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Hyperglycemic tissue injury: Pathogenesis of diabetic complications and its prevention

高血糖组织损伤：糖尿病并发症的发病机制及其预防

基本信息

批准号：
10470054
负责人：
YAGIHASHI Soroku
金额：
$ 2.69万
依托单位：
Hirosaki University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2001
项目状态：
已结题

项目摘要

Drastic increase in diabetic population poses serious problems in the medical care and cost m modern world. There is an urgent need for clarification of the cause of diabetic complications and for the establishment of effective prevention. The aim of the author's project is to explore the mechanisms of tissue injury in diabetic complication-prone organs; peripheral nerve and kidney and to establish effective means to prevent these abnormalities. To determine the possible role of polyol pathway, we used transgenic mice which express human aldose reductase (hAR), a key enzyme of polyol pathway and compared with non-transgenic animals. Production of advanced glycation end-products (AGE) was also attempted to examine the in vivo effects of AGE on the tissue damage in kidney and peripheral nerve. Furthermore, autopsy materials from diabetic patients were exploited to identify the overexpression of AR as well as AGE in the injured site in diabetic organs. As a result, we confirmed that AR is a major determinant for the onset and severity of diabetic complications in transgenic mice as well as in human diabetic patients. It was also confirmed that AGE had a pathogenetic role in the microvascular injury in diabeteic condition and excessive oxidative stress mediates the AGE-induced tissue injury. These tissue injuries are the major process not only in the diabetic peripheral nerve or kidney, but also in diabetic pancreas, where progressive decline of islet beta cell mass is the natural history of type 2 diabetes. Use of AR inhibitors, anti-glycation agents and meticulous control of blood glucose are all essential for the prevention of diabetic complications and progressive islet lesions in diabetes. Further elucidation of precise mechanisms of hyperglycemia-induced tissue injury is required for the complete protection of diabetes and its complications.

糖尿病人口的急剧增加给现代世界的医疗保健和费用带来了严重的问题。迫切需要澄清糖尿病并发症的原因，并建立有效的预防措施。本课题的目的是探讨糖尿病易并发器官、周围神经和肾脏的组织损伤机制，并建立预防这些异常的有效手段。为了确定多元醇途径的可能作用，我们使用了表达多元醇途径的关键酶--人醛糖还原酶(HAR)的转基因小鼠，并与非转基因动物进行了比较。此外，还尝试了晚期糖基化终末产物(AGE)的产生，以检测AGE对肾脏和周围神经组织损伤的体内影响。此外，利用来自糖尿病患者的尸检材料来确定AR和AGE在糖尿病器官损伤部位的过度表达。结果，我们证实AR是转基因小鼠和人类糖尿病患者糖尿病并发症发生和严重程度的主要决定因素。也证实了AGE在糖尿病微血管损伤中的致病作用，过度氧化应激介导了AGE诱导的组织损伤。这些组织损伤不仅是糖尿病周围神经或肾脏的主要过程，也是糖尿病胰腺的主要过程，胰岛β细胞质量进行性下降是2型糖尿病的自然病程。使用AR抑制剂、抗糖基化药物和严格控制血糖对于预防糖尿病并发症和糖尿病的进行性胰岛病变都是必不可少的。为了完全预防糖尿病及其并发症，需要进一步阐明高血糖所致组织损伤的确切机制。