Sato Takashi, Iwaki Mina, Shimogaito Noriko, Wu Xuegang, Yamagishi Sho-Ichi, Takeuchi Masayoshi
Department of Pathophysiological Science, Faculty of Pharmaceutical Sciences, Hokuriku University, Ho-3 Kanagawa-machi, Kanazawa 920-1181, Japan.
Curr Mol Med. 2006 May;6(3):351-8. doi: 10.2174/156652406776894536.
Diabetic complication is a leading cause of acquired blindness, end-stage renal failure, a variety of neuropathies and accelerated atherosclerosis. Chronic hyperglycemia is initially involved in the pathogenesis of diabetic micro- and macro-vascular complications via various metabolic derangements. High glucose increased production of various types of advanced glycation end-products (AGEs). Recently, we found that glyceraldehyde-derived AGEs (AGE-2) play an important role in the pathogenesis of angiopathy in diabetic patients. There is considerable interest in receptor for AGEs (RAGE) found on many cell types, particularly those affected in diabetes. Recent studies suggest that interaction of AGE-2 (predominantly structure of toxic AGEs; TAGE) with RAGE alters intracellular signaling, gene expression, release of pro-inflamatory molecules and production of reactive oxygen species (ROS) that contribute towards the pathology of diabetic complications. We propose three pathways for the in vivo formation of AGE-2 precursor, glyceraldehyde, such as i) glycolytic pathway, ii) polyol pathway, and iii) fructose metabolic pathway. Glyceraldehyde can be transported or can leak passively across the plasma membrane. It can react non-enzymatically with proteins to lead to accelerated formation of TAGE at both intracellularly and extracellularly. In this review, we discuss the molecular mechanisms of diabetic complications, especially focusing on toxic AGEs (TAGE) and their receptor (RAGE) system.
糖尿病并发症是导致后天性失明、终末期肾衰竭、多种神经病变以及动脉粥样硬化加速的主要原因。慢性高血糖最初通过各种代谢紊乱参与糖尿病微血管和大血管并发症的发病机制。高糖会增加各种晚期糖基化终产物（AGEs）的生成。最近，我们发现甘油醛衍生的AGEs（AGE-2）在糖尿病患者血管病变的发病机制中起重要作用。人们对在许多细胞类型上发现的AGEs受体（RAGE），尤其是在糖尿病中受影响的那些细胞类型上的受体，有着浓厚的兴趣。最近的研究表明，AGE-2（主要是有毒AGEs的结构；TAGE）与RAGE的相互作用会改变细胞内信号传导、基因表达、促炎分子的释放以及活性氧（ROS）的产生，这些都有助于糖尿病并发症的病理过程。我们提出了AGE-2前体甘油醛在体内形成的三条途径，如i）糖酵解途径，ii）多元醇途径，以及iii）果糖代谢途径。甘油醛可以被转运或被动地穿过质膜。它可以与蛋白质发生非酶反应，导致在细胞内和细胞外加速形成TAGE。在这篇综述中，我们讨论糖尿病并发症的分子机制，尤其关注有毒AGEs（TAGE）及其受体（RAGE）系统。
