Faculty Profiles - SUGIYAMA Mariko

Papers - SUGIYAMA Mariko

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

Takashi Miyata, Daisuke Hagiwara, Yuichi Hodai, Tsutomu Miwata, Yohei Kawaguchi, Junki Kurimoto, Hajime Ozaki, Kazuki Mitsumoto, Hiroshi Takagi, Hidetaka Suga, Tomoko Kobayashi, Mariko Sugiyama, Takeshi Onoue, Yoshihiro Ito, Shintaro Iwama, Ryoichi Banno, Mami Matsumoto, Natsuko Kawakami, Nobuhiko Ohno, Hirotaka Sakamoto, Hiroshi Arima

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

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

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

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

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

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

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

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

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

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

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

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

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

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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. International journal Open Access

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

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

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

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. International journal Open Access

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

BMJ open diabetes research & care Vol. 8 ( 1 ) 2020.1

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

INTRODUCTION: The present study aimed to evaluate the effects of flash glucose monitoring (FGM) and conventional self-monitoring of blood glucose (SMBG) on glycemic control in patients with non-insulin-treated type 2 diabetes. RESEARCH DESIGN AND METHODS: In this 24-week, multicenter, open-label, randomized (1:1), parallel-group study, patients with non-insulin-treated type 2 diabetes at five hospitals in Japan were randomly assigned to the FGM (n=49) or SMBG (n=51) groups and were provided each device for 12 weeks. The primary outcome was change in glycated hemoglobin (HbA1c) level, and was compared using analysis of covariance model that included baseline values and group as covariates. RESULTS: Forty-eight participants in the FGM group and 45 in the SMBG group completed the study. The mean HbA1c levels were 7.83% (62.1 mmol/mol) in the FGM group and 7.84% (62.2 mmol/mol) in the SMBG group at baseline, and the values were reduced in both FGM (-0.43% (-4.7 mmol/mol), p<0.001) and SMBG groups (-0.30% (-3.3 mmol/mol), p=0.001) at 12 weeks. On the other hand, HbA1c was significantly decreased from baseline values in the FGM group, but not in the SMBG group at 24 weeks (FGM: -0.46% (-5.0 mmol/mol), p<0.001; SMBG: -0.17% (-1.8 mmol/mol), p=0.124); a significant between-group difference was also observed (difference -0.29% (-3.2 mmol/mol), p=0.022). Diabetes Treatment Satisfaction Questionnaire score was significantly improved, and the mean glucose levels, SD of glucose, mean amplitude of glycemic excursions and time in hyperglycemia were significantly decreased in the FGM group compared with the SMBG group. CONCLUSIONS: Glycemic control was better with FGM than with SMBG after cessation of glucose monitoring in patients with non-insulin-treated type 2 diabetes. TRIAL REGISTRATION NUMBER: UMIN000026452, jRCTs041180082.

DOI： 10.1136/bmjdrc-2019-001115

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. International journal Open Access

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 ) 2020

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

高脂肪食の継続投与はグリア細胞の極性変化を伴い視床下部炎症が増悪する

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

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

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