Establishing a base for tailor-made therapy on diabetes from the view point of the pancreatic beta cell mass

• Project/Area Number: 24390235
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Yokohama City University
• Principal Investigator: TERAUCHI Yasuo 横浜市立大学, 医学(系)研究科(研究院), 教授 (40359609)
• Co-Investigator(Kenkyū-buntansha): SHIRAKAWA Jun 横浜市立大学, 医学(系)研究科(研究院), 客員研究員 (70625532) ; 木村 真理 横浜市立大学, 附属病院, 准教授 (40363840) ; 中村 昭伸 横浜市立大学, 附属病院, 助教 (70552420)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥18,200,000 (Direct Cost: ¥14,000,000、Indirect Cost: ¥4,200,000); Fiscal Year 2014: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2013: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2012: ¥9,620,000 (Direct Cost: ¥7,400,000、Indirect Cost: ¥2,220,000)
• Keywords: 膵β細胞 / グルコキナーゼ / グルコースシグナル / グルコース / 増殖 / アポトーシス / 分化

Outline of Final Research Achievements

We investigated changes in the expression of genes involved in beta cell function and proliferation in mouse islets stimulated with glucokinase activator (GKA) in order to elucidate the mechanisms by which GKA stimulates beta cell function and proliferation. GKA-stimulated IRS2 production affected beta cell proliferation but not beta cell function. We investigated the impact of glucokinase activation by GKA on ER stress in β cells. GKA administration improved β-cell apoptosis in Akita mice, a model of ER stress-mediated diabetes. GKA ameliorated ER stress-mediated apoptosis by harmonizing IRS-2 upregulation and the IRS-2-independent control of apoptosis in β cells. IRS-2 knockout mice exhibited an enhancement in β-cell proliferation after a pancreatectomy equal to that observed in wild-type mice. A pancreatectomy stimulated β-cell proliferation via a signaling pathway different from that involved in high-fat diet-induced β-cell expansion.

Research Products

• [Journal Article] Present status of clinical deployment of glucokinase activators. (2015)
  • Author(s): Nakamura A, Terauchi Y.
  • Journal Title: J Diabetes Investig Volume: 6 Pages: 124-132
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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(5) Pages: 1643-52
  • 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: 155(6) Pages: 2102-11
  • 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: 155
  • Peer Reviewed
• [Journal Article] Trefoil factor 2 promotes cell proliferation in pancreatic β 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 Pages: 54-64
  • 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] 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] Factors associated with the glucose-lowering effect of vildagliptin identified from the results of the oral glucose tolerance test in Japanese patients with type 2 diabetes. (2013)
  • Author(s): Nakamura A, et al.
  • Journal Title: Endocr J Volume: (In press)
  • NAID: 10031156721
  • 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, et al.
  • Journal Title: PloS ONE Volume: (In press)
  • Peer Reviewed
• [Journal Article] Impact of the dipeptidyl peptidase-4 inhibitor vildagliptin on glucose tolerance, beta cell function and mass in insulin receptor substrate-2-knockout mice fed a high-fat diet. (2012)
  • Author(s): Sato K, et al.
  • Journal Title: Endocrinology Volume: 153 Pages: 1093-1102
  • Peer Reviewed
• [Journal Article] Effects of liraglutide on B cell-specific glucokinase-deficient neonatal mice. (2012)
  • Author(s): Shirakawa J, et al.
  • Journal Title: Endocrinology Volume: 153 Pages: 3066-3075
  • Peer Reviewed
• [Journal Article] Control of beta cell function and proliferation in mice stimulated by small molecule glucokinase activator under various conditions. (2012)
  • Author(s): Nakamura A, et al.
  • Journal Title: Diabetologia Volume: 55 Pages: 1745-1754
  • Peer Reviewed
• [Journal Article] Pleiotropic effects of sitagliptin in the treatment of type 2 diabetes mellitus patients. (2012)
  • Author(s): Kubota A, et al.
  • Journal Title: J Clin Med Res Volume: 4 Pages: 309-313
  • Peer Reviewed
• [Presentation] Different effect of short-term and long-term high-fat diet feeding on pancreatic beta cell proliferation. (2014)
  • Author(s): Kitao N, Nakamura A, Nomoto H, Miyoshi H, Terauchi Y, Atsumi T
  • Organizer: 10th IDF-WPR Congress/6th AASD Scientific Meeting
  • Place of Presentation: Singapore, Singapore
  • Year and Date: 2014-11-20 – 2014-11-21
• [Presentation] The role of S100A8 and S100A9 in inflammatory interaction between pancreatic islets and macrophages. (2014)
  • Author(s): Inoue H, Shirakawa J, Orime K, Togashi Y, Tajima K, Terauchi Y
  • Organizer: 50th Annual Meeting of the European Association for the Study of Diabetes
  • Place of Presentation: Vienna, Austria.
  • Year and Date: 2014-09-15 – 2014-09-19
• [Presentation] Isolation of target genes of liraglutide, a GLP-1 receptor agonist, in pancreatic islets by using nano-LC-MS/MS system. (2014)
  • Author(s): Yoshida E, Shirakawa J, Okuyama T, Kyohara M, Togashi Y, Kimura A, Hirano H, Terauchi Y
  • Organizer: 50th Annual Meeting of the European Association for the Study of Diabetes
  • Place of Presentation: Vienna, Austria.
  • Year and Date: 2014-09-15 – 2014-09-19
• [Presentation] β cell proliferation in glucokinase haploinsufficient mice and IRS-2 deficient mice after a partial pancreatectomy. (2013)
  • Author(s): Togashi Y, Shirakawa J, Terauchi Y
  • Organizer: Beta Cell Workshop 2013 Kyoto
  • Place of Presentation: 国立京都国際会館（京都府京都市）
• [Presentation] Glucokinase activation ameliorates ER stress-induced apoptosis in pancreatic β cells. (2013)
  • Author(s): Shirakawa J, Terauchi Y
  • Organizer: Beta Cell Workshop 2013 Kyoto
  • Place of Presentation: 国立京都国際会館（京都府京都市）
  • Invited
• [Presentation] Impact of glucokinase activation on proliferation and apoptosis of pancreatic beta cells. (2013)
  • Author(s): Terauchi Y
  • Organizer: Beta Cell Workshop 2013 Kyoto
  • Place of Presentation: 国立京都国際会館（京都府京都市）
  • Invited
• [Presentation] Partial pancreatectomy facilitated β cell proliferation in glucokinase haploinsufficient mice and IRS-2 deficient mice. (2013)
  • Author(s): Togashi Y, Shirakawa J, Orime K, Inoue H, Nakamura A, Terauchi Y.
  • Organizer: 73rd American Diabetes Association (ADA) meeting
  • Place of Presentation: Chicago, USA.
• [Presentation] Characterization of target genes of glucokinase activator (GKA) in pancreatic islets. (2013)
  • Author(s): Shirakawa J, Terauchi Y
  • Organizer: 73rd American Diabetes Association (ADA) meeting
  • Place of Presentation: Chicago, USA.
• [Presentation] Coordinated effects of macrophages and free fatty acids on the inflammatory gene expression in pancreatic islets. (2013)
  • Author(s): Inoue H, Shirakawa J, Orime K, Togashi Y, Terauchi Y
  • Organizer: 49th Annual Meeting of the European Association for the Study of Diabetes
  • Place of Presentation: Barcelona, Spain
• [Presentation] Recent progress in blood glucose control. (2012)
  • Author(s): 寺内康夫
  • Organizer: The 30^<th> Annual Meeting of the International Society of Blood Purification.
  • Place of Presentation: パシフィコ横浜(神奈川県)(招待講演)
  • Year and Date: 2012-09-07
• [Presentation] Glucokinase activator ameliorates B cell ER stress and apoptosis by both IRS-2-dependent and -independent pathways. (2012)
  • Author(s): Shirakawa J, et al.
  • Organizer: 第72回米国糖尿病学会
  • Place of Presentation: フィラデルフィア(米国)
  • Year and Date: 2012-06-10
• [Presentation] Trefoil factor 2 promotes cell proliferation in pancreatic B cells through A CXCR4-mediated ERK1/2 pathway. (2012)
  • Author(s): Orime K, et al.
  • Organizer: 第72回米国糖尿病学会
  • Place of Presentation: フィラデルフィア(米国)
  • Year and Date: 2012-06-10
• [Presentation] Signaling pathway of 8 cell proliferation after partial pancreatectomy is distinct from that on a high-fat diet in mice. (2012)
  • Author(s): Togashi Y, et al.
  • Organizer: 第72回米国糖尿病学会
  • Place of Presentation: フィラデルフィア(米国)
  • Year and Date: 2012-06-10
• [Presentation] The regulatory mechanism of incretin receptor expressions by dephosphorylation of AMPK in islet. (2012)
  • Author(s): Tajima K, et al.
  • Organizer: 第72回米国糖尿病学会
  • Place of Presentation: フィラデルフィア(米国)
  • Year and Date: 2012-06-10
• [Presentation] Effects of glucokinase activator (GKA)on the regulation of B cell ER stress and incretin receptor expressions. (2012)
  • Author(s): 白川 純
  • Organizer: 第55回日本糖尿病学会
  • Place of Presentation: パシフィコ横浜(神奈川県)(招待講演)
  • Year and Date: 2012-05-17
• [Remarks] 横浜市立大学大学院医学研究科 分子内分泌・糖尿病内科学教室
  • URL: http://www-user.yokohama-cu.ac.jp/~nai3naib/
• [Remarks] 横浜市立大学大学院 医学研究科 分子内分泌・糖尿病内科学教室
  • URL: http://www-user.yokohama-cu.ac.jp/~nai3naib/
• [Remarks]