the molecular mechanism of ER stress response in pancreatic beta cells : type 2 diabets

• Project/Area Number: 22790842
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Metabolomics
• Research Institution: Nihon University (2011); Tohoku University (2010)
• Principal Investigator: YAMAGUCHI Suguru 日本大学, 医学部, 助教 (70451614)
• Project Period (FY): 2010 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2011: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2010: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 膵β細胞 / 小胞体ストレス / 4E-BP1 / ATF6α / DPP-4阻害薬 / 糖尿病

Research Abstract

In the current study, we investigated 4E-BP1 expression, which is important for beta-cell survival, in MIN6 cells under ER stress and oxidative stress. We found that JNK activated by oxidative stress is involved in the modulation of 4E-BP1 expression and phosphorylation in MIN6 cells.
In this study, we analyzed Atf6α-null mice. ATF6α protects β-cells from ER stress and suppresses hepatosteatosis, but plays a role in the development of hyperlipidemia and insulin resistance.
The study is designed to investigate whether the activation of the incretin system by DPP-4 inhibition ameliorates β-cell failure in WFS1-deficient mice, a genetically defined model of human diabetes caused by ER stress in β-cells. These findings provide evidence that activation of the incretin system by vildagliptin plays a protective role against β-cells with WFS1-deficiency.

Research Products

• [Journal Article] Atf6α-null mice are glucose intolerant due to pancreatic β-cell failure on a high-fat diet but partially resistant to diet-induced insulin resistance (2012)
  • Author(s): Masahiro Usui, Suguru Yamaguchi, Yasuhiro Tanji, Ryu Tominaga, Yasushi Ishigaki, Manabu Fukumoto, Hideki Katagiri, Kazutoshi Mori, Yoshitomo Oka, Hisamitsu Ishihara
  • Journal Title: Metabolism Volume: (in press)
• [Journal Article] Involvement of endoplasmic stress protein C/EBP homologous protein in arteriosclerosis acceleration with augmented biological stress responses (2011)
  • Author(s): Gao J, Ishigaki Y, Yamada T, Kondo K, Yamaguchi S, Imai J, Uno K, HasegawaY, Sawada S, Ishihara H, Oyadomari S, Mori M, Oka Y, Katagiri H
  • Journal Title: Circulation Volume: 124 Issue: 7 Pages: 830-839
  • DOI: 10.1161/circulationaha.110.014050
  • Peer Reviewed
• [Journal Article] The JNK pathway modulates expression and phosphorylation of the translational suppressor 4E-BP1 in MIN6 pancreatic beta-cells under oxidative stress conditions (2010)
  • Author(s): Tominaga R, Yamaguchi S, Satake C, Usui M, Tanji Y, Kondo K, Katagiri H, Oka Y, Ishihara H
  • Journal Title: Cell Biochem Funct Volume: 28 Issue: 5 Pages: 387-393
  • DOI: 10.1002/cbf.1667
  • Peer Reviewed
• [Journal Article] The JNK pathway modulates expression and phosphorylation of the translational suppressor 4E-BP1 in MIN6 pancreatic β-cells under oxidative stress conditions (2010)
  • Author(s): Ryu Tominaga, Suguru Yamaguchi, Chihiro Satake, Masahiro Usui, Yasuhiro Tanji, Keiichi Kondo, Hideki Katagiri, Yoshitomo Oka, Hisamitsu Ishihara
  • Journal Title: cell biochemistry and function Volume: 28(5) Pages: 387-393
  • Peer Reviewed
• [Journal Article] Atf6α-null mice are glucose intolerant due to pancreatic β-cell failure on a high-fat diet but partially resistant to diet-induced insulin resistance
  • Author(s): Masahiro Usui, Suguru Yamaguchi Yasuhiro Tanji, Ryu Tominaga, Yasushi Ishigaki, Manabu Fukumoto, Hideki Katagiri, Kazutoshi Mori, Yoshitomo Oka, Hisamitsu Ishihara
  • Journal Title: Metabolism Volume: (In press)
  • Peer Reviewed
• [Presentation] ATF6α欠損マウスを用いた、ATF6α欠損が耐糖能に与える影響についての検討 (2011)
  • Author(s): 薄井正寛、石原寿光、鈴木千登世、山口賢、、石垣泰、福本学、森和俊、岡芳知、片桐秀樹
  • 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: 2011-05-20
• [Presentation] WFS1遺伝子欠損マウスにおけるDPP-4阻害薬(vildagliptin)の膵β細胞保護効果の検討 (2011)
  • Author(s): 丹治泰裕、山口賢、薄井正寛、冨永竜、近藤敬一、、石垣泰、岡芳知、片桐秀樹、石原寿光
  • 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: 2011-05-20
• [Presentation] GLP-1 exerts a protective role in pancreatic β-cells with WFS1-deficiency (2011)
  • Author(s): Suguru Yamaguchi, Yasuhiro Tanji, Masahiro Usui, Ryu Tominaga, Keiichi Kondo, Yasushi Ishigaki, Hideki Katagiri, Yoshitomo Oka, Hisamitsu Ishihara
  • Organizer: The 47th EASD Annual Meeting
  • Place of Presentation: Lisbon, Portugal
• [Presentation] GLP-1 exerts a protective role in pancreatic β-cells with WFS1-deficiency (2011)
  • Author(s): Suguru Yamaguchi, Yasuhiro Tanji, Masahiro Usui, Ryu Tominaga, Keiichi Kondo, Yasushi Ishigaki, Hideki Katagiri, Yoshitomo Oka, Hisamitsu Ishihara
  • Organizer: the 47th EASD Annual Meeting
  • Place of Presentation: Lisbon, Portugal
• [Presentation] WFS1遺伝子欠損マウスに発表演目おけるDPP-4阻害薬(ビルダグリプチン)の膵β細胞保護効果の検討 (2010)
  • Author(s): 丹治泰裕、山口賢、薄井正寛、冨永竜、近藤敬一、石垣泰、片桐秀樹、岡芳知、石原寿光
  • Organizer: 第22回分子糖尿病学シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2010-12-04
• [Presentation] ATF6α欠損マウスを用いた、ATF6α欠損が耐糖能に与える影響についての検討 (2010)
  • Author(s): 薄井正寛、石原寿光、鈴木千登世、山口賢、石垣泰、福本学、森和俊、岡芳知、片桐秀樹
  • 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: 2010-05-20
• [Presentation] 動脈硬化発症・進展におけるWFS1の役割の検討 (2010)
  • Author(s): 高俊弘、片桐秀樹、石垣泰、石原寿光、山田哲也、今井淳太、澤田正二郎、宇野健司、長谷川豊、山口賢、金子慶三、鈴木俊伸、齋藤徳郎、突田壮平、近藤敬一、高橋圭、檜尾好徳、岡芳知
  • Organizer: 第53回日本糖尿病学会年次学術集会
  • Place of Presentation: 岡山
• [Presentation] 膵β細胞における小胞体ストレス応答と酸化ストレス応答のクロストーク (2010)
  • Author(s): 冨永竜、石原寿光、山口賢、佐竹千尋、薄井正寛、丹治泰裕、鈴木千登世、石垣泰、山田哲也、檜尾好徳、片桐秀樹、岡芳知
  • Organizer: 第53回日本糖尿病学会年次学術集会
  • Place of Presentation: 岡山
• [Presentation] 新規小胞体ストレス蛋白・CRELD2の蛋白特性についての検討 (2010)
  • Author(s): 山口賢、石原寿光、宗像佑一郎、佐竹千尋、薄井正寛、冨永竜、丹治泰裕、鈴木千登世、石垣泰、山田哲也、檜尾好徳、片桐秀樹、岡芳知
  • Organizer: 第53回日本糖尿病学会年次学術集会
  • Place of Presentation: 岡山