HUMAN ALDOSE REDUCTASE AND DIABETIC COMPLICATIONS

糖尿病并发症从高血糖影响健康的两种类型 1型和2型糖尿病患者。 有几种理论可以解释 并发症的发展。 事实上， 还原酶预防实验性糖尿病并发症提示 这种酶的核心作用。 这项研究的核心假设是 醛糖还原酶参与了所有糖尿病的发展， 并发症和醛糖还原酶的表达水平是 并发症发展的决定因素。 第二 假设人醛糖还原酶显著不同于 其他的醛糖还原酶和动物的醛糖还原酶是不好的 人醛糖还原酶的模型。 这项建议的目标是： 1)开发一个糖尿病并发症的综合模型， 醛糖还原酶的核心作用，并容纳实验 支持当前并发症理论的证据; 2） 对人醛糖还原酶进行详细的动力学和化学研究 重点在于抑制剂结合位点。 具体目标是 建议集中于人醛糖还原酶，包括酶、化学品 细胞和组织研究。 这些研究旨在验证 糖尿病的并发症是由两种反应引起的， 葡萄糖和涉及丙酮醇和甲基乙二醛的反应， 源自葡萄糖。 葡萄糖、丙酮醛和丙酮醇是底物 用于醛糖还原酶。 此外，所有这些化合物反应 非酶促地与蛋白质结合。 长期目标是：（1）建立 我们对人类醛糖了解的酶学基础 这将有助于开发新的醛糖还原酶 抑制剂;和2）开发一种预测哪些糖尿病患者 将出现并发症，并将受益于醛糖治疗 还原酶抑制剂

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.