Epalrestat, an aldose reductase inhibitor, reduces the levels of Nε-(carboxymethyl)lysine protein adducts and their precursors in erythrocytes from diabetic patients
Epalrestat, an aldose reductase inhibitor, reduces the levels of Nε-(carboxymethyl)lysine protein adducts and their precursors in erythrocytes from diabetic patients
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DOI：
10.2337/diacare.23.10.1539
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发表时间：
2000-10-01
期刊：
影响因子：
16.2
通讯作者：
Hotta, N
中科院分区：
文献类型：
--
作者：
Hamada, Y;Nakamura, J;Hotta, N
目的 - 为了阐明多元醇途径在人体组织细胞内晚期糖基化终产物形成中的作用，我们检测了依帕司他（一种醛糖还原酶抑制剂）对糖尿病患者红细胞中 N-ε-（羧甲基）赖氨酸（CML）以及 3-脱氧葡萄糖酮（3-DG）和磷酸三糖水平的影响。血浆硫代巴比妥酸反应物质 (TBARS) 也被测定为氧化应激指标。 研究设计和方法 - 从 12 名非糖尿病志愿者、38 名未经治疗的 2 型糖尿病患者和 16 名每天接受 150 mg 依帕司他治疗的 2 型糖尿病患者采集血样。还从 14 名未经治疗的 2 型糖尿病患者服用依帕司他 2 个月之前和之后采集了血液样本。通过竞争性酶联免疫吸附测定法测定红细胞 CML 的量，并通过高效液相色谱法测定 3-DG。 结果 - 在未接受依帕司他治疗的糖尿病患者中，红细胞 CML 水平显着高于非糖尿病个体的水平（49.9 +/- 5.0 vs. 31.0 +/- 5.2 U/g 蛋白，P < 0.05），并且在患者中显着降低接受依帕司他（33.1 +/- 3.8 U/g 蛋白质，P < 0.05）。 5-DG 也观察到类似的结果。接受依帕司他治疗 2 个月的患者显着降低了红细胞 CML 水平（基线时为 46.2 +/- 5.6 vs. 34.4 +/- 5.0 U/g 蛋白，P < 0.01）以及红细胞 3-DG（P < 0.05）、磷酸三糖（P < 0.05）、果糖（P < 0.05）、山梨醇 (P < 0.05) 和血浆 TBARS (P < 0.05)，但血浆葡萄糖和 HbA(1c) 水平没有变化。糖尿病患者的红细胞 CML 与山梨醇（r = 0.49，P < 0.01）或果糖（r = 0.40，P < 0.05）水平之间存在明显的正相关性。结论 - 结果表明，依帕司他给药可降低 CML 和相关变量，并且多元醇代谢物与糖尿病患者红细胞中的 CML 相关。观察到的结果表明，醛糖还原酶活性可能在介导反应性中间代谢物和氧化应激的 CML 细胞内形成中发挥重要作用。
OBJECTIVE - To clarify the role of the polyol pathway in the intracellular formation of advanced glycation end products in human tissues, we examined the effects of epalrestat, an aldose reductase inhibitor, on the level of N-epsilon-(carboxymethyl)lysine (CML) along with 3-deoxyglucosone (3-DG) and triosephosphates in erythrocytes from diabetic patients. Plasma thiobarbituric acid-reactive substances (TBARS) were also determined as indicators of oxidative stress.RESEARCH DESIGN AND METHODS - Blood samples were collected from 12 nondiabetic volunteers, 38 untreated type 2 diabetic patients, and 16 type 2 diabetic patients who had been treated with 150 mg epalrestat/day. Blood samples were also collected from 14 of the untreated type 2 diabetic patients before and after the administration of epalrestat for 2 months. The amount of erythrocyte CML was determined by a competitive enzyme-linked immunosorbent assay, and 3-DG was measured by high-performance liquid chromatography.RESULTS - In diabetic patients not treated with epalrestat, the erythrocyte CML level was significantly elevated above levels seen in nondiabetic individuals (49.9 +/- 5.0 vs. 31.0 +/- 5.2 U/g protein, P < 0.05) and was significantly lower in patients receiving epalrestat (33.1 +/- 3.8 U/g protein, P < 0.05). Similar results were observed with 5-DG. The treatment of patients with epalrestat for 2 months significantly lowered the level of erythrocyte CML (46.2 +/- 5.6 at baseline vs. 34.4 +/- 5.0 U/g protein, P < 0.01) along with erythrocyte 3-DG (P < 0.05), triosephosphates (P < 0.05), fructose (P < 0.05), sorbitol (P < 0.05), and plasma TBARS (P < 0.05) without changes in plasma glucose and HbA(1c) levels. A positive correlation was evident between the erythrocyte CML and sorbitol (r = 0.49, P < 0.01) or fructose (r= 0.40, P < 0.05) levels in diabetic patients.CONCLUSIONS - The results indicate that epalrestat administration lowers CML and associated variables and that polyol metabolites are correlated with CML in the erythrocytes of diabetic patients. The observed results suggest that aldose reductase activity may play a substantial role in the intracellular formation of CML in the mediation of reactive intermediate metabolites and oxidative stress.