Deletion of CDKAL1 affects first-phase glucose stimulated insulin exocytosis

2013 Fiscal Year Final Research Report

• 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
• 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 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
  • 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 Pages: 4513-4524
  • DOI: 10.1172/JCI68807
  • 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 Pages: e47381
  • DOI: 10.1371/journal.pone.0047381
  • Peer Reviewed
• [Journal Article] Dissociation of inositol polyphosphates from the C2B domain of synaptotagmin facilitates spontaneous release of catecholamines in adrenal chromaffin cells (2011)
  • Author(s): Sasakawa, N., Ohara-Imaizumi, M., Fukuda, M., Kabayama, H., Mikoshiba, K. and Kumakura, K.
  • Journal Title: Neuropharmacology Volume: 60 Pages: 1364-1370
  • 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 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
• [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
  • Year and Date: 20130917-18
• [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
  • Year and Date: 20130911-13
• [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
  • Year and Date: 20130621-25
• [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)
  • Year and Date: 20130425-27
• [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
  • Year and Date: 20130423-36
• [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
  • Year and Date: 20130423-26
• [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
  • Year and Date: 20130327-29
• [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
  • Year and Date: 20121214-16
• [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
  • Year and Date: 20120903-04
• [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
  • Year and Date: 20120811-12
• [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
  • Year and Date: 20120613-15
• [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
  • Year and Date: 20120613-15
• [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
  • Year and Date: 20120517-19
• [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
  • Year and Date: 20120517-19
• [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
  • Year and Date: 20120426-27
  • 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 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
  • Year and Date: 20110921-24
• [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
  • Year and Date: 20110601-03
• [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
  • Year and Date: 20110519-21
• [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
  • Total Pages: 55-74
  • Publisher: Humana Press
• [Remarks]
  • URL: http://www.kyorin-u.ac.jp/univ/user/medicine/insulin/