Deletion of CDKAL1 affects first-phase glucose stimulated insulin exocytosis

• Project/Area Number: 23590369
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Kyorin University
• Principal Investigator: OHARA-IMAIZUMI Mica 杏林大学, 医学部, 教授 (40201941)
• Co-Investigator(Renkei-kenkyūsha): AOYAGI Kyota 杏林大学, 医学部, 助教 (50453527) ; NAGAMATSU Shinya 杏林大学, 医学部, 教授 (80231489) ; OKAMURA Tadashi 独立行政法人国立国際医療センター, 研究所, 室長 (00333790)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: インスリン分泌 / 開口放出 / 糖尿病 / GWAS / CDKAL1

Research Abstract

A variant of the CDKAL1 gene was reported to be associated with type 2 diabetes. To determine the role of CDKAL1 in beta-cells, we studied insulin release profiles in CDKAL1 gene knockout (KO) mice. Total internal reflection fluorescence imaging of CDKAL1 KO beta-cells showed that the number of fusion events during first-phase insulin secretion was reduced with delayed and slow cytosolic Ca2+ increase. The responsiveness of KATP channels to glucose was blunted in KO cells. Although CDKAL1 is homologous to CDK5RAP1, there was no difference in CDK5 activity between WT and KO islets. Thus, CDKAL1 controls first-phase insulin exocytosis in beta-cells by facilitating KATP channel responsiveness and subsequent Ca2+ channels activity through pathways other than CDK5-mediated regulation. Defects in this process caused by decreased CDKAL1 expression levels may confer an increased risk of type 2 diabetes.

Research Products

• [Journal Article] Serotonin regulates glucose-stimulated insulin secretion from pancreatic ß cells during pregnancy. (2013)
  • Author(s): Ohara-Imaizumi, M., Kim, H., Yoshida, M., Fujiwara, T., Aoyagi, K., Toyofuku, Y., Nakamichi, Y., Nishiwaki, C., Okamura, T., Uchida, T., Fujitani, Y., Akagawa, K., Kakei, M., Watada, H., German, M.S., and Nagamatsu, S.
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 110 Issue: 48 Pages: 19420-19425
  • DOI: 10.1073/pnas.1310953110
  • Peer Reviewed
• [Journal Article] The diabetes-susceptible gene SLC30A8/ZnT8 regulates hepatic insulin clearance (2013)
  • Author(s): Tamaki, M., Fujitani, Y, Uchida, T., Tamura, Y., Takeno, K., Kawaguchi, M., Watanabe, T., Hara, A., Ogihara, T., Shimizu, T., Mita, T., Hirose, T., Ohara-Imaizumi, M., Abe, T., Kiyonari, H., Hojyo, S., Fukada, T., Nagamatsu, S., Hirano, T., Kawamori, R., Watada, H.
  • Journal Title: J Clin Invest Volume: 123 Issue: 10 Pages: 4513-4524
  • DOI: 10.1172/jci68807
  • Peer Reviewed
• [Journal Article] Serotonin regulates glucose stimulated insulin secretion from pancreatic β cells during pregnancy. (2013)
  • Author(s): Ohara-Imaizumi, M., Kim, H., Yoshida, M., Fujiwara, T., Aoyagi, K., Toyofuku, Y., Nakamichi, Y., Nishiwaki, C., Okamura, T., Uchida, T., Fujitani, Y., Akagawa, K., Kakei, M., Watada, H., German, M.S., and Nagamatsu, S.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 110 Pages: 19420-19425
  • Peer Reviewed
• [Journal Article] Insulin homeostasis through zinc-mediated pancreas-to-liver metabolic communication. (2013)
  • Author(s): Tamaki, M., Fujitani, Y, Uchida, T., Tamura, Y., Takeno, K., Kawaguchi, M., Watanabe, T., Hara, A., Ogihara, T., Shimizu, T., Mita, T., Hirose, T., Ohara-Imaizumi, M., Abe, T., Kiyonari, H., Hojyo, S., Fukada, T., Nagamatsu, S., Hirano, T., Kawamori, R., Watada, H.
  • Journal Title: J Clin Invest. Volume: 123 Pages: 4513-4524
  • Peer Reviewed
• [Journal Article] Acute inhibition of PI3K-PDK1-Akt pathway potentiates insulin secretion through upregulation of newcomer granule fusions in pancreatic beta-cells (2012)
  • Author(s): Aoyagi, K., Ohara-Imaizumi, M., Nishiwaki, C., Nakamichi, Y., Ueki, K., Kadowaki, T. and Nagamatsu, S.
  • Journal Title: PLoS One Volume: 7 Issue: 10 Pages: e47381-e47381
  • DOI: 10.1371/journal.pone.0047381
  • Peer Reviewed
• [Journal Article] Acute inhibition of PI3K-PDK1-Akt pathway potentiates insulin secretion through upregulation of newcomer granule fusions in pancreatic beta-cells. (2012)
  • Author(s): Aoyagi K, Ohara-Imaizumi M, Nishiwaki C, Nakamichi Y, Ueki K, Kadowaki T and Nagamatsu, S.
  • Journal Title: PLoS One. Volume: 7
  • Peer Reviewed
• [Journal Article] Dissociation of inositol polyphosphates from the C2B domain of synaptotagmin facilitates spontaneous release of catechol amines in adrenal chromaffin cells. A suggestive evidence of a fusion clamp by synaptotagmin (2011)
  • Author(s): Sasakawa N
  • Journal Title: Neuropharmacology Volume: 60(7-8) Issue: 7-8 Pages: 1364-70
  • DOI: 10.1016/j.neuropharm.2011.03.005
  • Peer Reviewed
• [Journal Article] DPP-4 inhibitor des-F-sitagliptin treatment increased insulin exocytosis from db/db mice beta cells (2011)
  • Author(s): Nagamatsu, S., Ohara-Imaizumi, M., Nakamichi, Y., Aoyagi, K. and Nishiwaki, C.
  • Journal Title: Biochem Biophys Res Commun Volume: 412 Issue: 4 Pages: 556-560
  • DOI: 10.1016/j.bbrc.2011.07.119
  • Peer Reviewed
• [Journal Article] Regulation of resident and newcomer insulin granules by calcium and SNARE proteins (2011)
  • Author(s): Aoyagi, K., Ohara-Imaizumi, M., Nagamatsu, S.
  • Journal Title: Front Biosci Volume: 16 Pages: 1197-1210
  • URL: http://www.bioscience.org/2011/V16/af/3784/fulltext.htm
  • Peer Reviewed
• [Journal Article] DPP-4 inhibitor des-F-sitagliptin treatment increased insulin exocytosis from db/db mice β cells. (2011)
  • Author(s): Nagamatsu S., Ohara-Imaizumi M.(他3名)
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 412 Pages: 556-560
  • Peer Reviewed
• [Journal Article] Dissociation of inositol polyphosphates from the C2B domain of synaptotagmin facilitates spontaneous release of catecholamines in adrenal chromaffin cells. A suggestive evidence of a fusion clamp by synaptotagmin. (2011)
  • Author(s): Sasakawa N, Ohara-Imaizumi M (他4名)
  • Journal Title: Neuropharmacology Volume: 60 Pages: 1364-1370
  • Peer Reviewed
• [Journal Article] 若年性パーキンソン病の病態解明：インスリン開口機構からその病因に迫る (2011)
  • Author(s): 服部信孝, 江口博人、今泉美佳(他３名)
  • Journal Title: 臨床神経 Volume: 51 Pages: 986-987
• [Presentation] 膵β細胞からのインスリン分泌におけるNALCN/mNLF-1 の役割 (2013)
  • Author(s): 青柳共太, 今泉美佳, Mei Zhen, 永松信哉
  • Organizer: 文部科学省科学研究費補助金「新学術領域研究」細胞内ロジスティクス・シンポジウム
  • Place of Presentation: 兵庫
• [Presentation] 膵β細胞からのインスリン分泌におけるNALCN/mNLF-1 の役割 (2013)
  • Author(s): 青柳共太, 今泉美佳, Mei Zhen, 永松信哉
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: 横浜
• [Presentation] Serotonin regulates glucose stimulated insulin secretion from pancreatic β cells during pregnancy (2013)
  • Author(s): Ohara-Imaizumi M, Kim H, Yoshida M, Fujiwara T, Aoyagi K, Toyofuku Y, Nakamichi Y, Nishiwaki C, Okamura T, Uchida T, Fujitani Y, Akagawa K, Kakei M, Watada H, German MS, Nagamatsu S
  • Organizer: 73th Scientific Session of American Diabetes Association
  • Place of Presentation: Chicago, USA
• [Presentation] ホルモン開口分泌の分子イメージング (2013)
  • Author(s): 今泉美佳
  • Organizer: 第86回日本内分泌学会学術総会
  • Place of Presentation: 仙台(教育講演)
• [Presentation] Serotonin regulates glucose stimulated insulin secretion from pancreatic β cells during pregnancy (2013)
  • Author(s): Ohara-Imaizumi M, Kim H, Yoshida M, Fujiwara T, Aoyagi K, Toyofuku Y, Nakamichi Y, Nishiwaki C, Okamura T, Uchida T, Fujitani Y, Akagawa K, Kakei M, Watada H, German MS, Nagamatsu S
  • Organizer: Beta Cell Workshop 2013
  • Place of Presentation: 京都
• [Presentation] Acute inhibition of PI3K-PDK1-Akt pathway potentiates glucose-induced insulin secretion through myosinVa pathway in pancreatic beta cells (2013)
  • Author(s): Aoyagi K, Ohara-Imaizumi M, Nagamatsu S
  • Organizer: Beta Cell Workshop 2013
  • Place of Presentation: 京都
• [Presentation] 5-HT receptor 3a signaling regulates insulin release from pancreatic beta cells during pregnancy (2013)
  • Author(s): 今泉美佳、吉田昌史、青柳共太、豊福優希子、綿田裕孝、加計正文
  • Organizer: 第90回日本生理学会大会シンポジウム
  • Place of Presentation: 東京
• [Presentation] ホルモン開口分泌の分子イメージング (2013)
  • Author(s): 今泉美佳
  • Organizer: 第86回日本内分泌学会学術総会
  • Place of Presentation: 仙台
  • Invited
• [Presentation] Serotonin regulates glucose stimulated insulin secretion from pancreatic β cells during pregnancy. (2013)
  • Author(s): Ohara-Imaizumi M, Kim H, Yoshida M, Fujiwara T, Aoyagi K, Toyofuku Y, Nakamichi Y, Nishiwaki C, Okamura T, Uchida T, Fujitani Y, Akagawa K, Kakei M, Watada H, German MS and Nagamatsu S.
  • Organizer: 73th Scientific Session of American Diabetes Association
  • Place of Presentation: Chicago, USA
• [Presentation] Serotonin regulates glucose stimulated insulin secretion from pancreatic β cells during pregnancy. (2013)
  • Author(s): Ohara-Imaizumi M, Kim H, Yoshida M, Fujiwara T, Aoyagi K, Toyofuku Y, Nakamichi Y, Nishiwaki C, Okamura T, Uchida T, Fujitani Y, Akagawa K, Kakei M, Watada H, German MS and Nagamatsu S.
  • Organizer: Beta Cell Workshop 2013
  • Place of Presentation: 京都
• [Presentation] Acute inhibition of PI3K-PDK1-Akt pathway potentiates glucose-induced insulin secretion through myosinVa pathway in pancreatic beta cells. (2013)
  • Author(s): Aoyagi K, Ohara-Imaizumi M, Nagamatsu S.
  • Organizer: Beta Cell Workshop 2013
  • Place of Presentation: 京都
• [Presentation] 膵β細胞からのインスリン分泌におけるNALCN/mNLF-1の役割 (2013)
  • Author(s): 青柳 共太, 今泉 美佳, Mei Zhen, 永松 信哉.
  • Organizer: 文部科学省 科学研究費補助金「新学術領域研究」細胞内ロジスティクス・シンポジウム
  • Place of Presentation: 兵庫
• [Presentation] 膵β細胞からのインスリン分泌におけるNALCN/mNLF-1の役割 (2013)
  • Author(s): 青柳 共太, 今泉 美佳, Mei Zhen, 永松 信哉.
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: 横浜
• [Presentation] 5-HT receptor 3a signaling regulates insulin release from pancreatic beta cells during pregnancy. (2013)
  • Author(s): 今泉美佳、吉田昌史、青柳共太、豊福優希子、綿田裕孝、加計正文、永松信哉.
  • Organizer: 第90回日本生理学会大会
  • Place of Presentation: 東京
  • Invited
• [Presentation] 「シナプス伝達機構の理解」膵β細胞からのインスリン開口放出の可視化解析 (2012)
  • Author(s): 今泉美佳
  • Organizer: 生物科学領域記念シンポジウム
  • Place of Presentation: 上智大学理工学研究科
  • Year and Date: 2012-03-10
• [Presentation] 第2相インスリン分泌制御におけるPI-3 kinaseとPDK1-Akt経路の役割の検討 (2012)
  • Author(s): 青柳共太, 今泉美佳, 永松信哉
  • Organizer: 第16回東京インスリン分泌研究会
  • Place of Presentation: 東京
  • Year and Date: 2012-02-23
• [Presentation] Acute inhibition of PI3K-PDK1-Akt pathway potentiates glucose-induced insulin secretion through MyosinVa in pancreatic beta-cells (2012)
  • Author(s): 青柳共太, 今泉美佳, 西脇知世乃, 中道洋子, 永松信哉
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 博多
• [Presentation] 妊娠期膵β細胞でのセロトニンによるインスリン分泌亢進機構 (2012)
  • Author(s): 今泉美佳,青柳共太,永松信哉
  • Organizer: 第14回応用薬理シンポジウム
  • Place of Presentation: 甲府
• [Presentation] Serotonin signaling regulates insulin release from pancreatic beta cells during pregnancy (2012)
  • Author(s): Ohara-Imaizumi M
  • Organizer: 第6回Diabetes Leading-edge Conference
  • Place of Presentation: 千葉
• [Presentation] 糖尿病原因究明のためのイメージングによるインスリン開口放出機構解明 (2012)
  • Author(s): 今泉美佳, 青柳共太, 永松信哉
  • Organizer: 文部科学省科学研究費補助金「新学術領域研究」第4回「細胞内ロジスティクス」班会議
  • Place of Presentation: 仙台、宮城
• [Presentation] 第2相インスリン分泌制御におけるPI3K-PDK1-Akt経路の役割の検討 (2012)
  • Author(s): 青柳共太、今泉美佳、永松信哉
  • Organizer: 文部科学省科学研究費補助金「新学術領域研究」第4回「細胞内ロジスティクス」班会議
  • Place of Presentation: 仙台、宮城
• [Presentation] 妊娠期膵β細胞でのセロトニンによるインスリン分泌亢進機構 (2012)
  • Author(s): 今泉美佳, 吉田昌史, 豊福優希子, 青柳共太, 中道洋子, 西脇知世乃, 加計正文, 綿田裕孝, 永松信哉
  • Organizer: 第54回日本糖尿病学会年次学術集会
  • Place of Presentation: 横浜
• [Presentation] 第2相インスリン分泌制御におけるPI3K-PDK1-Akt経路の役割の検討 (2012)
  • Author(s): 青柳共太, 今泉美佳, 西脇知世乃, 中道洋子, 永松信哉
  • Organizer: 第54回日本糖尿病学会年次学術集会
  • Place of Presentation: 横浜
• [Presentation] Serotonin signaling regulates insulin secretion from pancreatic beta cells during pregnancy (2012)
  • Author(s): Ohara-Imaizumi, M, Aoyagi K, Yoshida M, Kakei M, Nagamatsu S
  • Organizer: Exocytosis in endocrine cells-linking experiments and theory Lund University Diabetes Centre
  • Place of Presentation: Malmö, Sweden
  • Invited
• [Presentation] Serotonin signaling regulates insulin secretion from pancreatic beta cells during pregnancy. (2012)
  • Author(s): Ohara-Imaizumi M, Aoyagi K, Yoshida M, Kakei M and Nagamatsu S.
  • Organizer: Exocytosis in endocrine cells -linking experiments and theory
  • Place of Presentation: Malmo, Sweden
  • Invited
• [Presentation] 妊娠期膵β細胞でのセロトニンによるインスリン分泌亢進機構. (2012)
  • Author(s): 今泉 美佳, 吉田 昌史, 豊福 優希子, 青柳 共太, 中道 洋子, 西脇 知世乃, 加計 正文, 綿田 裕孝, 永松 信哉
  • Organizer: 第54回日本糖尿病学会年次学術集会
  • Place of Presentation: 横浜
• [Presentation] 第2相インスリン分泌制御におけるPI3K-PDK1-Akt経路の役割の検討. (2012)
  • Author(s): 青柳 共太, 今泉 美佳, 西脇 知世乃, 中道 洋子, 永松 信哉.
  • Organizer: 第54回日本糖尿病学会年次学術集会
  • Place of Presentation: 横浜
• [Presentation] 糖尿病原因究明のためのイメージングによるインスリン開口放出機構解明 (2012)
  • Author(s): 今泉美佳,青柳共太,永松信哉
  • Organizer: 文部科学省 科学研究費補助金 「新学術領域研究」第 4 回 「細胞内ロジスティクス」班会議
  • Place of Presentation: 仙台
• [Presentation] 第2相インスリン分泌制御における PI3K-PDK1-Akt 経路の役割の検討 (2012)
  • Author(s): 青柳共太、今泉美佳、永松信哉
  • Organizer: 文部科学省 科学研究費補助金 「新学術領域研究」第 4 回 「細胞内ロジスティクス」班会議
  • Place of Presentation: 仙台
• [Presentation] Serotonin signaling regulates insulin release from pancreatic beta cells during pregnancy. (2012)
  • Author(s): Ohara-Imaizumi M.
  • Organizer: 第6回Diabetes Leading-edge Conference.
  • Place of Presentation: 千葉
• [Presentation] 妊娠期膵β細胞でのセロトニンによるインスリン分泌亢進機構. (2012)
  • Author(s): 今泉美佳，青柳共太，永松信哉.
  • Organizer: 第14回 応用薬理シンポジウム.
  • Place of Presentation: 甲府
• [Presentation] Acute inhibition of PI3K-PDK1-Akt pathway potentiates glucose-induced insulin secretion in pancreatic b-cells (2011)
  • Author(s): Aoyagi K, Ohara-Imaizumi, M, Nishiwaki C, Nakamichi Y, Nagamatsu S
  • Organizer: 第84回日本生化学会
  • Place of Presentation: 京都
• [Presentation] 糖尿病原因究明のためのイメージングによるインスリン開口放出機構解明 (2011)
  • Author(s): 今泉美佳, 青柳共太, 永松信哉
  • Organizer: 文部科学省科学研究費補助金「新学術領域研究」第3回細胞内ロジスティクス班会議
  • Place of Presentation: 鳥羽
• [Presentation] CDKAL1 の第1相インスリン分泌における役割 (2011)
  • Author(s): 今泉美佳, 青柳共太, 吉田昌史, 斎藤太郎, 岡村匡史, 竹中均, 中道洋子, 西脇知世乃, 久永真市, 加計正文, 永松信哉
  • Organizer: 第54回日本糖尿病学会年次学術集会
  • Place of Presentation: 札幌
• [Presentation] CDKAL1の第１相インスリン分泌における役割 (2011)
  • Author(s): 今泉美佳,青柳共太(他9名)
  • Organizer: 第54回日本糖尿病学会年次学術集会
  • Place of Presentation: 東京
• [Presentation] 糖尿病原因究明のためのイメージングによるインスリン開口放出機構解明
  • Author(s): 今泉美佳， 青柳共太， 永松信哉
  • Organizer: 文部科学省 科学研究費補助金「新学術領域研究」第３回 細胞内ロジスティクス班会議
  • Place of Presentation: 2011年6月1日～3日
• [Presentation] Acute inhibition of PI3K-PDK1-Akt pathway potentiates glucose-induced insulin secretion in pancreatic b-cells.
  • Author(s): 青柳共太,今泉美佳 (他3名)
  • Organizer: 第84回日本生化学会
  • Place of Presentation: 2011年9月21～24日
• [Presentation] 第２相インスリン分泌制御におけるPI-3 kinaseとPDK1-Akt経路の役割の検討
  • Author(s): 青柳共太、今泉美佳、永松信哉
  • Organizer: 第16回東京インスリン分泌研究会
  • Place of Presentation: 2012年2月23日
• [Presentation] 膵β細胞からのインスリン開口放出の可視化解析
  • Author(s): 今泉美佳
  • Organizer: 上智大学理工学研究科生物科学領域シンポジウム 「シナプス伝達機構の理解」(招待講演)
  • Place of Presentation: 2012年 3月10日
• [Book] Imaging of insulin exocytosis from pancreatic beta cells. Exocytosis Methods. Neuromethods 83. Springer Protocols. Thorn P. (ed.) (2013)
  • Author(s): Ohara-Imaizumi M, Aoyagi K, Nagamatsu S
  • Publisher: Humana Press
• [Book] Exocytosis Methods. (Neuromethods 83. Springer Protocols. ) (2013)
  • Author(s): Ohara-Imaizumi M, Aoyagi K, Nagamatsu S.
  • Total Pages: 248
  • Publisher: Humana Press.
• [Remarks]
  • URL: http://www.kyorin-u.ac.jp/univ/user/medicine/insulin/
• [Remarks] 杏林大学医学部生化学教室
  • URL: http://www.kyorin-u.ac.jp/univ/faculty/medicine/education/labo/biochemistry/