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Development of disease model in mice on the basis of mechanisms for pathogenesis of gestational diabetes.

Research Project

Project/Area Number 18K19755
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 59:Sports sciences, physical education, health sciences, and related fields
Research InstitutionUniversity of Shizuoka

Principal Investigator

Ishikawa Tomohisa  静岡県立大学, 薬学部, 教授 (10201914)

Co-Investigator(Kenkyū-buntansha) 金子 雪子  静岡県立大学, 薬学部, 講師 (00381038)
Project Period (FY) 2018-06-29 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2019: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords糖尿病 / β細胞 / メラトニン / メラトニン受容体 / N‐アセチルセロトニン / 膵β細胞 / インスリン分泌 / 妊娠糖尿病 / N-アセチルセロトニン / インスリン
Outline of Final Research Achievements

In mouse pancreatic islets, the expression of melatonin MT1 and MT2 receptors and AANAT, an enzyme that catalyzes production of N-acetylserotonin (NAS) from serotonin, was detected, although sexual differences were not observed in the levels of expression. The expression of HIOMT, an enzyme that catalyzes production of melatonin from NAS, was not detected in mouse pancreatic islets even in female gestation period. We also found that the expression of AANAT in pancreatic β cells was increased by the adenylate cyclase activator forskolin and that NAS suppresses glucose-stimulated insulin secretion (GSIS) via suppressing intracellular Ca2+ elevation.
In summary, the results obtained here suggest that NAS is produced in pancreatic β cells in a cAMP-dependent manner and plays a role as a suppressor in GSIS; however, the evidence supporting the involvement of melatonin-related signaling in gestational diabetes has not been obtained.

Academic Significance and Societal Importance of the Research Achievements

末梢体内時計の同調因子として知られる松果体ホルモン・メラトニンは、主に松果体でセロトニンからAANATとHIOMTという2つの酵素を介して生成される。我々は、マウス膵島にAANATが発現していることを見出し、さらにセロトニンが妊娠中期に特異的に生成されることに着目して、膵β細胞におけるメラトニン関連シグナルが、発症機序が未だに不明な妊娠糖尿病と関連する可能性を考えた。残念ながら、メラトニン関連シグナルの妊娠糖尿病への関与を示す結果は得られなかったが、メラトニン産生の中途物質であるNASが膵β細胞で産生されてインスリン分泌調節に関与する可能性を示し、新たなインスリン分泌調節機構を提唱した。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (47 results)

All 2021 2020 2019 2018

All Journal Article (12 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 12 results,  Open Access: 3 results) Presentation (35 results) (of which Int'l Joint Research: 6 results,  Invited: 5 results)

  • [Journal Article] The sialidase inhibitor 2,3-dehydro-2-deoxy-N-acetylneuraminic acid is a glucose-dependent potentiator of insulin secretion2020

    • Author(s)
      Minami Akira、Fujita Yuka、Shimba Sumika、Shiratori Mako、Kaneko Yukiko K.、Sawatani Toshiaki、Otsubo Tadamune、Ikeda Kiyoshi、Kanazawa Hiroaki、Mikami Yasuyo、Sekita Risa、Kurebayashi Yuuki、Takahashi Tadanobu、Miyagi Taeko、Ishikawa Tomohisa、Suzuki Takashi
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 5198-5198

    • DOI

      10.1038/s41598-020-62203-8

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Renoprotective Effects of a Novel Receptor-Interacting Protein Kinase 2 Inhibitor, AS3334034, in Uninephrectomized Adriamycin-Induced Chronic Kidney Disease Rats2020

    • Author(s)
      Wada Yusuke、Kondo Mitsuhiro、Sakairi Kumi、Nagashima Akira、Tokita Kenichi、Tominaga Hiroaki、Tomiyama Hiroshi、Ishikawa Tomohisa
    • Journal Title

      Journal of Pharmacology and Experimental Therapeutics

      Volume: 374 Issue: 3 Pages: 428-437

    • DOI

      10.1124/jpet.120.265678

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Mechanism of Membrane Depolarization Involved in α<sub>1A</sub>-Adrenoceptor-Mediated Contraction in Rat Tail and Iliac Arteries2019

    • Author(s)
      Ishida Hirotake、Saito Shin-ya、Dohi Naoki、Ishikawa Tomohisa
    • Journal Title

      Biological and Pharmaceutical Bulletin

      Volume: 42 Issue: 10 Pages: 1741-1745

    • DOI

      10.1248/bpb.b19-00473

    • NAID

      130007722436

    • ISSN
      0918-6158, 1347-5215
    • Year and Date
      2019-10-01
    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] GDP-Bound Rab27a Dissociates from the Endocytic Machinery in a Phosphorylation-Dependent Manner after Insulin Secretion2019

    • Author(s)
      Kimura Toshihide、Yamaoka Mami、Terabayashi Takeshi、Kaibuchi Kozo、Ishikawa Tomohisa、Ishizaki Toshimasa
    • Journal Title

      Biological and Pharmaceutical Bulletin

      Volume: 42 Issue: 9 Pages: 1532-1537

    • DOI

      10.1248/bpb.b19-00242

    • NAID

      130007700076

    • ISSN
      0918-6158, 1347-5215
    • Year and Date
      2019-09-01
    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] TRPV2 channels mediate insulin secretion induced by cell swelling in mouse pancreatic β-cells2019

    • Author(s)
      Toshiaki Sawatani, Yukiko K. Kaneko, Isao Doutsu, Ai Ogawa, Tomohisa Ishikawa
    • Journal Title

      Am J Physiol Cell Physiol

      Volume: 316 Issue: 3 Pages: C434-C443

    • DOI

      10.1152/ajpcell.00210.2017

    • Related Report
      2019 Research-status Report 2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Dual effect of reduced type I diacylglycerol kinase activity on insulin secretion from MIN6 β-cells2019

    • Author(s)
      Sawatani Toshiaki、Kaneko Yukiko K.、Ishikawa Tomohisa
    • Journal Title

      Journal of Pharmacological Sciences

      Volume: 140 Issue: 2 Pages: 178-186

    • DOI

      10.1016/j.jphs.2019.06.001

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Alleviation of mechanical stress-induced allodynia by improving blood flow in chronic constriction injury mice2019

    • Author(s)
      Ishida Hirotake、Saito Shin-ya、Horie Ayaka、Ishikawa Tomohisa
    • Journal Title

      European Journal of Pharmacology

      Volume: 849 Pages: 67-74

    • DOI

      10.1016/j.ejphar.2019.02.002

    • Related Report
      2019 Research-status Report 2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] IRR is involved in glucose-induced endocytosis after insulin secretion2019

    • Author(s)
      Yamaoka Mami、Terabayashi Takeshi、Nishioka Tomoki、Kaibuchi Kozo、Ishikawa Tomohisa、Ishizaki Toshimasa、Kimura Toshihide
    • Journal Title

      Journal of Pharmacological Sciences

      Volume: 140 Issue: 3 Pages: 300-304

    • DOI

      10.1016/j.jphs.2019.07.002

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Differentiation-inducing factor-1 prevents hepatic stellate cell activation through inhibiting GSK3β inactivation2019

    • Author(s)
      Furukawa Shohei、Yamaguchi Momoka、Ooka Akira、Kikuchi Haruhisa、Ishikawa Tomohisa、Saito Shin-ya
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 520 Issue: 1 Pages: 140-144

    • DOI

      10.1016/j.bbrc.2019.09.117

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Differential contribution of calcium channels to α 1 -adrenoceptor-mediated contraction is responsible for diverse responses to cooling between rat tail and iliac arteries2018

    • Author(s)
      Ishida Hirotake、Saito Shin-ya、Hishinuma Eita、Kitayama Tomoaki、Ishikawa Tomohisa
    • Journal Title

      European Journal of Pharmacology

      Volume: 826 Pages: 9-16

    • DOI

      10.1016/j.ejphar.2018.02.023

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Concise synthesis of polymethoxyflavone sudachitin and its derivatives, and biological evaluations2018

    • Author(s)
      Sagara Hiroto、Kanakogi Masaki、Tara Yuki、Ouchi Hitoshi、Kimura Junko、Kaneko Yukiko、Inai Makoto、Asakawa Tomohiro、Ishikawa Tomohisa、Kan Toshiyuki
    • Journal Title

      Tetrahedron Letters

      Volume: 59 Issue: 19 Pages: 1816-1818

    • DOI

      10.1016/j.tetlet.2018.03.064

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] α1A-Adrenoceptors, but not α1B- or α1D-adrenoceptors, contribute to enhanced contractile response to phenylephrine in cooling conditions in the rat tail artery2018

    • Author(s)
      Ishida Hirotake、Saito Shin-ya、Ishikawa Tomohisa
    • Journal Title

      European Journal of Pharmacology

      Volume: 838 Pages: 120-128

    • DOI

      10.1016/j.ejphar.2018.09.004

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Presentation] アデノシン関連遺伝子の変化が炎症時において肝星細胞の活性化を促進する可能性2021

    • Author(s)
      土肥直貴、山口桃生、齊藤真也、石川智久
    • Organizer
      第94回日本薬理学会年会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 膵β細胞脂質代謝分子によるインスリン分泌制御および2型糖尿病病態形成への関与2021

    • Author(s)
      金子雪子、石川智久
    • Organizer
      日本薬学会第141年会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] DGKδ発現抑制による膵β細胞増殖機序の解析2021

    • Author(s)
      渡邉直也、金子雪子、青島育美、大川里桜、石川揚子、石渡千裕、佐藤太治、石川智久
    • Organizer
      日本薬学会第141年会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 自律神経による肝臓の血流調節において肝星細胞が責任細胞となる可能性2020

    • Author(s)
      土肥直貴、山口桃生、長谷怜奈、鈴木良輔、齊藤真也、石川智久
    • Organizer
      第143回日本薬理学会関東部会
    • Related Report
      2020 Annual Research Report
  • [Presentation] ノビレチンとその類縁体の膵β細胞機能に対する活性の比較研究2020

    • Author(s)
      梶 萌、金子雪子、多良勇輝、山本萌絵、青柳有紀、秋山季理子、菅敏幸、石川智久
    • Organizer
      第143回日本薬理学会関東部会
    • Related Report
      2020 Annual Research Report
  • [Presentation] ET-1による静止型肝星細胞の収縮に関わる分子メカニズムの解明2020

    • Author(s)
      土肥直貴、山口桃生、長谷怜奈、鈴木良輔、若林夢人、齊藤真也、石川智久
    • Organizer
      日本病院薬剤師会東海ブロック・日本薬学会東海支部 合同学術大会2020
    • Related Report
      2020 Annual Research Report
  • [Presentation] マウス膵β細胞におけるDGKδ欠損はSTZ誘発糖尿病を改善する2019

    • Author(s)
      木村悠希、金子雪子、中山貴寛、石川揚子、松田有加里、青島育美、石川智久
    • Organizer
      第92回日本薬理学会年会
    • Related Report
      2019 Research-status Report
  • [Presentation] 膵β細胞機能に対する柑橘類フラボノイドの作用2019

    • Author(s)
      金子雪子、石川智久
    • Organizer
      第92回日本薬理学会年会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] ノビレチンはインスリン分泌促進および膵β細胞保護作用により糖尿病を改善させる2019

    • Author(s)
      多良勇輝、金子雪子、山本萌絵、青柳有紀、秋山季理子、菅敏幸、石川智久
    • Organizer
      日本薬学会第139年会
    • Related Report
      2019 Research-status Report
  • [Presentation] 膵β細胞機能の新たなメッセンジャー:その生理と病態2019

    • Author(s)
      金子雪子、澤谷俊明、石川智久
    • Organizer
      第62回日本糖尿病学会年次学術集会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] DGKγ欠損による膵α細胞機能への影響の検討2019

    • Author(s)
      芹澤 環、金子 雪子、戸倉 広貴、松浦 朋哉、澤谷 俊明、石川 智久
    • Organizer
      第140回日本薬理学会関東部会
    • Related Report
      2019 Research-status Report
  • [Presentation] インスリン分泌後のエンドサイトーシス制御機構の解析2019

    • Author(s)
      木村俊秀、山岡真美、石崎敏理、石川智久
    • Organizer
      第140回日本薬理学会関東部会
    • Related Report
      2019 Research-status Report
  • [Presentation] 新たな視点からの治療を指向した糖尿病研究の新潮流 細胞内脂質シグナリングによる膵β細胞量の制御2019

    • Author(s)
      金子雪子、石川智久
    • Organizer
      生体機能と創薬シンポジウム2019
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] obiletin は膵β細胞機能障害を抑制することで糖尿病改善効果を示す2019

    • Author(s)
      梶 萌、金子雪子、多良勇輝、山本萌絵、石川智久
    • Organizer
      生体機能と創薬シンポジウム2019
    • Related Report
      2019 Research-status Report
  • [Presentation] 膵β細胞I型DGKの糖尿病下での発現と血糖調節への影響の解析2019

    • Author(s)
      松浦 朋哉、金子雪子、芹澤 環、澤谷 俊明、白井 康仁、石川 智久
    • Organizer
      第21回応用薬理シンポジウム
    • Related Report
      2019 Research-status Report
  • [Presentation] 柑橘フラボノイドの膵β細胞に対する抗糖尿病効果の解析2019

    • Author(s)
      梶 萌、金子雪子、多良勇輝、山本萌絵、青柳有紀、秋山季理子、石川智久
    • Organizer
      第141回日本薬理学会関東部会
    • Related Report
      2019 Research-status Report
  • [Presentation] Nobiletin は膵β細胞機能障害を抑制することで糖尿病改善効果を示す2019

    • Author(s)
      梶 萌、金子雪子、多良勇輝、山本萌絵、青柳有紀、石川智久
    • Organizer
      静岡実験動物研究会 令和元年度大会 第47回研究発表会
    • Related Report
      2019 Research-status Report
  • [Presentation] Diacylglycerol kinase: an intracellular regulator of insulin secretion from pancreatic β-cells2019

    • Author(s)
      Tomohisa Ishikawa, Yukiko Kaneko
    • Organizer
      KKU and University of Shizuoka joint symposium on medical and pharmaceutical sciences
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] 膵β細胞機能に対するノビレチンの抗糖尿病活性効果の検討2019

    • Author(s)
      梶萌、金子雪子、山本萌絵、石川智久
    • Organizer
      第3回ノビレチン研究会
    • Related Report
      2019 Research-status Report
  • [Presentation] 膵β細胞機能に対するノビレチンの抗糖尿病活性効果の検討2019

    • Author(s)
      金子雪子、石川智久
    • Organizer
      第3回ノビレチン研究会
    • Related Report
      2019 Research-status Report
  • [Presentation] β細胞におけるDGKδ機能抑制による細胞増殖および糖尿病病態への効果の解析2018

    • Author(s)
      木村悠希、金子雪子、石川揚子、中山貴寛、石川智久
    • Organizer
      第60回日本糖尿病学会年次学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] 膵β細胞におけるDGKαおよびγ機能抑制によるDAG蓄積は細胞内Ca2+濃度に対して二面性を示す2018

    • Author(s)
      澤谷俊明、金子雪子、石川智久
    • Organizer
      第60回日本糖尿病学会年次学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] DAG accumulation due to type 1 DGK inhibition has contradictory dual effect on Ca2+ signaling in pancreatic β cells2018

    • Author(s)
      Toshiaki Sawatani, Yukiko Kaneko, Tomohisa Ishikawa
    • Organizer
      American Diabetes Association 78th Scientific Sessions
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Modulation of DDAH/ADMA/NOS pathway in pancreatic β-cells under diabetic condition.2018

    • Author(s)
      Yukiko Y Kaneko, Misaki Sano, Ami Morioka, Masato Nojiri, Nahoko Kasahara, Tomohisa Ishikawa
    • Organizer
      18th World Congress of Basic and Clinical Pharmacology
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] TRPV2 channels mediate cell swelling-induced insulin secretion in mouse pancreatic β cells.2018

    • Author(s)
      Toshiaki Sawatani, Yukiko Kaneko, Isao Doutsu, Ai Ogawa, Tomohisa Ishikawa
    • Organizer
      18th World Congress of Basic and Clinical Pharmacology
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] 膵β細胞においてI型ジアシルグリセロールキナーゼ機能低下はインスリン分泌を二面性に制御する2018

    • Author(s)
      澤谷俊明、金子雪子、石川智久
    • Organizer
      生体機能と創薬シンポジウム2018
    • Related Report
      2018 Research-status Report
  • [Presentation] 膵β細胞におけるメラトニンシグナリング関連分子の発現および機能解析2018

    • Author(s)
      八木雄也、金子雪子、鴨志田ありさ、石川智久
    • Organizer
      日本病院薬剤師会東海ブロック・日本薬学会東海支部合同学術大会 2018
    • Related Report
      2018 Research-status Report
  • [Presentation] 植物ポリフェノールの膵β細胞機能に対する効果の解析2018

    • Author(s)
      山本萌絵、金子雪子、多良勇輝、青柳有紀、秋山季理子、菅敏幸、石川智久
    • Organizer
      日本病院薬剤師会東海ブロック・日本薬学会東海支部合同学術大会 2018
    • Related Report
      2018 Research-status Report
  • [Presentation] 膵β細胞におけるDGKδ機能抑制による糖尿病病態改善効果とそのメカニズムの解析2018

    • Author(s)
      松田有加里、金子雪子、木村悠希、石川揚子、中山貴寛、石川智久
    • Organizer
      日本病院薬剤師会東海ブロック・日本薬学会東海支部合同学術大会 2018
    • Related Report
      2018 Research-status Report
  • [Presentation] Effects of citrus flavonoids on pancreatic β-cell function2018

    • Author(s)
      Yuki Tara, Yukiko Kaneko, Yuki Aoyagi, Megumi Kaji, Kiriko Akiyama, Toshiyuki Kan, Tomohisa Ishikawa
    • Organizer
      The 4th International Conference on Pharma and Food
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Diacylglycerol accumulation due to type-1 diacylglycerol kinase dysfunction has a dual response on insulin secretion in pancreatic β-cells2018

    • Author(s)
      Toshiaki Sawatani, Yukiko Kaneko, Tomohisa Ishikawa
    • Organizer
      The 4th International Conference on Pharma and Food
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] DGKδ deficiency in mouse pancreatic β-cells improves STZ-induced hyperglycemia2018

    • Author(s)
      Yuki Kimura, Yukiko Kaneko, Taiji Sato, Chihiro Ishiwatari, Yoko Ishikawa, Yukari Matsuda, Tomohisa Ishikawa
    • Organizer
      The 4th International Conference on Pharma and Food
    • Related Report
      2018 Research-status Report
  • [Presentation] マウス膵β細胞におけるDGKδ欠損はSTZ誘発糖尿病を改善する2018

    • Author(s)
      木村悠希、金子雪子、中山貴寛、石川揚子、松田有加里、青島育美、石川智久
    • Organizer
      第92回日本薬理学会年会
    • Related Report
      2018 Research-status Report
  • [Presentation] 膵β細胞機能に対する柑橘類フラボノイドの作用2018

    • Author(s)
      金子雪子、石川智久
    • Organizer
      第92回日本薬理学会年会
    • Related Report
      2018 Research-status Report
  • [Presentation] ノビレチンはインスリン分泌促進および膵β細胞保護作用により糖尿病を改善させる2018

    • Author(s)
      多良勇輝、金子雪子、山本萌絵、青柳有紀、秋山季理子、菅敏幸、石川智久
    • Organizer
      日本薬学会第139年会
    • Related Report
      2018 Research-status Report

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Published: 2018-07-25   Modified: 2022-01-27  

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