Molecular mechanism of type 2 diabetes based on pancreatic-cell enriched transcription factors

• Project/Area Number: 21390281
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Kumamoto University
• Principal Investigator: YAMAGATA Kazuya 熊本大学, 大学院・生命科学研究部, 教授 (70324770)
• Co-Investigator(Kenkyū-buntansha): SENOKUCHI Takafumi 熊本大学, 大学院・生命科学研究部, 助教 (00530320) ; HATTA Mitsutoki 熊本大学, 大学院・生命科学研究部, 助教 (30344518)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000); Fiscal Year 2011: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2010: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2009: ¥7,670,000 (Direct Cost: ¥5,900,000、Indirect Cost: ¥1,770,000)
• Keywords: 糖尿病 / インスリン / 遺伝子 / 転写因子 / hepatocyte nuclear factor / β細胞 / ERストレス / GRP78 / 標的遺伝子

Research Abstract

Mutation in the gene encoding hepatocyte nuclear factor 4(HNF4) cause impaired insulin secretion and type 2 diabetes, but the molecular mechanism is unknown. In the present work, I found that Anks4b is a novel target gene of HNF4 in-cells. Furthermore, I also identified that Anks4b regulates the sensitivity of ER stress in-cells. This study revealed that HNF4 regulates ER stress in-cells through Anks4b expression.

Research Products

• [Journal Article] Clinical features of Japanese type 2 diabetics with insulinogenic index in normal range after treatment of glucotoxicity (2011)
  • Author(s): Iwahashi H, Akita E, Tokunaga A, Okita K, Horikawa Y, Imagawa A, Funahashi T, Shimomura I, Yamagata K
  • Journal Title: Diabetol Int Volume: 2 Pages: 208-213
• [Journal Article] Deficit of Lys-tRNA Modification by Cdkal1 Causes the Development of Type 2 Diabetes in Mice (2011)
  • Author(s): Wei F-Y, Suzuki T, Watanabe S, Kimura S, Kaitsuka T, Fujimura A, Matsui H, Atta M, Michiue H, Fontecave M, Yamagata K, Suzuki T, Tomizawa K
  • Journal Title: J. Clin. Invest Volume: 121 Pages: 3598-3608
• [Journal Article] Voltage-gated K^+channel KCNQ1 regulates insulin secretion in MIN6-cell line (2011)
  • Author(s): Yamagata K, Senokuchi T, Lu M, Takemoto M, Karim MF, Go C, Sato Y, Hatta M, Yoshizawa T, Araki E, Miyazaki J, Song W-J
  • Journal Title: Biochem Biophys Res Commun Volume: 407 Pages: 620-625
• [Journal Article] Cellular hypoxia of pancreatic-cells due to high levels of oxygen consumption for insulin secretion in vitro (2011)
  • Author(s): Sato Y, Endo H, Okuyama H, Takeda T, Iwahashi H, Imagawa A, Yamagata K, Shimomura I, Inoue M
  • Journal Title: J Biol. Chem Volume: 286 Pages: 12524-12532
• [Journal Article] Mitochondrial dysfunction and increased reactive oxygen species impair insulin secretion in sphingomyelin synthase 1 null mice (2011)
  • Author(s): Yano M, Watanabe K, Yamamoto T, Ikeda K, Senokuchi T, Lu M, Kadomatsu T, Tsukano H, Ikawa M, Okabe M, Yamaoka S, Okazaki T, Umehara H, Gotoh T, Song WJ, Node K, Taguchi R, Yamagata K, Oike Y
  • Journal Title: J Biol Chem Volume: 286 Pages: 3992-4002
  • NAID: 120006957387
• [Journal Article] Voltage-gated K^+ channel KCNQ1 regulates insulin secretion in MIN6 β-cell line (2011)
  • Author(s): Yamagata K., et al
  • Journal Title: Biochem Biophys Res Commun Volume: 407 Pages: 620-625
  • Peer Reviewed
• [Journal Article] Deficit of Lys-tRNA Modification by Cdkall Causes the Development of Type 2 Diabetes in Mice (2011)
  • Author(s): Wei FY., et al
  • Journal Title: J.Clin.Invest. Volume: 121 Pages: 3598-3608
  • Peer Reviewed
• [Journal Article] Clinical features of Japanese type 2 diabetics with insulinogenic index in normal range after treatment of giucotoxicity (2011)
  • Author(s): Iwahashi H., et al
  • Journal Title: Diabetol Int Volume: 2 Pages: 208-213
  • Peer Reviewed
• [Journal Article] Voltage-gated K^+ channel KCNQ1 regulates insulin secretion in MIN6 β-cell line. (2011)
  • Author(s): Yamagata K., et al.
  • Journal Title: Biochem Biophys Res Commun. Volume: (印刷中)
  • Peer Reviewed
• [Journal Article] Cellular hypoxia of pancreatic β-cells due to high levels of oxygen consumption for insulin secretion in vitro. (2011)
  • Author(s): Sato Y., et al.
  • Journal Title: J Biol.Chem. Volume: 286 Pages: 12524-12532
  • Peer Reviewed
• [Journal Article] Mitochondrial dysfunction and increased reactive oxygen species impair insulin secretion in sphingomyelin synthase 1 null mice. (2011)
  • Author(s): Yano M., et al.
  • Journal Title: J Biol.Chem. Volume: 286 Pages: 3992-4002
  • Peer Reviewed
• [Journal Article] Synthesized basement membranes direct the differentiation of mouse embryonic stem cells into pancreatic lineages (2010)
  • Author(s): Higuchi Y, Shiraki N, Yamane K, Qin Z, Mochitate K, Araki K, Senokuchi T, Yamagata K, Hara M, Kume K, Kume S
  • Journal Title: J Cell Sci Volume: 123 Pages: 2733-2742
• [Journal Article] Similar incretin secretion in obese and non-obese Japanese subjects with type 2 diabetes (2010)
  • Author(s): Kozawa J, Okita K, Imagawa A, Iwahashi H, Holst JJ, Yamagata K, Shimomura I
  • Journal Title: Biochem Biophys Res Commun Volume: 393 Pages: 410-413
• [Journal Article] Glucose enhances collectrin protein expression in insulin-producing MIN6 cells (2009)
  • Author(s): Saisho K, Fukuhara A, Yasuda T, Sato Y, Fukui K, Iwahashi H, Imagawa A, Hatta M, Shimomura I, Yamagata K
  • Journal Title: Biochem. Biophys. Res. Commun Volume: 389 Pages: 133-137
• [Journal Article] Construction of a prediction model for type 2 diabetes mellitus in the Japanese population based on eleven genes with strong evidence of the association (2009)
  • Author(s): Miyake K, et al.
  • Journal Title: J Hum Genet. 54 Pages: 236-241
  • Peer Reviewed
• [Journal Article] Glucagonoma diagnosed by arterial stimulation and venous sampling(ASVS) (2009)
  • Author(s): Okauchi Y, et al.
  • Journal Title: Intern Med. 48 Pages: 1025-1030
  • Peer Reviewed
• [Journal Article] Glucose enhances collectrin protein expression in insulin-producing MIN6 β cells (2009)
  • Author(s): Saisho K, et al.
  • Journal Title: Biochem.Biophys.Res.Commun. 389 Pages: 133-137
  • Peer Reviewed
• [Journal Article] (2009)
  • Author(s): 山縣和也
  • Journal Title: 糖尿病と遺伝子(診断と治療社) Pages: 73-76
• [Journal Article] Anks4b, a novel target of HNF4α interacts with GRP78 and regulates endoplasmic reticulum stress-induced apoptosis in pancreaticβ-cells
  • Author(s): Sato Y, Hatta M, Karim Fazlul, Sawa T, Wei F-W, Sato S, Magnuson MA, Gonzalez FJ, Tomizawa K, Akaike T, Yoshizawa T, Yamagata K
  • Journal Title: J Biol. Chem Volume: (in press)
• [Presentation] Analysis of a novel HNF4 target gene Anks4b in pancreaticβ-cells (2011)
  • Author(s): Yoshifumi Sato, Mitsutoki Hatta, Md. Fazlul Karim, Tatsuya Yoshizawa, Kazuya Yamagata
  • Organizer: 第34回日本分子生物学会
  • Place of Presentation: パシフィコ横浜(横浜)
  • Year and Date: 2011-12-13
• [Presentation] Analysis of a novel HNF4α target gene Anks4b in pancreatic β-cells (2011)
  • Author(s): Sato Y., et al
  • Organizer: 第34回日本分子生物学会
  • Place of Presentation: パシフィコ横浜(横浜)
  • Year and Date: 2011-12-13
• [Presentation] シンポジウム1「酸素センサーとシグナル応答」膵β細胞における低酸素ストレス (2011)
  • Author(s): 山縣和也
  • Organizer: 第17回MPO研究会
  • Place of Presentation: アークホテル熊本(熊本)
  • Year and Date: 2011-10-28
• [Presentation] 2型糖尿病疾患感受性遺伝子KCNQ1によるインスリン分泌 (2011)
  • Author(s): 山縣和也
  • Organizer: 第49回日本糖尿病学会九州地方会
  • Place of Presentation: アクロス福岡(博多)
  • Year and Date: 2011-10-14
• [Presentation] 核小体因子SIRT7による糖脂質代謝制御 (2011)
  • Author(s): 山縣和也
  • Organizer: 第32回日本肥満学会淡路夢舞台国際会議場
  • Place of Presentation: 兵庫
  • Year and Date: 2011-09-24
• [Presentation] 膵β細胞と低酸素ストレス (2011)
  • Author(s): 山縣和也
  • Organizer: 第5回Diabetes Leading-edge Conferenceロイヤルオークホテル
  • Place of Presentation: 滋賀
  • Year and Date: 2011-08-07
• [Presentation] NAD依存性脱アセチル化酵素SIRT7の糖代謝への関与の検討 (2011)
  • Author(s): 瀬ノ口隆文、郷知佐、吉澤達也、宮田敬士、Eva Bober、尾池雄一、荒木栄一、山縣和也
  • Organizer: 第54回日本糖尿病学会年次学術集会
  • Place of Presentation: ロイトン札幌(北海道)
  • Year and Date: 2011-05-21
• [Presentation] HIF-1αによる酸素消費の抑制は膵β細胞の細胞内低酸素を回避する (2011)
  • Author(s): 佐藤叔史、今川彰久、山縣和也、下村伊一郎、井上正宏
  • Organizer: 第54回日本糖尿病学会年次学術集会
  • Place of Presentation: ロイトン札幌(北海道)
  • Year and Date: 2011-05-21
• [Presentation] Regulation of insulin secretion by HNF4 transcription factor (2010)
  • Author(s): 山縣和也
  • Organizer: BMB2010(第33回日本分子生物学会・第83回日本生化学会大会)
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-09
• [Presentation] 膵β細胞における新規HNF-4標的遺伝子Anks4bの機能解析BMB2010 (2010)
  • Author(s): 八田光世、MD. Fazlul Karim、佐藤叔史、瀬ノ口隆文、山縣和也
  • Organizer: 第33回日本分子生物学会・第83回日本生化学会大会
  • Place of Presentation: 神戸ポートピアホテル(兵庫)
  • Year and Date: 2010-12-07
• [Presentation] Regulation of insulin secretion by HNF-4 transcription factor BMB2010 (2010)
  • Author(s): Kazuya Yamagata
  • Organizer: 第33回日本分子生物学会・第83回日本生化学会大会
  • Place of Presentation: 神戸ポートピアホテル(兵庫)
  • Year and Date: 2010-12-07
• [Presentation] Regulation of insulin secretion by HNF transcription factors (2009)
  • Author(s): Kazuya Yamagata
  • Organizer: The 4^<th> International Workshop on Cell Regulations in Division and Arrest
  • Place of Presentation: Okinawa OIST Seaside House
• [Book] 糖尿病ナビゲーター (2010)
  • Author(s): 山縣和也, 他
  • Publisher: メヂィカルレビュー社
• [Book] 糖尿病ナビゲーター第2版「転写因子によるβ細胞機能の調節」 (2010)
  • Author(s): 山縣和也
  • Publisher: メディカルレビュー社
• [Remarks]
  • 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]
  • 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