1998 Fiscal Year Annual Research Report

動脈硬化発症におけるインスリン抵抗性の役割の解明

Research Project

Project/Area Number	10177206
Research Institution	The University of Tokyo
Principal Investigator	戸辺一之東京大学, 医学部・附属病院, 助手 (30251242)
Co-Investigator(Kenkyū-buntansha)	原一雄東京大学, 医学部・附属病院, 医員山内敏正東京大学, 医学部・附属病院, 医員鏑木康志東京大学, 医学部・附属病院, 医員門脇孝東京大学, 医学部・附属病院, 講師 (30185889)
Keywords	細胞接着 / 細胞遊走 / 接着斑 / インスリン / インスリン抵抗性 / 高インスリン血症 / 動脈硬化 / 高血圧
Research Abstract	インスリン抵抗性・高インスリン血症は、動脈硬化危険因子の一つである。細胞レベル及び個体レベルでその分子的機序を検討した。(1)血管平滑筋細胞などの動脈硬化巣を形成する細胞群の細胞接着や遊走能に対する影響を検討するため、インスリンの接着斑のチロシンリン酸化蛋白質(FAK,paxillin,cas)に対する影響を検討した。インスリンを投与したところFAK,paxillin,casの脱リン酸化が亢進した。また、この脱リン酸化作用はCsk依存性と考えられた。インスリンは、接着斑に存在するチロシンリン酸化蛋白質の脱リン酸化を亢進させ細胞外基質との接着能を調節し動脈硬化巣での平滑筋細胞などの接着や遊走などに関与している可能性がある。(Tobe,K.et al:.Mol.Cell.Biol.16:4765-4772,1996)(2)インスリン受容体基質1(IRS-1)欠損マウスは、骨格筋でのインスリン作用障害によっておこる高インスリン血症・インスリン抵抗性の非肥満マウスである(Tamemoto,H.et al:Nature 372:182-186,1994:Tobe,K.et al:: J.Biol.Chem.270:5698-5701,1995)。血圧、血中脂質濃度、血管内皮細胞機能について検討した。IRS-1欠損マウスは野生型に比べ血圧が有意に高く、アセチルコリンによる大動脈輪の弛緩は低下していた。また、IRS-1欠損マウスでは中性脂肪は有意に高値を示し、HDLは有意に低値であった。肥満を伴わず、耐糖能障害もともなわない高インスリン血症/骨格筋インスリン抵抗性マウスで高血圧、脂質代謝異常をきたすことが明らかになった。(Abe,H.et al:J.Clin.Invest.101:1784-88,1998)

Research Products

(12 results)

All Other

All Publications (12 results)

[Publications] Tamemoto,H.,and Kadowaki,T.,et al: "Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1." Nature. 372. 182-186 (1994)
[Publications] Tobe,K.,et al: "Identification of a 190-kDa protein as a novel substrate for the insulin receptor kinase functionally similar to insulin receptor substrate-1." J.Biol.Chem.270. 5698-5701 (1995)
[Publications] Yamauchi,T.,et al: "Insulin signaling and insulin actions in the muscle and liver of insulin resistant IRS-1 deficient mice." Mol.Cell.Biol.16. 3074-3084 (1996)
[Publications] Tobe,K.,et al: "Csk enhances insulin-stimulated dephosphorylation of focal adhesion proteins." Mol.Cell.Biol.16. 4765-4772 (1996)
[Publications] Kaburagi,Y.,et al: "Role of insulin receptor substrate-1 and pp60 in the regulation of insulin-induced glucose transport and GLUT4 translocation in primary adipocytes." J.Biol.Chem.272. 25839-25844 (1997)
[Publications] Terauchi,Y.,et al: "Development of non-insulin-dependent diabetes mellitus in the double knockout mice with disruption of insulin receptor substrate-1 and β-cell glucokinase genes : genetic reconstitution of diabetes as a polygenic disease." J.Clin.Invest.99. 861-866 (1997)
[Publications] Yamauchi,T.,et al: "Tyrosine phosphorylation of EGF receptor induced by growth hormone via JAK2 kinase." Nature. 390. 91-96 (1997)
[Publications] Ueki,K.,et al: "Protein kinase B (c-Akt) regulates glucose transport,glycogen synthesis and protein synthesis by insulin." J.Biol.Chem.273. 5315-22 (1998)
[Publications] Okuno,A.,et al: "Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats." J.Clin,Invest.101. 1354-1361 (1998)
[Publications] Yamauchi,T.,et al: "Growth hormone and prolactin stimulate tyrosine phosphorylation of insulin receptor substrate-1,-2,and -3,their association with p85 phosphatidylinositol 3-kinase (PI3-kinase),and concomitantly PI3-kinase activation via JAK2 kinase." J.Biol.Chem.273. 15719-26 (1998)
[Publications] Murakami,K.,et al: "A Novel Insulin Sensitizer Acts as a Coligand for Peroxisome Proliferator-Acticvated Receptor-α(PPAR-α) and PPARγ Effect of PPAR-α Activation on Abnormal Lipid Metabolism in Liver of Zucker Fatty Rats" Diabetes. 47. 1841-1847 (1998)
[Publications] Terauchi,Y.,et al: "Increased insulin sensitivity and hypoglycaemia in mice lacking the p85 α subunit of phosphoinositide 3-kinase" Nature Genetics. 21. 230-235 (1999)

1998 Fiscal Year Annual Research Report

動脈硬化発症におけるインスリン抵抗性の役割の解明

Principal Investigator

戸辺 一之 東京大学, 医学部・附属病院, 助手 (30251242)

Research Products

[Publications] Tamemoto,H.,and Kadowaki,T.,et al: "Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1." Nature. 372. 182-186 (1994)

[Publications] Tobe,K.,et al: "Identification of a 190-kDa protein as a novel substrate for the insulin receptor kinase functionally similar to insulin receptor substrate-1." J.Biol.Chem.270. 5698-5701 (1995)

[Publications] Yamauchi,T.,et al: "Insulin signaling and insulin actions in the muscle and liver of insulin resistant IRS-1 deficient mice." Mol.Cell.Biol.16. 3074-3084 (1996)

[Publications] Tobe,K.,et al: "Csk enhances insulin-stimulated dephosphorylation of focal adhesion proteins." Mol.Cell.Biol.16. 4765-4772 (1996)

[Publications] Kaburagi,Y.,et al: "Role of insulin receptor substrate-1 and pp60 in the regulation of insulin-induced glucose transport and GLUT4 translocation in primary adipocytes." J.Biol.Chem.272. 25839-25844 (1997)

[Publications] Terauchi,Y.,et al: "Development of non-insulin-dependent diabetes mellitus in the double knockout mice with disruption of insulin receptor substrate-1 and β-cell glucokinase genes : genetic reconstitution of diabetes as a polygenic disease." J.Clin.Invest.99. 861-866 (1997)

[Publications] Yamauchi,T.,et al: "Tyrosine phosphorylation of EGF receptor induced by growth hormone via JAK2 kinase." Nature. 390. 91-96 (1997)

[Publications] Ueki,K.,et al: "Protein kinase B (c-Akt) regulates glucose transport,glycogen synthesis and protein synthesis by insulin." J.Biol.Chem.273. 5315-22 (1998)

[Publications] Okuno,A.,et al: "Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats." J.Clin,Invest.101. 1354-1361 (1998)

[Publications] Murakami,K.,et al: "A Novel Insulin Sensitizer Acts as a Coligand for Peroxisome Proliferator-Acticvated Receptor-α(PPAR-α) and PPARγ Effect of PPAR-α Activation on Abnormal Lipid Metabolism in Liver of Zucker Fatty Rats" Diabetes. 47. 1841-1847 (1998)

[Publications] Terauchi,Y.,et al: "Increased insulin sensitivity and hypoglycaemia in mice lacking the p85 α subunit of phosphoinositide 3-kinase" Nature Genetics. 21. 230-235 (1999)

戸辺一之東京大学, 医学部・附属病院, 助手 (30251242)