2002 Fiscal Year Annual Research Report

発生工学による糖尿病の発症機序の解明

Research Project

Project/Area Number	13470224
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, 助教授 (30185889) 鏑木康志東京大学, 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
Keywords	インスリン抵抗性 / インスリン受容体 / SREBP-1 / レプチン抵抗性 / 脂肪肝 / IRS-2
Research Abstract	我々は、相同組換え法を用いて、様々なインスリン抵抗性及び糖尿病発症のモデルマウスとなる遺伝子欠損マウスを作製してきた。現在までに、インスリン作用の情報伝達分子としては、インスリン受容体基質1(IRS-1) (Tamemoto, et al.:Nature 372:182-186,1994)、PI3キナーゼp85欠損マウス(Terauchi, et al.:Nature Genetics 21:230-235,1999)、また、高脂肪食下にも肥満やインスリン抵抗性を来しにくいPPARγ欠損マウス(Kubota, et al.:Mol.Cell 4:567-609,1999)を作製解析してきた。この結果、(1)糖尿病発症におけるインスリン分泌低下やインスリン抵抗性の役割及び諸臓器(肝臓・骨格筋・脂肪細胞や膵β細胞)の役割を解明したり、(2)欠損マウスで欠損したパスウェイを代償する分子を見出すことが可能となった。その一例として、我々は、IRS-1欠損マウスを作製し、耐糖能障害を伴わず高インスリン血症で代償されることを明らかにし(Tamemoto, et al.:Nature 372:182-186,1994)、インスリン抵抗性の原因が骨格筋での情報伝達異常にあることを証明した(Yamauchi, et al.:Mol.Cell.Biol 16:3074-3084,1996)。さらに、インスリン分泌低下型のグルコキナーゼ欠損マウスと掛け合わせることにより糖尿病の発症には、インスリン抵抗性とインスリン分泌低下の両者が必要であることを明らかにした(Terauchi, et al.:J.Clin.Invest. 99:861-866,1997)。また、IRS-1欠損マウスは、骨格筋でのインスリン抵抗性を呈し、高中性脂肪血症・低HDL-Chol血症・高血圧・血管内皮細胞障害を呈する「シンドロームX(インスリン抵抗性症候群)」のモデルであることを明らかにした(Abe, et al.:J.Clin.Invest. 101:1784-1788,1998)。また、欠損したIRS-1を代償する新たな基質としてIRS-2を見出し(Tobe, et al.:J.Biol.Chem. 270:5698-5701, 1995)、このIRS-2の欠損マウスを作製し糖尿病を発症することを明らかにしている(Kubota, et al.:Diabetes 49:1880-1889,2000)。また、我々はIRS-2欠損マウスが肥満と脂肪肝をきたし、レプチン抵抗性を呈することを明らかにした(Tobe, et al.:J.Biol.Chem. 276:38337-38340,2001)。

Research Products

(18 results)

All Other

All Publications (18 results)

[Publications] Terauchi, Y., et al.: "Impact of genetic background and ablation of IRS-3 on IRS-2 knockout mice"J. Biol. Chem.. (in press). (2003)
[Publications] Tobe, K., et al.: "Cytoskeletal reorganization induced byinsulin : involvement of Grb2/Ash, Ras and phosphatidylinositol 3-kinase signaling"Genes to Cells. 8. 29-40 (2003)
[Publications] Yamauchi, T., et al.: "Globular adiponectin protected ob/ob mice from diabetes and ApoE-deficient mice from atherosclerosis"J. Biol. Chem.. 24. 2461-2468 (2003)
[Publications] Yamauchi, T., et al.: "Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase"Nat Med.. 8. 1288-1295 (2002)
[Publications] Kubota, N., et al.: "Disruption of adiponectin causes insulin resistance and neointimal formation"J. Biol. Chem.. 19. 25863-25866 (2002)
[Publications] Yamauchi, T., et al.: "Increased insulin sensitivity despite lipodystrophy in Crebbp heterozygous mice"Nat Genet.. 30. 221-226 (2002)
[Publications] Imai, Y., et al.: "Resistance to neointimal hyperplasia and Fatty streak formation in mice with adrenomedullin overexpression"Arterioscler Thromb Vasc Biol. 22. 1310-1315 (2002)
[Publications] Kadowaki, T., et al.: "The role of PPARgamma in high-fat diet-induced obesity and insulin resistance"J. Diabetes Complications. 16. 41-45 (2002)
[Publications] Hara, K., et al.: "A genetic variation in the PGC-1 gene could confer insulin resistance and susceptibility to Type II diabetes"Diabetologia. 45. 740-743 (2002)
[Publications] Hara, K., et al.: "Maturity-onset diabetes of the young resulting from a novel mutation in the HNF-4alpha gene"Intern Med.. 41. 848-852 (2002)
[Publications] Eto, K., et al.: "Phosphatidylinositol 3-kinase suppresses glucose-stimulated insulin secretion by affecting post-cytosolic [Ca(2+)] elevation signals"Diabetes. 51. 87-97 (2002)
[Publications] Mori, Y., et al.: "Genome-wide search for type 2 diabetes susceptibility genes in Japanese affected sibpairs. Autosomal scan supplemented with markers for 12 transcription factor genes and adiponectin gene"Diabetes. 51. 1247-1255 (2002)
[Publications] Hara, K., et al.: "Genetic variation in the gene encoding adiponectin is associated with increased risk of type 2 diabetes in the Japanese population"Diabetes. 51. 536-540 (2002)
[Publications] Akune, T., et al.: "Insulin receptor substrate-2 maintains predominance of anabolic function over catabolic function of osteoblasts"J. Cell Biol.. 159. 147-156 (2002)
[Publications] Shindo, T., et al.: "Kruppel-like zinc-finger transcription factor KLF5/BTEB2 is a target for angiotensin II signaling and an essential regulator of cardiovascular remodeling"Nature Medicine. 8. 856-863 (2002)
[Publications] Hara, K., et al.: "Role of PPARγ as a thrifty gene in high-fat diet-induced adipocyte hypertrophy and insulin resistance"Brit. J. Nutr.. 84. 235-239 (2001)
[Publications] Tsuji, Y., et al.: "Distinct subcellular localization and IRS family proteins associating PI3-kinase activity following insulin stimulation and its functional implications in primary mice adipocytes"Diabetes. 50. 1455-1463 (2001)
[Publications] Miki, H., et al.: "Essential role of IRS-1 and IRS-2 in adipocyte differentiation"Mol. Cell. Biol.. 21. 2521-2531 (2001)

2002 Fiscal Year Annual Research Report

発生工学による糖尿病の発症機序の解明

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.: "Impact of genetic background and ablation of IRS-3 on IRS-2 knockout mice"J. Biol. Chem.. (in press). (2003)

[Publications] Tobe, K., et al.: "Cytoskeletal reorganization induced byinsulin : involvement of Grb2/Ash, Ras and phosphatidylinositol 3-kinase signaling"Genes to Cells. 8. 29-40 (2003)

[Publications] Yamauchi, T., et al.: "Globular adiponectin protected ob/ob mice from diabetes and ApoE-deficient mice from atherosclerosis"J. Biol. Chem.. 24. 2461-2468 (2003)

[Publications] Yamauchi, T., et al.: "Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase"Nat Med.. 8. 1288-1295 (2002)

[Publications] Kubota, N., et al.: "Disruption of adiponectin causes insulin resistance and neointimal formation"J. Biol. Chem.. 19. 25863-25866 (2002)

[Publications] Yamauchi, T., et al.: "Increased insulin sensitivity despite lipodystrophy in Crebbp heterozygous mice"Nat Genet.. 30. 221-226 (2002)

[Publications] Imai, Y., et al.: "Resistance to neointimal hyperplasia and Fatty streak formation in mice with adrenomedullin overexpression"Arterioscler Thromb Vasc Biol. 22. 1310-1315 (2002)

[Publications] Kadowaki, T., et al.: "The role of PPARgamma in high-fat diet-induced obesity and insulin resistance"J. Diabetes Complications. 16. 41-45 (2002)

[Publications] Hara, K., et al.: "A genetic variation in the PGC-1 gene could confer insulin resistance and susceptibility to Type II diabetes"Diabetologia. 45. 740-743 (2002)

[Publications] Hara, K., et al.: "Maturity-onset diabetes of the young resulting from a novel mutation in the HNF-4alpha gene"Intern Med.. 41. 848-852 (2002)

[Publications] Eto, K., et al.: "Phosphatidylinositol 3-kinase suppresses glucose-stimulated insulin secretion by affecting post-cytosolic [Ca(2+)] elevation signals"Diabetes. 51. 87-97 (2002)

[Publications] Mori, Y., et al.: "Genome-wide search for type 2 diabetes susceptibility genes in Japanese affected sibpairs. Autosomal scan supplemented with markers for 12 transcription factor genes and adiponectin gene"Diabetes. 51. 1247-1255 (2002)

[Publications] Hara, K., et al.: "Genetic variation in the gene encoding adiponectin is associated with increased risk of type 2 diabetes in the Japanese population"Diabetes. 51. 536-540 (2002)

[Publications] Akune, T., et al.: "Insulin receptor substrate-2 maintains predominance of anabolic function over catabolic function of osteoblasts"J. Cell Biol.. 159. 147-156 (2002)

[Publications] Shindo, T., et al.: "Kruppel-like zinc-finger transcription factor KLF5/BTEB2 is a target for angiotensin II signaling and an essential regulator of cardiovascular remodeling"Nature Medicine. 8. 856-863 (2002)

[Publications] Hara, K., et al.: "Role of PPARγ as a thrifty gene in high-fat diet-induced adipocyte hypertrophy and insulin resistance"Brit. J. Nutr.. 84. 235-239 (2001)

[Publications] Tsuji, Y., et al.: "Distinct subcellular localization and IRS family proteins associating PI3-kinase activity following insulin stimulation and its functional implications in primary mice adipocytes"Diabetes. 50. 1455-1463 (2001)

[Publications] Miki, H., et al.: "Essential role of IRS-1 and IRS-2 in adipocyte differentiation"Mol. Cell. Biol.. 21. 2521-2531 (2001)

戸辺一之東京大学, 医学部附属病院, 助手 (30251242)