1995 Fiscal Year Annual Research Report

糖尿病における動脈硬化症危険因子の血管分子生物学:酸化ストレスと高インスリン血症

Research Project

Project/Area Number	07671127
Research Category	Grant-in-Aid for General Scientific Research (C)
Research Institution	Shiga University of Medical Science
Principal Investigator	柏木厚典滋賀医科大学, 医学部, 助教授 (20127210)
Keywords	動脈硬化症危険因子 / 血管生物学 / 酸化ストレス / 高インスリン血症 / リソホスファチジルコリン / 単球走化性因子 / 血管内皮細胞
Research Abstract	インスリン非依存型糖尿病における動脈硬化症発症の危険因子として酸化LDL産生、高インスリン血症の意義が検討されている。本研究では、糖尿病患者血清中LDLに酸化変性LDLが増加しているかどうかをLDL酸化修飾の指標であるLysophosphatidylcholine(LPC)濃度を測定し、LPC濃度と臨床的指標との関連を検討し、更にLPCによる血管内皮細胞遺伝子発現の修飾とその調節に関して明らかにした。一方インスリンの血管平滑筋細胞増殖作用について平滑筋細胞増殖におけるインスリン作用の特徴を明らかにした。 1.糖尿病患者におけるアポB含有リポ蛋白中LPCの増加とその生物活性:正脂血症の糖尿病患者のアポB含有リポ蛋白中のLPC濃度は対照群に比較し高値であり、血糖コントロールと関連していた。糖尿病群のアポB含有リポ蛋白は、対照群に比べて血管内皮細胞のMonocyte chemoatracttant protein-1(MCP-1)mRNA発現を強く誘導した。(Diabetologia submitted) 更にLPCによりMCP-1mRNA発現が増加し、培養液中にMCP-1が40%増加した(Metabolism,1996 in press)2.高血糖による内皮細胞機能異常:高血糖では活性酸素分解能が低下し、血管内皮細胞は酸化障害を受けやすくなる事、その機構としてグルタチオン還元サイクルに連結した五炭糖リン酸回路の活性化異常が明らかとなった。(Diabetologia 1994,Diabetes 1995)更に高血糖では血管内皮細胞における接着分子の発現が増加した(Life Science 1996,in press)。3.血管平滑筋細胞におけるインスリン作用:生理的濃度インスリンによりインスリンは、直接的細胞増殖促進作用はないが、IRS-1,PI3´キナーゼの活性化によりアミノ酸輸送系が促進される(Atherosclerosis 1995,Circulation Res,submitted)。

Research Products
(16 results)

All Other

All Publications (16 results)

[Publications] Kashiwage,A.,et al.: "Abnormal glutathione metabolism and increased cytotoxicity caused by H_2O_2 in human umbilical vein endothelial cells cultured in high glucose medium." Diabetologia. 37. 264-269 (1994)
[Publications] Takagi,Y,et al.: "Insulin-specific activation of S6 kinase and its desensitization in cultured vascular smooth muscle cells" Atherosclerosis. 113. 19-27 (1995)
[Publications] Ide R,et al.: "High glucose concentration desensitizes insulin action at the levels of receptor kinase." Endocine J. 42. 1-8 (1995)
[Publications] Hidaka H,et al.: "Effects of an HMG-CoA reductase inhibitor,pravastatin,and bile sequestering resin,cholestyramine,on plasma plant sterol levels in hypercholesterolemic subjects." J.Atheroscler Thromb. 2. 60-65 (1995)
[Publications] Takagi Y,et al.: "Significance of fructose autoxidation in protein oxidation and formation of advanced glycation end product." J Diabetic Compl. 9. 87-91 (1995)
[Publications] Ogawa T,et al.: "The increase of voltage-sensitive calcium channels and calcium accumulation in skeletal muscles of streptozocin-induced diabetic rats." Metabolism. 44. 1456-1461 (1995)
[Publications] Asahina T,et al.: "Impaired activation of glucose oxidation and NADPH supply in human endothelial cells exposed to H_2O_2 in high glucose medium." Diabetes. 44. 520-526 (1995)
[Publications] Kashiwagi A,et al.: "Rationale and hurdles of inhibitors of hepatic gluconeogenesis in treatment of diabetes mellitus" Diabetes Res Clin Pract. 28. S195-S200 (1995)
[Publications] Iwanishi M,et al.: "Clinical and laboratory characteristics in the families with diabetes and a mitochondrial tRNA^<LEU(UUR)> gene mutation." Diabetes Res Clin Pract. 29. 75-82 (1995)
[Publications] Maegawa H,et al.: "Thiazolidine derivatives ameliorate high glucose-induced insulin resistance via the normalization of protein-tyrosine phosphatase activities." J Biol Chem. 270. 7724-7730 (1995)
[Publications] Sugimoto T,et al.: "Atrial natriuretic peptide induces the expression of MKP-1,a mitogen activated protein kinase phosphatase,in glomerular mesangial cells." J Biol Chem. 271. 544-547 (1996)
[Publications] Takahara N,et al.: "Lysophosphatidylcholine stimulates the expression and production of MCP-1 by by human vascular endothelial cells." Metabolism. (in press). (1996)
[Publications] Kashiwagi A,et al.: "Glucose metabolism and radical scavenger dysfunction in endothelial cells." Diabetes(Supplement). (In press). (1996)
[Publications] Ugi S,et al.: "Expression of dominant negative mutant SHPTP2 attenuates phosphatidylinositol 3´-kinase activity via modulation of phosphorylation of insulin receptor substrate-1." J Biol Chem. (in press). (1996)
[Publications] Taki H,et al.: "Specific expression of intracellular adhesion molecules 1(ICAM-1)via an osmotic effect in human umbilical vein endothelial cells exposed to high glucose medium." Life Sci. (in press). (1996)
[Publications] Kashiwagi A,et al.: "In Endothelial Cells Dysfunction in Diabetes" Churchill Livingstone, 14 (1994)

1995 Fiscal Year Annual Research Report

糖尿病における動脈硬化症危険因子の血管分子生物学:酸化ストレスと高インスリン血症

Principal Investigator

柏木 厚典 滋賀医科大学, 医学部, 助教授 (20127210)

Research Products

[Publications] Kashiwage,A.,et al.: "Abnormal glutathione metabolism and increased cytotoxicity caused by H_2O_2 in human umbilical vein endothelial cells cultured in high glucose medium." Diabetologia. 37. 264-269 (1994)

[Publications] Takagi,Y,et al.: "Insulin-specific activation of S6 kinase and its desensitization in cultured vascular smooth muscle cells" Atherosclerosis. 113. 19-27 (1995)

[Publications] Ide R,et al.: "High glucose concentration desensitizes insulin action at the levels of receptor kinase." Endocine J. 42. 1-8 (1995)

[Publications] Hidaka H,et al.: "Effects of an HMG-CoA reductase inhibitor,pravastatin,and bile sequestering resin,cholestyramine,on plasma plant sterol levels in hypercholesterolemic subjects." J.Atheroscler Thromb. 2. 60-65 (1995)

[Publications] Takagi Y,et al.: "Significance of fructose autoxidation in protein oxidation and formation of advanced glycation end product." J Diabetic Compl. 9. 87-91 (1995)

[Publications] Ogawa T,et al.: "The increase of voltage-sensitive calcium channels and calcium accumulation in skeletal muscles of streptozocin-induced diabetic rats." Metabolism. 44. 1456-1461 (1995)

[Publications] Asahina T,et al.: "Impaired activation of glucose oxidation and NADPH supply in human endothelial cells exposed to H_2O_2 in high glucose medium." Diabetes. 44. 520-526 (1995)

[Publications] Kashiwagi A,et al.: "Rationale and hurdles of inhibitors of hepatic gluconeogenesis in treatment of diabetes mellitus" Diabetes Res Clin Pract. 28. S195-S200 (1995)

[Publications] Iwanishi M,et al.: "Clinical and laboratory characteristics in the families with diabetes and a mitochondrial tRNA^<LEU(UUR)> gene mutation." Diabetes Res Clin Pract. 29. 75-82 (1995)

[Publications] Maegawa H,et al.: "Thiazolidine derivatives ameliorate high glucose-induced insulin resistance via the normalization of protein-tyrosine phosphatase activities." J Biol Chem. 270. 7724-7730 (1995)

[Publications] Sugimoto T,et al.: "Atrial natriuretic peptide induces the expression of MKP-1,a mitogen activated protein kinase phosphatase,in glomerular mesangial cells." J Biol Chem. 271. 544-547 (1996)

[Publications] Takahara N,et al.: "Lysophosphatidylcholine stimulates the expression and production of MCP-1 by by human vascular endothelial cells." Metabolism. (in press). (1996)

[Publications] Kashiwagi A,et al.: "Glucose metabolism and radical scavenger dysfunction in endothelial cells." Diabetes(Supplement). (In press). (1996)

[Publications] Ugi S,et al.: "Expression of dominant negative mutant SHPTP2 attenuates phosphatidylinositol 3´-kinase activity via modulation of phosphorylation of insulin receptor substrate-1." J Biol Chem. (in press). (1996)

[Publications] Taki H,et al.: "Specific expression of intracellular adhesion molecules 1(ICAM-1)via an osmotic effect in human umbilical vein endothelial cells exposed to high glucose medium." Life Sci. (in press). (1996)

[Publications] Kashiwagi A,et al.: "In Endothelial Cells Dysfunction in Diabetes" Churchill Livingstone, 14 (1994)

柏木厚典滋賀医科大学, 医学部, 助教授 (20127210)