahashi, K; Kato, N; Ishimoto, T; Soga, T; Nakagawa, T; Koike, T; Arima, H; Yuzawa, Y; Minokoshi, Y; Maruyama, S; Kadomatsu, K

JCI INSIGHT Vol. 6 ( 20 ) 2021.10

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

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

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

AIMS/HYPOTHESIS: Patients with GAD antibodies (GADAb) showing clinical features of type 2 diabetes typically exhibit progression to an insulin-dependent state in several months or years. This condition is diagnosed as slowly progressive insulin-dependent (type 1) diabetes mellitus (SPIDDM) or latent autoimmune diabetes in adults, a subtype of adult-onset autoimmune diabetes. However, some patients diagnosed with adult-onset autoimmune diabetes do not progress to an insulin-dependent state. We conducted a retrospective cohort study to identify patients with non-insulin-dependent diabetes among those diagnosed with adult-onset autoimmune diabetes using measurable indicators in routine clinical practice. METHODS: We surveyed data from the electronic medical records of all patients with GADAb from eight medical centres in Japan for selecting and analysing patients who matched the diagnostic criteria of SPIDDM. RESULTS: Overall, 345 patients were analysed; of these, 162 initiated insulin therapy (insulin therapy group), whereas 183 did not (non-insulin therapy group) during the follow-up period (median 3.0 years). Patients in the non-insulin therapy group were more likely to be male and presented a later diabetes onset, shorter duration of diabetes, higher BMI, higher blood pressure levels, lower HbA1c levels, lower GADAb levels and lesser antidiabetic agent use than those in the insulin therapy group when GADAb was first identified as positive. A Cox proportional hazards model showed that BMI, HbA1c levels and GADAb levels were independent factors for progression to insulin therapy. Kaplan-Meier analyses revealed that 86.0% of the patients with diabetes having GADAb who presented all three factors (BMI ≥ 22 kg/m2, HbA1c < 75 mmol/mol [9.0%] and GADAb <10.0 U/ml) did not require insulin therapy for 4 years. CONCLUSIONS/INTERPRETATION: Higher BMI (≥22 kg/m2), lower HbA1c (<75 mmol/mol [9.0%]) and lower GADAb levels (<10.0 U/ml) can predict a non-insulin-dependent state for at least several years in Japanese patients with diabetes having GADAb.

DOI： 10.1007/s00125-021-05516-1

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

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

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

Prevention of Worsening Diabetes through Behavioral Changes by an IoT-based Self-Monitoring System in Japan (PRISM-J): Study design and rationale for a multicenter, open-label, randomized parallel-group trial.

Bouchi R, Izumi K, Ohtsu H, Miyo K, Tanaka S, Satoh-Asahara N, Hara K, Odawara M, Kusunoki Y, Koyama H, Onoue T, Arima H, Tsushita K, Watada H, Kadowaki T, Ueki K

GHM open Vol. 1 ( 1 ) page： 3 - 11 2021.8

Deficiency of WFS1 leads to the impairment of AVP secretion under dehydration in male mice. Reviewed 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

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1007/s11102-021-01135-6

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

Furukawa, M; Onoue, T; Kato, K; Wada, T; Shinohara, Y; Kinoshita, F; Goto, M; Arima, H; Tsushita, K

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

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. Invited 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

Glucocorticoid receptor signaling in ventral tegmental area neurons increases the rewarding value of a high-fat diet in mice. Reviewed 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, Taku Nagai, Kiyofumi Yamada, Hiroshi Arima

Scientific reports Vol. 11 ( 1 ) page： 12873 - 12873 2021.6

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

The reward system, which consists of dopaminergic neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens and caudate-putamen in the striatum, has an important role in the pathogenesis of not only drug addiction but also diet-induced obesity. In the present study, we examined whether signaling through glucocorticoid receptors (GRs) in the reward system affects the rewarding value of a high-fat diet (HFD). To do so, we generated mice that lack functional GRs specifically in dopaminergic neurons (D-KO mice) or corticostriatal neurons (CS-KO mice), subjected the mice to caloric restriction stress conditions, and evaluated the rewarding value of a HFD by conditioned place preference (CPP) test. Caloric restriction induced increases in serum corticosterone to similar levels in all genotypes. While CS-KO as well as WT mice exhibited a significant preference for HFD in the CPP test, D-KO mice exhibited no such preference. There were no differences between WT and D-KO mice in consumption of HFD after fasting or cognitive function evaluated by a novel object recognition test. These data suggest that glucocorticoid signaling in the VTA increases the rewarding value of a HFD under restricted caloric stress.

DOI： 10.1038/s41598-021-92386-7

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

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

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.

DOI： 10.1159/000510081

【内分泌疾患2】(Part 2)どこまでを専門家がみて,どこから総合内科医がみるのか? 下垂体中枢性尿崩症,SIADH

須賀英隆, 高木博史, 有馬寛

Hospitalist Vol. 9 ( 2 ) page： 417 - 423 2021.6

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：(株)メディカル・サイエンス・インターナショナル

＜文献概要＞key point 中枢性尿崩症 ▼尿崩症を疑うきっかけの多くは多尿であるが,頻尿との判別に注意する。▼多尿の症例では尿浸透圧を評価し,低浸透圧尿であれば,内分泌専門医へ紹介する。▼デスモプレシン(経鼻製剤または経口製剤)による治療が開始され,その管理を内分泌専門医から引き継いだ場合,薬効が切れて尿量が増加する時間帯を適宜設けさせ,過量投与による水中毒の発生を回避する。特に渇感障害を合併する症例は管理が難しく,毎日の体重測定が投与量調整に有効である。抗利尿ホルモン分泌過剰症(SIADH) ▼SIADHを疑うきっかけは,主に低ナトリウム血症であり,無症状のことが多いが,重症例や急速進行例では倦怠感などの症状を呈することがある。▼水分制限を実施しても低ナトリウム血症が改善しない症例は,内分泌専門医に紹介する。▼内分泌専門医からトルバプタンによる治療を引き継いだ場合,状況に合わせた飲水方針を決定したうえで,血清ナトリウム値の定期フォローを行う。

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. Reviewed

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

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

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

The programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) axis is vital for immune resistance during tumor development, while PD-L1 inhibitors can also inhibit the PD-L1/B7-1 (CD80) interaction, indicating one of the molecular differences between PD-1 and PD-L1 inhibitors. However, the clinical benefits of PD-L1 inhibitors in patients previously treated with PD-1 inhibitors remain unknown. In this study, we retrospectively analyzed the clinical data of eight patients with non-small cell lung cancer who received the PD-L1 inhibitor atezolizumab and previously treated with the PD-1 inhibitor nivolumab. The median progression-free survival was 2.1 months (1.8-18.7 months), and 4 of 8 patients achieved at least stable disease. In two of these patients, atezolizumab treatment resulted in longer progression-free survival (PFS) compared with that of nivolumab. Conversely, one patient exhibited grade 4 diabetic ketoacidosis (DKA) within 2 weeks after the initial administration of atezolizumab. Another patient had developed type 1 diabetes mellitus (T1DM) during the prior nivolumab treatment and then developed DKA due to an infection after the initiation of atezolizumab. Both of them had high-risk human leukocyte antigen-DR/DQ types relevant to T1DM. These results demonstrate the potential efficacy of PD-L1 inhibitors to some tumors that have acquired resistance to PD-1 inhibitors and suggest that appropriate managements are required for not only a newly onset of T1DM but also blood glucose control after the development of T1DM during a reiteration of the PD-1/PD-L1 blockade.

DOI： 10.1507/endocrj.EJ20-0769

Macrophages rely on extracellular serine to suppress aberrant cytokine production Reviewed

Kurita, K; Ohta, H; Shirakawa, I; Tanaka, M; Kitaura, Y; Iwasaki, Y; Matsuzaka, T; Shimano, H; Aoe, S; Arima, H; Ogawa, Y; Ito, A; Suganami, T

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

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

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

<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.

DOI： 10.1038/s41598-021-90209-3

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

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

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1126/scitranslmed.abb7495

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

Neuroscience Vol. 461 page： 72 - 79 2021.5

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1016/j.neuroscience.2021.02.009

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

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

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：BMJ

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

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

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

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.

DOI： 10.1016/j.peptides.2021.170517

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

Clinical Characteristics, Management, and Potential Biomarkers of Endocrine Dysfunction Induced by Immune Checkpoint Inhibitors Invited Reviewed

Iwama, S; Kobayashi, T; Arima, H

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

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

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

Wolfram症候群モデルマウスは脱水負荷によりバソプレシン分泌不全を呈する

栗本隼樹, 高木博史, 津村哲郎, 蓬臺優一, 川口頌平, 宮田崇, 萩原大輔, 須賀英隆, 田部勝也, 谷澤幸生, 有馬寛

日本内分泌学会雑誌 Vol. 97 ( 1 ) page： 261 - 261 2021.4

AVPニューロン特異的BiPノックダウンはAVPニューロンにおけるオートファジーと細胞死を誘導する

川口頌平, 萩原大輔, 津村哲郎, 蓬臺優一, 栗本隼樹, 宮田崇, 高木博史, 須賀英隆, Grinevich Valery, 有馬寛

日本内分泌学会雑誌 Vol. 97 ( 1 ) page： 261 - 261 2021.4

食塩過剰摂取は高脂肪食によって惹起される膵β細胞増殖を抑制して耐糖能を悪化させる

滝啓吾, 高木博史, 廣瀬友矩, 孫汝楠, 柳沼裕史, 杉山摩利子, 伊藤禎浩, 坂野僚一, 有馬寛

日本内分泌学会雑誌 Vol. 97 ( 1 ) page： 321 - 321 2021.4

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

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

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

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

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.

DOI： 10.1371/journal.pone.0248065

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

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

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

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

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

Hajime Ozaki, Hidetaka Suga, Hiroshi Arima

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

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

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

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

胆管癌に伴う閉塞性黄疸の解除後、約3ヵ月でインスリン離脱となった1例

木下珠希, 杉山摩利子, 有馬寛

糖尿病 Vol. 64 ( 2 ) page： 151 - 151 2021.2

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. Reviewed

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

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

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

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

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

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

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

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：JAPANESE PHARMACOLOGICAL SOC

We investigated whether peripheral combination treatment of a sodium-glucose cotransporter 2 (SGLT2) inhibitor and leptin improves glucose metabolism in insulin-dependent diabetes mellitus (IDDM) model mice. Twelve-week-old male C57BL6 mice were intraperitoneally administered a high dose of streptozotocin to produce IDDM. IDDM mice were then divided into five groups: SGLT2 inhibitor treatment alone, leptin treatment alone, leptin and SGLT2 inhibitor co-treatment, untreated IDDM mice, and healthy mice groups. The blood glucose (BG) level at the end of the dark cycle was measured, and a glucose tolerance test (GTT) was performed and compared between the five groups. Leptin was peripherally administered at 20 mu g/day using an osmotic pump, and an SGLT2 inhibitor, ipragliflozin, was orally administered at 3 mg/kg/day. Monotherapy with SGLT2 inhibitor or leptin significantly improved glucose metabolism in mice as evaluated by BG and GTT compared with the untreated group, whereas the co-treatment group with SGLT2 inhibitor and leptin further improved glucose metabolism as compared with the monotherapy group. Notably, glucose metabolism in the co-treatment group improved to the same level as that in the healthy mice group. Thus, peripheral combination treatment with leptin and SGLT2 inhibitor improved glucose metabolism in IDDM mice without the use of insulin. (C) 2021 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society.

DOI： 10.1016/j.jphs.2021.08.010

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

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 Reviewed

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

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

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

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

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

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

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

<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.

DOI： 10.1038/s41598-020-76839-z

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

Degradation of Mutant Protein Aggregates within the Endoplasmic Reticulum of Vasopressin Neurons. Reviewed 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

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1016/j.isci.2020.101648

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 Invited

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

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) Open Access

Matsushita, M; Muramoto, A; Nomura, E; Eguchi, Y; Kato, A; Sano, Y; Kabayama, M; Arakawa, M; Oguma, Y; Yabe, D; Matsunaga, M; Yatsuya, H; Arima, H; Tsushita, K

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

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

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

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

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

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

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

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

【糖尿病・内分泌代謝疾患における妊娠と出産】中枢性尿崩症

高木博史, 有馬寛

糖尿病・内分泌代謝科 Vol. 51 ( 3 ) page： 211 - 214 2020.9

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

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

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.

DOI： 10.1038/s41387-020-00136-x

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

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

インスリン依存性糖尿病モデルマウスの糖代謝はインスリン非投与下でレプチンおよびSGLT2阻害剤の併用投与により改善する

柳沼裕史, 坂野僚一, 孫汝楠, 滝啓吾, 杉山摩利子, 恒川卓, 高木博史, 伊藤禎浩, 有馬寛

糖尿病 Vol. 63 ( Suppl.1 ) page： S - 199 2020.8

高脂肪食負荷マウスにおいて食塩過剰摂取はインスリン分泌低下を介して耐糖能を悪化させる

滝啓吾, 高木博史, 孫汝楠, 柳沼裕史, 杉山摩利子, 恒川卓, 伊藤禎浩, 坂野僚一, 有馬寛

糖尿病 Vol. 63 ( Suppl.1 ) page： S - 131 2020.8

報酬系による糖代謝調節機構の解明 GABAB受容体ノックアウトマウスを用いた検討

恒川卓, 坂野僚一, 孫汝楠, 柳沼裕史, 滝啓吾, 杉山摩利子, 高木博史, 伊藤禎浩, 有馬寛

糖尿病 Vol. 63 ( Suppl.1 ) page： S - 111 2020.8

タモキシフェン誘導性Creマウスを用いたアストロサイト特異的PTP1B欠損マウスの表現型解析

杉山摩利子, 坂野僚一, 孫汝楠, 柳沼裕史, 滝啓吾, 恒川卓, 高木博史, 伊藤禎浩, 有馬寛

日本内分泌学会雑誌 Vol. 96 ( 1 ) page： 352 - 352 2020.8

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. Invited 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

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

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.

DOI： 10.1016/j.scr.2020.101846

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

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier BV

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.

DOI： 10.1016/j.neuint.2020.104733

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

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

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

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

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

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

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

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

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

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.

DOI： 10.1371/journal.pone.0228004

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

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

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.

DOI： 10.1038/s41598-020-57935-6

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

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

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.

DOI： 10.1016/j.celrep.2019.12.009

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

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

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

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

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

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

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.

DOI： 10.1507/endocrj.EJ19-0569

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

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

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

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

Anti-pituitary antibodies as a marker of autoimmunity in pituitary glands Reviewed

Iwama Shintaro, Arima Hiroshi

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

Hormone replacement therapy using human iPS cell-derived pituitary organoids

Shiori Taga, Hidetaka Suga, Toru Kimura, Hiroshi Arima

Drug Delivery System Vol. 35 ( 4 ) page： 285 - 292 2020

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japan Society of Drug Delivery System

The pituitary is a major endocrine center for systemic hormones, secreting various hormones such as ACTH and GH that are critical for survival, homeostasis and growth. Therefore, once it DDS becomes dysfunctional, it will cause a wide range of serious symptoms. The current treatment for hypopituitarism is hormone replacement therapy, but not a curative treatment, so it is hoped regenerative medicine will become a superior treatment. We have succeeded in generating a functional anterior pituitary from mouse and human embryonic stem cells, and showed its therapeutic efficacy for pituitary disorders. In this article, we discuss the current research progression in and future perspectives of pituitary regenerative medicine.

DOI： 10.2745/dds.35.285

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

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

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

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

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

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

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

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.

DOI： 10.1172/JCI124481

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

Tanycyte-Like Cells Derived From Mouse Embryonic Stem Culture Show Hypothalamic Neural Stem/Progenitor Cell Functions Reviewed 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

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

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

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

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

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

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

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

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

ヒトiPS細胞から下垂体PRL産生細胞への分化誘導

永井孝, 須賀英隆, 大須賀智子, 有馬寛

日本内分泌学会雑誌 Vol. 95 ( 1 ) page： 490 - 490 2019.4

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

Short-Term Steroid Regimen for Adult Steroid-Sensitive Minimal Change Disease Reviewed 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

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

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.

DOI： 10.1159/000495352

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

Yasuda Yoshinori, Iwama Shintaro, Arima Hiroshi

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

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

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

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

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

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.

DOI： 10.1507/endocrj.EJ19-0163

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

マウスES細胞視床下部分化誘導系後期に残存するRax+細胞はTanycytesと類似する

加納麻弓子, 須賀英隆, 有馬寛

日本内分泌学会雑誌 Vol. 94 ( 4 ) page： 1319 - 1319 2018.12

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

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

傍鞍部腫瘍術後遅発性低Na血症の発症と予防法の検討

竹内和人, 川端哲平, 永田雄一, 秋禎樹, 石川隆之, 高木博史, 有馬寛, 若林俊彦

日本内分泌学会雑誌 Vol. 94 ( Suppl.HPT ) page： 37 - 40 2018.9

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：(一社)日本内分泌学会

当院で傍鞍部腫瘍に対しeTSS(内視鏡下経鼻経蝶形骨手術)を施行した98例(男性50例、女性48例、平均年齢55.9歳)を対象に、術後の遅発性低Na血症(DHN)発症について検討した。その結果、DHNは37例(37.8%)に認められた。DHN発症患者ではDHN発症時のAVP分泌が抑制されていないことが確認された。また、術後7日目においてDHN非発症患者では約3%程度の体重低下を認めるのに対し、DHN発症例では体重減少は1%程度と軽微であり、体内への水分貯留が示唆された。術前より尿崩症が認められた患者群ではDHN発症が少なかったものの、DHN発症例では渇感中枢障害を伴っていた。これは術後の脱水を危惧したADH補充による医原性のものと考えられた。以上、傍鞍部腫瘍の術後DHNの発症にはSIADHが強く関与していることが考えられた。尚、術後早期からの水分制限はDHN発症予防に有効と考えられたが、より適切なプロトコールならびに予測法の確立が必要である。

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

Language：English Publishing type：Research paper (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

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

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

2018.8

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

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

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

JOURNAL OF CLINICAL ONCOLOGY Vol. 36 ( 15 ) 2018.5

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

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

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

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

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

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

マウスES細胞視床下部誘導系におけるTanycytes様細胞の検討

加納麻弓子, 須賀英隆, 山田登美子, 有馬寛

日本内分泌学会雑誌 Vol. 94 ( 1 ) page： 313 - 313 2018.4

小胞体ストレスのin vitro実験系の確立家族性中枢性尿崩症の疾患特異的iPS細胞を用いた検討

光本一樹, 須賀英隆, 加納麻弓子, 大曽根親文, 宮田崇, 橡谷昌佳, 萩原大輔, 佐藤慧太, 坂本浩隆, 有馬寛

日本内分泌学会雑誌 Vol. 94 ( 1 ) page： 290 - 290 2018.4

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

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

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

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

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

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

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

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

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

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

下垂体の発生 in vitro下垂体分化法を生体により近づける試み

須賀英隆, 加納麻弓子, 光本一樹, 笠井貴敏, 有馬寛

日本内分泌学会雑誌 Vol. 93 ( 4 ) page： 1210 - 1210 2017.12

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

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

Language：English Publishing type：Research paper (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

Magnetic-activated cell sorting法を用いた視床下部アストロサイトの単離と機能解析

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

杉山摩利子, 坂野僚一, 滝啓吾, 溝口暁, 恒川卓, 高木博, 伊藤禎浩, 小峯起, 山中宏二, 有馬寛

肥満研究 Vol. 23 ( Suppl. ) page： 212 - 212 2017.9

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

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：NAGOYA UNIV, SCH MED

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

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

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER PHYSIOLOGICAL SOC

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

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

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

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

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

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：(一社)日本内分泌学会

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

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

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

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

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

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

疾患特異的iPS細胞を用いた家族性中枢性尿崩症の病態解明

光本一樹, 須賀英隆, 山田登美子, 加納麻弓子, 橡谷昌佳, 大曽根親文, 笠井貴敏, 萩原大輔, 有馬寛

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

Deficiency of PTP1B Attenuates Hypothalamic Inflammation via Activation of the JAK2-STAT3 Pathway in Microglia Open Access

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

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

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

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

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

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

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

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 <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

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

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

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

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

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

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

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

マウスES細胞から視床下部神経への誘導法ではグリア細胞も出現する

須賀英隆, 光本一樹, 山田登美子, 加納麻弓子, 水野正明, 有馬寛

日本内分泌学会雑誌 Vol. 92 ( 3 ) page： 732 - 732 2017.1

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

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japan Society for Clinical Immunology

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