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Analysis of glucagon seceretion mechanisms and its modulation by anti-diabetes drugs

Research Project

Project/Area Number 24591343
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Metabolomics
Research InstitutionNihon University

Principal Investigator

ISHIHARA Hisamitsu  日本大学, 医学部, 教授 (60361086)

Co-Investigator(Kenkyū-buntansha) YAMAGUCHI Suguru  日本大学, 医学部, 助教 (70451614)
Co-Investigator(Renkei-kenkyūsha) OKAMOTO Mayumi  日本大学, 医学部, 講師 (80349993)
Project Period (FY) 2012-04-01 – 2015-03-31
Project Status Completed (Fiscal Year 2014)
Budget Amount *help
¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywordsグルカゴン / インクレチン / スルホニル尿素受容体 / DPP-4阻害薬 / メトホルミン / 膵α細胞 / 膵ランゲルハンス島 / インスリン / スルホニル尿素薬
Outline of Final Research Achievements

Increased glucagon secretion is an essential pathogenic abnormality found in type 2 diabetes patients. In this study, we have conducted several experiments aiming to elucidate mechanisms of glucagon secretion and to apply the results for analyzing pathogenesis of type 2 diabetes in humans. We found that modulation of the sulfonylurea receptor signaling by zinc and GLP-1 could be involved in glucagon secretion, providing insights for further analysis on its mechanisms. We have also conducted a clinical study in which type 2 diabetes patients on insulin monotherapy were treated either with sitagliptin, a DPP-4 inhibitor, or metformin, a biguanide compound. We have demonstrated that sitagliptin improved glycemic control by reducing glucagon secretion. In parallel, we have compared glucagon immunoassays, and found that a newly developed glucagon ELISA revealed more dynamic changes in glucagon after a meal challenge test.

Report

(4 results)
  • 2014 Annual Research Report   Final Research Report ( PDF )
  • 2013 Research-status Report
  • 2012 Research-status Report
  • Research Products

    (17 results)

All 2015 2014 2013 2012

All Journal Article (5 results) (of which Peer Reviewed: 4 results,  Open Access: 1 results,  Acknowledgement Compliant: 1 results) Presentation (12 results) (of which Invited: 4 results)

  • [Journal Article] Addition of sitagliptin or metformin to insulin monotherapy improves blood glucose control <i>via</i> different effects on insulin and glucagon secretion in hyperglycemic Japanese patients with type 2 diabetes2015

    • Author(s)
      Otsuka Y, Yamaguchi S, Furukawa A, Kosuda M, Nakazaki M, Ishihara H.
    • Journal Title

      Endocrine Journal

      Volume: 62 Issue: 2 Pages: 133-143

    • DOI

      10.1507/endocrj.EJ14-0148

    • NAID

      130004699224

    • ISSN
      0918-8959, 1348-4540
    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] The cutting-edge of medicine: glucagon renaissance2013

    • Author(s)
      Ishihara H
    • Journal Title

      Nihon Naika Gakkai Zasshi

      Volume: 102 Pages: 3237-3243

    • NAID

      40019918166

    • Related Report
      2013 Research-status Report
  • [Journal Article] Clinical Experiences in the Treatment of Pancreatic Arteriovenous Malformation by Total Pancreatectomy With Islet Autotransplantation.2013

    • Author(s)
      Sakata N, Goto M, Motoi F, Hayashi H, Nakagawa K, Mizuma M, Yamaya H, Hasegawa Y, Yamaguchi S, Sawada S, Ottomo S, Okada T, Fukase K, Yoshida H, Ito T, Hirota M, Ishigaki Y, Sekiguchi S, Rikiyama T, Katayose Y, Fujimori K, Egawa S, Shimosegawa T, Katagiri H, Satomi S, Unno M
    • Journal Title

      Transplantation

      Volume: 96(5) Issue: 5 Pages: e38-e40

    • DOI

      10.1097/tp.0b013e3182a01333

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Atf6α-null mice are glucose intolerant due to pancreatic β-cell failure on a high-fat diet but partially resistant to diet-induced insulin resistance2012

    • Author(s)
      M.Usui, S.Yamaguchi, Y.Tanji, R.Tominaga, Y.Ishigaki, M.Fukumoto, H.Katagiri, K.Mori, Y.Oka, H.Ishihara
    • Journal Title

      Metabol

      Volume: (in press) Issue: 8 Pages: 1118-28

    • DOI

      10.1016/j.metabol.2012.01.004

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Hepatic glucokinase modulates obesity predisposition by regulating BAT thermogenesis via neural signals2012

    • Author(s)
      Tsukita S, Yamada T, Uno K, Takahashi K, Kaneko K, Ishigaki Y, Imai J, Hasegawa Y, Sawada S, Ishihara H, Oka Y, Katagiri H.
    • Journal Title

      Cell Metab

      Volume: 16 Issue: 6 Pages: 825

    • DOI

      10.1016/j.cmet.2012.11.006

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Presentation] 2型糖尿病患者における血漿グルカゴン値の新規ELISA法と従来型RIA法を用いた測定の比較検討2014

    • Author(s)
      山口賢,小須田南,田中彩,古川麻美,大塚雄一郎,中崎満浩,石原寿光
    • Organizer
      第15回日本内分泌学会関東甲信越支部学術集会
    • Place of Presentation
      ラフレさいたま(埼玉県・さいたま市)
    • Year and Date
      2014-09-06
    • Related Report
      2014 Annual Research Report
  • [Presentation] Generation of a MIN6 beta-cell clone horboring platform for introduction of an inducible expression unit by recombinase-mediated cassette exchange2014

    • Author(s)
      Ishihara H, Furukawa A, Tanaka A, Otsuka Y, Yamaguchi S
    • Organizer
      The 74th Scientific Sessions of American Diabetes Association
    • Place of Presentation
      San Francisco (USA)
    • Year and Date
      2014-06-13 – 2014-06-17
    • Related Report
      2014 Annual Research Report
  • [Presentation] Modulation of glucagon and insulin secretion by DPP-4 and DPP-4 inhibitors2014

    • Author(s)
      Yamaguchi S, Otsuka Y, Ishihara H
    • Organizer
      第57回日本糖尿病学会年次学術集会
    • Place of Presentation
      大阪国際会議場(大阪府・大阪市)
    • Year and Date
      2014-05-22 – 2014-05-24
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] 腹部症状を契機に発症した抗インスリン抗体比較的強陽性の劇症1型糖尿病の1例2014

    • Author(s)
      小須田 南,岡本 真由美, 荒井 秀仁, 東海林 忍, 山口 賢, 江頭 富士子, 石原 寿光
    • Organizer
      第57回日本糖尿病学会年次学術集会
    • Place of Presentation
      大阪国際会議場(大阪府・大阪市)
    • Year and Date
      2014-05-22 – 2014-05-24
    • Related Report
      2014 Annual Research Report
  • [Presentation] DPP-4阻害薬とSU薬による遷延性低血糖に対してオクトレオチド投与が奏効した症例2014

    • Author(s)
      古川 麻美,山口 賢, 池島 碧, 田中 彩, 上野 のぶ子, 東海林 忍, 江頭 富士子, 岡本 真由美, 吉田 好徳, 阿部 雅紀, 石原 寿光
    • Organizer
      第57回日本糖尿病学会年次学術集会
    • Place of Presentation
      大阪国際会議場(大阪府・大阪市)
    • Year and Date
      2014-05-22 – 2014-05-24
    • Related Report
      2014 Annual Research Report
  • [Presentation] Modulation of glucagon and insulin secretion by DPP-4 and DPP-4 inhibitors2014

    • Author(s)
      Yamaguchi S, Otsuka Y, Ishihara H
    • Organizer
      第57回日本糖尿病学会年次学術集会
    • Place of Presentation
      大阪市
    • Related Report
      2013 Research-status Report
    • Invited
  • [Presentation] Sitagliptin improves blood glucose control by suppressing glucagon secretion in insulin-treated type 2 diabetic patients2013

    • Author(s)
      Otsuka Y,Kosuda M,Ueno N,Yamaguchi S,Nakazaki M,Ishihara H
    • Organizer
      The 49th European Association for Study of Diabetes Annual Meeting.
    • Place of Presentation
      Balcerona, Spain
    • Related Report
      2013 Research-status Report
  • [Presentation] Zinc regulates insulin secretion through interaction with histidine residues of SUR1.2013

    • Author(s)
      Ishihara H,Otsuka Y,Yamaguchi S,Hurukawa A,Nakazaki M.
    • Organizer
      The 73nd Scientific sessions of American Diabetes Association.
    • Place of Presentation
      Chicago, USA
    • Related Report
      2013 Research-status Report
  • [Presentation] グルコース反応性インスリンノーマの一例2013

    • Author(s)
      古川麻美,大川原奈々,上野のぶ子,大塚雄一郎,東海林忍,山口賢,江頭富士子,岡本真由美,中崎満浩,武市奈緒美,杉原仁,内田英二,及川眞一,石原寿光
    • Organizer
      第56回日本糖尿病学会総会
    • Place of Presentation
      熊本市
    • Related Report
      2013 Research-status Report
  • [Presentation] DPP-4阻害薬とGLP-1受容体作動薬2013

    • Author(s)
      石原寿光
    • Organizer
      第47回糖尿病学の進歩
    • Place of Presentation
      四日市市
    • Related Report
      2012 Research-status Report
    • Invited
  • [Presentation] グルコース応答性インスリノーマの一例2013

    • Author(s)
      古川麻美,山口賢,江頭富士子,大塚雄一郎,大川原奈々,東海林忍,岡本真由美,中崎満浩,石原寿光
    • Organizer
      第56回日本糖尿病学会年次学術集会
    • Place of Presentation
      熊本市
    • Related Report
      2012 Research-status Report
  • [Presentation] Regulation of islet hormone secretion by intracellular and intercellular mechanisms2012

    • Author(s)
      Ishihara H, Yamaguchi S, Otsuka Y, Furukawa A, Nakazaki M
    • Organizer
      The 9th Iinternational Diabete Fedeation Western Pacific Region Congress
    • Place of Presentation
      京都市
    • Related Report
      2012 Research-status Report
    • Invited

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Published: 2013-05-31   Modified: 2019-07-29  

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