Elucidation of local, niche environment that determines pancreatic islet regeneration.

• Project/Area Number: 25670116
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Environmental physiology(including physical medicine and nutritional physiology)
• Research Institution: Chiba University
• Principal Investigator: MIKI Takashi 千葉大学, 医学(系)研究科(研究院), 教授 (50302568)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 膵島 / 再生 / 前駆細胞 / 糖尿病 / インスリン

Outline of Final Research Achievements

Acceleration of islet regeneration can be a radical therapy for diabetes mellitus. However, the cells involved in the regeneration have not been characterized and its regulatory mechanism remains unclarified. By analyzing the precise regeneration processes in our mouse model, we found that β-cell proliferation is regulated by the changes in β-cell mass, that the mass is maintained by the frequent cell division of the highly proliferative cells, and that several genes involved in the maintenance of stem/progenitor niche environment or in β-cell development are highly expressed during regeneration.

Research Products

• [Journal Article] Distinct action of the alpha-glucosidase inhibitor miglitol on SGLT3, enteroendocrine cells, and GLP1 secretion (2015)
  • Author(s): Lee EY, Kaneko S, Jutabha P, Zhang X, Seino S, Jomori T, Anzai N, Miki T
  • Journal Title: J Endocrinol Volume: 224 Issue: 3 Pages: 205-214
  • DOI: 10.1530/joe-14-0555
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Haploinsufficiency of the c-myc transcriptional repressor FIR, as a dominant negative-alternative splicing model, promoted p53-dependent T-cell acute lymphoblastic leukemia progression by activating Notch1. (2015)
  • Author(s): Matsushita K, Kitamura K, Rahmutulla B, Tanaka N, Ishige T, Satoh M, Hoshino T, Miyagi S, Mori T, Itoga S, Shimada H, Tomonaga T, Kito M, Nakajima-Takagi Y, Kubo S, Nakaseko C, Hatano M, Miki T, Matsuo M, Fukuyo M, Kaneda A, Iwama A, Nomura F.
  • Journal Title: Oncotarget Volume: 6 Pages: 5102-5117
  • Peer Reviewed / Open Access
• [Journal Article] Refeeding with glucose rather than fructose elicits greater hepatic inflammatory gene expression in mice (2015)
  • Author(s): Oarada M, et al.
  • Journal Title: Nutrition Volume: 31 Issue: 5 Pages: 757-65
  • DOI: 10.1016/j.nut.2014.11.014
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Fructose induces KATP channel-independent GIP and GLP-1 secretion and KATP channel-dependent insulin secretion. (2015)
  • Author(s): Seino, Y., Ogata, H., Maekawa, R., Iida, A., Harada, N., Miki, T., Inagaki, N., Tsunekawa, S., Seino, S., Oiso, Y., Hamada, Y.
  • Journal Title: J Diabetes Investig Volume: in press
  • Peer Reviewed / Open Access
• [Journal Article] グルカゴン抑制作用を有する抗糖尿病薬 (2015)
  • Author(s): 三木隆司
  • Journal Title: 実験医学 Volume: 33 Pages: 908-913
• [Journal Article] KATP channel as well as SGLT1 participates in GIP secretion in the diabetic state (2014)
  • Author(s): Ogata H, Seino Y, Harada N, Iida A, Suzuki K, Izumoto T, Ishikawa K, Uenishi E, Ozaki N, Hayashi Y, Miki T, Inagaki N, Tsunekawa S, Hamada Y, Seino S, Oiso Y
  • Journal Title: J Endocrinol Volume: 222 Issue: 2 Pages: 191-200
  • DOI: 10.1530/joe-14-0161
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Murine insulinoma cell-conditioned medium with ΒETA2/Neurod1 transduction efficiently induces the differentiation of adipose-derived mesenchymal stem cells into β-like cells both in vitro and in vivo. (2014)
  • Author(s): Kawamoto, K., Yabe, S., Konno, M., Ishii, H., Nishida. N., Jun Koseki, J., Fukuda, S., Tomimaru, Y., Hama, N., Wada, H., Kobayashi, S., Eguchi, H., Tanemura, M., Ito, T., Lee, E-Y., Mukai, E., Miki, T., Doki, Y., Mori, M., Hamazaki, T., Nagano, H., Okochi, H.
  • Journal Title: J Stem Cell Res Ther Volume: 4
  • Peer Reviewed / Open Access
• [Journal Article] Enhanced vascular endothelial growth factor signaling in islets contributes to β cell injury and consequential diabetes in Spontaneously Diabetic Torii rats. (2014)
  • Author(s): Mukai E, Ohta T, Kawamura H, Lee EY, Morita A, Sasase T, Miyajima K, Inagaki N, Iwanaga T, Miki T.
  • Journal Title: Diabetes Res Clin Pract Volume: 106 Issue: 2 Pages: 303-311
  • DOI: 10.1016/j.diabres.2014.08.023
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] GLP-1の膵α細胞における作用とその機序 (2014)
  • Author(s): 三木隆司
  • Journal Title: 内分泌糖尿病代謝内科 Volume: 38 Pages: 424-430
• [Journal Article] Refeeding with a standard diet after a 48-h fast elicits an inflammatory response in the mouse liver (2013)
  • Author(s): Oarada M, Miki T, Kohno S, Sakai K, Nikawa T, Yoneyama M, Gonoi T.
  • Journal Title: J Nutr Biochem Volume: (in press) Issue: 7 Pages: 1314-1323
  • DOI: 10.1016/j.jnutbio.2012.10.006
  • Peer Reviewed
• [Journal Article] Cephalic phase insulin secretion is KATP channel-independent. (2013)
  • Author(s): Seino, Y., Miki, M., Fujimoto, W., Lee, EY., Takahashi, Y., Minami, K., Oiso, Y., Seino, S.
  • Journal Title: J Endocrinol Volume: 218 Issue: 1 Pages: 25-33
  • DOI: 10.1530/joe-12-0579
  • Peer Reviewed
• [Journal Article] A case of Type 1 diabetes with nocturnal hypoglycemia after desensitization therapy for insulin allergy. (2013)
  • Author(s): Kitamoto, T., Sakurai, K., Tachibana K., Yokoh H., Ishikawa, K., Miki, T., Yokote K.
  • Journal Title: Diabetes Care Volume: 36 Issue: 7 Pages: 89-89
  • DOI: 10.2337/dc12-2591
  • Peer Reviewed
• [Presentation] Metabolite sensing and regulation of glucose metabolism in liver. Symposium in A better understanding of liver metabolism by multifaceted approaches (2015)
  • Author(s): Takashi Miki, Eun Young Lee, Yasuhiko Minokoshi
  • Organizer: 第92回日本生理学会大会
  • Place of Presentation: 神戸交際会議場（兵庫県、神戸市）
  • Year and Date: 2015-03-21
  • Invited
• [Presentation] Dual roles of a DPP-4 inhibitor on cytoprotection and proliferation of pancreatic β-cells in a mouse model of β-cell injury/regeneration. (2014)
  • Author(s): Mukai, E., Morita, A., Hiratsuka, A., Takatani, T., Lee, EY., Miki, T.
  • Organizer: 50th EASD Annual Meeting
  • Place of Presentation: Vienna (Austria)
  • Year and Date: 2014-09-19
• [Presentation] Mechanism and physiological roles of glucose sensing in enteroendocrine cells. (2014)
  • Author(s): Lee, EY., Zhang, X., Miki, T.
  • Organizer: 50th EASD Annual Meeting
  • Place of Presentation: Vienna (Austria)
  • Year and Date: 2014-09-16
• [Presentation] 単糖類はKATPチャネル依存性の経路と非依存性の経路によりGIP分泌を惹起する (2014)
  • Author(s): 尾方秀忠、清野祐介、原田範雄、飯田淳史、鈴木和代、泉本貴子、石川孝太、上西栄太、尾崎信暁、林良敬、三木隆司、稲垣暢也、清野進、濱田洋司、恒川新、大磯ユタカ
  • Organizer: 第57回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪交際会議場（大阪府、大阪市）
  • Year and Date: 2014-05-24
• [Presentation] 腸内分泌L細胞のグルコース感知と脳への情報伝達 (2014)
  • Author(s): 李恩瑛 、張錫麟、 三木隆司
  • Organizer: 第57回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪交際会議場（大阪府、大阪市）
  • Year and Date: 2014-05-24
• [Presentation] DPP-Ⅳ阻害薬による膵β細胞死抑制と増殖促進-膵β細胞傷害/再生マウスを用いた検討- (2014)
  • Author(s): 森田亜州華、向英里、平塚文乃、高谷具純、李恩瑛、三木隆司
  • Organizer: 第57回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪交際会議場（大阪府、大阪市）
  • Year and Date: 2014-05-22
• [Presentation] VEGFシグナル阻害はSDTラットにおけるβ細胞傷害と糖尿病発症を抑制する
  • Author(s): 向英里、太田毅、河村治清、李恩瑛、森田亜州華、笹瀬智彦、稲垣暢也、岩永敏彦、三木隆司
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: 熊本
• [Presentation] インスリン受容体変異マウスの高脂肪食感受性糖尿病発症のメカニズム
  • Author(s): 李恩瑛 櫻井健一 戸田知得 箕越靖彦 三木隆司
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: 熊本
• [Presentation] 高脂肪餌により糖尿病を発症する変異インスリン受容体ノックインマウスの肝臓における遺伝子発現
  • Author(s): 櫻井健一、李恩瑛、橘香穂里、石川耕、三木隆司
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: 熊本
• [Presentation] Unsuppressed Lipolysis in Adipose Tissue by Insulin Is Critical for Glucose Homeostasis under High Fat Diet
  • Author(s): Lee, E-Y., Sakurai, K., Toda,C., Minokoshi, Y., Miki, T.
  • Organizer: 49th EASD Annual Meeting
  • Place of Presentation: Barcelona, Spain
• [Presentation] Dynamic regulation of metabolite flow between adipose tissues and liver by insulin
  • Author(s): Miki, T.
  • Organizer: 第91回日本生理学会
  • Place of Presentation: 鹿児島
• [Book] ギャノング生理学 原書24版、「肝臓の輸送機能と代謝機能」 (2014)
  • Author(s): 三木隆司
  • Total Pages: 860
  • Publisher: 丸善出版株式会社
• [Book] イオンチャネル病の全て．「ATP感受性K+チャネルと疾患」 (2013)
  • Author(s): 三木隆司
  • Total Pages: 100
  • Publisher: 医歯薬出版株式会社
• [Remarks] 研究室ホームページ
  • URL: http://www.m.chiba-u.ac.jp/class/physiol/index.html
• [Remarks] 代謝生理学ホームページ
  • URL: http://www.m.chiba-u.ac.jp/class/physiol/index.html