AGE/RAGE as a Mediator of Insulin Resistance or Metabolic Syndrome: Another Aspect of Metabolic Memory?
AGE/RAGE as a Mediator of Insulin Resistance or Metabolic Syndrome: Another Aspect of Metabolic Memory?
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AGE/RAGE 作为胰岛素抵抗或代谢综合征的中介：代谢记忆的另一个方面？
作者：
H. Koyama;Tetsuya Yamamoto
糖尿病大型随机研究已经确定，早期强化血糖控制可以降低糖尿病微血管并发症的风险，对大血管并发症的影响较小1，2。在2型糖尿病患者中，以正常糖化血红蛋白水平为目标的进一步强化治疗也未能降低死亡率和主要心血管事件3，4，但可能相当有害5。然而，这些试验的随访数据显示，早期代谢控制对长期心血管结局有长期影响，尽管在试验6、7后对血糖控制的影响立即消失。这种现象最近被定义为“代谢记忆”。在2型糖尿病高危患者中，多种药物组合和行为矫正的强化干预在血管并发症以及任何原因和心血管原因的死亡率方面具有类似的持续有益效果8。类似地，在终末期肾病（ESRD）患者中，对一般风险因素（如高LDL胆固醇或C反应蛋白）的强化干预未能成功改善其心血管结局9，10，这表明风险降低的有益效果可能会被肾衰竭进展期间长期暴露于氧化应激的累积“代谢记忆”所淹没。传播这种“记忆”的潜在机制是细胞和组织蛋白的非酶糖化，其被概念化为晚期糖化终产物（AGEs），其产生与氧化应激增加以及高血糖症密切相关。AGEs及其受体（receptor for AGEs，AGEs）可能介导导致代谢记忆的分子和细胞途径。此外，与AGEs的相互作用，导致关键的生物医学途径产生细胞内的氧化应激和炎症介质，这可能会导致进一步放大的途径参与AGE的产生。通过利用基因工程小鼠模型，新出现的证据表明AGE/AGEs轴也被发现与非糖尿病、非尿毒症病理生理学状况深刻相关，包括1）动脉粥样硬化形成，2）血管生成反应，3）血管损伤和4）炎症反应（参见11中的综述），其中许多现在与代谢综合征有关。也已经描述了许多截短形式的α-淀粉酶，
Large randomized studies in diabetes have established that early intensive glycemic control reduces the risk of diabetic microvascular complications, with less impact on macrovascular complications 1, 2. In type 2 diabetic patients, further intensive therapy to target normal glycated hemoglobin levels also failed to reduce mortality and major cardiovascular events 3, 4, while it may be rather harmful 5. However, follow-up data of these trials reveal a longterm influence of early metabolic control on longer cardiovascular outcomes, even though the influence on glycemic control has been immediately disappeared after the trials 6, 7. This phenomenon has recently been defined as "metabolic memory". In at-risk patients with type 2 diabetes, intensive intervention with multiple drug combinations and behavior modification had similar sustained beneficial effects with respect to vascular complications and on rates of death from any cause and from cardiovascular causes 8. Similarly in patients with end-stage renal disease (ESRD), intensive interventions to the general risk factors, such as high LDL-cholesterol or C-reactive protein, have not been successful in improving their cardiovascular outcomes 9, 10, suggesting that the beneficial effect of risk reduction may be overwhelmed by accumulated “metabolic memory” by long-term exposure to oxidative stress during the progression of renal failure. Potential mechanisms for propagating this "memory" are the non-enzymatic glycation of cellular and tissue proteins which are conceptualized as advanced glycation end-products (AGEs), the generation of which has been implicated to be deeply associated with increased oxidative stress as well as hyperglycemia. AGEs, with their receptor (receptor for AGEs, RAGE), potentially mediate molecular and cellular pathway leading to metabolic memory. Moreover, interaction of the RAGE with AGEs leads to crucial biomedical pathway generating intracellular oxidative stress and inflammatory mediators, which could result in further amplification of the pathway involved in AGE generation. By utilizing genetically engineered mouse models, emerging evidence suggests that AGE/RAGE axis is also found to be profoundly associated with non-diabetic, non-uremic pathophysiological conditions including 1) atherogenesis, 2) angiogenic response, 3) vascular injury, and 4) inflammatory response (see review in 11), many of which are now implicated in metabolic syndrome. Numerous truncated forms of RAGE have also been described, and the
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11
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