Glyceraldehyde-3-phosphate dehydrogenase activity as an independent modifier of methylglyoxal levels in diabetes
Glyceraldehyde-3-phosphate dehydrogenase activity as an independent modifier of methylglyoxal levels in diabetes
复制标题
DOI：
10.1016/s09254439(02)00219-3
复制
发表时间：
2003-01-20
影响因子：
6.2
通讯作者：
Szwergold, BS
中科院分区：
文献类型：
--
作者：
Beisswenger, PJ;Howell, SK;Szwergold, BS
甲基乙二醛（MG）可能是糖尿病并发症的重要原因。其主要来源是磷酸二羟丙酮（DHAP），其水平部分受甘油醛-3-磷酸脱氢酶（GAPDH）控制。使用人红细胞（RBC）培养物，我们检查了修饰GAPDH活性对MG产生的影响。使用抑制剂康宁酸（KA），我们显示出线性的、浓度依赖性的GAPDH抑制，5 μ M KA导致GAPDH活性降低79%，MG增加6倍。由升高的pH产生的氧化还原状态的变化也导致MG产量在pH 7.5时增加2.4倍，在pH 7.8时增加13.4倍。我们发现DHAP和MG水平的个体间差异很大，GAPDH活性与2型糖尿病MG产生呈负相关（R=0.57，P=0.005）。在1型糖尿病患者体内，GAPDH活性与MG之间存在相似的相关性（R=0.29，P=0.0018）。我们假设GAPDH的环境因素或遗传失调的修改和由此产生的MG生产的差异，可以至少部分解释这一观察。(C)2002 Elsevier Science B.V保留所有权利。
Methylglyoxal (MG) may be an important cause of diabetic complications. Its primary source is dihydroxyacetone phosphate (DHAP) whose levels are partially controlled by glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Using a human red blood cell (RBC) culture, we examined the effect of modifying GAPDH activity on MG production. With the inhibitor koningic acid (KA), we showed a linear, concentration-dependent GAPDH inhibition, with 5 muM KA leading to a 79% reduction of GAPDH activity and a sixfold increase in MG. Changes in redox state produced by elevated pH also resulted in a 2.4-fold increase in MG production at pH 7.5 and a 13.4-fold increase at pH 7.8. We found substantial inter-individual variation in DHAP and MG levels and an inverse relationship between GAPDH activity and MG production (R=0.57, P=0.005) in type 2 diabetes. A similar relationship between GAPDH activity and MG was observed in vivo in type 1 diabetes (R=0.29, P=0.0018).Widely varying rates of progression of diabetic complications are seen among individuals. We postulate that modification of GAPDH by environmental factors or genetic dysregulation and the resultant differences in MG production could at least partially account for this observation. (C) 2002 Elsevier Science B.V All rights reserved.