Pathophysiological role of pancreatic beta-cell hypoxia

• Project/Area Number: 16K09758
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Kumamoto University
• Principal Investigator: SATO YOSHIFUMI 熊本大学, 大学院生命科学研究部(医), 助教 (90622598)
• Research Collaborator: Inoue Masahiro 京都大学, 大学院医学研究科クリニカルバイオリソース研究開発講座 ; Tasaki Masayoshi 熊本大学, 大学院生命科学研究部(保健学系)構造機能解析学分野
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 糖尿病 / β細胞 / β細胞代償機構 / 低酸素 / 膵β細胞

Outline of Final Research Achievements

This study demonstrated the pathophysiological role of beta cell hypoxia as follows. 1) Hypoxic stress caused beta-cell dysfunction via a HIF-independent (AMPK/HNF4a) pathway(Sato Y. JBC 2017). 2) Bhlhe40 and Phd3 were identified as novel regulators of beta cell hypoxia response. 3) These 2 protein can regulate insulin secretion and beta cell death in diabetes. 4) An imaging model mouse for visualizing islet vessels became available. 5) GLP-1 can escape beta cells from hypoxia by modulating intra-cellular cAMP levels.

Academic Significance and Societal Importance of the Research Achievements

糖尿病におけるβ細胞低酸素の病態および成因は明らかではない。本研究は、①低酸素によるβ細胞障害分子メカニズムの解明、②糖尿病時に膵島が低酸素化される機序の解明、および③β細胞低酸素化に対するGLP-1の防御機構の解明についての検討を行うものである。本研究の成果により、糖尿病におけるβ細胞低酸素の病態的意義が明らかになればβ細胞低酸素を標的とした新たな糖尿病治療法開発への応用が期待される。

Research Products

• [Journal Article] SIRT7 is an important regulator of cartilage homeostasis and osteoarthritis development. (2018)
  • Author(s): Korogi W, Yoshizawa T, Karim MF, Tanoue H, Yugami M, Sobuz SU, Hinoi E, Sato Y, Oike Y, Mizuta H, Yamagata K
  • Journal Title: Biochem Biophys Res Commun Volume: 印刷中 Issue: 3 Pages: 891-897
  • DOI: 10.1016/j.bbrc.2018.01.129
  • Peer Reviewed
• [Journal Article] Sirtuin 7 Deficiency Ameliorates Cisplatin-induced Acute Kidney Injury Through Regulation of the Inflammatory Response (2018)
  • Author(s): Miyasato Yoshikazu、Yoshizawa Tatsuya、Sato Yoshifumi、Nakagawa Terumasa、Miyasato Yuko、Kakizoe Yutaka、Kuwabara Takashige、Adachi Masataka、Ianni Alessandro、Braun Thomas、Komohara Yoshihiro、Mukoyama Masashi、Yamagata Kazuya
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 5927-5927
  • DOI: 10.1038/s41598-018-24257-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] SIRT7 has a critical role in bone formation by regulating lysine acylation of SP7/Osterix (2018)
  • Author(s): Fukuda Masatoshi、Yoshizawa Tatsuya et al.
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 2833-2833
  • DOI: 10.1038/s41467-018-05187-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hypoxia reduces HNF4alpha/MODY1 protein expression in pancreatic beta-cells by activating AMP-activated protein kinase. (2017)
  • Author(s): Sato Y, Karim MF et al.
  • Journal Title: J. Biol. Chem. Volume: 印刷中 Issue: 21 Pages: 8716-8728
  • DOI: 10.1074/jbc.m116.767574
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 低酸素応答因子HIF-1/AMPKによる膵β細胞障害の分子機構 (2018)
  • Author(s): 佐藤叔史
  • Organizer: 第91回日本生化学会大会
  • Invited
• [Presentation] Bhlhe40-Mafa経路を介した低酸素ストレスによるインスリン分泌抑制 (2018)
  • Author(s): 津山友徳、佐藤叔史、松岡孝昭、山縣和也
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] 膵β細胞における低酸素誘導因子BHLHE40の機能解析 (2017)
  • Author(s): 佐藤叔史
  • Organizer: ConBio2017
• [Remarks] ホームページ
  • URL: http://srv02.medic.kumamoto-u.ac.jp/dept/biochem2/biochem2.html
• [Remarks]
  • URL: http://srv02.medic.kumamoto-u.ac.jp/dept/biochem2/biochem2.html
• [Remarks] 熊本大学大学院生命科学研究部 病態生化学分野ホームページ
  • URL: http://srv02.medic.kumamoto-u.ac.jp/dept/biochem2/biochem2.html