Hyperglycemic tissue injury: Pathogenesis of diabetic complications and its prevention

糖尿病人口的急剧增加给现代社会的医疗保健和成本带来了严重的问题。目前迫切需要明确糖尿病并发症的病因，建立有效的预防措施。作者项目的目的是探讨糖尿病并发症易发器官的组织损伤机制；并建立周围神经和肾脏的有效手段来预防这些异常。为了确定多元醇途径可能的作用，我们利用表达多元醇途径关键酶人醛糖还原酶（hAR）的转基因小鼠与非转基因小鼠进行了比较。晚期糖基化终产物（AGE）的产生也试图研究AGE对肾脏和周围神经组织损伤的体内影响。此外，研究人员利用糖尿病患者的尸检资料，确定了糖尿病器官损伤部位的AR和AGE的过表达。因此，我们证实，在转基因小鼠和人类糖尿病患者中，AR是糖尿病并发症发生和严重程度的主要决定因素。同时证实AGE在糖尿病微血管损伤中具有致病作用，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，而且也是糖尿病胰腺的主要过程，其中胰岛β细胞团的进行性下降是2型糖尿病的自然史。使用AR抑制剂、抗糖化药物和严格控制血糖是预防糖尿病并发症和糖尿病进行性胰岛病变的必要条件。进一步阐明高血糖诱导的组织损伤的确切机制是全面保护糖尿病及其并发症的必要条件。

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.