ADVANCED GLYCOSYLATION END-PRODUCTS IN PATIENTS WITH DIABETIC NEPHROPATHY
ADVANCED GLYCOSYLATION END-PRODUCTS IN PATIENTS WITH DIABETIC NEPHROPATHY
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DOI：
10.1056/nejm199109193251202
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发表时间：
1991-09-19
影响因子：
158.5
通讯作者：
VLASSARA, H
中科院分区：
文献类型：
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作者：
MAKITA, Z;RADOFF, S;VLASSARA, H
背景葡萄糖在体内与蛋白质发生非酶反应，化学形成共价连接的葡萄糖加成产物和蛋白质之间的交联。晚期糖基化终产物（AGEs）的过度积累被认为是糖尿病慢性并发症的原因之一。为了阐明AGEs与糖尿病并发症的关系，我们采用放射受体分析法测定了不同肾功能水平的糖尿病（I型和II型）和非糖尿病患者的血清和组织AGEs。血清AGEs以低分子量（小于或等于10 kd）肽组分和高分子量（> 10 kd）蛋白组分的形式测定。9名糖尿病患者动脉壁胶原蛋白样本的平均（+/- SD）AGE含量显著高于18名非糖尿病患者样本（14.5 +/- 5.2 vs. 3.6 +/- 1.5 AGE单位/毫克，P < 0.001）。此外，糖尿病终末期肾病患者的组织中AGE几乎是无肾病糖尿病患者的两倍（每毫克21.3 +/- 2.8 vs. 11.5 +/- 1.9 AGE单位，P < 0.001）。2型糖尿病患者两种血清AGE水平均升高，且AGE肽水平与血清肌酐呈正相关（P < 0.001），与肌酐清除率呈负相关（P < 0.005），提示AGE肽水平随糖尿病肾病的严重程度而升高。在6名需要血液透析的糖尿病患者中，AGE肽水平比8名正常受试者高5倍（82.8 +/- 9.4 vs. 15.6 +/- 3.4 AGE单位/毫升，P < 0.001）。在另一组糖尿病患者中，平均血清肌酐水平在血液透析期间下降了75%，而AGE肽水平仅下降了24%。肾移植术后血清肌酐水平正常的2例患者血清AGE肽水平正常。AGEs在糖尿病患者的动脉和循环中以高于正常的速度积累;循环AGE肽的增加与糖尿病肾病肾功能损害的严重程度平行。
Background. Glucose reacts nonenzymatically with proteins in vivo, chemically forming covalently attached glucose-addition products and cross-links between proteins. The excessive accumulation of rearranged late-glucose-addition products, or advanced glycosylation end products (AGEs), is believed to contribute to the chronic complications of diabetes mellitus.Methods. To elucidate the relation of AGEs to diabetic complications, we used a radioreceptor assay to measure serum and tissue AGEs in diabetic (Types I and II) and nondiabetic patients with different levels of renal function. Serum AGEs were measured as a low-molecular-weight (less-than-or-equal-to 10 kd) peptide fraction and a high-molecular-weight (> 10 kd) protein fraction.Results. The mean (+/- SD) AGE content of samples of arterial-wall collagen from 9 diabetic patients was significantly higher than that of samples from 18 nondiabetic patients (14.5 +/- 5.2 vs. 3.6 +/- 1.5 AGE units per milligram, P < 0.001). Moreover, diabetic patients with end-stage renal disease had almost twice as much AGE in tissue as diabetic patients without renal disease (21.3 +/- 2.8 vs. 11.5 +/- 1.9 AGE units per milligram, P < 0.001). The AGE levels in both serum fractions were elevated in the patients with-diabetes, and the levels of AGE peptides correlated directly with serum creatinine (P < 0.001) and inversely with creatinine clearance (P < 0.005), suggesting that levels of AGE peptides increased with the severity of diabetic nephropathy. In six patients with diabetes who required hemodialysis, the levels of AGE peptides were five times higher than in eight normal subjects (82.8 +/- 9.4 vs. 15.6 +/- 3.4 AGE units per milliliter, P < 0.001). In another group of diabetic patients, the mean serum creatinine level decreased by 75 percent during a session of hemodialysis, whereas the level of AGE peptides decreased by only 24 percent. Serum levels of AGE peptides were normal in two patients with normal serum creatinine levels after renal transplantation.Conclusions. AGEs accumulate at a faster-than-normal rate in arteries and the circulation of patients with diabetes; the increase in circulating AGE peptides parallels the severity of renal functional impairment in diabetic nephropathy.