1999 Fiscal Year Annual Research Report

発生工学手法を用いたインスリン作用機序及びインスリン抵抗性機序の解明

Research Project

Project/Area Number	10470229
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)	江藤一弘東京大学, 医学部附属病院, 医員寺内康夫東京大学, 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) 鏑木康志東京大学, 医学部附属病院, 医員本田律子東京大学, 医学部附属病院, 医員
Keywords	インスリン受容体 / インスリン受容体基質 / IRS-1 / IRS-2 / IRS-3 / インスリン作用 / インスリン抵抗性 / 発生工学
Research Abstract	我々は、インスリン抵抗性の機序を明らかにし、糖尿病の発症におけるインスリン抵抗性の役割を解明するため、インスリン受容体基質ファミリー蛋白質の欠損マウスの作製・解析をすすめてきた。IRS-1欠損マウスは、耐糖能障害を伴わない高インスリン血症、すなわち軽度のインスリン抵抗性を示すのみで、代替する基質であるIRS-2によりインスリン作用はかなりの部分保たれていることが明らかとなった(Tamemoto et al.,Nature 372:182-186,1994,Tobe et al.,J.Biol.Chem.270:5698-5701,1995)。IRS-1欠損マウスの骨格筋ではIRS-2の発現が少なく、インスリン作用は野生型の約30%に低下しており全身でのインスリン抵抗性の原因と考えられた(Yamauchi et al.,Mol.Cell.Biol.16: 3074-3084,1996)。また、脂肪細胞でのインスリン作用は約半分に低下していたが、保たれているインスリン作用はIRS-3によるものと考えられた(Kaburagi et al.,J.Biol.Chem.272:25839-25844,1997)。個々のIRSファミリー蛋白質のインスリンの標的臓器における役割が明らかとなった。また、IRSファミリーに結合するPI3キナーゼの85kDaサブユニットの欠損マウスを作製し、インスリン作用の亢進により低血糖傾向になることを明らかにした(Terauchi,Y.et al:Nature Genetics 21:230-235,1999)。

Research Products
(12 results)

All Other

All Publications (12 results)

[Publications] Terauchi,Y.et al.: "Increased insulin sensitivity and hypoglycemia in mice lacking p85α subunit of phosphoinostitide-3-kinase"Nature Genetics. 21. 230-235 (1999)
[Publications] Kubota,N.et al.: "PPARγ mediates high-fat diet-induced adipocyte hypertrophy and insulin resisitance"Mol.Cell.. 4. 597-609 (1999)
[Publications] Ueki,K.et al.: "Potential role of protein kinase B in insulin-induced glucose transport,glucogen synthesis and protein synthesis"J.Biol.Chem.. 273. 3515-5322 (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 prolaction stimulate tyrosime phosphorylation of IRS-1,2,3 their association with p85 PI3-kinase and concomitantly PI3-kinase activation via JAK2 kinae"J.Biol.Chem.. 273. 15719-15726 (1998)
[Publications] Murakami,K.et al.: "Novel insulin sensitizer acting as a coligand for PPAR α and γ"Diabetes. 47. 1841-1847 (1998)
[Publications] Yamauchi,T.et al.: "Tyrosine phosphorylation of EGF receptor induced by growth hormone via JAK2 kinase"Nature. 390. 91-96 (1997)
[Publications] Takahashi,Y.et al.: "Roles of insulin receptor substrate-1 and shc on insulin-like growth factor I receptor signaling in early passages of cultured human fibroblast"Endocrinology. 138. 741-750 (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 gene : genetic reconstitution of diabetes as a polygenic disease"J.Clin.Invest.. 99. 861-866 (1997)
[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.. 16. 25839-25844 (1997)
[Publications] Yamauchi,T.et al.: "Insulin signaling and insulin actions in the muscles and livers insulin resisitant,insulin receptor substrate 1-deficient mice"Mol.Cell.Biol.. 16. 3074-3084 (1996)
[Publications] Tobe,Cell.Biol.: "Csk enhances insulin-stimulated dephosphorylation of focal adhesion proteins"Mol.Cell.Biol.. 16. 4765-4772 (1996)

1999 Fiscal Year Annual Research Report

発生工学手法を用いたインスリン作用機序及びインスリン抵抗性機序の解明

Principal Investigator

戸辺 一之 東京大学, 医学部附属病院, 助手 (30251242)

Research Products

[Publications] Terauchi,Y.et al.: "Increased insulin sensitivity and hypoglycemia in mice lacking p85α subunit of phosphoinostitide-3-kinase"Nature Genetics. 21. 230-235 (1999)

[Publications] Kubota,N.et al.: "PPARγ mediates high-fat diet-induced adipocyte hypertrophy and insulin resisitance"Mol.Cell.. 4. 597-609 (1999)

[Publications] Ueki,K.et al.: "Potential role of protein kinase B in insulin-induced glucose transport,glucogen synthesis and protein synthesis"J.Biol.Chem.. 273. 3515-5322 (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 prolaction stimulate tyrosime phosphorylation of IRS-1,2,3 their association with p85 PI3-kinase and concomitantly PI3-kinase activation via JAK2 kinae"J.Biol.Chem.. 273. 15719-15726 (1998)

[Publications] Murakami,K.et al.: "Novel insulin sensitizer acting as a coligand for PPAR α and γ"Diabetes. 47. 1841-1847 (1998)

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

[Publications] Takahashi,Y.et al.: "Roles of insulin receptor substrate-1 and shc on insulin-like growth factor I receptor signaling in early passages of cultured human fibroblast"Endocrinology. 138. 741-750 (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 gene : genetic reconstitution of diabetes as a polygenic disease"J.Clin.Invest.. 99. 861-866 (1997)

[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.. 16. 25839-25844 (1997)

[Publications] Yamauchi,T.et al.: "Insulin signaling and insulin actions in the muscles and livers insulin resisitant,insulin receptor substrate 1-deficient mice"Mol.Cell.Biol.. 16. 3074-3084 (1996)

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

戸辺一之東京大学, 医学部附属病院, 助手 (30251242)