Autophagic failure in islets

• Project/Area Number: 17H04202
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Juntendo University
• Principal Investigator: WATADA HIROTAKA 順天堂大学, 医学(系)研究科(研究院), 教授 (60343480)
• Co-Investigator(Kenkyū-buntansha): 西田 友哉 順天堂大学, 医学部, 准教授 (10581449) ; 宮塚 健 順天堂大学, 医学(系)研究科(研究院), 准教授 (60622363)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000); Fiscal Year 2019: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2018: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2017: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
• Keywords: 糖尿病 / 膵β細胞 / インスリン / グルカゴン / オートファジー / マイトファジー / 膵α細胞 / ２型糖尿病

Outline of Final Research Achievements

We have previously demonstrated that autophagy plays an important role in maintenance of pancreatic β-cell function. However, it is not clear whether the acquired autophagy deficiency observed in type 2 diabetes causes pancreatic β-cell failure. Therefore, this time, we established the mice with inducible autophagy deficiency of pancreatic β cells, and examined the glucose metabolism of the mice. As a result, it was revealed that continuation of autophagy deficiency for several weeks causes pancreatic β-cell failure. Furthermore, we revealed that autophagy deficiency in pancreatic α cells is not directly involved in abnormal glucose metabolism, and BCL2L13, a mammalian homologue of Atg32, a recently identified molecule essential for mitophagy, is not involved in the maintenance of pancreatic β cell function.

Academic Significance and Societal Importance of the Research Achievements

我々の研究グループは、膵β細胞におけるオートファジー機能不全が膵β細胞機能不全に関与することを世界に先駆けて解明し、この分野における世界のリーダー的立場にいる。本研究はこれまでの研究を継承し、膵β細胞機能不全とオートファジー機能不全の一端を解明した。本研究の結果は、２型糖尿病における膵島不全の病態解明に貢献し、新規糖尿病治療薬の分子標的の発見につながる可能性がある。

Research Products

• [Int'l Joint Research] University of Pittsburgh(米国)
• [Journal Article] Cellular autophagy in α cells plays a role in the maintenance of islet architecture (2019)
  • Author(s): Himuro Miwa、Miyatsuka Takeshi、Suzuki Luka、Miura Masaki、Katahira Takehiro、Goto Hiromasa、Nishida Yuya、Sasaki Shugo、Koike Masato、Shiota Chiyo、Gittes George K、Fujitani Yoshio、Watada Hirotaka
  • Journal Title: Journal of the Endocrine Society Volume: 3 Pages: 1979-92
  • DOI: 10.1210/js.2019-00075
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Normal pancreatic β-cell function in mice with <i>RIP-Cre</i>-mediated inactivation of p62/SQSTM1 (2018)
  • Author(s): Honda A, Komiya K, Hara A, Fukunaka A, Suzuki L, Miyatsuka T, Ogihara T, Fujitani Y, Watada H.
  • Journal Title: Endocrine Journal Volume: 65 Issue: 1 Pages: 83-89
  • DOI: 10.1507/endocrj.EJ17-0333
  • NAID: 130006321958
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed
• [Journal Article] Heterogeneity of autophagic status in pancreatic β cells under metabolic stress. (2018)
  • Author(s): Kamitani M, Miyatsuka T, Miura M, Azuma K, Suzuki L, Himuro M, Katahira T, Nishida Y, Fujitani Y, Watada H.
  • Journal Title: Biochem Biophys Res Commun. Volume: 496 Issue: 2 Pages: 328-334
  • DOI: 10.1016/j.bbrc.2018.01.070
  • Peer Reviewed
• [Presentation] Exploring the Role of Autophagy in Pancreatic Alpha Cells (2019)
  • Author(s): Himuro, M., Miyatsuka, T., Suzuki, L., Miura, M., Katahira, T., Goto, H., Nishida, Y., Sasaki, S., Fujitani, Y.,Watada, H.
  • Organizer: 79th American Diabetes Association, San Francisco(USA), 2019.6.7-11
  • Int'l Joint Research
• [Presentation] Autophagy Deficiency Cumulatively Causes β-Cell Failure in Mice (2019)
  • Author(s): Suzuki, L., Miyatsuka, T., Himuro, M., Miura, M., Katahira, T., Komiya, K., Fujitani, Y., Nishida, Y.,Watada, H.
  • Organizer: 79th American Diabetes Association, San Francisco(USA), 2019.6.7-11
  • Int'l Joint Research
• [Presentation] Role of autophagy in pancreatic beta cells and atherosclerosis (2018)
  • Author(s): Watada H.
  • Organizer: The 4th IMCR Symposium on Endocrine and Metabolim: At the Cutting Edge of Metabolic Regulation Research Gunmaken
  • Int'l Joint Research / Invited
• [Presentation] 膵β細胞における時間特異的Atg7欠損マウスの作製と機能解析 (2017)
  • Author(s): 鈴木路可, 宮塚健, 氷室美和, 神谷麻衣, 三浦正樹, 小宮幸次, 藤谷与士夫, 西田友哉, 綿田裕孝
  • Organizer: 第60回日本糖尿病学会年次学術集会
• [Presentation] 膵α細胞特異的オートファジー不全モデルマウスの作成とその機能解析 (2017)
  • Author(s): 氷室美和, 宮塚健, 鈴木路可, 神谷麻衣, 三浦正樹, 片平雄大, 小池正人, Shiota C., Gittes G. K., 藤谷与士夫, 綿田裕孝
  • Organizer: 第60回日本糖尿病学会年次学術集会
• [Presentation] Cumulative autophagy deficiency causes progressive β-cell failure. (2017)
  • Author(s): Suzuki L., Miyatsuka T., Himuro M., Miura M., Fujitani Y., Nishida Y., Watada H.
  • Organizer: The 8th International Symposium on Autophagy
  • Int'l Joint Research
• [Presentation] Exploring the autophagy mechanism in pancreatic alpha cell (2017)
  • Author(s): Himuro M., Miyatsuka T., Suzuki L., Koike M., Shiota C., Gittes G. K., Fujitani Y., Watada H.
  • Organizer: 53rd Annual meeting of the European Association for the Study of Diabetes
  • Int'l Joint Research
• [Remarks] 順天堂大学大学院代謝内分泌内科学
  • URL: http://www.juntendo.ac.jp/graduate/laboratory/labo/taisya_naibunpitsu/