Research activity information

• Nov. 2016 公益財団法人MSD生命科学財団, 第5回万有医学奨励賞, 2型糖尿病候補遺伝子Kcnq1遺伝子領域による膵β細胞量調節機構の解明

  Asahara Shunichirou

  Publisher


• Oct. 2013 AASD2013, JADEC International Research promotion Award, Paternal allelic mutation at the Kcnq1 locus reduces pancreatic beta-cell mass via epigenetic modification of Cdkn1c

  ASAHARA Shunichirou


• Feb. 2012 日本糖尿病・肥満動物学会, 第26回日本糖尿病・肥満動物学会年次学術集会若手研究奨励賞, 2型糖尿病候補遺伝子Kcnq1遺伝子領域が膵細胞に及ぼす影響の解析

  Asahara Shunichirou

  Japan society


• Dec. 2010 分子糖尿病学研究会, 第22回分子糖尿病学シンポジウム研究奨励賞, 2型糖尿病候補遺伝子Kcnq1の膵β細胞に及ぼす役割の検討

  Asahara Shunichirou

  Others


• Jul. 2008 日本臨床分子医学会, 第45回日本臨床分子医学会学術集会学術奨励賞, 膵β細胞における低分子量GタンパクRac1の機能解析

  Asahara Shunichirou

  Japan society

• Dapagliflozin administration to a mouse model of type 2 diabetes induces DNA methylation and gene expression changes in pancreatic islets.

  Aisha Yokoi, Shun-Ichiro Asahara, Hiroyuki Inoue, Masako Seike, Nozomi Kido, Hirotaka Suzuki, Ayumi Kanno, Maki Kimura-Koyanagi, Yoshiaki Kido, Wataru Ogawa

  Decreased pancreatic β-cell volume is a serious problem in patients with type 2 diabetes mellitus, and there is a need to establish appropriate treatments. Increasingly, sodium/glucose cotransporter 2 (SGLT2) inhibitors, which have a protective effect on pancreatic β-cells, are being prescribed to treat diabetes; however, the underlying mechanism is not well understood. We previously administered SGLT2 inhibitor dapagliflozin to a mouse model of type 2 diabetes and found significant changes in gene expression in the early-treated group, which led us to hypothesize that epigenetic regulation was a possible mechanism of these changes. Therefore, we performed comprehensive DNA methylation analysis by methylated DNA immunoprecipitation using isolated pancreatic islets after dapagliflozin administration to diabetic model mice. As a result, we identified 31 genes with changes in expression due to DNA methylation changes. Upon immunostaining, cystic fibrosis transmembrane conductance regulator and cadherin 24 were found to be upregulated in islets in the dapagliflozin-treated group. These molecules may contribute to the maintenance of islet morphology and insulin secretory capacity, suggesting that SGLT2 inhibitors' protective effect on pancreatic β-cells is accompanied by DNA methylation changes, and that the effect is long-term and not temporary. In future diabetes care, SGLT2 inhibitors may be expected to have positive therapeutic effects, including pancreatic β-cell protection.

  Sep. 2024, Biochemical and biophysical research communications, 725, 150254 - 150254, English, International magazine

  Scientific journal


• Comparison over Time of Adverse Drug Reactions in Diabetes Patients Treated with Sodium-Glucose Cotransporter 2 Inhibitors.

  Mai Ueda, Masako Zenibayashi, Tomoko Yamada, Shun-Ichiro Asahara, Wataru Ogawa

  BACKGROUNDS: The prescription of sodium-glucose cotransporter-2 (SGLT2) inhibitors have been increasing due to their additional benefits, including weight loss, cardioprotection and renoprotection. Accordingly, there are concerns about the potential rise in severe adverse drug reactions (ADRs), such as urinary tract infections, diabetic ketoacidosis, volume depletion, and hypoglycemia. The Society has announced recommendations on the proper use of SGLT2 inhibitors. We aimed to elucidate the recent occurrence of severe ADRs which need discontinuation of SGLT2 inhibitors or hospitalization. METHODS: In this retrospective cohort study, we identified 391 diabetic patients who were prescribed SGLT2 inhibitors upon admission to our hospital between April 2017 and March 2023. Of these, 68 patients who discontinued SGLT2 inhibitors for reasons other than ADRs were excluded. Patients were classified into the 2017 group and the 2020 group based on the treatment period of SGLT2 inhibitors, and the occurrence of ADRs and patient backgrounds were compared between the two groups. RESULTS: A total of 323 eligible patients were identified. Discontinuations of SGLT2 inhibitors decreased in the 2020 group (p < 0.05). However, discontinuations due to frailty increased (p < 0.05). Hospitalization due to ADRs, specifically those due to urinary tract infections, diabetic ketoacidosis, or volume depletion, did not specifically decrease (p = 0.273). CONCLUSIONS: This study indicated that there has been some improvement in the awareness of the proper use of SGLT2 inhibitors and there is still a need to continue enlightenment activities.

  Jul. 2024, The Kobe journal of medical sciences, 70(3) (3), E81-E88, English, Domestic magazine

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Effects of soy or whey protein on weight reduction in patients with obesity: An exploratory, three-arm, placebo-controlled, double-blind, randomized clinical trial

  Michiko Takahashi, Takumi Imai, Tomoko Yamada, Naokazu Muramae, Kai Yoshimura, Yuji Mitomo, Hironori Bando, Kenji Sugawara, Shun-Ichiro Asahara, Yushi Hirota, Yoshikazu Tamori, Yutaka Takahashi, Wataru Ogawa

  Elsevier BV, Jun. 2024, Clinical Nutrition Open Science, 55, 223 - 233

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• A High Fibrosis-4 Index is Associated with a Reduction in the Estimated Glomerular Filtration Rate in Non-obese Japanese Patients with Type 2 Diabetes Mellitus.

  Hiroyuki Inoue, Shun-Ichiro Asahara, Fumihiko Nakamura, Yoshiaki Kido

  Liver fibrosis is associated with non-alcoholic fatty liver disease (NAFLD), and one of the most important risk factors for NAFLD is type 2 diabetes (T2DM). The Fibrosis-4 (FIB-4) index, a noninvasive liver fibrosis score, has been found to be useful for estimating liver fibrosis. Because individuals with non-obese NAFLD were recently reported to be metabolically unhealthy and have a higher risk of T2DM than individuals with obese NAFLD, we hypothesized that the clinical factors related to a high FIB-4 index would differ between non-obese and obese Japanese T2DM patients. Accordingly, we examined the relationship between clinical factors and the FIB-4 index in non-obese and obese Japanese patients with T2DM. We divided 265 patients into two groups by BMI level - a non-obese group (n = 149) and an obese group (n = 116) - and examined the correlation between the FIB-4 index and clinical parameters. Single regression analysis revealed that a high FIB-4 index was correlated with a reduction in the estimated glomerular filtration rate and hypertension in the non-obese group. Importantly, multiple regression analysis showed that only a reduction in the estimated glomerular filtration rate was significantly associated with a high FIB-4 index in the non-obese group. These results demonstrated that non-obese T2DM patients with a high FIB-4 index might be at risk of kidney dysfunction. Our findings may enable the more appropriate treatment of T2DM patients based on BMI level.

  Apr. 2024, The Kobe journal of medical sciences, 70(1) (1), E39-E45, English, Domestic magazine

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• 膵β細胞におけるmTORC1活性化が膵島可塑性に及ぼす影響の検討

  木戸 希, 淺原 俊一郎, 清家 雅子, 木村 真希, 鈴木 宏隆, 横井 愛紗, 椎木 幾久子, 田部 勝也, 木戸 良明, 小川 渉

  (一社)日本糖尿病学会, Apr. 2024, 糖尿病, 67(Suppl.1) (Suppl.1), S - 160, Japanese


• 膵β細胞におけるmTORC1活性化が膵島可塑性に及ぼす影響の検討

  木戸 希, 淺原 俊一郎, 清家 雅子, 椎木 幾久子, 田部 勝也, 水上 浩哉, 木戸 良明, 小川 渉

  日本臨床分子医学会, Apr. 2024, 日本臨床分子医学会学術総会プログラム・抄録集, 59回, 47 - 47, Japanese


• 炎症・感染とこれからの眼科診療 眼炎症を克服するための精密医療の実現に向けて

  楠原 仙太郎, 松宮 亘, 吉川 敦子, 淺原 俊一郎, 木戸 良明, 小川 渉, 西庄 龍東, 曽谷 尭之, 岸 真椰, 橘 吉寿, 内匠 透, 金 景佑, 村井 佑輔, 荒井 美奈, 坂本 麻里, 盛 崇太朗, 牧 仁美, 今井 尚徳, 田上 瑞記, 園田 康平, 蕪城 俊克, 柳井 亮二, 丸山 和一, 金子 優, 篠原 正和, 浅井 義之, 中津井 雅彦, 早野 崇英, 柏木 賢治, 中村 誠

  精密医療とは臨床情報・遺伝情報・環境因子を含む多くのデータセットから患者を層別化し,それぞれのグループに最適な治療法や予防法を提供するものである.ぶどう膜炎診療では,ぶどう膜炎の病期,眼炎症の活動性とその程度,眼炎症が眼組織に及ぼす影響などを考慮しながら,目の前のぶどう膜炎患者に最適な治療を適宜選択する必要がある.このアプローチ法は精密医療そのものであるが,現状の検査法と治療法から得られるデータセットは質・量ともに十分とはいえない.この問題を解決するために我々は,従来とは異なる検査情報の取得,新規治療法の開発,大規模データベースの構築に取り組んできた.1.眼炎症の「見える化」を目指した生体イメージングの開発古くからぶどう膜炎における炎症評価方法のゴールドスタンダードは検眼鏡所見である.ぶどう膜炎では検眼鏡的に炎症所見が軽微であっても網膜組織障害が慢性に進行する場合があり,そのような症例では治療の匙加減に悩むことがしばしばある.我々は光干渉断層計(OCT)を活用することによって,硝子体細胞の特徴がぶどう膜炎の分類に有用であることを見出し,en face slab OCT imagingによりぶどう膜炎に伴う網膜内層障害を二次元的に評価することに成功した.さらに,二光子顕微鏡によるマウス網膜のin vivo imagingでは,炎症惹起に伴うミクログリアの動的な反応を評価できることを明らかにした.ヒト生体網膜での炎症細胞の動的な可視化は現実的ではないが,マウス網膜で得られた知見を適切な生体プローブの動態に関連づけることによって,構造異常が認められない段階での網膜細胞異常の有無を臨床で可視化できるようになると思われる.これらの生体イメージングによる眼炎症の「見える化」は,眼炎症と網膜組織障害の詳細な評価を介して,きめ細やかな眼炎症管理に貢献するものと期待される.2.ぶどう膜炎続発緑内障の克服を目指した新しい濾過手術近年の生物学的製剤の登場と硝子体手術の低侵襲化によって,ぶどう膜炎における主要な失明原因は黄斑病変から続発緑内障へとシフトしていくことが予想される.ぶどう膜炎続発緑内障は原発開放隅角緑内障に比べ高眼圧であり視野障害の進行が速いことから,原発開放隅角緑内障とは異なる治療戦略で長期的な視機能維持を目指す必要がある.我々は,ぶどう膜炎続発緑内障ではRho-associated coiled-coil forming kinase(ROCK)阻害薬点眼が著効する症例が存在すること,谷戸フックを用いた線維柱帯切開術(眼内法)の治療成績が原発開放隅角緑内障と遜色がないことを明らかにした.一方,濾過手術の進化はぶどう膜炎続発緑内障の管理に必須である.著者が発明したTenon開創器は術中にTenon嚢-強膜間のスペースを確保することによって結膜への影響を最小限にマイトマイシンCの効果を得ることを目的としたデバイスである.これに独特な強膜フラップ処理と独自の結膜縫合法を組み合わせることによって,濾過胞管理の不要な新しい線維柱帯切除術が誕生した.また,我々が行ったロングチューブシャント手術の改良もぶどう膜炎続発緑内障に対する低侵襲濾過手術の実現に貢献している.ぶどう膜炎続発緑内障に対するこれらの治療法の登場によって,ぶどう膜炎患者の視機能が長期的に維持されることを期待したい.3.自己免疫網膜症に対する精密医療への取り組み自己免疫網膜症は網膜細胞を標的とする自己免疫反応が亜急性に網膜視細胞を不可逆的に障害するまれな疾患である.自己免疫網膜症の診断については抗網膜自己抗体の特異度が低いこと,治療に関しては標準化された治療アルゴリズムがないことがそれぞれ問題となっている.また,視機能が不可逆的に障害される前に治療効果を判定できる他覚的な疾患バイオマーカーがないことも自己免疫網膜症診療を難しくしている主因となっている.そこで我々は,日本眼炎症学会とJapan Ocular Imaging Registryの助力を得て,自己免疫網膜症患者の大規模臨床データベースの作成,患者血液を用いた網羅的プロテインアレイによる主要な抗網膜抗体の決定,患者血液を用いた代謝物データと臨床データの統合解析による臨床バイオマーカーの探索を目指した多機関研究を行うこととした.本研究で得られる質の高いデータセットを活用することによって,自己免疫網膜症の精密医療が進むものと考えている.(著者抄録)

  (公財)日本眼科学会, Mar. 2024, 日本眼科学会雑誌, 128(3) (3), 234 - 255, Japanese


• Dietary Intervention for Control of Clinical Symptom in Patients with Systemic Metal Allergy: A Single Center Randomized Controlled Clinical Study.

  Reiko Mikajiri, Atsushi Fukunaga, Makoto Miyoshi, Noriaki Maeshige, Ken Washio, Taro Masaki, Chikako Nishigori, Ikuko Yamamoto, Akiyo Toda, Michiko Takahashi, Shun-Ichiro Asahara, Yoshiaki Kido, Makoto Usami

  Patients with eczema with a systemic metal allergy, such as nickel (Ni), cobalt (Co), chromium (Cr), and tin (Sn), should pay attention to symptomatic exacerbation by excessive metal intake in food. However, dietary intervention for systemic metal allergy can be difficult. In this study, we evaluated the effect of dietary intervention by a registered dietitian on clinical symptoms in patients with a systemic metal allergy. Forty-four patients with cutaneous symptoms who were diagnosed with a metal allergy were randomly assigned to the dietary intervention group (DI group, n = 29) by a registered dietitian or the control group (C group, n = 15). The DI group was individually instructed by a registered dietitian how to implement a metal-restricted diet and then evaluated 1 month later. Dermatologists treated skin lesions of patients in both groups. Skin symptoms assessed by the Severity Scoring of Atopic Dermatitis (SCORAD) index, blood tests, and urinary metal excretion were evaluated. The DI group showed decreased Ni, Co, Cr, and Sn intake (all P ≤ 0.05), and an improved total SCORAD score, eczema area, erythema, edema/papulation, oozing/crust, excoriation, lichenization and dryness after 1 month of intervention compared with before the intervention (all P ≤ 0.05). However, the C group showed decreased Ni and Sn intake and an improved oozing/crust score (all P < 0.05). It showed the effective reduction of dietary metal intake controls dermatitis due to a metal allergy. In conclusion, dietary intervention by a registered dietitian is effective in improving skin symptoms with a reduction in metal intake.

  Jan. 2024, The Kobe journal of medical sciences, 69(4) (4), E129-E143, English, Domestic magazine

  Scientific journal


• Cyb5r3 activation rescues secondary failure to sulfonylurea but not β-cell dedifferentiation.

  Hitoshi Watanabe, Shun-Ichiro Asahara, Jinsook Son, Wendy M McKimpson, Rafael de Cabo, Domenico Accili

  Diabetes mellitus is characterized by insulin resistance and β-cell failure. The latter involves impaired insulin secretion and β-cell dedifferentiation. Sulfonylurea (SU) is used to improve insulin secretion in diabetes, but it suffers from secondary failure. The relationship between SU secondary failure and β-cell dedifferentiation has not been examined. Using a model of SU secondary failure, we have previously shown that functional loss of oxidoreductase Cyb5r3 mediates effects of SU failure through interactions with glucokinase. Here we demonstrate that SU failure is associated with partial β-cell dedifferentiation. Cyb5r3 knockout mice show more pronounced β-cell dedifferentiation and glucose intolerance after chronic SU administration, high-fat diet feeding, and during aging. A Cyb5r3 activator improves impaired insulin secretion caused by chronic SU treatment, but not β-cell dedifferentiation. We conclude that chronic SU administration affects progression of β-cell dedifferentiation and that Cyb5r3 activation reverses secondary failure to SU without restoring β-cell dedifferentiation.

  2024, PloS one, 19(2) (2), e0297555, English, International magazine

  Scientific journal


• Hepatic FASN deficiency differentially affects nonalcoholic fatty liver disease and diabetes in mouse obesity models.

  Toshiya Matsukawa, Takashi Yagi, Tohru Uchida, Mashito Sakai, Masaru Mitsushima, Takao Naganuma, Hiroyuki Yano, Yuka Inaba, Hiroshi Inoue, Keisuke Yanagida, Masaaki Uematsu, Kazuki Nakao, Harumi Nakao, Atsu Aiba, Yoji Nagashima, Tetsuya Kubota, Naoto Kubota, Yoshihiko Izumida, Naoya Yahagi, Hiroyuki Unoki-Kubota, Yasushi Kaburagi, Shun-Ichiro Asahara, Yoshiaki Kido, Hideo Shindou, Michiko Itoh, Yoshihiro Ogawa, Shiro Minami, Yasuo Terauchi, Kazuyuki Tobe, Kohjiro Ueki, Masato Kasuga, Michihiro Matsumoto

  Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes are interacting comorbidities of obesity, and increased hepatic de novo lipogenesis (DNL), driven by hyperinsulinemia and carbohydrate overload, contributes to their pathogenesis. Fatty acid synthase (FASN), a key enzyme of hepatic DNL, is upregulated in association with insulin resistance. However, the therapeutic potential of targeting FASN in hepatocytes for obesity-associated metabolic diseases is unknown. Here, we show that hepatic FASN deficiency differentially affects NAFLD and diabetes depending on the etiology of obesity. Hepatocyte-specific ablation of FASN ameliorated NAFLD and diabetes in melanocortin 4 receptor-deficient mice but not in mice with diet-induced obesity. In leptin-deficient mice, FASN ablation alleviated hepatic steatosis and improved glucose tolerance but exacerbated fed hyperglycemia and liver dysfunction. The beneficial effects of hepatic FASN deficiency on NAFLD and glucose metabolism were associated with suppression of DNL and attenuation of gluconeogenesis and fatty acid oxidation, respectively. The exacerbation of fed hyperglycemia by FASN ablation in leptin-deficient mice appeared attributable to impairment of hepatic glucose uptake triggered by glycogen accumulation and citrate-mediated inhibition of glycolysis. Further investigation of the therapeutic potential of hepatic FASN inhibition for NAFLD and diabetes in humans should thus consider the etiology of obesity.

  Sep. 2023, JCI insight, 8(17) (17), English, International magazine

  Scientific journal


• Distinct hypoglycemic effect of different formulations of a fixed ratio of basal insulin plus glucagon-like peptide-1 receptor agonist in a patient with pancreatic diabetes.

  Tomoko Yamada, Shun-Ichiro Asahara, Maki Kimura-Koyanagi, Yoshikazu Tamori, Naokazu Muramae, Kenta Mori, Mitsumasa Okano, Kazunori Otsui, Kazuhiko Sakaguchi

  UNLABELLED: Fixed-ratio combination injection therapy (FRC) is a fixed-ratio mixture containing basal insulin and glucagon-like peptide-1 receptor agonist (GLP-1 RA) in a single injection for the treatment of patients with type 2 diabetes. The two types of FRC products contain different concentrations and mixing ratios of basal insulin and GLP-1 RA. Both products demonstrated satisfactory blood glucose control throughout the day, with less hypoglycemia and weight gain. However, few studies have examined the differences in the actions of the two formulations. Herein, we present a case of a 71-year-old man with pancreatic diabetes and significantly impaired intrinsic insulin secretion capacity, who demonstrated a marked difference in glycemic control following treatment with two different FRC formulations. Treatment with IDegLira, an FRC product, demonstrated suboptimal glucose control in the patient. However, after a change in therapy to another FRC product, IGlarLixi, his glucose control markedly improved, even with a decrease in the injection dose. This difference could have been due to lixisenatide, a short-acting GLP-1RA contained in IGlarLixi, which exerts a postprandial hypoglycemic effect irrespective of intrinsic insulin secretion capacity. In conclusion, IGlarLixi has the potential to achieve good fasting and postprandial glucose control with a once-daily injection, even in patients with type 2 diabetes who have a reduced intrinsic insulin secretion capacity. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13340-023-00621-5.

  Jul. 2023, Diabetology international, 14(3) (3), 294 - 297, English, Domestic magazine


• 膵β細胞におけるmTORC1活性化は膵外分泌細胞への分化を誘導する

  清家 雅子, 淺原 俊一郎, 木村 真希, 鈴木 宏隆, 横井 愛紗, 椎木 幾久子, 田部 勝也, 木戸 良明, 小川 渉

  (一社)日本糖尿病学会, Apr. 2023, 糖尿病, 66(Suppl.1) (Suppl.1), S - 186, Japanese


• A case of multiple glucagonomas with no clinical manifestations of excess glucagon despite hyperglucagonemia.

  Shogo Amano, Shigeyuki Suenaga, Kaori Hamamoto, Shoko Yada, Takanori Tsuyama, Shuhei Shinoda, Yuya Tanaka, Yoshihiro Takemoto, Eijiro Harada, Katsuya Tanabe, Shunichiro Asahara, Kazunobu Hoshii, Taro Takami

  Herein we report the case of a patient with multiple glucagonomas that have been precisely described with endoscopic ultrasound. A 36-year-old woman was referred to our hospital for computed tomography investigation of multiple pancreatic masses. Physical examination was unremarkable; on contrast-enhanced computed tomography, mass lesions were evident in the head, body, and tail of the pancreas. The mass in the pancreatic head was poorly demarcated and exhibited a faint contrast effect, the one in the pancreatic body was a cystic lesion, and the one in the pancreatic tail was hypervascular. Blood investigations showed that serum glucagon was abnormally high at 7670 pg/ml; glucose tolerance was not impaired. There was no family history that suggested multiple endocrine neoplasia type 1 or von Hippel-Lindau disease. Endoscopic ultrasound revealed that there were additional masses, which were scattered isoechoic to hyperechoic lesions a few millimeters in size. Ultrasound-guided fine needle biopsy of the lesion in the pancreatic tail resulted in a diagnosis of a neuroendocrine tumor. Based on these pathologic findings, we performed a total pancreatectomy. A large number of nodules with tumor cells were evident in all cut surfaces of the surgical specimen. Immunostaining was positive for chromogranin A and glucagon, and glucagonoma was therefore diagnosed. It is conceivable that attenuated glucagon action could have contributed to the development of the multiple glucagonomas.

  Apr. 2023, DEN open, 3(1) (1), e230, English, International magazine

  [Refereed]


• 膵β細胞におけるmTORC1活性化は膵外分泌細胞への分化を誘導する

  清家 雅子, 淺原 俊一郎, 木村 真希, 鈴木 宏隆, 横井 愛紗, 椎木 幾久子, 田部 勝也, 木戸 良明, 小川 渉

  (一社)日本糖尿病学会, Apr. 2023, 糖尿病, 66(Suppl.1) (Suppl.1), S - 186, Japanese


• 膵β細胞におけるmTORC1活性化が膵島可塑性に及ぼす影響の検討

  淺原 俊一郎, 清家 雅子, 横井 愛紗, 鈴木 宏隆, 椎木 幾久子, 田部 勝也, 木戸 良明, 小川 渉

  日本臨床分子医学会, Apr. 2023, 日本臨床分子医学会学術総会プログラム・抄録集, 58回, 53 - 53, Japanese


• Chlorogenic Acid and Caffeine in Coffee Restore Insulin Signaling in Pancreatic Beta Cells.

  Yuka Ihara, Shun-Ichiro Asahara, Hiroyuki Inoue, Masako Seike, Misaki Ando, Hiroki Kabutoya, Maki Kimura-Koyanagi, Yoshiaki Kido

  The incidence of type 2 diabetes is reported to be lower in frequent coffee drinkers than in non-coffee drinkers. To elucidate the mechanism by which coffee prevents the onset of type 2 diabetes, we analyzed how caffeine and chlorogenic acid, which are components of coffee, alter insulin signaling in MIN6 cells, a mouse pancreatic Β cell line. The results showed that caffeine improved insulin signaling under endoplasmic reticulum stress, and chlorogenic acid protected pancreatic Β cells by enhancing the expression of insulin receptor substrate 2 via cAMP response element-binding protein and promoting insulin signaling downstream of insulin receptor substrate 2. In addition, chlorogenic acid was a potent antioxidant for the protection of pancreatic Β cells. Furthermore, in vivo and in vitro analyses revealed that the pancreatic Β cell-protective effect of chlorogenic acid was mediated by the alleviation of endoplasmic reticulum stress. The results suggest that these components of coffee have the potential to reduce the pathogenesis of type 2 diabetes and improve pancreatic Β cell insufficiency.

  Mar. 2023, The Kobe journal of medical sciences, 69(1) (1), E1-E8, English, Domestic magazine

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• l-Asparaginase regulates mTORC1 activity via a TSC2-dependent pathway in pancreatic beta cells.

  Masako Seike, Shun-Ichiro Asahara, Hiroyuki Inoue, Michiyo Kudo, Ayumi Kanno, Aisha Yokoi, Hirotaka Suzuki, Maki Kimura-Koyanagi, Yoshiaki Kido, Wataru Ogawa

  Eif2ak4, a susceptibility gene for type 2 diabetes, encodes GCN2, a molecule activated by amino acid deficiency. Mutations or deletions in GCN2 in pancreatic β-cells increase mTORC1 activity by decreasing Sestrin2 expression in a TSC2-independent manner. In this study, we searched for molecules downstream of GCN2 that suppress mTORC1 activity in a TSC2-dependent manner. To do so, we used a pull-down assay to identify molecules that competitively inhibit the binding of the T1462 phosphorylation site of TSC2 to 14-3-3. l-asparaginase was identified. Although l-asparaginase is frequently used as an anticancer drug for acute lymphoblastic leukemia, little is known about endogenous l-asparaginase. l-Asparaginase, which is expressed downstream of GCN2, was found to bind 14-3-3 and thereby to inhibit its binding to the T1462 phosphorylation site of TSC2 and contribute to TSC2 activation and mTORC1 inactivation upon TSC2 dephosphorylation. Further investigation of the regulation of mTORC1 activity in pancreatic β-cells by l-asparaginase should help to elucidate the mechanism of diabetes and insulin secretion failure during anticancer drug use.

  Feb. 2023, Biochemical and biophysical research communications, 652, 121 - 130, English, International magazine

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Cyb5r3-based mechanism and reversal of secondary failure to sulfonylurea in diabetes.

  Hitoshi Watanabe, Wen Du, Jinsook Son, Lina Sui, Shun-Ichiro Asahara, Irwin J Kurland, Taiyi Kuo, Takumi Kitamoto, Yasutaka Miyachi, Rafael de Cabo, Domenico Accili

  Sulfonylureas (SUs) are effective and affordable antidiabetic drugs. However, chronic use leads to secondary failure, limiting their utilization. Here, we identify cytochrome b5 reductase 3 (Cyb5r3) down-regulation as a mechanism of secondary SU failure and successfully reverse it. Chronic exposure to SU lowered Cyb5r3 abundance and reduced islet glucose utilization in mice in vivo and in ex vivo murine islets. Cyb5r3 β cell-specific knockout mice phenocopied SU failure. Cyb5r3 engaged in a glucose-dependent interaction that stabilizes glucokinase (Gck) to maintain glucose utilization. Hence, Gck activators can circumvent Cyb5r3-dependent SU failure. A Cyb5r3 activator rescued secondary SU failure in mice in vivo and restored insulin secretion in ex vivo human islets. We conclude that Cyb5r3 is a key factor in the secondary failure to SU and a potential target for its prevention, which might rehabilitate SU use in diabetes.

  Feb. 2023, Science translational medicine, 15(681) (681), eabq4126, English, International magazine

  Scientific journal


• The transcription factor ATF3 switches cell death from apoptosis to necroptosis in hepatic steatosis in male mice

  Yuka Inaba, Emi Hashiuchi, Hitoshi Watanabe, Kumi Kimura, Yu Oshima, Kohsuke Tsuchiya, Shin Murai, Chiaki Takahashi, Michihiro Matsumoto, Shigetaka Kitajima, Yasuhiko Yamamoto, Masao Honda, Shun-ichiro Asahara, Kim Ravnskjaer, Shin-ichi Horike, Shuichi Kaneko, Masato Kasuga, Hiroyasu Nakano, Kenichi Harada, Hiroshi Inoue

  Abstract Hepatocellular death increases with hepatic steatosis aggravation, although its regulation remains unclear. Here we show that hepatic steatosis aggravation shifts the hepatocellular death mode from apoptosis to necroptosis, causing increased hepatocellular death. Our results reveal that the transcription factor ATF3 acts as a master regulator in this shift by inducing expression of RIPK3, a regulator of necroptosis. In severe hepatic steatosis, after partial hepatectomy, hepatic ATF3-deficient or -overexpressing mice display decreased or increased RIPK3 expression and necroptosis, respectively. In cultured hepatocytes, ATF3 changes TNFα-dependent cell death mode from apoptosis to necroptosis, as revealed by live-cell imaging. In non-alcoholic steatohepatitis (NASH) mice, hepatic ATF3 deficiency suppresses RIPK3 expression and hepatocellular death. In human NASH, hepatocellular damage is correlated with the frequency of hepatocytes expressing ATF3 or RIPK3, which overlap frequently. ATF3-dependent RIPK3 induction, causing a modal shift of hepatocellular death, can be a therapeutic target for steatosis-induced liver damage, including NASH.

  Springer Science and Business Media LLC, Jan. 2023, Nature Communications, 14(1) (1), English

  [Refereed]

  Scientific journal


• Roles of mTOR in the Regulation of Pancreatic β-Cell Mass and Insulin Secretion.

  Shun-Ichiro Asahara, Hiroyuki Inoue, Hitoshi Watanabe, Yoshiaki Kido

  Pancreatic β-cells are the only type of cells that can control glycemic levels via insulin secretion. Thus, to explore the mechanisms underlying pancreatic β-cell failure, many reports have clarified the roles of important molecules, such as the mechanistic target of rapamycin (mTOR), which is a central regulator of metabolic and nutrient cues. Studies have uncovered the roles of mTOR in the function of β-cells and the progression of diabetes, and they suggest that mTOR has both positive and negative effects on pancreatic β-cells in the development of diabetes.

  Apr. 2022, Biomolecules, 12(5) (5), English, International magazine

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• 膵β細胞におけるmTORC1恒常的活性化と膵島可塑性の関連についての検討

  清家 雅子, 淺原 俊一郎, 伊東 春香, 木村 真希, 鈴木 宏隆, 横井 愛紗, 神野 歩, 木戸 良明, 小川 渉

  (一社)日本糖尿病学会, Apr. 2022, 糖尿病, 65(Suppl.1) (Suppl.1), S - 217, Japanese


• Regulation of Pancreatic β-Cell Mass by Gene-Environment Interaction.

  Shun-Ichiro Asahara, Hiroyuki Inoue, Yoshiaki Kido

  The main pathogenic mechanism of diabetes consists of an increase in insulin resistance and a decrease in insulin secretion from pancreatic β-cells. The number of diabetic patients has been increasing dramatically worldwide, especially in Asian people whose capacity for insulin secretion is inherently lower than that of other ethnic populations. Causally, changes of environmental factors in addition to intrinsic genetic factors have been considered to have an influence on the increased prevalence of diabetes. Particular focus has been placed on "gene-environment interactions" in the development of a reduced pancreatic β-cell mass, as well as type 1 and type 2 diabetes mellitus. Changes in the intrauterine environment, such as intrauterine growth restriction, contribute to alterations of gene expression in pancreatic β-cells, ultimately resulting in the development of pancreatic β-cell failure and diabetes. As a molecular mechanism underlying the effect of the intrauterine environment, epigenetic modifications have been widely investigated. The association of diabetes susceptibility genes or dietary habits with gene-environment interactions has been reported. In this review, we provide an overview of the role of gene-environment interactions in pancreatic β-cell failure as revealed by previous reports and data from experiments.

  Jan. 2022, Diabetes & metabolism journal, 46(1) (1), 38 - 48, English, International magazine

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Oral administration of D-serine prevents the onset and progression of colitis in mice.

  Takehito Asakawa, Michio Onizawa, Chikako Saito, Rie Hikichi, Daiki Yamada, Ai Minamidate, Tomoaki Mochimaru, Shun-Ichiro Asahara, Yoshiaki Kido, Shigeru Oshima, Takashi Nagaishi, Kiichiro Tsuchiya, Hiromasa Ohira, Ryuichi Okamoto, Mamoru Watanabe

  BACKGROUND: L-amino acids are the predominant forms of organic molecules on the planet, but recent studies have revealed that various foods contain D-amino acids, the enantiomers of L-amino acids. Though diet plays important roles in both the development and progression of inflammatory bowel disease (IBD), to our best knowledge, there has been no report on any potential interactions between D-amino acids and IBD. In this report, we aim to assess the effects of D-serine in a murine model of IBD. MATERIALS AND METHODS: To induce chronic colitis, naïve CD4 T cells (CD4+ CD62+ CD44low) from wild-type mice were adoptively transferred into Rag2-/- mice, after or before the mice were orally administered with D-serine. In vitro proliferation assays were performed to assess naïve CD4 T cell activation under the Th-skewing conditions in the presence of D-serine. RESULTS: Mice treated with D-serine prior to the induction of colitis exhibited a reduction in T-cell infiltration into the lamina propria and colonic inflammation that were not seen in mice fed with water alone or L-serine. Moreover, D-serine suppressed the progression of chronic colitis when administered after the disease induction. Under in vitro conditions, D-serine suppressed the proliferation of activated CD4 T cells and limited their ability to differentiate to Th1 and Th17 cells. CONCLUSION: Our results suggest that D-serine not only can prevent, but also has efficacious effects as a treatment for IBD.

  Aug. 2021, Journal of gastroenterology, 56(8) (8), 732 - 745, English, Domestic magazine

  Scientific journal


• Patch-seq shows the heterogeneity of pancreatic islet cells.

  Shun-Ichiro Asahara

  In 2016, Patch-seq was established to analyze electrophysiology, gene expression and morphology in neuronal cells. Recently, Camunas-Soler et al. used Patch-seq to analyze the functions and gene expression profiles of individual cells in pancreatic islets. I believe this analysis is expected to contribute to the complete characterization of pancreatic islets in diabetes patients.

  May 2021, Journal of diabetes investigation, 12(5) (5), 691 - 693, English, Domestic magazine

  Scientific journal


• Glutamate is an essential mediator in glutamine-amplified insulin secretion.

  Guirong Han, Harumi Takahashi, Naoya Murao, Ghupurjan Gheni, Norihide Yokoi, Yoshiyuki Hamamoto, Shun-Ichiro Asahara, Yutaka Seino, Yoshiaki Kido, Susumu Seino

  AIMS/INTRODUCTION: Glutamine is the most abundant amino acid in the circulation. In this study, we investigated cell signaling in the amplification of insulin secretion by glutamine. MATERIALS AND METHODS: Clonal pancreatic β-cells MIN6-K8, wild-type B6 mouse islets, glutamate dehydrogenase (GDH) knockout clonal β-cells (Glud1KOβCL), and glutamate-oxaloacetate transaminase 1 (GOT1) knockout clonal β-cells (Got1KOβCL) were studied. Insulin secretion from these cells and islets was examined under various conditions, and intracellular glutamine metabolism was assessed by metabolic flux analysis. Intracellular Ca2+ concentration ([Ca2+ ]i ) was also measured. RESULTS: Glutamine dose-dependently amplified insulin secretion in the presence of high glucose in both MIN6-K8 cells and Glud1KOβCL. Inhibition of glutaminases, the enzymes that convert glutamine to glutamate, dramatically reduced the glutamine-amplifying effect on insulin secretion. A substantial amount of glutamate was produced from glutamine through direct conversion by glutaminases. Glutamine also increased [Ca2+ ]i at high glucose, which was abolished by inhibition of glutaminases. Glutamic acid dimethylester (dm-Glu), a membrane permeable glutamate precursor that is converted to glutamate in cells, increased [Ca2+ ]i as well as induced insulin secretion at high glucose. These effects of glutamine and dm-Glu were dependent on calcium influx. Glutamine also induced insulin secretion in clonal β-cells MIN6-m14, which otherwise exhibit no insulin secretory response to glucose. CONCLUSIONS: Glutamate converted from glutamine is an essential mediator that enhances calcium signaling in the glutamine-amplifying effect on insulin secretion. Our data also suggest that glutamine exerts a permissive effect on glucose-induced insulin secretion.

  Jan. 2021, Journal of diabetes investigation, 12(6) (6), 920 - 930, English, Domestic magazine

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Histone deacetylase 6 regulates insulin signaling in pancreatic β cells

  Hiroyuki Inoue, Shun-ichiro Asahara, Yumiko Sugiura, Yukina Kawada, Asuka Imai, Chisako Hara, Ayumi Kanno, Maki Kimura-Koyanagi, Yoshiaki Kido

  Elsevier BV, Nov. 2020, Biochemical and Biophysical Research Communications

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• GCN2 regulates pancreatic β cell mass by sensing intracellular amino acid levels.

  Ayumi Kanno, Shun-Ichiro Asahara, Ayuko Furubayashi, Katsuhisa Masuda, Risa Yoshitomi, Emi Suzuki, Tomoko Takai, Maki Kimura-Koyanagi, Tomokazu Matsuda, Alberto Bartolome, Yushi Hirota, Norihide Yokoi, Yuka Inaba, Hiroshi Inoue, Michihiro Matsumoto, Kenichi Inoue, Takaya Abe, Fan-Yan Wei, Kazuhito Tomizawa, Wataru Ogawa, Susumu Seino, Masato Kasuga, Yoshiaki Kido

  EIF2AK4, which encodes the amino acid deficiency-sensing protein GCN2, has been implicated as a susceptibility gene for type 2 diabetes in the Japanese population. However, the mechanism by which GCN2 affects glucose homeostasis is unclear. Here, we show that insulin secretion is reduced in individuals harboring the risk allele of EIF2AK4 and that maintenance of GCN2-deficient mice on a high-fat diet results in a loss of pancreatic β cell mass. Our data suggest that GCN2 senses amino acid deficiency in β cells and limits signaling by mechanistic target of rapamycin complex 1 to prevent β cell failure during the consumption of a high-fat diet.

  May 2020, JCI insight, 5(9) (9), English, International magazine

  [Refereed]

  Scientific journal


• CK2活性化は膵β細胞において小胞体ストレスを改善する

  高井 智子, 松田 友和, 清家 雅子, 淺原 俊一郎, 木村 真希, 生城 浩子, 矢野 貴人, 小林 憲太, 小川 渉, 木戸 良明

  日本臨床分子医学会, Apr. 2020, 日本臨床分子医学会学術総会プログラム・抄録集, 57回, 76 - 76, Japanese


• En face slab optical coherence tomography imaging successfully monitors progressive degenerative changes in the innermost layer of the diabetic retina.

  Atsuko Katsuyama, Sentaro Kusuhara, Shun-Ichiro Asahara, Shun-Ichiro Nakai, Sotaro Mori, Wataru Matsumiya, Akiko Miki, Takuji Kurimoto, Hisanori Imai, Yoshiaki Kido, Wataru Ogawa, Makoto Nakamura

  OBJECTIVE: To evaluate the usefulness of en face slab optical coherence tomography (OCT) imaging for monitoring diabetic retinal neurodegeneration with supporting animal experimental data. RESEARCH DESIGN AND METHODS: We retrospectively examined 72 diabetic eyes over 3 years using Cirrus-HD OCT. Two-dimensional en face slab OCT images of the innermost retina were reconstructed and graded according to the ratio of dark area to total area, and relative red, green, and blue color area ratios were calculated and used as indexes for each en face slab OCT image. Values from en face OCT images were used for statistical analyses. To obtain insight into the pathogenesis of diabetic retinal neurodegeneration, we used the InsPr-Cre;Pdk1flox/flox diabetic mouse model. RESULTS: Both OCT grade and relative red color area ratio significantly increased with the advancing stage of diabetic retinopathy (p=0.018 and 0.006, respectively). After a mean follow-up period of 4.6 years, the trend was unchanged in the analyses of 42 untreated eyes (p<0.001 and 0.001, respectively). Visual acuity showed a weak but significant negative correlation with the red color ratio on en face slab OCT images, but central retinal thickness did not exhibit a clinically meaningful correlation with values obtained from en face slab OCT images. Immunohistochemical analyses of InsPr-Cre;Pdk1flox/flox diabetic mice demonstrated the loss of ganglion axon bundles and thinning of laminin without apparent retinal vascular change at the age of 20 weeks. CONCLUSIONS: En face slab OCT imaging would be a novel useful modality for the assessment of diabetic retinal neurodegeneration as it could detect subtle optical changes occurring in the innermost retina in diabetic eyes. Our animal experimental data suggest that dark areas observed on en face slab OCT images might be the impairment of the extracellular matrix as well as neurons.

  Mar. 2020, BMJ open diabetes research & care, 8(1) (1), English, International magazine

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Sex difference in the association of obesity with personal or social background among urban residents in Japan.

  Shun-Ichiro Asahara, Hiroshi Miura, Wataru Ogawa, Yoshikazu Tamori

  The development of obesity is influenced by genetic and environmental factors and is associated with a variety of health problems. To gain insight into environmental factors that contribute to obesity, we analyzed the relation of personal or social background to obesity in men and women separately with the use of data from a community-based questionnaire survey of 5425 residents aged 20 to 64 years of Kobe, a representative large city in Japan. Obesity and normal weight were defined as a body mass index (BMI) of ≥25 and of ≥ 18.5 and < 25 kg/m2, respectively, according to the diagnostic criteria of the Japan Society for the Study of Obesity. The personal or social background factors examined included marital status, family structure, employment, household income, residence type, welfare enrollment, economic conditions of current life, educational level, extracurricular activity in school, living conditions at 15 years of age, and childhood adversity. We found that the prevalence of obesity was 27.2% and 10.6% in men and women, respectively. Among women, unmarried status, a low household income, welfare enrollment, difficult current economic conditions, a low educational level, and childhood adversity were associated with obesity, whereas none of the personal or social background factors examined were associated with obesity in men. Our results suggest that the development of obesity in women is strongly influenced by personal or social background, and such factors should be taken into consideration in the management of this condition in women.

  2020, PloS one, 15(11) (11), e0242105, English, International magazine

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Association between mean platelet volume in the pathogenesis of type 2 diabetes mellitus and diabetic macrovascular complications in Japanese patients.

  Hiroyuki Inoue, Mayumi Saito, Kumiko Kouchi, Shun-Ichiro Asahara, Fumihiko Nakamura, Yoshiaki Kido

  AIMS/INTRODUCTION: Mean platelet volume (MPV) is a widely used biological marker of platelet function and activity. Increased MPV is associated with accelerated thrombopoiesis and an elevated risk of cardiovascular disease. However, it is not known whether higher MPV is related to the pathogenesis of type 2 diabetes and diabetic macrovascular complications in Japanese patients. Therefore, we analyzed MPV and its correlation with atherosclerosis in Japanese patients with type 2 diabetes and those who had prediabetes. MATERIALS AND METHODS: We divided the patients into three groups: normoglycemic patients (n = 56), prediabetes patients (n = 44) and type 2 diabetes patients group, (n = 115). We measured platelet parameters and evaluated arterial stiffness in the three groups. RESULTS: Significantly higher MPV was found in the type 2 diabetes mellitus and prediabetes patients compared with normoglycemic patients. MPV was significantly correlated with fasting blood glucose and glycated hemoglobin levels. Multiple linear regression analysis showed that MPV was positively correlated with HbA1c, even after adjustment for confounding factors. In the evaluation of arterial stiffness by measuring the cardio-ankle vascular index and maximum intima-media thickness, MPV showed a positive correlation with these parameters. CONCLUSIONS: These findings suggest that MPV was significantly increased in the early stage of type 2 diabetes. We showed positive correlations between MPV and HbA1c levels, and between MPV and arterial stiffness in Japanese patients with type 2 diabetes.

  Dec. 2019, Journal of diabetes investigation, English, Domestic magazine

  [Refereed]

  Link to Kobe Univ. Repository (Kernel)


• 造血幹細胞移植10年後に部分性脂肪萎縮症を発症したと考えられた1例

  淺原 俊一郎, 穂積 かおり, 廣田 勇士, 山本 雅昭, 福岡 秀規, 小川 渉

  (一社)日本肥満学会, Oct. 2019, 肥満研究, 25(Suppl.) (Suppl.), 312 - 312, Japanese

  [Refereed]


• Early administration of dapagliflozin preserves pancreatic beta cell mass through a legacy effect in type 2 diabetic mice.

  Kanno A, Asahara S, Kawamura M, Suzuki E, Takai T, Kimura-Koyanagi M, Matsuda T, Okada Y, Ogawa W, KIDO YOSHIAKI

  AIMS/INTRODUCTION: The preservation of pancreatic β-cell mass is an essential factor in the onset and development of type 2 diabetes mellitus. Recently, sodium-glucose cotransporter 2 inhibitors have been launched as antihyperglycemic agents, and their organ-protective effects are attracting attention. They are also reported to have favorable effects on the preservation of pancreatic β-cell mass, but the appropriate timing for the administration of sodium-glucose cotransporter 2 inhibitors is obscure. MATERIALS AND METHODS: In the present study, we administered a sodium-glucose cotransporter 2 inhibitor, dapagliflozin, to an animal model of type 2 diabetes mellitus, db/db mice, and investigated the adequate timing and duration for its administration. We also carried out microarray analysis using pancreatic islets from db/db mice. RESULTS: We found that dapagliflozin preserved pancreatic β-cell mass depending on the duration of administration and markedly improved blood glucose levels. If the duration was the same, the earlier administration of dapagliflozin was more effective in preserving pancreatic β-cell mass, increasing serum insulin levels and improving blood glucose levels. From microarray analysis, we discovered that the expression of Agr2, Tff2 and Gkn3 was significantly upregulated after the early administration of dapagliflozin. This upregulated gene expression might provide a legacy effect for the preservation of pancreatic β-cell mass. CONCLUSIONS: We expect that the early administration of dapagliflozin would provide a long-lasting effect in preserving pancreatic β-cell mass.

  May 2019, J. Diab. Invest., 10(3) (3), 577 - 590, English, Domestic magazine

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• 膵β細胞の小胞体ストレス誘導性アポトーシスにおけるCK2βの役割

  高井 智子, 松田 友和, 井上 佳歩, 淺原 俊一郎, 神野 歩, 木村 真希, 小川 渉, 木戸 良明

  日本臨床分子医学会, Apr. 2019, 日本臨床分子医学会学術総会プログラム・抄録集, 56回, 65 - 65, Japanese


• 膵β細胞特異的TSC2ノックアウトマウスにおける膵β細胞不全発症機序の解明

  伊東 春香, 淺原 俊一郎, 原 千佐子, 木村 真希, 神野 歩, 高井 智子, 木戸 良明

  (一社)日本糖尿病学会, Apr. 2019, 糖尿病, 62(Suppl.1) (Suppl.1), S - 257, Japanese


• 2型糖尿病の病態把握におけるMPV(平均血小板容積)の有用性に関する検討

  井上 裕行, 斉藤 真裕美, 胡内 久美子, 淺原 俊一郎, 木戸 良明, 中村 文彦

  (一社)日本糖尿病学会, Apr. 2019, 糖尿病, 62(Suppl.1) (Suppl.1), S - 112, Japanese


• PHD3 regulates glucose metabolism by suppressing stress-induced signalling and optimising gluconeogenesis and insulin signalling in hepatocytes

  Yano H, Sakai M, Matsukawa T, Yagi T, Naganuma T, Mitsushima M, Iida S, Inaba Y, Inoue H, Unoki-Kubota H, Kaburagi Y, Asahara Shunichirou, Kido Y, Minami S, Kasuga M, Matsumoto M

  Glucagon-mediated gene transcription in the liver is critical for maintaining glucose homeostasis. Promoting the induction of gluconeogenic genes and blocking that of insulin receptor substrate (Irs)2 in hepatocytes contributes to the pathogenesis of type 2 diabetes. However, the molecular mechanism by which glucagon signalling regulates hepatocyte metabolism is not fully understood. We previously showed that a fasting-inducible signalling module consisting of general control non-repressed protein 5, co-regulator cAMP response element-binding protein binding protein/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2, and protein kinase A is required for glucagon-induced transcription of gluconeogenic genes. The present study aimed to identify the downstream effectors of this module in hepatocytes by examining glucagon-induced potential target genes. One of these genes was prolyl hydroxylase domain (PHD)3, which suppressed stress signalling through inhibition of the IκB kinase-nuclear factor-κB pathway in a proline hydroxylase-independent manner to maintain insulin signalling. PHD3 was also required for peroxisome proliferator-activated receptor γ coactivator 1α-induced gluconeogenesis, which was dependent on proline hydroxylase activity, suggesting that PHD3 regulates metabolism in response to glucagon as well as insulin. These findings demonstrate that glucagon-inducible PHD3 regulates glucose metabolism by suppressing stress signalling and optimising gluconeogenesis and insulin signalling in hepatocytes.

  Sep. 2018, Sci Rep, 8(1) (1), 14290 - 14290, English, International magazine

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Docosahexaenoic Acid Reduces Palmitic Acid-Induced Endoplasmic Reticulum Stress in Pancreatic Β Cells

  Suzuki E, Matsuda T, Kawamoto T, Takahashi H, Mieda Y, Matsuura Y, Takai T, Kanno A, Koyanagi-Kimura M, Asahara Shunichirou, Inoue H, Ogawa Wataru, Kido Y

  Endoplasmic reticulum (ER) stress leads to peripheral insulin resistance and the progression of pancreatic beta cell failure in type 2 diabetes. Although ER stress plays an important role in the pathogenesis of diabetes, it is indispensable for cellular activity. Therefore, when assessing the pathological significance of ER stress, it is important to monitor and quantify ER stress levels. Here, we have established a novel system to monitor ER stress levels quickly and sensitively, and using this method, we have clarified the effect of differences in glucose concentration and various fatty acids on the ER of pancreatic β cells. First, we developed a cell system that secretes Gaussia luciferase in culture medium depending on the activation of the GRP78 promoter. This system could sensitively monitor ER stress levels that could not be detected with real-time RT-PCR and immunoblotting. This system revealed that hyperglycemia does not induce unfolded protein response (UPR) in a short period of time in MIN6 cells, a mouse pancreatic β cell line. Physiological concentrations of palmitic acid, a saturated fatty acid, induced ER stress quickly, while physiological concentrations of oleic acid, an unsaturated fatty acid, did not. Docosahexaenoic acid, an n-3 unsaturated fatty acid, inhibited palmitic acid-induced ER stress. In this study, we have established a system that can sensitively detect ER stress levels of living cells in a short period of time. This system can be used to monitor the state of the ER in living cells and lead to the investigation of the significance of physiological or pathological ER stress levels.

  Sep. 2018, Kobe J Med Sci, 64(2) (2), E43 - E55, English, Domestic magazine

  [Refereed]

  Research institution

  Link to Kobe Univ. Repository (Kernel)


• 2型糖尿病感受性遺伝子GCN2はSestrin2を介して膵β細胞量の調節に関与する

  古林 鮎子, 神野 歩, 淺原 俊一郎, 松田 友和, 木村 真希, 木戸 良明

  (一社)日本内分泌学会, Apr. 2018, 日本内分泌学会雑誌, 94(1) (1), 323 - 323, Japanese


• 2型糖尿病に対する新規分子標的治療薬の確立

  松田 友和, 高井 智子, 鈴木 江美, 神野 歩, 木村 真希, 淺原 俊一郎, 小川 渉, 木戸 良明

  (一社)日本糖尿病学会, Apr. 2018, 糖尿病, 61(Suppl.1) (Suppl.1), S - 133, Japanese


• 膵β細胞の小胞体ストレス誘導性アポトーシスにおけるCK2βの役割

  高井 智子, 松田 友和, 井上 佳歩, 鈴木 江美, 木村 真希, 淺原 俊一郎, 小川 渉, 木戸 良明

  (一社)日本糖尿病学会, Apr. 2018, 糖尿病, 61(Suppl.1) (Suppl.1), S - 261, Japanese


• ヒトiPS細胞を用いた膵内分泌細胞への分化誘導

  山田 瑞姫, 淺原 俊一郎, 下野 名奈子, 原 瑞季, 松田 友和, 高井 智子, 鈴木 江美, 木村 真希, 神野 歩, 青井 貴之, 木戸 良明

  (一社)日本糖尿病学会, Apr. 2018, 糖尿病, 61(Suppl.1) (Suppl.1), S - 386, Japanese


• Casein kinase 2 phosphorylates and stabilizes C/EBPβ in pancreatic β cells

  Tomoko Takai, Tomokazu Matsuda, Yuki Matsuura, Kaho Inoue, Emi Suzuki, Ayumi Kanno, Maki Kimura-Koyanagi, Shun-ichiro Asahara, Naoya Hatano, Wataru Ogawa, Yoshiaki Kido

  During the development of type 2 diabetes, endoplasmic reticulum (ER) stress leads to pancreatic β cell failure. CCAAT/enhancer-binding protein (C/EBP) β is highly induced by ER stress and AMP-activated protein kinase (AMPK) suppression in pancreatic β cells, and its accumulation reduces pancreatic β cell mass. We investigated the phosphorylation state of C/EBPβ under these conditions. Casein kinase 2 (CK2) was found to co-localize with C/EBPβ in MIN6 cells. It phosphorylated S222 of C/EBPβ a previously unidentified phosphorylation site. We found that C/EBPβ is phosphorylated by CK2 under AMPK suppression and ER stress, which are important from the viewpoint of the worsening pathological condition of type 2 diabetes, such as decreased insulin secretion and apoptosis of pancreatic β cells.

  Elsevier B.V., Feb. 2018, Biochemical and Biophysical Research Communications, 497(1) (1), 451 - 456, English

  [Refereed]

  Scientific journal


• 膵β細胞の小胞体ストレス誘導性アポトーシスにおけるCK2βの役割

  井上 佳歩, 高井 智子, 松田 友和, 鈴木 江美, 神野 歩, 木村 真希, 淺原 俊一郎, 木戸 良明

  生命科学系学会合同年次大会運営事務局, Dec. 2017, 生命科学系学会合同年次大会, 2017年度, [1P - 1157], Japanese


• 高脂肪食負荷GCN2欠損マウスの膵島におけるmTORC1シグナル調節機構の解明

  古林 鮎子, 神野 歩, 増田 勝久, 吉冨 理紗, 木村 真希, 松田 友和, 淺原 俊一郎, 木戸 良明

  生命科学系学会合同年次大会運営事務局, Dec. 2017, 生命科学系学会合同年次大会, 2017年度, [2P - 0995], Japanese


• ヒトiPS細胞を用いた膵内分泌細胞への分化誘導法の確立

  山田 瑞姫, 淺原 俊一郎, 下野 名奈子, 田中 孝一, 松田 友和, 木村 真希, 神野 歩, 高井 智子, 鈴木 江美, 青井 貴之, 木戸 良明

  生命科学系学会合同年次大会運営事務局, Dec. 2017, 生命科学系学会合同年次大会, 2017年度, [3P - 0838], Japanese


• MTORC1 Regulates both General Autophagy and Mitophagy Induction after Oxidative Phosphorylation Uncoupling

  Alberto Bartolome, Ana Garcia-Aguilar, Shun-Ichiro Asahara, Yoshiaki Kido, Carlos Guillen, Utpal B. Pajvani, Manuel Benito

  Mechanistic target of rapamycin complex 1 (MTORC1) is a critical negative regulator of general autophagy. We hypothesized that MTORC1 may specifically regulate autophagic clearance of damaged mitochondria. To test this, we used cells lacking tuberous sclerosis complex 2 (TSC2(-/-) cells), which show constitutive MTORC1 activation. TSC2(-/-) cells show MTORC1-dependent impaired autophagic flux after chemical uncoupling of mitochondria, increased mitochondrial-protein aging, and accumulation of p62/SQSTM1-positive mitochondria. Mitochondrial autophagy (mitophagy) was also deficient in cells lacking TSC2, associated with altered expression of PTEN-induced putative kinase 1 (PINK1) and PARK2 translocation to uncoupled mitochondria, all of which were recovered by MTORC1 inhibition or expression of constitutively active forkhead box protein O1 (FoxO1). These data prove the necessity of intact MTORC1 signaling to regulate two synergistic processes required for clearance of damaged mitochondria: (i) general autophagy initiation and (ii) PINK1/PARK2-mediated selective targeting of uncoupled mitochondria to the autophagic machinery.

  AMER SOC MICROBIOLOGY, Dec. 2017, MOLECULAR AND CELLULAR BIOLOGY, 37(23) (23), English

  [Refereed]

  Scientific journal


• Histone deacetylase regulates insulin signaling via two pathways in pancreatic beta cells

  Yukina Kawada, Shun-ichiro Asahara, Yumiko Sugiura, Ayaka Sato, Ayuko Furubayashi, Mao Kawamura, Alberto Bartolome, Emi Terashi-Suzuki, Tomoko Takai, Ayumi Kanno, Maki Koyanagi-Kimura, Tomokazu Matsuda, Naoko Hashimoto, Yoshiaki Kido

  Recent studies demonstrated that insulin signaling plays important roles in the regulation of pancreatic beta cell mass, the reduction of which is known to be involved in the development of diabetes. However, the mechanism underlying the alteration of insulin signaling in pancreatic beta cells remains unclear. The involvement of epigenetic control in the onset of diabetes has also been reported. Thus, we analyzed the epigenetic control of insulin receptor substrate 2 (IRS2) expression in the MIN6 mouse insulinoma cell line. We found concomitant IRS2 up-regulation and enhanced insulin signaling in MIN6 cells, which resulted in an increase in cell proliferation. The H3K9 acetylation status of the Irs2 promoter was positively associated with IRS2 expression. Treatment of MIN6 cells with histone deacetylase inhibitors led to increased IRS2 expression, but this occurred in concert with low insulin signaling. We observed increased IRS2 lysine acetylation as a consequence of histone deacetylase inhibition, a modification that was coupled with a decrease in IRS2 tyrosine phosphorylation. These results suggest that insulin signaling in pancreatic beta cells is regulated by histone dea-cetylases through two novel pathways affecting IRS2: the epigenetic control of IRS2 expression by H3K9 promoter acetylation, and the regulation of IRS2 activity through protein modification. The identification of the histone deacetylase isoform(s) involved in these mechanisms would be a valuable approach for the treatment of type 2 diabetes.

  PUBLIC LIBRARY SCIENCE, Sep. 2017, PLOS ONE, 12(9) (9), e0184435, English

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• 膵β細胞の小胞体ストレス誘導性アポトーシスにおけるCK2βの役割

  高井 智子, 松田 友和, 井上 佳歩, 松浦 有希, 鈴木 江美, 神野 歩, 木村 真希, 淺原 俊一郎, 小川 渉, 木戸 良明

  (一社)日本糖尿病学会, Apr. 2017, 糖尿病, 60(Suppl.1) (Suppl.1), S - 464, Japanese


• 脂肪酸が膵β細胞の小胞体に及ぼす影響

  鈴木 江美, 松田 友和, 川本 剛士, 松浦 有希, 高井 智子, 神野 歩, 木村 真希, 淺原 俊一郎, 小川 渉, 木戸 良明

  (一社)日本糖尿病学会, Apr. 2017, 糖尿病, 60(Suppl.1) (Suppl.1), S - 464, Japanese


• ヒトiPS細胞を用いた2型糖尿病発症機序の解明

  下野 名奈子, 淺原 俊一郎, 原 瑞季, 田中 孝一, 松田 友和, 木村 真希, 神野 歩, 高井 智子, 鈴木 江美, 青井 貴之, 木戸 良明

  (一社)日本糖尿病学会, Apr. 2017, 糖尿病, 60(Suppl.1) (Suppl.1), S - 465, Japanese


• 2型糖尿病の病態把握におけるMPV(平均血小板容積)の有用性に関する検討

  井上 裕行, 斉藤 真裕美, 胡内 久美子, 吉村 豊, 石田 英和, 中谷 敏也, 淺原 俊一郎, 木戸 良明, 菊池 英亮

  (一社)日本糖尿病学会, Apr. 2017, 糖尿病, 60(Suppl.1) (Suppl.1), S - 141, Japanese


• Dietary Mung Bean Protein Reduces Hepatic Steatosis, Fibrosis, and Inflammation in Male Mice with Diet-Induced, Nonalcoholic Fatty Liver Disease

  Hitoshi Watanabe, Yuka Inaba, Kumi Kimura, Shun-ichiro Asahara, Yoshiaki Kido, Michihiro Matsumoto, Takayasu Motoyama, Nobuhiko Tachibana, Shuichi Kaneko, Mitsutaka Kohno, Hiroshi Inoue

  Background: As the prevalence of nonalcoholic fatty liver disease (NAFLD), including steatosis and nonalcoholic steatohepatitis, is increasing, novel dietary approaches are required for the prevention and treatment of NAFLD. Objective: We evaluated the potential of mung bean protein isolate (MuPI) to prevent NAFLD progression. Methods: In Expts. 1 and 2, the hepatic triglyceride (TG) concentration was compared between 8-wk-old male mice fed a high-fat diet (61% of energy from fat) containing casein, MuPI, and soy protein isolate and an MuPI-constituent amino acid mixture as a source of amino acids (18% of energy) for 4 wk. In Expt. 3, hepatic fatty acid synthase (Fasn) expression was evaluated in 8-wk-old male Fasn-promoter-reporter mice fed a casein- or MuPI-containing high-fat diet for 20 wk. In Expt. 4, hepatic fibrosis was examined in 8-wk-old male mice fed an atherogenic diet (61 % of energy from fat, containing 1.3 g cholesterol/100 g diet) containing casein or MuPI (18% of energy) as a protein source for 20 wk. Results: In the high fat-diet mice, the hepatic TG concentration in the MuPI group decreased by 66% and 47% in Expt. 1 compared with the casein group (P < 0.001) and the soy protein isolate group (P = 0.001), respectively, and decreased by 56% in Expt. 2 compared with the casein group (P = 0.011). However, there was no difference between the MuPI-constituent amino acid mixture and casein groups in Expt. 2. In Expt. 3, Fasn-promoter-reporter activity and hepatic TG concentration were lower in the MuPI group than in those fed casein (P < 0.05). In Expt. 4, in mice fed an atherogenic diet, hepatic fibrosis was not induced in the MuPI group, whereas it developed overtly in the casein group. Conclusion: MuPI potently reduced hepatic lipid accumulation in mice and may be a potential foodstuff to prevent NAFLD onset and progression.

  AMER SOC NUTRITION-ASN, Jan. 2017, JOURNAL OF NUTRITION, 147(1) (1), 52 - 60, English

  [Refereed]

  Scientific journal


• 2型糖尿病感受性遺伝子GCN2は膵β細胞量の調節に関与する

  神野 歩, 増田 勝久, 淺原 俊一郎, 松田 友和, 木村 真希, 廣田 勇士, 横井 伯英, 小川 渉, 清野 進, 春日 雅人, 木戸 良明

  (一社)日本内分泌学会, Apr. 2016, 日本内分泌学会雑誌, 92(1) (1), 242 - 242, Japanese


• 膵β細胞不全関連分子CEBP/βの安定化に対するcasein kinase 2の役割

  高井 智子, 松田 友和, 松浦 有希, 川本 剛士, 淺原 俊一郎, 木村 真希, 神野 歩, 鈴木 江美, 小川 渉, 木戸 良明

  (一社)日本糖尿病学会, Apr. 2016, 糖尿病, 59(Suppl.1) (Suppl.1), S - 158, Japanese


• 生物発光イメージング法による生存細胞内小胞体ストレスの定量化

  鈴木 江美, 松田 友和, 川本 剛士, 松浦 有希, 高井 智子, 神野 歩, 木村 真希, 淺原 俊一郎, 小川 渉, 木戸 良明

  (一社)日本糖尿病学会, Apr. 2016, 糖尿病, 59(Suppl.1) (Suppl.1), S - 353, Japanese


• Central Insulin Action Activates Kupffer Cells by Suppressing Hepatic Vagal Activation via the Nicotinic Alpha 7 Acetylcholine Receptor

  Kumi Kimura, Mamoru Tanida, Naoto Nagata, Yuka Inaba, Hitoshi Watanabe, Mayumi Nagashimada, Tsuguhito Ota, Shun-ichiro Asahara, Yoshiaki Kido, Michihiro Matsumoto, Koji Toshinai, Masamitsu Nakazato, Toshishige Shibamoto, Shuichi Kaneko, Masato Kasuga, Hiroshi Inoue

  Central insulin action activates hepatic IL-6/STAT3 signaling, which suppresses the gene expression of hepatic gluconeogenic enzymes. The vagus nerve plays an important role in this centrally mediated hepatic response; however, the precise mechanism underlying this brain-liver interaction is unclear. Here, we present our findings that the vagus nerve suppresses hepatic IL-6/STAT3 signaling via alpha-nicotinic acetylcholine receptors (alpha 7-nAchR) on Kupffer cells, and that central insulin action activates hepatic IL-6/STAT3 signaling by suppressing vagal activity. Indeed, central insulin-mediated hepatic IL-6/STAT3 activation and gluconeogenic gene suppression were impeded in mice with hepatic vagotomy, pharmacological cholinergic blockade, or alpha 7-nAchR deficiency. In high-fat diet-induced obese and insulin-resistant mice, control of the vagus nerve by central insulin action was disturbed, inducing a persistent increase of inflammatory cytokines. These findings suggest that dysregulation of the alpha 7-nAchR-mediated control of Kupffer cells by central insulin action may affect the pathogenesis of chronic hepatic inflammation in obesity.

  CELL PRESS, Mar. 2016, CELL REPORTS, 14(10) (10), 2362 - 2374, English

  [Refereed]

  Scientific journal


• C/EBPβの蛋白安定化に関与する新規リン酸化部位の同定

  松浦 有希, 松田 友和, 高井 智子, 川本 剛士, 三枝 祐介, 鈴木 江美[寺師], 淺原 俊一郎, 木村 真希[小柳], 神野 歩, 木戸 良明

  (公社)日本生化学会, Dec. 2015, 日本生化学会大会・日本分子生物学会年会合同大会講演要旨集, 88回・38回, [2P1230] - [2P1230], Japanese


• 膵β細胞不全関連分子CEBP/βの安定化に対するcasein kinase βの役割

  高井 智子, 松田 友和, 川本 剛, 松浦 有希, 淺原 俊一郎, 神野 歩, 木村 真希, 鈴木 江美[寺師], 小川 渉, 木戸 良明

  (公社)日本生化学会, Dec. 2015, 日本生化学会大会・日本分子生物学会年会合同大会講演要旨集, 88回・38回, [4T特L - 08(3P1199)], Japanese


• Paternal allelic mutation at the Kcnq1 locus reduces pancreatic beta-cell mass by epigenetic modification of Cdkn1c

  Shun-ichiro Asahara, Hiroaki Etoh, Hiroyuki Inoue, Kyoko Teruyama, Yuki Shibutani, Yuka Ihara, Yukina Kawada, Alberto Bartolome, Naoko Hashimoto, Tomokazu Matsuda, Maki Koyanagi-Kimura, Ayumi Kanno, Yushi Hirota, Tetsuya Hosooka, Kazuaki Nagashima, Wataru Nishimura, Hiroshi Inoue, Michihiro Matsumoto, Michael J. Higgins, Kazuki Yasuda, Nobuya Inagaki, Susumu Seino, Masato Kasuga, Yoshiaki Kido

  Genetic factors are important determinants of the onset and progression of diabetes mellitus. Numerous susceptibility genes for type 2 diabetes, including potassium voltage-gated channel, KQT-like subfamily Q, member1 (KCNQ1), have been identified in humans by genome-wide analyses and other studies. Experiments with genetically modified mice have also implicated various genes in the pathogenesis of diabetes. However, the possible effects of the parent of origin for diabetes susceptibility alleles on disease onset have remained unclear. Here, we show that a mutation at the Kcnq1 locus reduces pancreatic beta-cell mass in mice by epigenetic modulation only when it is inherited from the father. The noncoding RNA KCNQ1 overlapping transcript1 (Kcnq1ot1) is expressed from the Kcnq1 locus and regulates the expression of neighboring genes on the paternal allele. We found that disruption of Kcnq1 results in reduced Kcnq1ot1 expression as well as the increased expression of cyclin-dependent kinase inhibitor 1C (Cdkn1c), an imprinted gene that encodes a cell cycle inhibitor, only when the mutation is on the paternal allele. Furthermore, histone modification at the Cdkn1c promoter region in pancreatic islets was found to contribute to this phenomenon. Our observations suggest that the Kcnq1 genomic region directly regulates pancreatic beta-cell mass and that genomic imprinting may be a determinant of the onset of diabetes mellitus.

  NATL ACAD SCIENCES, Jul. 2015, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 112(27) (27), 8332 - 8337, English

  [Refereed]

  Scientific journal


• Regulation of Pancreatic beta Cell Mass by Cross-Interaction between CCAAT Enhancer Binding Protein beta Induced by Endoplasmic Reticulum Stress and AMP-Activated Protein Kinase Activity

  Tomokazu Matsuda, Hiroaki Takahashi, Yusuke Mieda, Shinobu Shimizu, Takeshi Kawamoto, Yuki Matsuura, Tomoko Takai, Emi Suzuki, Ayumi Kanno, Maki Koyanagi-Kimura, Shun-ichiro Asahara, Alberto Bartolome, Norihide Yokoi, Hiroshi Inoue, Wataru Ogawa, Susumu Seino, Yoshiaki Kido

  During the development of type 2 diabetes, endoplasmic reticulum (ER) stress leads to not only insulin resistance but also to pancreatic beta cell failure. Conversely, cell function under various stressed conditions can be restored by reducing ER stress by activating AMP-activated protein kinase (AMPK). However, the details of this mechanism are still obscure. Therefore, the current study aims to elucidate the role of AMPK activity during ER stress-associated pancreatic beta cell failure. MIN6 cells were loaded with 5-amino-1-beta-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) and metformin to assess the relationship between AMPK activity and CCAAT enhancer binding protein beta (C/EBP beta) expression levels. The effect of C/EBP beta phosphorylation on expression levels was also investigated. Vildagliptin and metformin were administered to pancreatic beta cell-specific C/EBP beta transgenic mice to investigate the relationship between C/EBP beta expression levels and AMPK activity in the pancreatic islets. When pancreatic beta cells are exposed to ER stress, the accumulation of the transcription factor C/EBP beta lowers the AMP/ATP ratio, thereby decreasing AMPK activity. In an opposite manner, incubation of MIN6 cells with AICAR or metformin activated AMPK, which suppressed C/EBP beta expression. In addition, administration of the dipeptidyl peptidase-4 inhibitor vildagliptin and metformin to pancreatic beta cell-specific C/EBP beta transgenic mice decreased C/EBP beta expression levels and enhanced pancreatic beta cell mass in proportion to the recovery of AMPK activity. Enhanced C/EBP beta expression and decreased AMPK activity act synergistically to induce ER stress-associated pancreatic beta cell failure.

  PUBLIC LIBRARY SCIENCE, Jun. 2015, PLOS ONE, 10(6) (6), e0130757, English

  [Refereed]

  Scientific journal


• 2型糖尿病感受性遺伝子GCN2は膵β細胞量の調節に関与する

  増田 勝久, 神野 歩, 淺原 俊一郎, 吉冨 理紗, 松田 友和, 木村 真希, 渋谷 由紀, 廣田 勇士, 横井 伯英, 春日 雅人, 清野 進, 木戸 良明

  (一社)日本内分泌学会, Apr. 2015, 日本内分泌学会雑誌, 91(1) (1), 274 - 274, Japanese


• 膵β細胞におけるヒストン脱アセチル化酵素HDACの機能解析

  淺原 俊一郎, 杉浦 佑実子, 川田 有希奈, 伊原 佑香, 原 瑞季, 木村 真希, 松田 友和, 清野 進, 小川 渉, 木戸 良明

  (一社)日本内分泌学会, Apr. 2015, 日本内分泌学会雑誌, 91(1) (1), 318 - 318, Japanese


• C/EBPβの蛋白安定化に関与する新規リン酸化部位の同定

  川本 剛士, 松田 友和, 三枝 祐介, 高井 智子, 松浦 有希, 淺原 俊一郎, 木村 真希, 神野 歩, 木戸 良明

  (一社)日本内分泌学会, Apr. 2015, 日本内分泌学会雑誌, 91(1) (1), 319 - 319, Japanese


• DPP-4阻害薬MK-626が膵β細胞特異的mTORC1活性亢進モデルマウスに及ぼす影響

  木村 真希, 森田 愛梨, 三上 智子, 神野 歩, 松田 友和, 淺原 俊一郎, 清野 進, 小川 渉, 木戸 良明

  (一社)日本内分泌学会, Apr. 2015, 日本内分泌学会雑誌, 91(1) (1), 352 - 352, Japanese


• 膵β細胞不全関連因子C/EBPβの発現制御機構の解明

  高井 智子, 松田 友和, 川本 剛士, 松浦 有希, 三枝 祐介, 鈴木 江美, 淺原 俊一郎, 木村 真希, 神野 歩, 木戸 良明

  (一社)日本糖尿病学会, Apr. 2015, 糖尿病, 58(Suppl.1) (Suppl.1), S - 149, Japanese


• 膵β細胞におけるp38経路の活性化は膵島の慢性炎症を惹起することにより膵β細胞不全の病態形成に関与する

  森田 愛梨, 細岡 哲也, 竹村 侑己, 木村 真希, 鈴木 夏実, 淺原 俊一郎, 神野 歩, 松田 友和, 清野 進, 木戸 良明

  (一社)日本糖尿病学会, Apr. 2015, 糖尿病, 58(Suppl.1) (Suppl.1), S - 262, Japanese


• ヒストン脱アセチル化酵素(HDACs)による膵β細胞量調節機構の解析

  杉浦 佑実子, 淺原 俊一郎, 川田 有希奈, 佐藤 綾香, 木村 真希, 松田 友和, 木戸 良明

  (一社)日本糖尿病学会, Apr. 2015, 糖尿病, 58(Suppl.1) (Suppl.1), S - 443, Japanese


• 膵β細胞における細胞周期調節因子p57の機能解析

  原 瑞季, 淺原 俊一郎, 伊原 佑香, 井上 裕行, 照山 杏子, 松田 友和, 木村 真希, 中山 敬一, 木戸 良明

  (一社)日本糖尿病学会, Apr. 2015, 糖尿病, 58(Suppl.1) (Suppl.1), S - 263, Japanese


• Compensatory hyperinsulinemia in high-fat diet-induced obese mice is associated with enhanced insulin translation in islets

  Ayumi Kanno, Shun-ichiro Asahara, Katsuhisa Masuda, Tomokazu Matsuda, Maki Kimura-Koyanagi, Susumu Seino, Wataru Ogawa, Yoshiaki Kido

  A high-fat diet (HF) is associated with obesity, insulin resistance, and hyperglycemia. Animal studies have shown compensatory mechanisms in pancreatic beta-cells after high fat load, such as increased pancreatic beta-cell mass, enhanced insulin secretion, and exocytosis. However, the effects of high fat intake on insulin synthesis are obscure. Here, we investigated whether insulin synthesis was altered in correlation with an HF diet, for the purpose of obtaining further understanding of the compensatory mechanisms in pancreatic beta-cells. Mice fed an HF diet are obese, insulin resistant, hyperinsulinemic, and glucose intolerant. In islets of mice fed an HF diet, more storage of insulin was identified. We analyzed insulin translation in mouse islets, as well as in INS-1 cells, using non-radioisotope chemicals. We found that insulin translational levels were significantly increased in islets of mice fed an HF diet to meet systemic demand, without altering its transcriptional levels. Our data showed that not only increased pancreatic beta-cell mass and insulin secretion but also elevated insulin translation is the major compensatory mechanism of pancreatic beta-cells. (C) 2015 Elsevier Inc. All rights reserved.

  ACADEMIC PRESS INC ELSEVIER SCIENCE, Mar. 2015, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 458(3) (3), 681 - 686, English

  [Refereed]

  Scientific journal


• Pancreatic beta-Cell Failure Mediated by mTORC1 Hyperactivity and Autophagic Impairment

  Alberto Bartolome, Maki Kimura-Koyanagi, Shun-Ichiro Asahara, Carlos Guillen, Hiroyuki Inoue, Kyoko Teruyama, Shinobu Shimizu, Ayumi Kanno, Ana Garcia-Aguilar, Masato Koike, Yasuo Uchiyama, Manuel Benito, Tetsuo Noda, Yoshiaki Kido

  Hyperactivation of the mammalian target of rapamycin complex 1 (mTORC1) in -cells is usually found as a consequence of increased metabolic load. Although it plays an essential role in -cell compensatory mechanisms, mTORC1 negatively regulates autophagy. Using a mouse model with -cell-specific deletion of Tsc2 (Tsc2(-/-)) and, consequently, mTORC1 hyperactivation, we focused on the role that chronic mTORC1 hyperactivation might have on -cell failure. mTORC1 hyperactivation drove an early increase in -cell mass that later declined, triggering hyperglycemia. Apoptosis and endoplasmic reticulum stress markers were found in islets of older Tsc2(-/-) mice as well as accumulation of p62/SQSTM1 and an impaired autophagic response. Mitochondrial mass was increased in -cells of Tsc2(-/-) mice, but mitophagy was also impaired under these circumstances. We provide evidence of -cell autophagy impairment as a link between mTORC1 hyperactivation and mitochondrial dysfunction that probably contributes to -cell failure.

  AMER DIABETES ASSOC, Sep. 2014, DIABETES, 63(9) (9), 2996 - 3008, English

  [Refereed]

  Scientific journal


• 2型糖尿病感受性遺伝子GCN2は膵β細胞量の調節に関与する

  神野 歩, 吉冨 理紗, 増田 勝久, 淺原 俊一郎, 松田 友和, 木村 真希, 澁谷 由紀, 廣田 勇士, 横井 伯英, 春日 雅人, 清野 進, 木戸 良明

  (一社)日本内分泌学会, Apr. 2014, 日本内分泌学会雑誌, 90(1) (1), 252 - 252, Japanese


• 2型糖尿病感受性遺伝子GCN2は膵β細胞量の調節に関与する

  増田 勝久, 神野 歩, 吉冨 理紗, 淺原 俊一郎, 松田 友和, 木村 真希, 渋谷 由紀, 廣田 勇士, 横井 伯英, 春日 雅人, 清野 進, 木戸 良明

  (一社)日本糖尿病学会, Apr. 2014, 糖尿病, 57(Suppl.1) (Suppl.1), S - 141, Japanese


• AMPK活性依存的なC/EBPβの発現調節による膵β細胞量制御機構

  三枝 祐介, 松田 友和, 高橋 宏昌, 鈴木 江美, 川本 剛士, 淺原 俊一郎, 木村 真希, 神野 歩, 木戸 良明

  (一社)日本糖尿病学会, Apr. 2014, 糖尿病, 57(Suppl.1) (Suppl.1), S - 263, Japanese


• 2型糖尿病感受性遺伝子GCN2は膵β細胞量の調節に関与する

  神野 歩, 吉冨 理紗, 増田 勝久, 淺原 俊一郎, 松田 友和, 木村 真希, 渋谷 由紀, 廣田 勇士, 横井 伯英, 春日 雅人, 清野 進, 木戸 良明

  日本臨床分子医学会, Apr. 2014, 日本臨床分子医学会学術総会プログラム・抄録集, 51回, 78 - 78, Japanese


• 膵β細胞のKcnq1遺伝子領域におけるエピジェネティクス制御機構の解析

  淺原 俊一郎, 照山 杏子, 井上 裕行, 伊原 佑香, 江藤 博昭, 川田 有希奈, 松田 友和, 春日 雅人, 清野 進, 木戸 良明

  (一社)日本内分泌学会, Apr. 2014, 日本内分泌学会雑誌, 90(1) (1), 267 - 267, Japanese


• 膵β細胞のKcnq1遺伝子領域におけるエピジェネティクス制御機構の解析

  伊原 佑香, 淺原 俊一郎, 照山 杏子, 井上 裕行, 江藤 博昭, 木村 真希, 松田 友和, 春日 雅人, 清野 進, 木戸 良明

  (一社)日本糖尿病学会, Apr. 2014, 糖尿病, 57(Suppl.1) (Suppl.1), S - 142, Japanese


• Contribution of insulin signaling to the regulation of pancreatic beta-cell mass during the catch-up growth period in a low birth weight mouse model

  Yuri Yoshida, Megumi Fuchita, Maki Kimura-Koyanagi, Ayumi Kanno, Tomokazu Matsuda, Shun-ichiro Asahara, Naoko Hashimoto, Takayuki Isagawa, Wataru Ogawa, Hiroyuki Aburatani, Tetsuo Noda, Susumu Seino, Masato Kasuga, Yoshiaki Kido

  Children born with low birth weight have a high risk of developing type 2 diabetes mellitus later in life. In this study, we developed a mouse model for low birth weight induced by maternal caloric restriction and investigated its effects on pancreatic β-cells. At birth, the pancreatic β-cell mass in the restricted diet group (RG) offspring was significantly lower than in the control group (CG) offspring. At 8 weeks of age, the pancreatic β-cell mass was greater in the RG offspring than in the CG offspring. RG offspring showed upregulated expression of insulin receptor substrate 2 in islets at 10 weeks of age. Moreover, the activity of insulin signaling molecules in the pancreatic β-cell mass was increased during the period of catch-up growth during the early stage of life. To investigate the effect of insulin signaling on the regulation of pancreatic β-cell mass, we generated β-cell-specific 3-phosphoinositide-dependent protein kinase 1 (PDK1) heterozygous knockout (βPDK1+/-) mice. We detected delayed catch-up growth in the β-cell mass of βPDK1+/- mice that were undernourished as fetuses. Moreover, the insulin signaling pathway was impaired in the islets of βPDK1+/- mice exposed to fetal undernutrition. These findings indicate that fetal undernutrition affects the regulation of pancreatic β-cell mass through altered insulin signaling. © 2013 The Japan Diabetes Society.

  Springer-Verlag Tokyo, 2014, Diabetology International, 5(1) (1), 43 - 52, English

  [Refereed]

  Scientific journal


• 膵β細胞増殖機構におけるエピジェネティクス修飾の解析

  川田 有希奈, 井上 裕行, 小柳 真希, 松田 友和, 淺原 俊一郎, 木戸 良明

  (一社)日本臨床検査医学会, Sep. 2013, 臨床病理, 61(補冊) (補冊), 280 - 280, Japanese


• Histidine Augments the Suppression of Hepatic Glucose Production by Central Insulin Action

  Kumi Kimura, Yusuke Nakamura, Yuka Inaba, Michihiro Matsumoto, Yoshiaki Kido, Shun-ichiro Asahara, Tomokazu Matsuda, Hiroshi Watanabe, Akifumi Maeda, Fuyuhiko Inagaki, Chisato Mukai, Kiyoshi Takeda, Shizuo Akira, Tsuguhito Ota, Hajime Nakabayashi, Shuichi Kaneko, Masato Kasuga, Hiroshi Inoue

  Glucose intolerance in type 2 diabetes is related to enhanced hepatic glucose production (HGP) due to the increased expression of hepatic gluconeogenic enzymes. Previously, we revealed that hepatic STAT3 decreases the expression of hepatic gluconeogenic enzymes and suppresses HGP. Here, we show that increased plasma histidine results in hepatic STAT3 activation. Intravenous and intracerebroventricular (ICV) administration of histidine-activated hepatic STAT3 reduced G6Pase protein and mRNA levels and augmented HGP suppression by insulin. This suppression of hepatic gluconeogenesis by histidine was abolished by hepatic STAT3 deficiency or hepatic Kupffer cell depletion. Inhibition of HGP by histidine was also blocked by ICV administration of a histamine H-1 receptor antagonist. Therefore, histidine activates hepatic STAT3 and suppresses HGP via central histamine action. Hepatic STAT3 phosphorylation after histidine ICV administration was attenuated in histamine HI receptor knockout (Hrh1KO) mice but not in neuron-specific insulin receptor knockout (NIRKO) mice. Conversely, hepatic STAT3 phosphorylation after insulin ICV administration was attenuated in NIRKO but not in Hrh1KO mice. These findings suggest that central histidine action is independent of central insulin action, while both have additive effects on HGP suppression. Our results indicate that central histidine/histamine-mediated suppression of HGP is a potential target for the treatment of type 2 diabetes.

  AMER DIABETES ASSOC, Jul. 2013, DIABETES, 62(7) (7), 2266 - 2277, English

  [Refereed]

  Scientific journal


• Constitutive activation of Rac1 in pancreatic β cells facilitates F-actin depolymerization but exerts no influence on the increase of pancreatic β cell mass and facilitation of insulin secretion.

  Yuki Shibutani, Shun-Ichiro Asahara, Kyoko Teruyama, Hiroyuki Inoue, Tomokazu Matsuda, Susumu Seino, Yoshiaki Kido

  Insulin secretion from pancreatic β cells has an important role in the onset of type 2 diabetes. Insulin secretion from pancreatic β cells is regulated by pancreatic β cell mass and their insulin secretory function. By using pancreatic β cell-specific Rac1-knockout mice, we recently showed that Rac1 deletion, even with no reduction in pancreatic β cell mass, inhibits F-actin depolymerization, which causes insulin secretion to decline. However, the effect of Rac1 deficiency on the growth and apoptosis of pancreatic β cells was not clarified. Further, the effect of constitutive Rac1 activation on the secretion of insulin from pancreatic β cells has not been studied. Here, we used pancreatic islets isolated from pancreatic β cell-specific Rac1-knockout mice to evaluate the growth and apoptosis of pancreatic β cells. We found that Rac1 deficiency does not influence the growth or apoptosis of pancreatic β cells. Further, when a constitutively activated form of Rac1 (G12V) is expressed, F-actin depolymerization was increased in the pancreatic β cell lines, which had no effect on pancreatic β cell growth or glucose-stimulated insulin secretion. These findings indicate that excessive Rac1 expression or activation in pancreatic β cells facilitates F-actin depolymerization, but has no effect on insulin secretion.

  May 2013, The Kobe journal of medical sciences, 59(3) (3), E72-80 - 80, English, Domestic magazine

  [Refereed]


• Ras-related C3 botulinum toxin substrate 1 (RAC1) regulates glucose-stimulated insulin secretion via modulation of F-actin

  S. Asahara, Y. Shibutani, K. Teruyama, H. Y. Inoue, Y. Kawada, H. Etoh, T. Matsuda, M. Kimura-Koyanagi, N. Hashimoto, M. Sakahara, W. Fujimoto, H. Takahashi, S. Ueda, T. Hosooka, T. Satoh, H. Inoue, M. Matsumoto, A. Aiba, M. Kasuga, Y. Kido

  Aims/hypothesis The small G-protein ras-related C3 botulinum toxin substrate 1 (RAC1) plays various roles in mammalian cells, such as in the regulation of cytoskeletal organisation, cell adhesion, migration and morphological changes. The present study examines the effects of RAC1 ablation on pancreatic beta cell function. Methods Isolated islets from pancreatic beta cell-specific Rac1-knockout (betaRac1(-/-)) mice and RAC1 knockdown INS-1 insulinoma cells treated with small interfering RNA were used to investigate insulin secretion and cytoskeletal organisation in pancreatic beta cells. Results BetaRac1(-/-) mice showed decreased glucose-stimulated insulin secretion, while there were no apparent differences in islet morphology. Isolated islets from the mice had blunted insulin secretion in response to high glucose levels. In RAC1 knockdown INS-1 cells, insulin secretion was also decreased in response to high glucose levels, consistent with the phenotype of betaRac1(-/-) mice. Even under high glucose levels, RAC1 knockdown INS-1 cells remained intact with F-actin, which inhibits the recruitment of the insulin granules, resulting in an inhibition of insulin secretion. Conclusions/interpretation In RAC1-deficient pancreatic beta cells, F-actin acts as a barrier for insulin granules and reduces glucose-stimulated insulin secretion.

  SPRINGER, May 2013, DIABETOLOGIA, 56(5) (5), 1088 - 1097, English

  [Refereed]

  Scientific journal


• DPP4阻害薬MK-626が膵β細胞特異mTORC1活性亢進モデルマウスに及ぼす影響

  三上 智子, 小柳 真希, 松田 友和, 神野 歩, 淺原 俊一郎, 春日 雅人, 清野 進, 木戸 良明

  (一社)日本糖尿病学会, Apr. 2013, 糖尿病, 56(Suppl.1) (Suppl.1), S - 188, Japanese


• インスリノーマにおけるインスリン分泌特性と遺伝子発現の解析

  小柳 真希, 松田 友和, 廣田 勇士, 橋本 尚子, 淺原 俊一郎, 中村 友昭, 木戸 良明, 坂口 一彦, 小川 渉, 清野 進

  (一社)日本内科学会, Feb. 2013, 日本内科学会雑誌, 102(Suppl.) (Suppl.), 214 - 214, Japanese


• DPP4 inhibitor vildagliptin preserves beta-cell mass through amelioration of endoplasmic reticulum stress in C/EBPB transgenic mice

  Shinobu Shimizu, Tetsuya Hosooka, Tomokazu Matsuda, Shun-ichiro Asahara, Maki Koyanagi-Kimura, Ayumi Kanno, Alberto Bartolome, Hiroaki Etoh, Megumi Fuchita, Kyoko Teruyama, Hiroaki Takahashi, Hiroyuki Inoue, Yusuke Mieda, Naoko Hashimoto, Susumu Seino, Yoshiaki Kido

  The development of type 2 diabetes is accompanied by a progressive decline in beta-cell mass and function. Vildagliptin, a dipeptidyl peptidase 4 inhibitor, is representative of a new class of antidiabetic agents that act through increasing the expression of glucagon-like peptide-1. The protective effect of this agent on beta cells was studied in diabetic mice. Diabetic pancreatic beta cell-specific C/EBPB transgenic (TG) mice exhibit decreased beta-cell mass associated with increased apoptosis, decreased proliferation, and aggravated endoplasmic reticulum (ER) stress. Vildagliptin was orally administered to the TG mice for a period of 24 weeks, and the protective effects of this agent on beta cells were examined, along with the potential molecular mechanism of protection. Vildagliptin ameliorated hyperglycemia in TG mice by increasing the serum concentration of insulin and decreasing the serum concentration of glucagon. This agent also markedly increased beta-cell mass, improved aggravated ER stress, and restored attenuated insulin/IGF1 signaling. A decrease in pancreatic and duodenal homeobox 1 expression was also observed in beta cells isolated from our mouse model, but this was also restored by vildagliptin treatment. The expression of C/EBPB protein, but not mRNA, was unexpectedly downregulated in vildagliptin-treated TG mice and in exenatide-treated MIN6 cells. Activation of the GLP1 pathway induced proteasome-dependent C/EBPB degradation in beta cells as the proteasome inhibitor MG132 restored the downregulation of C/EBPB protein by exenatide. Vildagliptin elicits protective effects on pancreatic beta cells, possibly through C/EBPB degradation, and has potential for preventing the progression of type 2 diabetes. Journal of Molecular Endocrinology (2012) 49, 125-135

  BIOSCIENTIFICA LTD, Oct. 2012, JOURNAL OF MOLECULAR ENDOCRINOLOGY, 49(2) (2), 125 - 135, English

  [Refereed]

  Scientific journal


• 膵β細胞特異的C/EBPβトランスジェニックマウスに対するビルダグリプチンの膵β細胞保護効果に関する検討

  松田 友和, 清水 忍, 細岡 哲也, 浅原 俊一郎, 高橋 宏昌, 木村 真希, 清野 進, 木戸 良明

  (一社)日本糖尿病学会, Apr. 2012, 糖尿病, 55(Suppl.1) (Suppl.1), S - 298, Japanese


• 2型糖尿病発症におけるeIF2αキナーゼGCN2の機能解析

  神野 歩, 吉冨 理紗, 淺原 俊一郎, 松田 友和, 木村 真希, 渋谷 由紀, 春日 雅人, 清野 進, 木戸 良明

  (一社)日本糖尿病学会, Apr. 2012, 糖尿病, 55(Suppl.1) (Suppl.1), S - 298, Japanese


• Kcnq1遺伝子領域におけるエピジェネティクス制御が膵β細胞量に及ぼす影響の解析

  照山 杏子, 淺原 俊一郎, 江藤 博昭, 井上 裕行, 松田 友和, 春日 雅人, 清野 進, 木戸 良明

  (一社)日本糖尿病学会, Apr. 2012, 糖尿病, 55(Suppl.1) (Suppl.1), S - 297, Japanese


• Kcnq1遺伝子領域におけるエピジェネティクス制御が膵β細胞量に及ぼす影響の解析

  照山 杏子, 淺原 俊一郎, 江藤 博昭, 井上 裕行, 松田 友和, 清野 進, 春日 雅人, 木戸 良明

  日本臨床分子医学会, Apr. 2012, 日本臨床分子医学会学術総会プログラム・抄録集, 49回, 76 - 76, Japanese


• Endoplasmic Reticulum Stress Inhibits STAT3-Dependent Suppression of Hepatic Gluconeogenesis via Dephosphorylation and Deacetylation

  Kumi Kimura, Tomoko Yamada, Michihiro Matsumoto, Yoshiaki Kido, Tetsuya Hosooka, Shun-ichiro Asahara, Tomokazu Matsuda, Tsuguhito Ota, Hiroshi Watanabe, Yoshimichi Sai, Kenichi Miyamoto, Shuichi Kaneko, Masato Kasuga, Hiroshi Inoue

  In the liver, signal transducer and activator of transcription 3 (STAT3) plays an important role in the suppression of gluconeogenic enzyme expression. While obesity-associated endoplasmic reticulum (ER) stress has been shown to increase hepatic gluconeogenic enzyme expression, the role of ER stress in STAT3-dependent regulation of such expression is unclear. The current study aimed to elucidate the effect of ER stress on the STAT3-dependent regulation of hepatic gluconeogenic enzyme expression. Genetically obese/diabetic db/db mice and db/db mouse-derived isolated hepatocytes were used as ER stress models. A tyrosine phosphatase inhibitor, a deacetylation inhibitor, and an acetylated mutant of STAT3 were used to examine the effect of ER stress on hepatic STAT3 action. ER stress inhibited STAT3-dependent suppression of gluconeogenic enzyme gene expression by suppressing hepatic Janus kinase (JAK)2 and STAT3 phosphorylation. A tyrosine phosphatase inhibitor restored ER stress-induced suppression of JAK2 phosphorylation but exhibited no improving effect on suppressed STAT3 phosphorylation. STAT3 acetylation is known to correlate with its phosphorylation. ER stress also decreased STAT3 acetylation. An acetylated mutant of STAT3 was resistant to ER stress-induced inhibition of STAT3-phosphorylation and STAT3-dependent suppression of hepatic gluconeogenic enzyme gene expression in vitro and in vivo. Trichostatin A, a histone deacetylase (HDAC) inhibitor, ameliorated ER stress-induced inhibition of STAT3 acetylation and phosphorylation. The current study revealed that ER stress inhibits STAT3-dependent suppression of hepatic gluconeogenic enzymes via JAK2 dephosphorylation and HDAC-dependent STAT3 deacetylation, playing an important role in the increase of hepatic glucose production in obesity and diabetes. Diabetes 61:61-73, 2012

  AMER DIABETES ASSOC, Jan. 2012, DIABETES, 61(1) (1), 61 - 73, English

  [Refereed]

  Scientific journal


• 2型糖尿病関連遺伝子Kcnq1領域の膵β細胞に及ぼす影響の検討

  江藤 博昭, 淺原 俊一郎, 照山 杏子, 井上 裕行, 小柳 真希, 渋谷 由紀, 松田 友和, 長嶋 一昭, 西村 渉, 安田 和基, 稲垣 暢也, 清野 進, 春日 雅人, 木戸 良明

  (一社)日本肥満学会, Sep. 2011, 肥満研究, 17(Suppl.) (Suppl.), 160 - 160, Japanese


• Ablation of TSC2 Enhances Insulin Secretion by Increasing the Number of Mitochondria through Activation of mTORC1

  Maki Koyanagi, Shun-ichiro Asahara, Tomokazu Matsuda, Naoko Hashimoto, Yutaka Shigeyama, Yuki Shibutani, Ayumi Kanno, Megumi Fuchita, Tomoko Mikami, Tetsutya Hosooka, Hiroshi Inoue, Michihiro Matsumoto, Masato Koike, Yasuo Uchiyama, Tetsuo Noda, Susumu Seino, Masato Kasuga, Yoshiaki Kido

  Aim: We previously found that chronic tuberous sclerosis protein 2 (TSC2) deletion induces activation of mammalian target of rapamycin Complex 1 (mTORC1) and leads to hypertrophy of pancreatic beta cells from pancreatic beta cell-specific TSC2 knockout (beta TSC2(-/-)) mice. The present study examines the effects of TSC2 ablation on insulin secretion from pancreatic beta cells. Methods: Isolated islets from beta TSC2(-/-) mice and TSC2 knockdown insulin 1 (INS-1) insulinoma cells treated with small interfering ribonucleic acid were used to investigate insulin secretion, ATP content and the expression of mitochondrial genes. Results: Activation of mTORC1 increased mitochondrial DNA expression, mitochondrial density and ATP production in pancreatic beta cells of beta TSC2(-/-) mice. In TSC2 knockdown INS-1 cells, mitochondrial DNA expression, mitochondrial density and ATP production were increased compared with those in control INS-1 cells, consistent with the phenotype of beta TSC2(-/-) mice. TSC2 knockdown INS-1 cells also exhibited augmented insulin secretory response to glucose. Rapamycin inhibited mitochondrial DNA expression and ATP production as well as insulin secretion in response to glucose. Thus, beta TSC2(-/-) mice exhibit hyperinsulinemia due to an increase in the number of mitochondria as well as enlargement of individual beta cells via activation of mTORC1 Conclusion: Activation of mTORC1 by TSC2 ablation increases mitochondrial biogenesis and enhances insulin secretion from pancreatic beta cells.

  PUBLIC LIBRARY SCIENCE, Aug. 2011, PLOS ONE, 6(8) (8), e23238, English

  [Refereed]

  Scientific journal


• Ablation of C/EBP beta alleviates ER stress and pancreatic beta cell failure through the GRP78 chaperone in mice

  Tomokazu Matsuda, Yoshiaki Kido, Shun-ichiro Asahara, Tsuneyasu Kaisho, Takashi Tanaka, Naoko Hashimoto, Yutaka Shigeyama, Akihiko Takeda, Tae Inoue, Yuki Shibutani, Maki Koyanagi, Tetsuya Hosooka, Michihiro Matsumoto, Hiroshi Inoue, Tohru Uchida, Masato Koike, Yasuo Uchiyama, Shizuo Akira, Masato Kasuga

  Pancreatic beta cell failure is thought to underlie the progression from glucose intolerance to overt diabetes, and ER stress is implicated in such beta cell dysfunction. We have now shown that the transcription factor CCAAT/enhancer-binding protein beta (C/EBP beta) accumulated in the islets of diabetic animal models as a result of ER stress before the onset of hyperglycemia. Transgenic overexpression of C/EBP beta specifically in beta cells of mice reduced beta cell mass and lowered plasma insulin levels, resulting in the development of diabetes. Conversely, genetic ablation of C/EBP beta in the beta cells of mouse models of diabetes, including Akita mice, which harbor a heterozygous mutation in Ins2 (Ins2(WT/C96Y)), and leptin receptor-deficient (Lepr(-/-)) mice, resulted in an increase in beta cell mass and ameliorated hyperglycemia. The accumulation of C/EBP beta in pancreatic beta cells reduced the abundance of the molecular chaperone glucose-regulated protein of 78 kDa (GRP78) as a result of suppression of the transactivation activity of the transcription factor ATF6 alpha, thereby increasing the vulnerability of these cells to excess ER stress. Our results thus indicate that the accumulation of C/EBP beta in pancreatic beta cells contributes to beta cell failure in mice by enhancing susceptibility to ER stress.

  AMER SOC CLINICAL INVESTIGATION INC, Jan. 2010, JOURNAL OF CLINICAL INVESTIGATION, 120(1) (1), 115 - 126, English

  [Refereed]

  Scientific journal


• Effect of intrauterine undernutrition during late gestation on pancreatic beta cell mass

  Tae Inoue, Yoshiaki Kido, Shun-ichiro Asahara, Tomokazu Matsuda, Yuki Shibutani, Maki Koyanagi, Masato Kasuga

  We analyzed the effect of low birth weight oil pancreatic beta cell mass. We used pregnant C57BL6J mice, and we reduced their food Supply by 30% during the late gestational period and examined the changes in the metabolism and pancreatic beta cell mass. Pancreatic beta cell mass at birth was greatly decreased in the mice of the food restriction group (RG) as compared to the mice of the control group (CG). The body weight of RG mice exhibited a "catch-up growth" pattern and became equivalent to that of CG mice 7 days after birth, and thereafter exceeded that of CG mice; however, the pancreatic beta cell mass in RG mice remained lower than that in CG mice at the age of 4 weeks. A high-fat diet significantly increased the pancreatic beta cell mass in RG mice as compared to that in CG mice at 12 weeks of age. However, RG mice fed oil high-fat diets tended to exhibit a decrease in the pancreatic beta cell mass at approximately 20 weeks of age. The plasma insulin concentrations also tended to be decreased in RG mice after 24 weeks of age as compared to those of CG mice. These results thus indicate that the growth of pancreatic beta cells is insufficient in RG mice, and pancreatic beta cell Failure can easily develop as a consequence Of insulin resistance.

  BIOMEDICAL RESEARCH PRESS LTD, Dec. 2009, BIOMEDICAL RESEARCH-TOKYO, 30(6) (6), 325 - 330, English

  [Refereed]

  Scientific journal


• 膵β細胞におけるmTORシグナルとミトコンドリア機能の検討

  小柳 真希, 木戸 良明, 浅原 俊一郎, 茂山 豊, 松田 友和, 竹田 章彦, 井上 妙, 渋谷 由紀, 清野 進, 春日 雅人

  日本臨床分子医学会, Apr. 2009, 日本臨床分子医学会学術総会プログラム・抄録集, 46回, 73 - 73, Japanese


• 膵β細胞におけるmTORシグナルとミトコンドリア機能の検討

  小柳 真希, 木戸 良明, 浅原 俊一郎, 茂山 豊, 松田 友和, 竹田 章彦, 井上 妙, 渋谷 由紀, 清野 進, 春日 雅人

  (一社)日本糖尿病学会, Apr. 2009, 糖尿病, 52(Suppl.1) (Suppl.1), S - 217, Japanese


• Increased ribosomal biogenesis induces pancreatic beta cell failure in mice model of type 2 diabetes

  Shun-ichiro Asahara, Tomokazu Matsuda, Yoshiaki Kido, Masato Kasuga

  Aim: To Study the changes in gene expression by pancreatic beta cells under insulin resistance conditions. Method: Ail exhaustive gene expression analysis was performed, Using isolated pancreatic islets of obese diabetic model Lepr I mice. Overexpression of cyclin D2 was induced in cells from the pancreatic beta cell line, namely, INS-1. Results: Through a gene expression analysis using islets isolated from db/db mice, we found a significant increase in the expression of ribosome-related molecules. In addition, increased expression of cyclin D2 was found at certain protein levels. As INS-1 cells were induced to overexpress cyclin D2, We found an increase in the expression of ribosome-related molecules. Concurrently, an increase in the expression of endoplasmic reticulum stress (ER stress)-related molecules was also found. Conclusion: in cases of pancreatic p cell hyperplasia associated with insulin resistance, ribosomal biogenesis is increased, and ER stress is induced. (C) 2009 Elsevier Inc. All rights reserved.

  ACADEMIC PRESS INC ELSEVIER SCIENCE, Apr. 2009, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 381(3) (3), 367 - 371, English

  [Refereed]

  Scientific journal


• Biphasic response of pancreatic beta-cell mass to ablation of tuberous sclerosis complex 2 in mice

  Yutaka Shigeyama, Toshiyuki Kobayashi, Yoshiaki Kido, Naoko Hashimoto, Shun-ichiro Asahara, Tomokazu Matsuda, Akihiko Takeda, Tae Inoue, Yuki Shibutani, Maki Koyanagi, Tohru Uchida, Maki Inoue, Okio Hino, Masato Kasuga, Tetsuo Noda

  Recent studies have demonstrated the importance of insulin or insulin-like growth factor 1 (IGF-1) for regulation of pancreatic beta-cell mass. Given the role of tuberous sclerosis complex 2 (TSC2) as an upstream molecule of mTOR (mammalian target of rapamycin), we examined the effect of TSC2 deficiency on beta-cell function. Here, we show that mice deficient in TSC2, specifically in pancreatic beta cells (beta TSC2(-/-) mice), manifest increased IGF-1-dependent phosphorylation of p70 S6 kinase and 4E-BP1 in islets as well as an initial increased islet mass attributable in large part to increases in the sizes of individual beta cells. These mice also exhibit hypoglycemia and hyperinsulinemia at young ages (4 to 28 weeks). After 40 weeks of age, however, the beta TSC2(-/-) mice develop progressive hyperglycemia and hypoinsulinemia accompanied by a reduction in islet mass due predominantly to a decrease in the number of beta cells. These results thus indicate that TSC2 regulates pancreatic beta-cell mass in a biphasic manner.

  AMER SOC MICROBIOLOGY, May 2008, MOLECULAR AND CELLULAR BIOLOGY, 28(9) (9), 2971 - 2979, English

  [Refereed]

  Scientific journal


• Ablation of PDK1 in pancreatic beta cells induces diabetes as a result of loss of beta cell mass

  N Hashimoto, Y Kido, T Uchida, SI Asahara, Y Shigeyama, T Matsuda, A Takeda, D Tsuchihashi, A Nishizawa, W Ogawa, Y Fujimoto, H Okamura, KC Arden, PL Herrera, T Noda, M Kasuga

  The total mass of islets of Langerhans is reduced in individuals with type 2 diabetes(1), possibly contributing to the pathogenesis of this condition. Although the regulation of islet mass is complex, recent studies have suggested the importance of a signaling pathway that includes the insulin or insulin-like growth factor-1 receptors, insulin receptor substrate and phosphatidylinositol ( PI) 3-kinase(2-4). 3-Phosphoinositide dependent protein kinase 1 (PDK1) is a serine-threonine kinase that mediates signaling downstream of PI 3-kinase. Here we show that mice that lack PDK1 specifically in pancreatic beta cells (beta Pdk1(-/-) mice) develop progressive hyperglycemia as a result of a loss of islet mass. The mice show reductions in islet density as well as in the number and size of beta cells. Haploinsufficiency of the gene for the transcription factor Foxo1 resulted in a marked increase in the number, but not the size, of beta cells and resulted in the restoration of glucose homeostasis in beta bPdk1(-/-) mice. These results suggest that PDK1 is important in maintenance of pancreatic beta cell mass and glucose homeostasis.

  NATURE PUBLISHING GROUP, May 2006, NATURE GENETICS, 38(5) (5), 589 - 593, English

  [Refereed]

  Scientific journal


• Dermatomyositis and myelodysplastic syndrome with myelofibrosis responding to methotrexate therapy

  G Tsuji, S Maekawa, K Saigo, Y Nobuhara, T Nakamura, S Kawano, M Koshiba, S Asahara, T Chinzei, S Kumagai

  Dermatomyositis (DM) has not yet been reported as a complication of myelodysplastic syndrome (MDS). A 50-year-old man was diagnosed as having MDS because of the presence of anemia, the appearance of immature cells in peripheral blood, and the abnormal cellular morphology. A few months later, high fever, myalgia and erythema developed. Although DM symptoms were resistant to high-dose corticosteroid administration, methotrexate (MTX) therapy improved not only the symptoms of DM but also hematologic findings related to MDS. This indicates that immunosuppressive therapy including MTX administration can be useful for patients with MDS with autoimmune symptoms. (C) 2003 Wiley-Liss, Inc.

  WILEY-LISS, Nov. 2003, AMERICAN JOURNAL OF HEMATOLOGY, 74(3) (3), 175 - 178, English, International magazine

  [Refereed]

  Scientific journal


• Acute lymphoblastic leukemia accompanied by chromosomal abnormality of translocation (12;17)

  SI Asahara, K Saigo, N Hasuike, M Tamura, Y Maeda, Y Tomofuji, T Chinzei, E Tatsumi

  This report concerns a female patient with B-precursor acute lymphoblastic leukemia with concomitant expression of CD13 and CD33. A rare chromosomal abnormality, t(12;17)(p13;q21), was detected in 70% of metaphases analyzed. A new subgroup of acute leukemia is proposed, consisting of our case and 12 reported cases with similar chromosomal abnormalities. This subgroup has a poor prognosis and a high incidence of biphenotypic characteristics.

  VSP BV, 2001, HAEMATOLOGIA, 31(3) (3), 209 - 213, English

  [Refereed]

  Scientific journal

• 膵β細胞におけるmTORC1活性化は膵外分泌細胞への分化を誘導する

  清家雅子, 淺原俊一郎, 木村真希, 鈴木宏隆, 横井愛紗, 椎木幾久子, 田部勝也, 木戸良明, 木戸良明, 小川渉

  2023, 糖尿病(Web), 66(Suppl) (Suppl)


• Neuronatin and glucose-induced stress in pancreatic β-cells

  Asahara Shunichirou

  Dec. 2018, J Diabetes Investig, English

  Introduction scientific journal

  Link to Kobe Univ. Repository (Kernel)


• SGLT2 inhibitors and protection against pancreatic beta cell failure

  Asahara Shunichirou, Ogawa Wataru

  Sep. 2018, Diabetol Int, 10(1) (1), 1 - 2, English

  [Refereed]

  Introduction scientific journal


• 2型糖尿病の病態把握におけるMPV(平均血小板容積)の有用性に関する検討

  井上裕行, 斉藤真裕美, 胡内久美子, 吉村豊, 石田英和, 中谷敏也, 淺原俊一郎, 木戸良明, 木戸良明, 菊池英亮

  2017, 糖尿病(Web), 60(Suppl) (Suppl)


• Epigenetics and Anti-aging: Diabetes and Epigenetics

  Asahara S, Kido Y, Waki H, Yamauchi T, Kadowaki T

  Jan. 2017, Anti-aging Medicine, 12(6) (6), 783‐790 - 790, Japanese

  [Invited]


• GCN2, a type 2 diabetes mellitus susceptibility gene, is associated with the regulation of pancreatic beta cell mass

  K. Masuda, A. Kanno, S-I. Asahara, R. Yoshitomi, T. Matsuda, M. Kimura-Koyanagi, Y. Shibutani, N. Yokoi, M. Kasuga, S. Seino, Y. Kido

  SPRINGER, Sep. 2015, DIABETOLOGIA, 58, S240 - S240, English

  Summary international conference


• GCN2, a Type 2 Diabetes Mellitus Susceptibility Gene, Is Associated with the Regulation of Pancreatic beta-Cell Mass

  Ayumi Kanno, Katsuhisa Masuda, Shun-Ichiro Asahara, Maki Kimura, Tomokazu Matsuda, Masato Kasuga, Wataru Ogawa, Susumu Seino, Yoshiaki Kido

  AMER DIABETES ASSOC, Jun. 2015, DIABETES, 64, A599 - A599, English

  Summary international conference


• Reduction in Pancreatic beta-Cell Mass Caused by Enhanced Expression of Cdkn1c via Interaction between C/EBP beta and Epigenetic Control

  Shun-Ichiro Asahara, Yuka Ihara, Hiroyuki Inoue, Kyoko Teruyama, Mizuki Hara, Maki Kimura, Tomokazu Matsuda, Susumu Seino, Yoshiaki Kido

  AMER DIABETES ASSOC, Jun. 2015, DIABETES, 64, A578 - A578, English

  Summary international conference


• Pancreatic β-Cell Failure Mediated by mTORC1 Hyperactivity and Autophagic Impairment

  Bartolome Alberto, Kimura-Koyanagi Maki, Asahara Shun-Ichiro

  Blackwell Publishing, Mar. 2015, Diabetes : a journal of the American Diabetes Association, 8(2) (2), 25 - 37, Japanese


• Cross-interaction between C/EBPbeta and AMPK determines the pancreatic beta cell mass

  Y. Mieda, T. Matsuda, T. Kawamoto, E. Suzuki, S-I. Asahara, A. Kanno, M. Koyanagi, Y. Kido

  SPRINGER, Sep. 2014, DIABETOLOGIA, 57, S191 - S191, English

  Summary international conference


• 膵β細胞のKcnq1遺伝子領域におけるエピジェネティクス制御機構の解析

  淺原 俊一郎, 照山 杏子, 伊原 佑香, 井上 裕行, 川田 有希奈, 江藤 博昭, 松田 友和, 春日 雅人, 清野 進, 木戸 良明

  日本臨床分子医学会, Apr. 2014, 日本臨床分子医学会学術総会プログラム・抄録集, 51回, 77 - 77, Japanese


• 膵β細胞における細胞周期調節蛋白p57の機能解析

  原瑞季, 淺原俊一郎, 伊原佑香, 井上裕行, 照山杏子, 松田友和, 木村(小柳)真希, 中山敬一, 木戸良明, 木戸良明

  2014, 日本分子生物学会年会プログラム・要旨集(Web), 37th


• 膵β細胞特異的C/EBPβトランスジェニックマウスに対するビルダグリプチンとメトホルミン併用による膵β細胞保護作用

  高橋宏昌, 松田友和, 三枝祐介, 清水忍, 淺原俊一郎, 小柳真希, 神野歩, 清野進, 木戸良明

  2013, 糖尿病, 56(Supplement 1) (Supplement 1)


• インスリノーマにおけるインスリン分泌特性と遺伝子発現の解析

  小柳真希, 松田友和, 廣田勇士, 橋本尚子, 淺原俊一郎, 中村友昭, 木戸良明, 坂口一彦, 小川渉, 清野進

  2013, 日本内科学会雑誌, 102


• 2型糖尿病感受性遺伝子GCN2は膵β細胞量の調節に関与する

  神野歩, 吉冨理紗, 淺原俊一郎, 松田友和, 小柳真希, 渋谷由紀, 横井伯英, 春日雅人, 清野進, 木戸良明

  2013, 糖尿病, 56(Supplement 1) (Supplement 1)


• DPP4阻害薬MK-626が膵β細胞特異的mTORC1活性亢進モデルマウスに及ぼす影響

  三上智子, 小柳真希, 松田友和, 神野歩, 淺原俊一郎, 春日雅人, 清野進, 木戸良明

  2013, 糖尿病, 56(Supplement 1) (Supplement 1)


• Intrauterine Environment and Type 2 Diabetes

  淺原 俊一郎, 木戸 良明

  最新医学社, Jan. 2012, 最新医学, 67(1) (1), 93 - 99, Japanese


• 2型糖尿病候補遺伝子Kcnq1遺伝子領域が膵β細胞に及ぼす影響の解析

  井上裕行, 淺原俊一郎, 江藤博昭, 照山杏子, 伊原佑香, 渋谷由紀, 松田友和, 小柳真希, 神野歩, 西村渉, 長嶋一昭, 安田和基, 稲垣暢也, 清野進, 春日雅人, 木戸良明, 木戸良明

  2012, 日本分子生物学会年会プログラム・要旨集(Web), 35th


• 2型糖尿病候補遺伝子Kcnq1遺伝子領域が膵β細胞に及ぼす影響の解析

  淺原俊一郎, 江藤博昭, 照山杏子, 井上裕行, 渋谷由紀, 小柳真希, 松田友和, 長嶋一昭, 西村渉, 安田和基, 稲垣暢也, 清野進, 春日雅人, 木戸良明, 木戸良明

  2012, 日本糖尿病・肥満動物学会年次学術集会プログラム・講演抄録集, 26th


• インスリンシグナルが低出生体重モデルマウスの膵β細胞量調節に与える影響

  吉田有里, 淵田愛, 小柳真希, 淺原俊一郎, 松田友和, 井上妙, 春日雅人, 清野進, 木戸良明

  2012, 糖尿病, 55(Supplement 1) (Supplement 1)


• 膵β細胞におけるmTORC1シグナルはミトコンドリア数増加を介してインスリン分泌を亢進させる

  小柳 真希, 淺原 俊一郎, 松田 友和, 茂山 豊, 渋谷 由紀, 神野 歩, 淵田 愛, 小池 正人, 内山 安男, 清野 進, 春日 雅人, 木戸 良明

  (一社)日本内分泌学会, Apr. 2011, 日本内分泌学会雑誌, 87(1) (1), 279 - 279, Japanese


• 2型糖尿病候補遺伝子KCNQ1の膵β細胞に及ぼす役割の検討

  江藤博昭, 淺原俊一郎, 照山杏子, 小柳真希, 渋谷由紀, 松田友和, 長嶋一昭, 西村渉, 安田和基, 清野進, 春日雅人, 木戸良明, 木戸良明

  2011, 日本内分泌学会雑誌, 87(1) (1)


• 低出生体重モデルマウスにおける膵β細胞量調節機構の検討

  吉田有里, 淵田愛, 小柳真希, 淺原俊一郎, 井上妙, 春日雅人, 清野進, 木戸良明, 木戸良明

  2011, 日本分子生物学会年会プログラム・要旨集(Web), 34th


• 低出生体重モデルマウスにおける膵β細胞量調節機構の検討

  吉田有里, 淵田愛, 小柳真希, 淺原俊一郎, 松田友和, 春日雅人, 清野進, 木戸良明, 木戸良明

  2011, 肥満研究, 17(Supplement) (Supplement)


• 2型糖尿病候補遺伝子Kcnq1遺伝子領域が膵β細胞に及ぼす影響の解析

  淺原俊一郎, 江藤博昭, 照山杏子, 小柳真希, 渋谷由紀, 松田友和, 長嶋一昭, 西村渉, 安田和基, 清野進, 春日雅人, 木戸良明

  2011, 糖尿病, 54(Supplement 1) (Supplement 1)


• 膵β細胞特異的C/EBPβトランスジェニックマウスを用いた膵β細胞不全に対するDPP-4阻害剤(ビルダグリプチン)の効果の検討

  清水忍, 細岡哲也, 松田友和, 淺原俊一郎, 小柳真希, 清野進, 木戸良明

  2011, 糖尿病, 54(Supplement 1) (Supplement 1)


• 低出生体重モデルマウスにおける膵β細胞量調節機構の検討

  淵田愛, 吉田有里, 小柳真希, 淺原俊一郎, 松田友和, 井上妙, 春日雅人, 清野進, 木戸良明

  2011, 糖尿病, 54(Supplement 1) (Supplement 1)


• 膵β細胞におけるelF2αキナーゼGCN2の機能解析

  神野歩, 吉冨理紗, 淺原俊一郎, 松田友和, 小柳真希, 渋谷由紀, 春日雅人, 清野進, 木戸良明

  2011, 糖尿病, 54(Supplement 1) (Supplement 1)


• Ablation of TSC2 Enhances Mitochondrial Function Via Activation of mTORC1 in beta Cells

  Maki Koyanagi, Yoshiaki Kido, Shun-Ichiro Asahara, Yutaka Shigeyama, Tomokazu Matsuda, Yuki Shibutani, Megumi Fuchita, Tetsuo Noda, Susumu Seino, Masato Kasuga

  AMER DIABETES ASSOC, Jun. 2010, DIABETES, 59, A91 - A91, English

  Summary international conference


• 膵β細胞におけるmTORシグナルとミトコンドリア機能の検討

  小柳 真希, 木戸 良明, 浅原 俊一郎, 茂山 豊, 松田 友和, 渋谷 由紀, 淵田 愛, 小池 正人, 内山 安男, 春日 雅人, 清野 進

  (一社)日本糖尿病学会, Apr. 2010, 糖尿病, 53(Suppl.1) (Suppl.1), S - 156, Japanese


• Rac1 regulates glucose-induced insulin secretion through the modulation of cytoskeletal organization in beta cells

  Shun-ichiro Asahara, Yoshiaki Kido, Tomokazu Matsuda, Yuki Shibutani, Maki Koyanagi, Susumu Seino, Masato Kasuga

  JAPAN ENDOCRINE SOC, Mar. 2010, ENDOCRINE JOURNAL, 57, S386 - S386, English

  Summary international conference


• 2型糖尿病候補遺伝子KCNQ1の膵β細胞に及ぼす役割の検討

  江藤博昭, 木戸良明, 木戸良明, 淺原俊一郎, 小柳真希, 渋谷由紀, 松田友和, 清野進, 春日雅人

  2010, 糖尿病, 53(Supplement 1) (Supplement 1)


• 2型糖尿病候補遺伝子KCNQ1の膵β細胞に及ぼす役割の検討

  江藤博昭, 淺原俊一郎, 渋谷由紀, 小柳真希, 照山杏子, 荒木沙織, 清野進, 春日雅人, 木戸良明, 木戸良明

  2010, 生化学


• 膵β細胞における低分子量Gタンパク質Rac1の機能解析 (助成研究報告)

  木戸 良明, 淺原 俊一郎

  神戸大学, Aug. 2009, 神戸大学医学部神緑会学術誌, 25, 64 - 65, Japanese


• Involvement of epigenetics in diabetes mellitus

  浅原 俊一郎, 木戸 良明

  メディカルレビュー社, Jun. 2009, Genome medicine, 9(2) (2), 127 - 131, Japanese


• Effect of the Constitutive Activation of mTORC1 on Mitochondrial Function in Pancreatic beta Cells

  Maki Koyanagi, Yoshiaki Kido, Shun-Ichiro Asahara, Yutaka Shigeyama, Tomokazu Matsuda, Akihiko Takeda, Tae Inoue, Yuki Shibutani, Tohru Uchida, Susumu Seino, Masato Kasuga

  AMER DIABETES ASSOC, Jun. 2009, DIABETES, 58, A2 - A2, English

  Summary international conference


• 膵β細胞における低分子量GタンパクRac1の機能解析

  淺原俊一郎, 木戸良明, 橋本尚子, 茂山豊, 松田友和, 竹田章彦, 井上妙, 渋谷由紀, 小柳真希, 内田亨, 春日雅人

  2009, 日本内分泌学会雑誌, 85(1) (1)


• 2型糖尿病候補遺伝子KCNQ1の膵β細胞に及ぼす役割の検討

  渋谷由紀, 木戸良明, 淺原俊一郎, 松田友和, 竹田章彦, 井上妙, 小柳真希, 長嶋一昭, 清野進, 春日雅人

  2009, 糖尿病, 52(Supplement 1) (Supplement 1)


• Rac1 regulates glucose-induced insulin secretion through modulation of cytoskeletal organization in beta cells

  Shun-Ichiro Asahara, Yoshiaki Kido, Yutaka Shigeyama, Tomokazu Matsuda, Akihiko Takeda, Tae Inoue, Yuki Shibutani, Maki Koyanagi, Tohru Uchida, Masato Kasuga

  AMER DIABETES ASSOC, Jun. 2008, DIABETES, 57, A55 - A55, English

  Summary international conference


• mTORシグナルによる膵β細胞数・サイズ調節機構の解明

  小柳真希, 木戸良明, 茂山豊, 中野尚子, 浅原俊一郎, 松田友和, 竹田章彦, 井上妙, 渋谷由紀, 内田亨, 野田哲生, 春日雅人

  2008, 糖尿病, 51(Supplement 1) (Supplement 1)


• 膵β細胞における低分子量GタンパクRac1の機能解析

  浅原俊一郎, 木戸良明, 中野尚子, 茂山豊, 松田友和, 竹田章彦, 井上妙, 渋谷由紀, 小柳真希, 内田亨, 春日雅人

  2008, 糖尿病, 51(Supplement 1) (Supplement 1)


• Accumulation of C/EBP beta induces pancreatic beta cell failure by reducing the endoplasmic reticulum function

  Tomokazu Matsuda, Yoshiaki Kido, Naoko Hashimoto, Shun-Ichiro Asahara, Yutaka Shigeyama, Akihiko Takeda, Tae Inoue, Yuki Shibutani, Tohru Uchida, Masato Kasuga

  AMER DIABETES ASSOC, Jun. 2007, DIABETES, 56, A411 - A411, English

  Summary international conference


• Role of TSC2 in the regulation of pancreatic beta cell mass

  Yutaka Shigeyama, Yoshiaki Kido, Naoko Hashimoto, Shun-Ichiro Asahara, Tomokazu Matsuda, Akihiko Takeda, Tae Inoue, Yuki Shibutani, Tohru Uchida, Tetsuo Noda, Masato Kasuga

  AMER DIABETES ASSOC, Jun. 2007, DIABETES, 56, A422 - A422, English

  Summary international conference

• 膵β細胞特異的PDK1ノックアウトマウスにおける前糖尿病状態の解析

  土屋 匠子, ASAHARA SHUNICHIROU, 河村 真緒, 林田 彩花, KIDO YOSHIAKI

  日本分子生物学会年会, Nov. 2018, Japanese, 横浜, Domestic conference

  Poster presentation


• 膵β細胞特異的PDK1ノックアウトマウスにおける前糖尿病状態の解析

  土屋 匠子, ASAHARA SHUNICHIROU, 河村 真緒, 林田 彩花, KIDO YOSHIAKI

  第41回日本分子生物学会年会, Nov. 2018, Japanese, 横浜, Domestic conference

  Poster presentation


• 膵β細胞特異的PDK1ノックアウトマウスにおける血糖値推移とβ細胞量の検討

  伊東 春香, ASAHARA SHUNICHIROU, 原 千佐子, KIMURA MAKI, 神野 歩, 高井 智子, KIDO YOSHIAKI

  日本分子生物学会年会, Nov. 2018, Japanese, 横浜, Domestic conference

  Poster presentation


• 膵β細胞特異的PDK1ノックアウトマウスにおける血糖値推移とβ細胞量の検討

  伊東 春香, ASAHARA SHUNICHIROU, 原 千佐子, KIMURA MAKI, 神野 歩, 高井 智子, KIDO YOSHIAKI

  第41回日本分子生物学会年会, Nov. 2018, Japanese, 横浜, Domestic conference

  Poster presentation


• 膵β細胞の小胞体ストレス誘導性アポトーシスにおけるCK2の役割

  井上 佳歩, 高井 智子, 松田 友和, 鈴木 江美, 神野 歩, KIMURA MAKI, ASAHARA SHUNICHIROU, KIDO YOSHIAKI

  日本分子生物学会年会, Nov. 2018, Japanese, 横浜, Domestic conference

  Poster presentation


• 膵β細胞の小胞体ストレス誘導性アポトーシスにおけるCK2の役割

  井上 佳歩, 高井 智子, 松田 友和, 鈴木 江美, 神野 歩, KIMURA MAKI, ASAHARA SHUNICHIROU, KIDO YOSHIAKI

  第41回日本分子生物学会年会, Nov. 2018, Japanese, 横浜, Domestic conference

  Poster presentation


• 膵β細胞のUnfolded Protein ResponseにおけるCK2の役割

  高井 智子, 松田 友和, 井上 佳歩, 鈴木 江美, 神野 歩, KIMURA MAKI, ASAHARA SHUNICHIROU, KIDO YOSHIAKI

  日本分子生物学会年会, Nov. 2018, Japanese, 横浜, Domestic conference

  Poster presentation


• 膵β細胞のUnfolded Protein ResponseにおけるCK2の役割

  高井 智子, 松田 友和, 井上 佳歩, 鈴木 江美, 神野 歩, KIMURA MAKI, ASAHARA SHUNICHIROU, KIDO YOSHIAKI

  第41回日本分子生物学会年会, Nov. 2018, Japanese, 横浜, Domestic conference

  Poster presentation


• 膵β細胞におけるGCN2/asparaginase/ｍTORC1シグナルの同定

  工藤 倫代, 神野 歩, ASAHARA SHUNICHIROU, 松田 友和, KIMURA MAKI, KIDO YOSHIAKI

  日本分子生物学会年会, Nov. 2018, Japanese, 横浜, Domestic conference

  Poster presentation


• 膵β細胞におけるGCN2/asparaginase/ｍTORC1シグナルの同定

  工藤 倫代, 神野 歩, ASAHARA SHUNICHIROU, 松田 友和, KIMURA MAKI, KIDO YOSHIAKI

  第41回日本分子生物学会年会, Nov. 2018, Japanese, 横浜, Domestic conference

  Poster presentation


• Establishment of novel biomarkers for type 2 diabetes using T2DM model mice (2型糖尿病モデルマウスにおける早期診断のためのバイオマーカーの探索)

  河村 真緒, ASAHARA SHUNICHIROU, 土屋 匠子, 林田 彩花, KIDO YOSHIAKI

  日本細胞外小胞学会, Aug. 2018, Japanese, 広島, Domestic conference

  Oral presentation


• Establishment of novel biomarkers for type 2 diabetes using T2DM model mice (2型糖尿病モデルマウスにおける早期診断のためのバイオマーカーの探索)

  河村 真緒, ASAHARA SHUNICHIROU, 土屋 匠子, 林田 彩花, KIDO YOSHIAKI

  第5回日本細胞外小胞学会, Aug. 2018, Japanese, 広島, Domestic conference

  Oral presentation


• ヒトips細胞を用いた膵内分泌細胞への分化誘導

  山田 瑞姫, ASAHARA SHUNICHIROU, 遠山 春希, 下野 名奈子, 原 瑞希, 田中 孝一, 松田 友和, KIMURA MAKI, 神野 歩, 高井 智子, 鈴木 江美, AOI TAKASHI, KIDO YOSHIAKI

  第61回日本糖尿病学会年次学術集会, May 2018, Japanese, 東京, Domestic conference

  Others


• 2型糖尿病感受性遺伝子GCN2はSestrin2を介して膵β細胞量の調節に関与する

  古林 鮎子, 神野 歩, ASAHARA SHUNICHIROU, 松田 友和, KIMURA MAKI, KIDO YOSHIAKI

  日本内分泌学会, Apr. 2018, Japanese, 宮崎, Domestic conference

  Oral presentation


• 2型糖尿病感受性遺伝子GCN2はSestrin2を介して膵β細胞量の調節に関与する

  古林 鮎子, 神野 歩, ASAHARA SHUNICHIROU, 松田 友和, KIMURA MAKI, KIDO YOSHIAKI

  第91回日本内分泌学会学術総会, Apr. 2018, Japanese, 宮崎, Domestic conference

  Oral presentation


• GCN2, a type2 diabetes mellitus susceptibility gene, is associated with the regulation of pancreatic beta cell mass.

  Asahara Shunichirou

  The 2nd International Joint Symposium -UW, UO, KU-, Mar. 2018, English, International Joint Symposium -UW, UO, KU-, Honolulu, Hawaii, USA, International conference

  [Invited]

  Nominated symposium


• 膵β細胞の小胞体ストレス誘導性アポトーシスにおけるCK2βの役割

  井上 佳歩, 高井 智子, 松田 友和, 鈴木 江美, 神野 歩, KIMURA MAKI, ASAHARA SHUNICHIROU, KIDO YOSHIAKI

  第40回日本分子生物学会年会, Dec. 2017, Japanese, 神戸, Domestic conference

  Oral presentation


• 高脂肪食負荷GCN2欠損マウスの膵島におけるmTORC1シグナル調節機構の解明

  古林 鮎子, 神野 歩, 増田 勝久, 吉富 理紗, KIMURA MAKI, 松田 友和, ASAHARA SHUNICHIROU, KIDO YOSHIAKI

  第40回日本分子生物学会年会, Dec. 2017, Japanese, 神戸, Domestic conference

  Oral presentation


• ヒトiPS細胞を用いた膵内分泌細胞への分化誘導法の確立

  山田 瑞姫, ASAHARA SHUNICHIROU, 下野 名奈子, 田中 孝一, 松田 友和, KIMURA MAKI, 神野 歩, 高井 智子, 鈴木 江美, AOI TAKASHI, KIDO YOSHIAKI

  第40回日本分子生物学会年会, Dec. 2017, Japanese, 神戸, Domestic conference

  Poster presentation


• P-0503 Effect of removal of glucotoxicity by SGLT2 inhibitor dapagliflozin on the gene expression in pancreatic beta cells

  ASAHARA SHUNICHIROU, 大橋, KIDO YOSHIAKI

  International Diabetes Federation, Dec. 2017, English, Abu Dhabi, International conference

  Poster presentation


• 2型糖尿病モデルマウスにおける新規バイオマーカーの探索

  河村 真緒, 土屋 匠子, ASAHARA SHUNICHIROU, KIDO YOSHIAKI

  第40回日本分子生物学会年会, Dec. 2017, Japanese, 神戸, Domestic conference

  Oral presentation


• Analysis of Pathogenic Mechanism by Susceptibility Genes of T2DM Using Human iPS Cells

  ASAHARA SHUNICHIROU, KIDO YOSHIAKI

  77th Scientific Sessions of American Diabetes Association, Jun. 2017, English, San Diego, International conference

  Poster presentation


• 膵β細胞の小胞体ストレス誘導性アポトーシスにおけるCK2βの役割

  高井 智子, 松田 友和, 井上 佳歩, 松浦 有希, 鈴木 江美, 神野 歩, KIMURA MAKI, ASAHARA SHUNICHIROU, OGAWA WATARU, KIDO YOSHIAKI

  第60回日本糖尿病学会年次学術集会, May 2017, Japanese, 名古屋, Domestic conference

  Oral presentation


• 脂肪酸が膵β細胞の小胞体に及ぼす影響

  鈴木 江美, 松田 友和, 川本 剛士, 松浦 有希, 高井 智子, 神野 歩, KIMURA MAKI, ASAHARA SHUNICHIROU, OGAWA WATARU, KIDO YOSHIAKI

  第60回日本糖尿病学会年次学術集会, May 2017, Japanese, 名古屋, Domestic conference

  Poster presentation


• ヒトIps細胞を用いた2型糖尿病発症機序の解明

  下野 名奈子, ASAHARA SHUNICHIROU, 原 瑞季, 田中 孝一, 松田 友和, KIMURA MAKI, 神野 歩, 高井 智子, 鈴木 江美, AOI TAKASHI, KIDO YOSHIAKI

  第60回日本糖尿病学会年次学術集会, May 2017, Japanese, 名古屋, Domestic conference

  Poster presentation


• 2型糖尿病の病態把握におけるMPV(平均血小板容積）の有用性に関する検討

  井上 裕行, 斉藤 真裕美, 胡内 久美子, 吉村 豊, 石田 英和, 中谷 敏也, ASAHARA SHUNICHIROU, KIDO YOSHIAKI, 菊池 英亮

  第60回日本糖尿病学会年次学術集会, May 2017, Japanese, 名古屋, Domestic conference

  Oral presentation

• 膵β細胞におけるインスリンシグナルが可塑性に及ぼす影響の解明

  木戸 良明, 淺原 俊一郎

  日本学術振興会, 科学研究費助成事業 基盤研究(C), 基盤研究(C), 神戸大学, 01 Apr. 2021 - 31 Mar. 2024

  代表者が独自に作成した膵β細胞特異的Tsc2ノックアウトマウスは、若齢期において膵β細胞量増大、高インスリン血症、低血糖を呈するが、45週齢前後から徐々に血糖上昇を示すことが明らかとなった。その際の膵β細胞量は若齢期と比べて有意に減少しており、またインスリン染色をしたところ膵島内のインスリン陽性細胞が不均一となっていた。既報では、膵β細胞量減少の一機序として脱分化が近年注目されており、本マウスにおいても脱分化が起こっていることが示唆された。しかしながら、膵α細胞量増大は認められず、またインスリン・グルカゴン・PP・ソマトスタチン陰性クロモグラニンA陽性細胞が認められたことから、内分泌ホルモン陰性細胞が膵島内に存在することが明らかとなった。そこで、アミラーゼ染色を行ったところ、膵島内にアミラーゼ陽性細胞が多数認められた。アミラーゼ発現が膵内分泌細胞の脱分化であることを確認するために、若齢期においてPtf1a発現を免疫染色で確認したところ、Ptf1a、クロモグラニンA共発現細胞の存在が確認された。さらにこれらの結果を確認するために、YFPマウスと交配し、Lineage tracingを行ったところ、YFP陽性Ptf1a陽性細胞がTsc2ノックアウトマウスの膵島内においてのみ確認された。また、遺伝子発現変化を確認すべくRNA-seqをしたところ、Tsc2ノックアウトマウスの10週齢ではPdx1やMafA発現が低下しており、Aldh1a3発現が増加していた。これらの結果より、若齢期から脱分化が始まっている可能性が示唆された。


• Roles of aquaporin9 in diabetic retinal neurodegeneration

  楠原 仙太郎, 淺原 俊一郎, 橘 吉寿

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C), Grant-in-Aid for Scientific Research (C), Kobe University, 01 Apr. 2021 - 31 Mar. 2024

  1.研究内容:遺伝子改変糖尿病マウスを安定的に得るためにInsCre;Pdkflox/+マウスとPdkflox/floxマウスを用いた体外受精を行い凍結受精卵を作成した。このことによって、任意の時期にInsCre;Pdkflox/flox（糖尿病マウス）およびPdkflox/floxマウス（コントロールマウス）を得ることができるようになった。遺伝子改変マウスCx3cr1-GFPマウス（ミクログリア標識）およびアデノ随伴ウイルス（アストロサイト、網膜神経節細胞）による標識を適宜利用し、糖尿病マウスでの２光子顕微鏡による生体イメージングを行った。ミクログリアの動きおよび形態変化を定量化する方法につき複数のアルゴリズムをトライし、安定して評価できる系が確立されつつある。また、AQP9の糖尿病網膜神経変性における役割の解明を進めるために、InsCre;Pdkflox/flox;Aqp9-/-マウスおよびPdkflox/flox;Aqp9+/-マウス（コントロール）の安定供給に向けマウスの交配を続けていると同時にAqp9-/-マウスにストレプトゾトシンを投与し高血糖を誘発して解析を進めている。 2.研究の意義:多面的な神経保護作用を有する乳酸のトランスポーターであるAQP9は糖尿病早期における糖尿病網膜神経変性に関与している可能性が高い。慢性炎症の際に早期から異常が認められるミクログリアの変化が２光子顕微鏡による生体イメージングで解析できていることから、この研究を続けることによって糖尿病網膜におけるAQP9の役割が明らかになるものと思われる。 3. 研究の重要性:本研究によって糖尿病早期におけるAQP9の役割が明らかになれば、乳酸をターゲットにした糖尿病網膜症への早期介入への道筋が示されることになり将来の失明予防に大いに貢献できると考える。


• 2型糖尿病発症における膵β細胞でのmTORC1活性調節機構の解明

  淺原 俊一郎

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C), Grant-in-Aid for Scientific Research (C), Kobe University, 01 Apr. 2020 - 31 Mar. 2023


• 糖尿病網膜神経変性におけるneurovascular unitの役割の解明

  楠原 仙太郎

  学術研究助成基金助成金／基盤研究(C), Apr. 2018 - Mar. 2021

  Competitive research funding


• ヒトiPS細胞を用いた2型糖尿病感受性遺伝子による糖尿病発症機序の解明

  淺原 俊一郎

  学術研究助成基金助成金／基盤研究(C), Apr. 2017 - Mar. 2020, Principal investigator

  Competitive research funding


• The effect of antihyperglycemic drugs on prevention of the diabetes via mTORC1 signal

  Maki Koyanagi-Kimura, Kannno Ayumi, Asahara Shun-ichiro

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C), Grant-in-Aid for Scientific Research (C), Kobe University, 01 Apr. 2016 - 31 Mar. 2019

  The preservation of pancreatic βcell mass is an essential factior in the onset and development of type 2 diabetes mellitus.In this study, we aimed at indentification of antihyperglycemic drugs on prevention of the diabetes via mTORC1 signal. We administered βTSC2-/-mice to DPP-4 inhibitors, SGLT2 inhibitors to db/db mice. DPP-4 inhibitors prevented decrease in insulin signaling. SGLT2 inhibitors preserved pancreatic beta cell mass more effectively if administartion is earlier. Maintenance of GCN2-deficient mice on a high-fat diet results in a loss of pancreatic beta cell mass. Our data suggest that GCN2 senses amino acid deficiency in beta cells and limits signaling by mechanistic target of rapamycin complex 1 to prevent beta cell failure during the consumption of a high-fat diet. The present results provide an insight into the genetic predisposition to T2DM in non-obese Asian populations, and they may inform a strategy for intervention in those with the risk allele for this SNP.


• ヒト膵β細胞における2型糖尿病感受性遺伝子の機能解析

  淺原 俊一郎

  学術研究助成基金助成金／国際共同研究加速基金(国際共同研究強化(A)), 2019, Principal investigator

  Competitive research funding


• 2型糖尿病関連遺伝子Kcnq1遺伝子領域が膵β細胞に及ぼす影響の解明

  淺原 俊一郎

  学術研究助成基金助成金／基盤研究(C), Apr. 2014 - Mar. 2017, Principal investigator

  Competitive research funding


• アミノ酸が膵β細胞量に及ぼす影響の解明

  淺原 俊一郎

  科学研究費補助金／若手研究(B), Apr. 2012 - Mar. 2014, Principal investigator

  Competitive research funding