HUMAN ALDOSE REDUCTASE AND DIABETIC COMPLICATIONS

人醛糖还原酶与糖尿病并发症

• 批准号: 3244585
• 负责人: DAVID L VANDER JAGT
• 金额: $ 11.8万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-30 至 1995-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3244585
• 关键词: active sites; aldehyde reductase; carbohydrate transport; diabetes mellitus; diabetic nephropathy; enzyme activity; enzyme inhibitors; enzyme substrate; glucose; human tissue; intracellular transport; medical complication; oxidative stress; posttranslational modifications; protein structure; sorbitol; tissue /cell culture

Diabetic complications from hyperglycemia affect the health of both type 1 and type 2 diabetics. There are several theories to explain the development of complications. The fact that inhibitors of aldose reductase prevent complications in experimental diabetes suggests a central role for this enzyme. The central hypothesis of this study is that aldose reductase is involved in the development of all diabetic complications and that the level of expression of aldose reductase is the determining factor in the development of complications. A second hypothesis is that human aldose reductase differs significantly from other aldose reductases and that animal aldose reductases are not good models for human aldose reductase. The objectives of this proposal are: 1) to develop an integrative model of diabetic complications that has a central role for aldose reductase and that accommodates the experimental evidence that supports current theories of complications; and 2) to conduct a detailed kinetic and chemical study of human aldose reductase with emphasis on the inhibitor binding site. The Specific Aims of this proposal focus on human aldose reductase and include enzyme, chemical, cellular and tissue studies. These studies are designed to test the idea that the complication of diabetes result both from reactions involving glucose and from reactions involving acetol and methylglyoxal, which are derived from glucose. Glucose, methylglyoxal and acetol are substrates for aldose reductase. In addition, all of these compounds react nonenzymatically with proteins. The longterm goals are: 1) to establish an enzymological foundation to our understanding of human aldose reductase that will contribute to the development of new aldose reductase inhibitors; and 2) to develop a paradigm for predicting which diabetics will develop complications and will benefit from therapy with aldose reductase inhibitors.

高血糖引起的糖尿病并发症影响两种类型的健康