Study of Insulin resistance involving impaired GLUT4 translocation

• Project/Area Number: 22590969
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Tohoku University
• Principal Investigator: KANZAKI Makoto 東北大学, 大学院・医工学研究科, 准教授 (10272262)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2012: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2011: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2010: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: GLUT4 / 細胞内小胞輸送系 / 骨格筋 / 脂肪細胞 / 細胞内情報伝達系 / Vps10p / イメージング / 肥満 / ２型糖尿病 / 運動効果 / ソーティング / 細胞内小胞輸送 / 細胞内シグナル伝達 / インスリン抵抗性 / ソーティング障害 / ゴルジ体 / 筋細胞 / Sortlin / 2型糖尿病

Research Abstract

Defective insulin-responsive GLUT4 translocation is the earliest detectable feature of insulin resistance. Biochemical and nanometrological analyses herein revealed that sortilin, a member of the Vps10p-family sorting receptor, plays a critical role in establishing trans-Golgi network system specialized for generating the insulin-responsive GLUT4-strage vesicles that emerged to be severely deranged under certain insulin resistant conditions. This study thereby unmasks that insulin resistance is caused by not only defects in insulin signaling but also impairment of GLUT4 trafficking itself (“sorting disorder").

Research Products

• [Journal Article] Regulatory mode shift of Tbc1d1 is required for acquisition of insulin-responsive GLUT4 trafficking activity. (2013)
  • Author(s): Hatakeyama H. & Kanzaki M.
  • Journal Title: Molecular Biology of the Cell Volume: 24 Issue: 6 Pages: 809-817
  • DOI: 10.1091/mbc.e12-10-0725
  • Peer Reviewed
• [Journal Article] Regulation of IL-6 production by electric pulse stimulation in contractile C2C12 myotubes. (2013)
  • Author(s): Farmawati A, Kitajima, Nedachi T, Sato M,Kanzaki M, Nagatomi R.
  • Journal Title: Endocrine Journal Volume: 60(2) Pages: 137-147
  • URL: http://dx.doi.org/10.1507/endocrj.EJ12-0316
  • Peer Reviewed
• [Journal Article] Characterization of contraction-induced IL-6 up-regulation using contractile C2C12 myotubes (2013)
  • Author(s): A. Farmawati, Y. Kitajima, T. Nedachi, M. Sato, M. Kanzaki, R. Nagatomi
  • Journal Title: Endocrine Journal Volume: 60 Issue: 2 Pages: 137-147
  • DOI: 10.1507/endocrj.EJ12-0316
  • NAID: 10031156733
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed
• [Journal Article] オルガネラ膜の直接パッチクランプ解析によるTPC1/2機能の解明 (2013)
  • Author(s): 神崎 展
  • Journal Title: 実験医学 Volume: 31(1) Pages: 59-60
• [Journal Article] アストロサイト由来のglypicansと中枢神経ネットワークの構築 (2012)
  • Author(s): 神崎 展
  • Journal Title: 実験医学 Volume: 30(16) Pages: 2600-2601
• [Journal Article] 細胞移動を支配するメカノセンシングのしくみ (2012)
  • Author(s): 神崎 展
  • Journal Title: 実験医学 Volume: 30(6) Pages: 936-937
• [Journal Article] Molecular basis of insulin-responsive GLUT4 trafficking systems revealed by single molecule imaging (2011)
  • Author(s): Hatakeyama H., Kanzaki M.
  • Journal Title: Traffic Volume: 12 Issue: 12 Pages: 1805-1820
  • DOI: 10.1111/j.1600-0854.2011.01279.x
  • Peer Reviewed
• [Journal Article] Non-muscle myosin II induces disassembly of actin stress fibres independently of myosin light chain dephosphorylation (2011)
  • Author(s): Matsui, T.S., Kaunas, R., Kanzaki, M., Sato, M., Deguchi, S.
  • Journal Title: Interface Focus Volume: 1 Issue: 5 Pages: 754-766
  • DOI: 10.1098/rsfs.2011.0031
  • Peer Reviewed
• [Journal Article] Clustering of GLUT4, TUG and RUVBL2 protein levels correlate with myosin heavy chain isoform pattern in skeletal muscles, but AS160 and TBC1D1 levels do not (2011)
  • Author(s): C.M.Castorena
  • Journal Title: Journal of Applied Physiology Volume: 111 Issue: 4 Pages: 1106-1117
  • DOI: 10.1152/japplphysiol.00631.2011
  • Peer Reviewed
• [Journal Article] Spatiotemporally controlled contraction of micropatterned skeletal musclecells on a hydrogel sheet (2011)
  • Author(s): Nagamine K, Kawashima T, Sekine S, Ido Y,Takeda M, Otani S, Kumagai Y, Kanzaki, M, Nishizawa, M
  • Journal Title: Lab on aChip Volume: 11(3) Issue: 3 Pages: 513-517
  • DOI: 10.1039/c0lc00364f
  • Peer Reviewed
• [Journal Article] Sortilinとソーティング障害、そして生活習慣病 (2011)
  • Author(s): 神崎展
  • Journal Title: 生化学 Volume: 83(11) Pages: 1035-1039
  • NAID: 10030345686
• [Journal Article] 生活習慣病とSorting Disorder (2011)
  • Author(s): 神崎展
  • Journal Title: 実験医学 Volume: 29(3) Pages: 430-431
• [Journal Article] 温度センサーとして機能するロドプシンとTRPA1 (2011)
  • Author(s): 神崎展
  • Journal Title: 実験医学 Volume: 29(9) Pages: 1564-1565
• [Journal Article] カベオリンによる力学的微細環境構築とガンの浸潤 (2011)
  • Author(s): 神崎展
  • Journal Title: 実験医学 Volume: 29(16) Pages: 2655-2656
• [Journal Article] Role of p120 catenin in the morphological changes of endothelial cells exposed to shear stress (2010)
  • Author(s): N. Sakamoto, K. Segawa, M. Kanzaki, T. Ohashi, M. Sato
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: Vol. 398 Issue: 3 Pages: 426-432
  • DOI: 10.1016/j.bbrc.2010.06.092
  • Peer Reviewed
• [Journal Article] Electrically inducedcontraction of C2C12 myotubes cultured on a porous membrane-based substrate with muscle tissue-like stiffness (2010)
  • Author(s): Kaji H., Ishibashi T., Nagamine K., Kanzaki,M., Nishizawa M.
  • Journal Title: Biomaterials Volume: 31 Issue: 27 Pages: 6981-6986
  • DOI: 10.1016/j.biomaterials.2010.05.071
  • Peer Reviewed
• [Journal Article] Palmitate-induced Down-regulation of Sortilin and Impaired GLUT4 Trafficking inC2C12 myoutbues (2010)
  • Author(s): Tsuchiya Y., Hatakeyama H., Emoto N.,Wagatsuma F., Matsushita S., Kanzaki M.
  • Journal Title: J.Biol.Chem Volume: 285(45) Issue: 45 Pages: 34371-34381
  • DOI: 10.1074/jbc.m110.128520
  • Peer Reviewed
• [Journal Article] Identification ofthree distinct functional sites ofinsulin-mediated GLUT4 Trafficking in Adipocytes using Quantitative Single Molecule Imaging (2010)
  • Author(s): Fujita H, Hatakeyama H, Watanabe TM, SatoM, Higuchi H, Kanzaki M.
  • Journal Title: Mol Biol Cell Volume: 21(15) Issue: 15 Pages: 2721-2731
  • DOI: 10.1091/mbc.e10-01-0029
  • Peer Reviewed
• [Journal Article] Topographic Imaging of Convoluted Live Cells by Scanning IonConductance Microscopy in a Standing Approach Mode (2010)
  • Author(s): Takahashi Y, Murakami Y, Nagamine K,Shiku H, Aoyagi S, Yasukawa T, Kanzaki M, Matsue T.
  • Journal Title: Phys Chem Chem Phys Volume: 12(34) Issue: 34 Pages: 10012-10017
  • DOI: 10.1039/c002607g
  • Peer Reviewed
• [Journal Article] Cartee GD. In Vivo ExerciseFollowed by In Vitro Contraction AdditivelyElevates Subsequent Insulin-stimulatedGlucose Transport by Rat Skeletal Muscle (2010)
  • Author(s): Funai, K, Schweitzer GG, Castorena CM,Kanzaki, M
  • Journal Title: Am J Physiol Endocrinol Metab Volume: 298(5) Issue: 5 Pages: E999-E1010
  • DOI: 10.1152/ajpendo.00758.2009
  • Peer Reviewed
• [Journal Article] Micropatterning Contractile C2C12 Myotubes Embedded in a Fibrin Gel (2010)
  • Author(s): Nagamine K, Kawashima T, Ishibashi T., KajiH, Kanzaki M, Nishizawa M.
  • Journal Title: Biotechnology and Bioengineering Volume: 105(6) Issue: 6 Pages: 1161-1167
  • DOI: 10.1002/bit.22636
  • Peer Reviewed
• [Journal Article] Palmitate-induced Down-regulation of Sortilin and Impaired GLUT4 Trafficking in C2C12 myoutbues. (2010)
  • Author(s): Tsuchiya Y.
  • Journal Title: Journal of Biological Chemistry Volume: 285 Pages: 34371-34381
  • Peer Reviewed
• [Journal Article] Identification of three distinct functional sites of insulin-mediated GLUT4 Trafficking in Adipocytes using Quantitative Single Molecule Imaging (2010)
  • Author(s): Fujita H.
  • Journal Title: Molecular Bioiogy of the Cell Volume: 21 Pages: 2721-2731
  • Peer Reviewed
• [Journal Article] In Vivo Exercise Followed by In Vitro Contraction Additively Elevates Subsequent Insulin-stimulated Glucose Transport by Rat Skeletal Muscle (2010)
  • Author(s): Funai K.
  • Journal Title: American Journal of Physiology, Endocrinology & Metabolism Volume: 298
  • Peer Reviewed
• [Journal Article] Molecular Basis of Static GLUT4 Storage Compartment Formation in 3T3-L1 Adipocytes Revealed by Quantum Dot-Based Quantitative Single Molecular Imaging (2010)
  • Author(s): Hatakeyama H
  • Journal Title: Diabetes Volume: 59(Supple)
• [Journal Article] 収縮活動可能な培養筋管細胞系の構築とその代謝研究への応用 (2010)
  • Author(s): 神崎展
  • Journal Title: 内分泌・糖尿病・代謝内科 Volume: 31 Pages: 464-471
• [Presentation] Identification of Novel"Exercise Factors" using ContractileMyotube Model (2012)
  • Author(s): Kanzaki, M.
  • Organizer: International Symposium on Cellular Mechanobiology
  • Place of Presentation: Kyoto University Clock Tower Centennial Hall,Kyoto
  • Year and Date: 2012-03-16
• [Presentation] Identification of Novel "Exercise Factors" using Contractile Myotube Model (2012)
  • Author(s): Makoto Kanzaki
  • Organizer: International Symposium on Cellular Mechanobiology
  • Place of Presentation: Kyoto University, Clock Tower Centennial Hall (Kyoto)
  • Year and Date: 2012-03-16
• [Presentation] Impact of Akt1 and 2 on TBC1D1/D4 in response to glucose in beta-cells (2012)
  • Author(s): Rutti, S., Kaddai, V., Negro, V., Kanzaki,M., Halban, PA., Bouzakri, K.
  • Organizer: 48^<th> Annual Meeting of the European Association for the Studyof Diabetes. EASD meeting
  • Place of Presentation: Berlin, Germany
• [Presentation] Characterization of Unique RegulatoryMechanism of Tbc1d1 in GLUT4 Trafficking by Single Molecule Analysis of GLUT4 Behavior (2012)
  • Author(s): Hatakeyama, H and Kanzaki, M.
  • Organizer: 72^<nd> American Diabetes Association Scientific Meeting
  • Place of Presentation: Pennsylvania Convention Center,Philadelphia, PA, USA
• [Presentation] Characterization of Unique Regulatory Mechanism of Tbc1d1 in GLUT4 Trafficking by Single Molecule Analysis of GLUT4 Behavior. (2012)
  • Author(s): Hatakeyama H.
  • Organizer: American Diabetes Association Scientific Meeting,
  • Place of Presentation: Philadelphia, USA
• [Presentation] Unique Regulatory Mechanism of Tbc1d1 RabGAP in GLUT4 Trafficking Revealed by Single Molecule Imaging of GLUT4 Behavior. (2012)
  • Author(s): Hatakeyama H
  • Organizer: American Society for Cell Biology Annual Meeting
  • Place of Presentation: San Francisco, USA
• [Presentation] Impact of Akt1 and 2 on TBC1D1/D4 in response to glucose in beta-cells. (2012)
  • Author(s): Rutti, S
  • Organizer: 48th Annual Meeting of the European Association for the Study of Diabetes.
  • Place of Presentation: Berlin, Germany
• [Presentation] GLUT4輸送調節におけるAS160とTbc1d1の作用点とその分子機序 (2012)
  • Author(s): 畠山裕康
  • Organizer: 第55回日本糖尿病学会
  • Place of Presentation: 横浜 パシフィコ横浜
• [Presentation] Distinct Roles of Two Rab GAPs, AS160/Tbc1d4 and Tbc1d1, on Intracellular GLUT4 Trafficking Analyzed with Single Molecule Imaging of GLUT4 Behavior (2011)
  • Author(s): Hatakeyama H.
  • Organizer: 51^<st> American Society for Cell Biology Annual Meeting
  • Place of Presentation: Colorado Convention Center (CO, USA)
  • Year and Date: 2011-12-05
• [Presentation] 細胞内輸送の新規定量的解析系を用いたインスリン応答性GLUT4輸送システムの分子基盤解析 (2011)
  • Author(s): 畠山裕康
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 国立京都国際会館(京都)
  • Year and Date: 2011-09-22
• [Presentation] Critical roles of sortilin in GLUT4 trafficking systems and insulin resistant state revealed by single molecule imaging of GLUT4 behavior (2011)
  • Author(s): Hatakeyama H.
  • Organizer: FASEB Summer Research Conference "Glucose Transporters, Signaling and Diabetes"
  • Place of Presentation: Snowmass Village Conference Center (CO, USA)
  • Year and Date: 2011-08-16
• [Presentation] Impaired Biogenesis of the Insulin-responsive GLUT4 Storage Compartment under Insulin Resistance Revealed by Single Molecule Imaging (2011)
  • Author(s): Hatakeyama H.
  • Organizer: 71^<st> American Diabetes Association Scientific Sessions
  • Place of Presentation: San Diego Convention Center (CA, USA)
  • Year and Date: 2011-06-25
• [Presentation] GLUT4のソーティング障害と2型糖尿病 (2011)
  • Author(s): 神崎展
  • Organizer: 第6回トランスポーター研究会
  • Place of Presentation: 東北大学さくらホール(仙台)(招待講演)
  • Year and Date: 2011-06-12
• [Presentation] 一分子動態計測系に基づくインスリン応答性GLUT4輸送システムの分子基盤解析 (2011)
  • Author(s): 畠山裕康
  • Organizer: 第54回日本糖尿病学会学術集会
  • Place of Presentation: 札幌芸術文化の館(札幌)
  • Year and Date: 2011-05-19
• [Presentation] Distinct Roles of Two Rab GAPs, AS160/Tbc1d4and Tbc1d1, on Intracellular GLUT4Trafficking Analyzed with Single Molecule Imaging of GLUT4 Behavior (2011)
  • Author(s): Hatakeyama, H and Kanzaki, M.
  • Organizer: 51^<st> American Society for Cell Biology Annual Meeting
  • Place of Presentation: Denver, CO. USA
• [Presentation] Criticalroles of sortilin in GLUT4 trafficking systems and insulin resistant state revealedby single molecule imaging of GLUT4 behavior (2011)
  • Author(s): Hatakeyama, H and Kanzaki, M.
  • Organizer: FASEB Summer Research Conference "Glucose Transporters,Signaling and Diabetes"
  • Place of Presentation: Snowmass Village, CO. USA
• [Presentation] Impaired Biogenesis of theInsulin-responsive GLUT4 Storage Compartment under Insulin Resistance Revealed by Single Molecule Imaging (2011)
  • Author(s): Hatakeyama, H and Kanzaki, M.
  • Organizer: 71^<st> American Diabetes Association ScientificSessions 2011
  • Place of Presentation: San Diego, CA. USA
• [Presentation] GLUT4のソーティング障害と2型糖尿病 (2011)
  • Author(s): 神崎展
  • Organizer: 第6回トランスポーター研究会
  • Place of Presentation: 仙台
• [Presentation] Roles of Sortilim-Mediated Retrograde Trafficking in Insulin-Responsive GLUT4 Trafficking Systems Analyzed with Single Molecule Imaging of GLUT4 Behavior (2010)
  • Author(s): Hatakeyama H
  • Organizer: 50^<th> American Society for Cell Biology Meeting
  • Place of Presentation: San Diego, CA, USA
  • Year and Date: 2010-12-06
• [Presentation] 運動刺激によって活性化される細胞内シグナル伝達系とマイオカイン分泌制御 (2010)
  • Author(s): 神崎展
  • Organizer: 第22回運動器リハビリテーション学会・シンポジウム
  • Place of Presentation: 仙台
  • Year and Date: 2010-07-10
• [Presentation] Molecular Basis of Static GLUT4 Storage Compartment Formation in 3T3-L1 Adipocytes Revealed by Quantum Dot-Based Quantitative Single Molecular Imaging (2010)
  • Author(s): Hatakeyama H
  • Organizer: 70^<th> American Diabetes Association, Scientific Meeting
  • Place of Presentation: Orlando, FL, USA
  • Year and Date: 2010-06-26
• [Presentation] Palmitate-induced Down-regulation of Sortilin and Insulin Resistance in Skeletal Muscle Cells. (2010)
  • Author(s): Kanzaki M
  • Organizer: International Congress "Sortilins in Sorting and Disease"
  • Place of Presentation: Aarhus, DENMARK
  • Year and Date: 2010-06-17
• [Presentation] ナノ蛍光粒子を用いたインスリン反応性GLUT4分子挙動変化の解析 (2010)
  • Author(s): 神崎展
  • Organizer: 第53回日本糖尿病学会年次学術集会・シンポジウム
  • Place of Presentation: 岡山
  • Year and Date: 2010-05-30
• [Presentation] GLUT4一分子動態追跡系を用いたGLUT4 storage compartment形成機構の定量解析 (2010)
  • Author(s): 畠山裕康
  • Organizer: 第53回日本糖尿病学会年次学術集会
  • Place of Presentation: 岡山
  • Year and Date: 2010-05-28
• [Presentation] Quantum Dot(Qdot)を用いたGLUT4細胞内小胞輸送系の定量的解析 (2010)
  • Author(s): 神崎 展
  • Organizer: 第8回日本ナノ学会・シンポジウム
  • Place of Presentation: 岡崎
  • Year and Date: 2010-05-14
• [Remarks]
  • URL: https://www.researchgate.net/profile/Makoto_Kanzaki/
• [Remarks]
  • URL: http://www.ecei.tohoku.ac.jp/kanzaki/index.html
• [Remarks] ResearchGate
  • URL: https://www.researchgate.net/profile/Makoto_Kanzaki/
• [Patent(Industrial Property Rights)] Cultured Muscle Cells with High Metabolic Activity and Methods for Production of the Cultured Muscle Cells (2011)
  • Inventor(s): Kanzaki, M., Nedachi,T., Fujita, H.
  • Industrial Property Rights Holder: 東北大学
  • Filing Date: 2011-11-09
• [Patent(Industrial Property Rights)] インスリン反応性糖輸送担体の膜移行活性が測定可能な培養筋細胞 (2011)
  • Inventor(s): 神崎展・根建拓
  • Industrial Property Rights Holder: 東北大学
  • Filing Date: 2011-07-01