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Intracellular sorting of glucose transporter and insulin action

Research Project

Project/Area Number 10044296
Research Category

Grant-in-Aid for Scientific Research (B).

Allocation TypeSingle-year Grants
Section一般
Research Field 内分泌・代謝学
Research InstitutionYamaguchi University

Principal Investigator

OKA Yoshitomo  Yamaguchi University School of Medicine, Professor, 医学部, 教授 (70175256)

Co-Investigator(Kenkyū-buntansha) OKUYA Shigeru  Yamaguchi University School of Medicine, Research Associate,, 医学部, 助手 (20214083)
TANIZAWA Yukio  Yamaguchi University Hospital, Assistant Professor,, 医学部・附属病院, 講師 (00217142)
MATSUTANI Akira  Yamaguchi University School of Medicine, Associate Professor, 医学部, 助教授 (10190464)
KATAGIRI Hideki  Tokyo University Hospital, Clinical Fellow,, 医学部・附属病院, 医員(臨床)
MICHAEL P.Cz  マサチューセッツ大学, 分子医学部門, ディレクター教授
JAMES E.Davi  クイーンスランド大学, 分子生物学遺伝子工学センター, 教授
Project Period (FY) 1998 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥4,100,000 (Direct Cost: ¥4,100,000)
Fiscal Year 1999: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 1998: ¥2,200,000 (Direct Cost: ¥2,200,000)
KeywordsInsulin / Glucose transport / GLUT4 / PI3 kinase / Akt / PH domain / Grp1 / PDK1 / P13キナーゼ / ARNO
Research Abstract

Insulin rapidly stimulates glucose transport activity in muscle and adipose tissue. This increase in glucose transport activity is primarily due to translocation of glucose transporter GLUT4 from intracellular compartment to the plasma membrane. We have shown that activation of PI3 kinase is crucial for insulin-stimulation of glucose transport, based on our findings that overexpression of p110a catalytic subuniti of PI3 kinase and dominant negative p85 subunit mimic and inhibit, respectively, this insulin action. We have also studied signals downstream of PI3 kinase. Insulin stimulation phosphorylates AKt1 at both Thr308 and Ser473, leading to activation of various signals including those towards glucose metabolism. To investigate the role of PDK1 on the phosphorylation state of AKt1, the wild-type PDK1 (wt-PDK1) and its kinase dead mutant (kd-PDK1) were expressed in CHO-IR cells using adenovirus gene transduction system. Immunoblotting using antiphosphorylated AKt1 antibody revealed that Thr308 was maximally phosphorylated already at 1 min by insulin stimulation but almost completely dephosphorylated at 5 min. Insulin-stimulated phosphorylation state of Thr308 was markedly increased in CHO-IR cells overexpressing wt-PDK1 at 1 min, but it returned to the basal level at 5 min. On the contrary, insulin-stimulated phosphorylation state of Thr308 was maintained even at 15 min in cells overexpressing kd-PDK1, suggesting that kd-PDK1 overexpression inhibited insulin-stimulated phosphatase activity. Insulin-stimulated Ser473 phosphorylation was not affected by overexpression of we-PDK1 or kd-PDK1.

Report

(3 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • Research Products

    (26 results)

All Other

All Publications (26 results)

  • [Publications] Ishihara H,et al.: "Type I Phosphatidylinositol-4-phosphate 5-kinases.Cloning of the third isoform and deletion/substitution analysis of members of this novel lipid kinase family"J Biol Chem. 273. 8741-8748 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Terasaki J,et al.: "Pole of JTT-501,a new irshulin sensitiser,in rest;oring impaired GLUT4 translocation in adipocytes of rats fad a high fat diet"Diabetologia. 41. 400-408 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Anao M,et al.: "Different subcellular distribution and regulation of expression of insulin reccpror substrate(IRS)-3 from those of lRS-1 and lRS-2"J Biol Chem. 273. 29686-29692 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Hosaka T,et al.: "Regulation of insulin-stimulated glucose transport by chronic gfucose exposure in 3T3-L1 adipocytes"Endocrine Journal. 46. 349-357 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Funaki M,et al.: "p85/p110-type phophatidylinositol kinase phosphorylates not only the D-3,but also the D-4 position of the inositol ring"J Biol Chem. 274. 22019-22024 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Nawano M,et al.: "Hyperglycemia impairs the insulin signaling step between PI 3-Kinase and Akt/PKB activations in ZDF rat liver"Biochem Biophys Res Commun. 266. 252-256 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] ISHIHARA, H, et al.: "Type I Phosphatidylinositol-4-phosphate 5-Kinases. Cloning of the third isoform and deletion/substitution analysis of members of this novel lipid kinase family."J Biol Chem. 273. 8741-8748 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] TERASAKI, J, et al.: "Role of JTT-501, a new inshulin sensitiser, in restoring impaired GLUT4 translocation in adipocytes of rats fed a high fat diet."Diabetologia. 41. 400-408 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] ANAI, M, et al.: "Different subcellular distribution and regulation of expression of insulin receptor substrate (IRS)-3 from those of IRS-1 and IRS-2."J Biol Chem. 273. 29686-29692 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] HOSAKA, T, et al.: "Regulation of insulin-stimulated glucose transport by chronic glucose exposure in 3T3-L1 adipocytes."Endocrine Journal. 46(3). 349-357 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] FUNAKI, M, et al.: "Ip85/p110-type phosphatidylinositol kinase phosphorylates not only the D-3, but also the D-4 position of the inositol ring."J Biol Chem. 274. 22019-22024 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] NAWANO, M, et al.: "Hyperglycemia impairs the insulin signaling step between PI3-Kinase and Akt/PKB activations in ZDF rat liver."Biochem Biophys Res Commun. 226. 252-256 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ishihara H,et al.: "Enhanced phosphoinositide hydrolysis via overexpression of phospholipase C β1 or δ1 inhibits stimulus-induced insulin release in insulinoma MIN6 cells."Biochem Biophys Res Commun. 254. 77-82 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Hosaka T,et al.: "Regulation of insulin-stimulated glucose transport by chronic glucose exposure in 3T3-L1 adipocytes."Endocrine Journal. 46. 349-357 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kamei Y,et al.: "maternal epidermal growth factor deficiency causes fetal hypoglycemia and intrauterine growth retardation in mice:Possible involvement of placental glucose transporter GLUT3 expression."Endocrinology. 140. 4236-4243 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Funaki M,et al.: "p85/p110-type phosphatidylinositol kinase phosphorylates not only the D-3,but also the D-4 position of the inositol ring."J Biol Chem. 274. 22019-22024 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Nawano M,et al.: "Hyperglycemia impairs the insulin signaling step between PI 3-Kinase and Akt/PKB activations in ZDF rat liver."Biochem Biophys Res Commun. 266. 252-256 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 保坂利男: "医学のあゆみ「脂肪細胞におけるインスリンシグナルと糖輸送」"医歯薬出版株式会社. 5 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Ueda K,et al.: "Overexpression of mitochondrial FAD-linked glycerol-3-phosphate dehydrogenase does not correct glucose-stimulated insulin secretion from diabetic GK rat pancreatic islets." Diabetologia. 41. 649-653 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Nakazaki M,et al.: "Repetitive mitochondrial Ca^<2+> signals synchronize with cytosolic Ca^<2+> oscillations in the pancreatic beta-cell line, MIN6." Diabetologia. 41. 279-286 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Inoue H,et al.: "Isolation of full leng cDNA of mouse PAX4 gene and identification of its human homologue." Biochem Biophys Res Commun. 243. 628-633 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Ohta Y,et al.: "Identification snd functional analysis of SURI variants in Japanese with non-insulin-dependent diabetes mellitus." Diabetes. 47. 476-481 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Ishihara H,et al.: "Type I Phosphatidylinositol-4-phosphate 5-Kinases.Cloning of the third isoform and deletion/substitution analysis of members of this novel lipid kinase family." J Biol Chem. 273. 8741-8748 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Inoue H,et al.: "A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy(Wolfram syndrome)." Nature Genetics. 20. 143-148 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 井上康: "「肝の糖質代謝」肝臓病学" 医学書院, 15-22 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 松谷朗: "「チロシンキナーゼ、セリン/スレオニンキナーゼと情報伝達」肝臓病学" 医学書院, 314-319 (1998)

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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