van Deutekom A W, Niessen H W M, Schalkwijk C G, Heine R J, Simsek S
Department of Endocrinology/Diabetes Center, VU University Medical Center, PO Box 7057, 1007 MB, Boelelaan 1117, Amsterdam, The Netherlands.
Eur J Endocrinol. 2008 May;158(5):655-60. doi: 10.1530/EJE-08-0024.
Non-enzymatic glycation of proteins and their end products (advanced glycation end products, AGE) have been implicated in the pathogenesis of diabetic complications. Our aim was to evaluate the association between diabetes mellitus (DM) and the accumulation of one of the most abundant AGEs, Nepsilon-(carboxymethyl)-lysine (CML), in cerebral vessels.
Brain tissue samples were obtained by autopsy from 20 DM patients and 13 age-matched controls. In addition, we investigated brain tissue samples of seven rats after induction of diabetes with streptozotocin (STZ) and six non-diabetic control rats. We used an immunohistochemical staining method to examine the CML immunoreactivity in the cerebral vessels.
Staining intensity of CML was significantly higher in cerebral vessels of diabetic patients than in non-diabetic subjects (median of the immunohistochemical intensity score/cm(2) in the diabetic group of 0.85 (interquartile range (IQR) 0.66-1.52) vs 0.63 in the control group (IQR 0.44-0.70); P=0.002). Furthermore, there was a similar significant difference in CML staining intensity of cerebral vessels between STZ diabetic rats and non-diabetic control rats (median of the immunohistochemical intensity score/cm(2) in the diabetic group of 1.08 (IQR 0.73-1.43) vs 0.23 in the control group (IQR 0.12-0.43); P=0.003).
Accumulation of CML-modified proteins is significantly greater in the cerebral vessels of the diabetic patients than their age-matched controls. This association has been confirmed in the insulin-deficient diabetic rat model. It may be possible that the excessive accumulation of AGE-modified proteins in the cerebral vasculature alters the local environment and microcirculation and thereby contributes to the development of cognitive impairments in diabetes. Therefore, additional study on the causal link between AGE accumulation and cognitive dysfunction and the potential benefits of AGE-blocking and/or breaking compounds is indicated.
蛋白质的非酶糖基化及其终产物（晚期糖基化终产物，AGE）与糖尿病并发症的发病机制有关。我们的目的是评估糖尿病（DM）与脑血管中最丰富的AGE之一Nε-（羧甲基）-赖氨酸（CML）积累之间的关联。
通过尸检从20例DM患者和13例年龄匹配的对照者获取脑组织样本。此外，我们研究了7只经链脲佐菌素（STZ）诱导糖尿病的大鼠和6只非糖尿病对照大鼠的脑组织样本。我们使用免疫组织化学染色方法检测脑血管中的CML免疫反应性。
糖尿病患者脑血管中CML的染色强度显著高于非糖尿病受试者（糖尿病组免疫组织化学强度评分/平方厘米的中位数为0.85（四分位间距（IQR）0.66 - 1.52），而对照组为0.63（IQR 0.44 - 0.70）；P = 0.002）。此外，STZ糖尿病大鼠和非糖尿病对照大鼠脑血管中CML染色强度也存在类似的显著差异（糖尿病组免疫组织化学强度评分/平方厘米的中位数为1.08（IQR 0.73 - 1.43），而对照组为0.23（IQR 0.12 - 0.43）；P = 0.003）。
CML修饰蛋白在糖尿病患者脑血管中的积累显著高于其年龄匹配的对照者。这种关联在胰岛素缺乏的糖尿病大鼠模型中得到了证实。可能是脑血管中AGE修饰蛋白的过度积累改变了局部环境和微循环，从而导致糖尿病患者认知障碍的发生。因此，需要进一步研究AGE积累与认知功能障碍之间的因果关系以及AGE阻断和/或裂解化合物的潜在益处。
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