Monnier Vincent M, Sell David R, Dai Zhenyu, Nemet Ina, Collard Francois, Zhang Jianye
Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
Ann N Y Acad Sci. 2008 Apr;1126:81-8. doi: 10.1196/annals.1433.052.
Strong evidence has emerged in recent years in support of an association between advanced glycation and the complications of diabetes, whereby both glycoxidation products and oxoaldehydes have been implicated. In contrast, except for the fact that skin collagen-linked fructosamine (Amadori product) is a strong predictor of the risk of progression of microvascular disease in humans, Amadori products have not been associated with complications in most animal experiments. Below we develop the hypothesis that glucose-derived advanced glycation end products (AGEs), such as glucosepane, may inflict sustained damage to the extracellular matrix in diabetes and contribute to tissue stiffening and accelerated sclerosis in arteries, kidneys, and other organs as supported by immunochemical studies using a glucosepane antibody. We also hypothesize that many more structures derived from Amadori products with nucleophiles, such as primary amines and thiols, are expected. The selective prevention of Amadori-derived AGEs using deglycating enzymes would be desirable. However, x-ray diffraction studies of Amadoriase I crystals show that the active site of the enzyme is deeply embedded, explaining why this approach is unlikely to succeed in vivo. Preliminary experiments with nucleophiles show that aminoguanidine and other compounds block glucosepane in vitro.
近年来，有强有力的证据支持晚期糖基化与糖尿病并发症之间存在关联，糖化氧化产物和氧代醛都与此有关。相比之下，除了皮肤胶原连接果糖胺（阿马多利产物）是人类微血管疾病进展风险的有力预测指标外，在大多数动物实验中，阿马多利产物并未与并发症相关联。下面我们提出一个假说，即葡萄糖衍生的晚期糖基化终产物（AGEs），如葡糖胺聚糖，可能会对糖尿病患者的细胞外基质造成持续性损伤，并导致组织硬化以及动脉、肾脏和其他器官的硬化加速，这一假说得到了使用葡糖胺聚糖抗体的免疫化学研究的支持。我们还推测，预计会有更多由阿马多利产物与亲核试剂（如伯胺和硫醇）衍生而来的结构。使用去糖化酶选择性预防阿马多利衍生的AGEs将是理想的。然而，对阿马多利酶I晶体的X射线衍射研究表明，该酶的活性位点深埋其中，这就解释了为什么这种方法在体内不太可能成功。亲核试剂的初步实验表明，氨基胍和其他化合物在体外可阻断葡糖胺聚糖的形成。
