Faculty Profiles - ARIMA, Hiroshi

Scopus

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

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. Open Access

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. International journal Open Access

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. 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 International journal Open Access

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

橋に脱髄性病変を呈した1型糖尿病の1例

半田朋子, 小林朋子, 高木博史, 有馬寛

糖尿病 Vol. 62 ( 1 ) page： 55 - 55 2019.1

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

Yasuda Yoshinori, Iwama Shintaro, Arima Hiroshi

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

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. Open Access

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

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

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

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

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