Glucokinase Activation Ameliorates ER Stress-Induced Apoptosis in Pancreatic Beta-Cells

• Project/Area Number: 25860754
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Metabolomics
• Research Institution: Yokohama City University
• Principal Investigator: SHIRAKAWA JUN 横浜市立大学, 医学(系)研究科(研究院), 客員研究員 (70625532)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 膵β細胞 / 糖尿病 / アポトーシス / 小胞体ストレス / 2型糖尿病 / 炎症 / グルコキナーゼ

Outline of Final Research Achievements

Glucokinase upregulates insulin receptor substrate 2 (IRS-2) expression in beta-cells, but the role of glucokinase and IRS-2 in ER stress has been unclear. In this study, we investigated the impact of glucokinase activation by glucokinase activator (GKA) on ER stress in beta-cells. GKA administration improved beta-cell apoptosis in Akita mice, a model of ER stress-mediated diabetes. IRS-2-deficient islets were vulnerable, but bIRS-2-Tg islets were resistant to ER stress-induced apoptosis. Meanwhile, GKA regulated the expressions of C/EBP homologous protein (CHOP) and other ER stress-related genes in an IRS-2-independent fashion in islets. GKA suppressed the expressions of CHOP and Bcl2-associated X protein (Bax) and protected against beta-cell apoptosis under ER stress in an ERK1/2-dependent, IRS-2-independent manner. Taken together, GKA ameliorated ER stress-mediated apoptosis by harmonizing IRS-2 upregulation and the IRS-2-independent control of apoptosis in beta-cells.

Research Products

• [Journal Article] Selective and sequential loss of transcriptional factors: a hallmark of β cell failure in type 2 diabetes? (2014)
  • Author(s): Shirakawa J, Terauchi Y
  • Journal Title: J Diabetes Invest. Volume: in press Issue: 4 Pages: 359-61
  • DOI: 10.1111/jdi.12212
  • Peer Reviewed / Open Access
• [Journal Article] Using miglitol at 30 min before meal is effective in hyperinsulinemic hypoglycemia after a total gastrectomy (2014)
  • Author(s): Shirakawa J, Murohashi Y, Okazaki N, Yamazaki S, Tamura T, Okuyama T, Togashi Y, Terauchi Y.
  • Journal Title: Endocrine Journal Volume: 61 Issue: 11 Pages: 1115-1123
  • DOI: 10.1507/endocrj.EJ14-0290
  • NAID: 130004677955
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Effects of the antitumor drug OSI-906, a dual inhibitor of IGF-1 receptor and insulin receptor, on the glycemic control, β cell functions, and β cell proliferation in male mice. (2014)
  • Author(s): Shirakawa J, Okuyama T, Yoshida E, Shimizu M, Horigome Y, Tuno T, Hayasaka M, Abe S, Fuse M, Togashi Y, Terauchi Y.
  • Journal Title: Endocrinologｙ Volume: in press Issue: 6 Pages: 2102-11
  • DOI: 10.1210/en.2013-2032
  • Peer Reviewed
• [Journal Article] β cell proliferation after a partial pancreatectomy is independent of IRS-2 in mice. (2014)
  • Author(s): Togashi Y, Shirakawa J, Orime K, Kaji M, Sakamoto E, Tajima K, Inoue H, Nakamura A, Tochino Y, Goshima Y, Shimomura I, Terauchi Y.
  • Journal Title: Endocrinology Volume: 155 Issue: 5 Pages: 1643-52
  • DOI: 10.1210/en.2013-1796
  • Peer Reviewed
• [Journal Article] Metformin prevents liver tumorigenesis induced by high-fat diet in C57Bl/6 mice. (2014)
  • Author(s): Tajima K, Nakamura A, Shirakawa J, Togashi Y, Orime K, Sato K, Inoue H, Kaji M, Sakamoto E, Ito Y, Aoki K, Nagashima Y, Atsumi T, Terauchi Y.
  • Journal Title: Am J Physiol Endocrinol Metab Volume: 305
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Metformin prevents liver tumorigenesis induced by high-fat diet in C57Bl/6 Mice. (2013)
  • Author(s): Tajima K, Nakamura A, Shirakawa J, Togashi Y, Orime K, Sato K, Inoue H, Kaji M, Sakamoto E, Ito Y, Aoki K, Nagashima Y, Atsumi T, Terauchi Y.
  • Journal Title: Am. J. Physiol. Endocrinol. Metab. Volume: 305 Issue: 8 Pages: 987-998
  • DOI: 10.1152/ajpendo.00133.2013
  • Peer Reviewed
• [Journal Article] Glucokinase activation ameliorates ER stress-induced apoptosis in pancreatic β cells. (2013)
  • Author(s): Shirakawa J, Togashi Y, Sakamoto E, Kaji M, Tajima K, Orime K, Inoue H, Kubota N, Kadowaki T, Terauchi Y.
  • Journal Title: Diabetes Volume: 62 Issue: 10 Pages: 3448-58
  • DOI: 10.2337/db13-0052
  • Peer Reviewed
• [Journal Article] AMPK is involved in the regulation of incretin receptors expression in pancreatic islets under a low glucose concentration. (2013)
  • Author(s): Tajima K, Shirakawa J, Togashi Y, Inoue H, Sato K, Orime K, Ito Y, Kaji M, Sakamoto E, Nakamura A, Aoki K, Goshima Y, Atsumi T, Terauchi Y.
  • Journal Title: PLoS One. Volume: 8 Issue: 5 Pages: e64633-e64633
  • DOI: 10.1371/journal.pone.0064633
  • Peer Reviewed
• [Journal Article] Trefoil Factor 2 Promotes Cell Proliferation in Pancreaticβ-Cells through CXCR-4-Mediated ERK1/2 Phosphorylation (2013)
  • Author(s): Orime K, Shirakawa J, Togashi Y, Tajima K, Inoue H, Ito Y, Sato K, Nakamura A, Aoki K, Goshima Y, Terauchi, Y
  • Journal Title: Endocrinology Volume: 154(1) Issue: 1 Pages: 54-64
  • DOI: 10.1210/en.2012-1814
  • Peer Reviewed
• [Presentation] ワークショップ 膵島の単離とβ細胞の培養法 (2014)
  • Author(s): 白川純、寺内康夫
  • Organizer: 第28回 日本糖尿病・肥満動物学会年次学術集会
  • Place of Presentation: 宮崎市民プラザ（宮崎県宮崎市）
  • Invited
• [Presentation] シンポジウム１ 膵β細胞障害と再生 増殖およびアポトーシスの制御による膵β細胞量の調節機構 (2014)
  • Author(s): 白川純、寺内康夫
  • Organizer: 第28回 日本糖尿病・肥満動物学会年次学術集会
  • Place of Presentation: 宮崎市民プラザ（宮崎県宮崎市）
  • Invited
• [Presentation] Characterization of target genes of glucokinase activator (GKA) in pancreatic islets. (2013)
  • Author(s): Jun Shirakawa, Kazuki Orime, Yu Togashi, hideaki Inoue, Yasuo Terauchi
  • Organizer: 73th American Diabetes Association (ADA) meeting
  • Place of Presentation: Chicago, IL, USA
• [Presentation] シンポジウム 膵β細胞研究の進化と展望 増殖およびアポトーシスの制御による膵β細胞量の調節機構 (2013)
  • Author(s): 白川純, 井上英明, 田島一樹, 富樫優, 寺内康夫
  • Organizer: 第56回 日本糖尿病学会年次学術集会
  • Place of Presentation: ホテル日航熊本（熊本県熊本市）
  • Invited
• [Presentation] The roles of glucokinase activation and IRS-2 in ER stress-induced apoptosis in pancreatic β cells. (2013)
  • Author(s): Jun Shirakawa, Yu Togashi, Kazuki Orime, Kazuki Tajima, Mitsuyo Kaji, Eri Sakamoto, and Yasuo Terauchi
  • Organizer: 第56回 日本糖尿病学会年次学術集会
  • Place of Presentation: ホテル日航熊本（熊本県熊本市）