Molecular mechanisms of Insulin signal transduction and diabetes mellitus

• Project/Area Number: 20390095
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: The University of Tokushima
• Principal Investigator: EBINA Yousuke The University of Tokushima, 疾患酵素学研究センター, 教授 (00112227)
• Co-Investigator(Renkei-kenkyūsha): UCHIYAMA Keiji 徳島大学, 疾患酵素学研究センター, 准教授 (60294039) ; YUASA Tomoyuki 徳島大学, 疾患酵素学研究センター, 准教授 (50304556) ; NAGAYA Hisao 徳島大学, 疾患酵素学研究センター, 助教 (60464343) ; OGURA Yuko 徳島大学, 疾患酵素学研究センター, 研究員 (90464354)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥19,630,000 (Direct Cost: ¥15,100,000、Indirect Cost: ¥4,530,000); Fiscal Year 2010: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2009: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000); Fiscal Year 2008: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000)
• Keywords: 分子病態学 / インスリンシグナル伝達 / インスリン作用 / GLUT4 / TUG / sIR / 高血糖 / 超高感度sIR測定法 / シグナル伝達 / BFA / GLUT4トランスロケーション / ARF / BIG2

Research Abstract

Akt substrate of 160kDa (AS160) is a Rab GTPase activating protein (GAP) and was recently identified as a component of the insulin signaling pathway of glucose transporter type 4 (GLUT4) translocation. We and others, previously reported that the activation of Galphaq protein-coupled receptors (GalphaqPCRs) also stimulated GLUT4 translocation and glucose uptake in several cell lines. Here, we report that the activation of GalphaqPCRs also promoted phosphorylation of AS160 by the 5'-AMP activated proteinkinase (AMPK). Rat 3Y1 cells lacking AS160 did not show insulin-induced GLUT4 translocation. The cells stably expressing GLUT4 revealed GLUT4 vesicles that were mainly localized in the perinuclear region and less frequently on the cell surface. After expression of exogenous AS160, GLUT4 on the cell surface decreased and GLUT4 vesicles were redistributed throughout the cytoplasm. Although PMA-induced or sodium fluoride-induced GLUT4 translocation was significantly increased in these cells, insulin did not affect GLUT4 translocation. These results suggest that AS160 is a common regulator of insulin-and GalphaqPCR activation-mediated GLUT4 distribution in the cells.

Research Products

• [Journal Article] A novel ultra-sensitive enzyme immunoassay for soluble human insulin receptor ectodomain and its measurement in urine from healthy subjects and patients with diabetes mellitus. (2009)
  • Author(s): Umehara Asako, Nishioka Mamiko, Obata Toshiyuki, Ebina Yousuke, Shiota Hiroshi, Hashida Seiichi
  • Journal Title: Clinical biochemistry Vol.42, No.13-14 Pages: 1468-1475
  • Peer Reviewed
• [Journal Article] The Rab GTPase-Activating Protein AS160 as A Common Regulator of Insulin- and Gq-Mediated Intracellular GLUT4 Vesicle DistributionA (2009)
  • Author(s): Yuasa Tomoyuki, Uchiyama Keiji, Yuko OGURA, Kimura Masafumi, Kiyoshi TESHIGAWARA, Hosaka Toshio, Yoshinori TANAKA, Obata Toshiyuki, Hiroyuki SANO, Kishi Kazuhiro, Ebina Yousuke
  • Journal Title: Endocrine Journal Vol.56, No.3 Pages: 345-359
  • Peer Reviewed
• [Journal Article] The Rab GTPase-Activating Protein AS160 as A Common Regulator of Insulin-and Gαq-Mediated Intracellular GLUT4 Vesicle Distribution (2009)
  • Author(s): Yuasa T.
  • Journal Title: Endocrine Journal 56(3) Pages: 345-359
  • NAID: 10026913437
  • Peer Reviewed
• [Journal Article] A novel ultra-sensitive enzyme immunoassay for soluble human insulin receptor ectodomain and its measurement in urine from healthy subjects and patients with diabetes mellitus (2009)
  • Author(s): Umehara A.
  • Journal Title: Clinical Biochemistry 42(13-14) Pages: 1468-1475
  • Peer Reviewed
• [Journal Article] The Rab GTPase-Activating Protein AS160 as A Common Regulator of Insulin- and Gaq-Mediated Intracellular GLUT4 Vesicle DistributionA (2009)
  • Author(s): Tomoyuki YUASA, et al.
  • Journal Title: Endocrine Journal in press
  • Peer Reviewed
• [Presentation] Soluble insulin receptor ectodomain is elevated in the plasma of patients with diabetes. (2010)
  • Author(s): Yuasa T., et.al.
  • Organizer: XI INTERNATIONAL SYMPOSIUM ON INSULIN RECEPTORS AND INSULIN ACTION
  • Place of Presentation: イタリア・ナポリ
  • Year and Date: 2010-10-28
• [Presentation] 短期血糖コントロール指標としての血中可溶性インスリン受容体αサブ辛ニットの有用性 (2010)
  • Author(s): 本島寛之, 他
  • Organizer: 第53回日本糖尿病学会年次学術集会
  • Place of Presentation: 岡山市
  • Year and Date: 2010-05-28
• [Presentation] 尿中成長ホルモンを指標とした運動評価の検討 (2010)
  • Author(s): 梅原麻子, 他
  • Organizer: 第53回日本糖尿病学会年次学術集会
  • Place of Presentation: 岡山市
  • Year and Date: 2010-05-27
• [Presentation] Soluble insulin receptor ectodomain is elevated in the plasma of patients with diabetes. (2010)
  • Author(s): Yuasa Tomoyuki, Nagaya Hisao, Hashida Seiichi, Asako Umehara, Yokota Ichiro, Obata Toshiyuki, Ebina Yousuke
  • Organizer: XI INTERNATIONAL SYMPOSIUM ON INSULIN RECEPTORS AND INSULIN ACTION
  • Place of Presentation: Naples
• [Presentation] 可溶性インスリン受容体細胞外ドメイン(sIRα)は高血糖に相関して血中濃度が高まる (2009)
  • Author(s): 湯浅智之, 小畑利之, 横田一郎, 岡本英治, 長屋寿雄, 橋田誠一, 前川聡, 柏木厚典, 松本満, 松本俊夫, 岸和弘, 蛯名洋介
  • Organizer: 第7回1型糖尿病研究会
  • Place of Presentation: 日光
  • Year and Date: 2009-11-07
• [Presentation] 可溶性インスリン受容体細胞外ドメイン(sIRα)は高血糖に相関して血中濃度が高まる (2009)
  • Author(s): 湯浅智之, 他
  • Organizer: 第7回 1型糖尿病研究会
  • Place of Presentation: 日光
  • Year and Date: 2009-11-07
• [Presentation] Soluble insulin receptor ectodomain in the plasma is a possible broad-spectrum tumor marker (2009)
  • Author(s): Yuasa T., et. al.
  • Organizer: 第68回 日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2009-10-01
• [Presentation] 可溶化インスリン受容体細胞外ドメイン(sIR)は癌患者血清中で増加している (2009)
  • Author(s): 湯浅智之, 小畑利之, 矢野聖二, 岡本英治, 西岡安彦, 久保宜明, 高橋正幸, 中逵弘能, 長屋寿雄, 金山博臣, 荒瀬誠治, 曽根三郎, 蛯名洋介
  • Organizer: 第29回日本分子腫瘍マーカー研究会
  • Place of Presentation: 横浜
  • Year and Date: 2009-09-30
• [Presentation] Soluble insulin receptor ectodomain level was elevated in the plasma of cancer patients (2009)
  • Author(s): Yuasa T., et. al.
  • Organizer: 第29回 日本分子腫瘍マーカー研究会
  • Place of Presentation: 横浜
  • Year and Date: 2009-09-30
• [Presentation] Role of BIG2, a Guanine-Nucleotide Exchanging Factor for ADP-Ribosylation Factors, in Insulin-Regulated Glucose Transporter Translocation (2009)
  • Author(s): Uchiyama Keiji, Ebina Yousuke
  • Organizer: 第32回日本分子生物学会年会
  • Place of Presentation: Yokohama
• [Presentation] Soluble insulin receptor ectodomain in the plasma is a possible broad-spectrum tumor marker (2009)
  • Author(s): 湯浅智之, 矢野聖二, 西岡安彦, 久保宜明, 高橋正幸, 中逵弘能, 長屋寿雄, 金山博臣, 荒瀬誠治, 曽根三郎, 蛯名洋介
  • Organizer: 第68回 日本癌学会学術総会記事,pp.450-450
  • Place of Presentation: Yokohama
• [Presentation] Soluble insulin receptor ectodomain is elevated in the plasma of patients with diabetes. (2008)
  • Author(s): Yuasa Tomoyuki, Obata Toshiyuki, Yokota Ichiro, Okamoto Eiji, Kanezaki Yoshiko, Maegawa Hiroshi, Hirota Fumiko, Kishi Kazuhiro, Hashida Seiichi, Nagaya Hisao, Yuko Ogura, Kazuhiko Masuda, Matsumoto Mitsuru, Matsumoto Toshio, Kashiwagi Atsunori, Ebina Yousuke
  • Organizer: The 1st Insulin Resistance in Metabolic Disease Forum
  • Place of Presentation: Osaka
  • Year and Date: 2008-08-20
• [Patent(Industrial Property Rights)] インスリンレセプターαサブユニットの測定方法 (2010)
  • Inventor(s): 岡本英治、蛯名洋介、小畑利之
  • Industrial Property Rights Holder: (株)医学生物学研究所、蛯名洋介、小畑利之
  • Acquisition Date: 2010-06-18
  • Overseas