Development of a drug for diabetes using human genome information

利用人类基因组信息开发糖尿病药物

• 批准号: 13557011
• 负责人: EBINA Yousuke
• 金额: $ 8.9万
• 依托单位: The University of Tokushima
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13557011/
• 关键词: Insulin signalling; protein phosphorylation; proteome; drug; インスリン作用; 糖尿病薬; Akt; プロテオミクス; 経口糖尿病薬

Evidence suggesting that polygenetic factors contribute to the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM) is accumulating, but the nature of the genetic defect is unknown. The common form of NIDDM is a heterogeneous disorder in which at least two major defects contribute to the pathophysiology of the phenotype : insulin deficiency and insulin resistance. Insulin stimulates the disposal of blood glucose into skeletal muscles and adipose tissues by the translocation of glucose transporter type4 (GLUT4) from intracellular pools to the plasma membrane, and consequently the concentration of blood glucose levels decreases rapidly in vivo. Failure of this action of insulin seems to be one of the major causes of Type2 diabetes. Phosphatidylinositol 3-kinase (PI 3-kinase) and AKT play a pivotal role in the stimulation of glucose transport by insulin, but detailed mechanisms are unknownDur aim is to elucidate the new signalling factors after Akt and to develop the drug to stimulate the insulin signalling. we analyzed the proteins which bind to the PH domain of Akt2 using proteome analysis and found some factors which may participate the insulin signalling

提示多基因因素导致非胰岛素依赖型糖尿病（NIDDM）发病的证据越来越多，但遗传缺陷的性质尚不清楚。NIDDM的常见形式是一种异质性疾病，其中至少有两种主要缺陷导致表型的病理生理学：胰岛素缺乏和胰岛素抵抗。胰岛素通过葡萄糖转运蛋白4（GLUT 4）从细胞内库易位到质膜来刺激血糖向骨骼肌和脂肪组织的处置，并且因此血糖水平的浓度在体内迅速降低。胰岛素这种作用的失败似乎是2型糖尿病的主要原因之一。磷脂酰肌醇3-激酶（PI 3-kinase）和AKT在胰岛素刺激葡萄糖转运中起着关键作用，但其具体机制尚不清楚。我们利用蛋白质组学方法对Akt 2的PH结构域结合蛋白进行了分析，发现了一些可能参与胰岛素信号转导的因子

项目成果

Toshiyuki Obata: "Use of RNA-interference-mediated gene silencing and adenoviral overexpression to Elucidate the roles of AKT/PKB-isoforms in insulin actions"J.Biol.Chem. 278・30. 28312-28323 (2003)

Toshiyuki Obata：“利用 RNA 干扰介导的基因沉默和腺病毒过度表达来阐明 AKT/PKB 亚型在胰岛素作用中的作用”J.Biol.Chem. 278・30 (2003)。

Charles W.Heilig et al.: "Antisense GLUT-1 protects mesangial cells from glucose induction of GLUT-1 and fibronectin expression"Am J Physiol Renal Physiol. 280. F657-F666 (2001)

Charles W.Heilig 等人：“反义 GLUT-1 保护系膜细胞免受葡萄糖诱导的 GLUT-1 和纤连蛋白表达”Am J Physiol Renal Physiol。

Asako Minami et al.: "Increased insulin sensitivity and hypoinsulinemia in APS knockout mice"Diabetes. 52. 2657-2665 (2003)

Asako Minami 等人：“APS 基因敲除小鼠的胰岛素敏感性增加和低胰岛素血症”糖尿病。

Charles W.Heilig: "Antisense GLUT-1 protects mesangial cells from glucose induction of GLUT-1 and fibronectin expression"Am. J. Physiol. Renal. Physiol.. 280. F657-F666 (2001)

Charles W.Heilig：“反义 GLUT-1 保护系膜细胞免受葡萄糖诱导的 GLUT-1 和纤连蛋白表达”Am。

Toshiyuki Obata et al.: "Use of RNA-interference-mediated gene silencing and adenoviral overexpression to Elucidate the roles of AKTIPKB-isoforms in insulin actions"J.Biol.Chew.. 278. 28312-28323 (2003)

Toshiyuki Obata 等人：“使用 RNA 干扰介导的基因沉默和腺病毒过表达来阐明 AKTIPKB-亚型在胰岛素作用中的作用”J.Biol.Chew.. 278. 28312-28323 (2003)