晚期糖基化终末产物与骨质疏松症

骨质疏松的主要表现是低骨量和骨组织微结构退变,其发生的本质在于骨再造过程紊乱即骨吸收超过骨形成。骨吸收与骨形成分别与破骨细胞和成骨细胞的活动直接相关。目前研究发现众多激素、生长因子和细胞因子等参与均衡这两类细胞的数量和活性,影响骨代谢平衡,晚期糖基化终末产物也是目前其中研究较为广泛的因子之一。晚期糖基化终末产物随着年龄增长在体内积聚增多,通过直接或间接的作用导致骨代谢的失衡,出现骨质疏松。     

晚期糖基化终末产物与糖尿病性骨质疏松

晚期糖基化终末产物(AGEs)是由蛋白质经非酶催化的Maillard反应所形成,糖尿病时AGEs的形成和积累加速.AGEs与其受体(RAGE)结合后,引起氧化应激及炎性反应,继而导致成骨细胞、破骨细胞及骨髓间充质干细胞功能改变;同时AGEs与骨基质中胶原蛋白交联还可使骨强度下降,是造成糖尿病性骨质疏松的主要原因.检测血清及尿液中的AGEs成分,可作为评估糖尿病患者骨折发生风险的有效指标.     

晚期糖基化终末产物与纤维化

晚期糖基化终末产物形成增多是糖尿病的重要特征。目前多个研究显示，其在糖尿病并发症中的发生、发展起了重要作用。晚期糖基化终末产物能促进肾脏、血管、腹膜等组织纤维化。其促纤维化作用可通过直接修饰细胞外基质、促进细胞外基质分泌、促进致纤维化细胞因子的产生、促进间质细胞转化及抑制细胞外基质降解等环节实现。本文对晚期糖基化终末产物的促纤维化作用进行综述。     

晚期糖基化终末产物对糖尿病心肌病影响的研究进展

糖尿病心肌病是糖尿病患者严重的心血管并发症之一.已证实代谢紊乱、炎症反应、氧化应激和微血管病变等都参与糖尿病心肌病的发生和发展.近年研究表明,晚期糖基化终末产物可能与糖尿病心肌病的发生和发展密切相关,可能是糖尿病心肌病治疗的潜在靶点.本文主要综述晚期糖基化终末产物对糖尿病心肌病影响的研究进展.     

晚期糖基化终末产物与糖尿病神经病变

非酶糖基化反应是糖尿病神经病变的重要发病机制之一。持久高血糖使体内晚期糖基化终末产物（AGEs）不断积累,沉积于神经组织的AGEs不仅修饰了细胞骨架蛋白、髓鞘蛋白及基质蛋白等,从而直接损害神经结构与功能,而且还通过增强氧化应激反应,或与神经元表面AGEs受体（RAGE）作用进一步导致神经功能紊乱。AGEs还可引起神经微循环障碍。单用或联用AGEs抑制剂、抗氧化剂、可溶性RAGE及抗RAGE IgG在防止、缓解、逆转糖尿病神经病变中显示出巨大的潜力。     

糖基化终末产物与糖尿病慢性并发症

AGEs是指糖的醛基与蛋白质的氨基端在非酶催化的化学反应下生成的一类物质。人们最初认为AGEs只是蛋白质老化的标志，以便体内识别降解、清除老化的蛋白质。近年来，随着对糖尿病慢性病发症发病机制及病理改变的深入研究，对AGEs有了更全面的认识。人们最初认为AGEs只是蛋白质老化的标志。现在越来越多的事实表明，AGEs不仅与被修饰的大分子的降解有关．AGEs与其受体相互作用。能够激活多个信号传导通路，促进多种细胞因子的合成与释放。促使糖尿病并发症的发生发展。     

晚期糖基化终末产物致动脉粥样硬化的机制

晚期糖基化终末产物(advanced glycation end products,AGE)是由还原糖的羰基与游离氨基反应形成的复合物.AGE通过与其受体(RAGE)结合,改变细胞内信号转导、诱导炎症、增强氧化应激;与胶原交联、修饰脂蛋白等损害血管的完整性;这些导致血管内皮细胞功能紊乱,刺激平滑肌细胞迁移增殖,启动及加速糖尿病动脉粥样硬化和血管并发症的发生发展.阻断AGE-RAGE系统对防治糖尿病并发症具有重要意义.     

晚期糖基化终末产物致动脉粥样硬化的机制

晚期糖基化终末产物(advanced glycation end products,AGE)是由还原糖的羰基与游离氨基反应形成的复合物。AGE通过与其受体(RAGE)结合,改变细胞内信号转导、诱导炎症、增强氧化应激;与胶原交联、修饰脂蛋白等损害血管的完整性;这些导致血管内皮细胞功能紊乱,刺激平滑肌细胞迁移增殖,启动及加速糖尿病动脉粥样硬化和血管并发症的发生发展。阻断AGE-RAGE系统对防治糖尿病并发症具有重要意义。     

糖基化终末产物在糖尿病并发症中的作用

糖基化终末产物在糖尿病并发症中的作用［ＭｉｃｈａｅｌＢ．Ｄｉａｂｅｔｅｓ，１９９４，４３：８３６］糖尿病是一组病因和发病机制尚未完全阐明的内分泌代谢疾病，而以高血糖为其共同标志。近几年来，人们在研究高血糖的基础上，已形成了一个具有说服力的理论，即慢性...     

吡哆胺对动脉粥样硬化兔晚期糖基化终末产物及其受体的影响

目的观察吡哆胺对动脉粥样硬化兔晚期糖基化终末产物(AGEs)及其受体的影响。方法利用高脂饮食法诱导建立兔动脉粥样硬化模型。将新西兰白兔按随机数字表法随机分为正常对照组、动脉硬化组、吡哆胺小剂量组和吡哆胺大剂量组。正常对照组给予普通食物;动脉硬化组给予高脂饮食;吡哆胺小剂量组给予高脂饮食+吡哆胺100 mg/(kg·d);吡哆胺大剂量组给予高脂饮食+吡哆胺150 mg/(kg·d),共观察12周。实验12周末监测所有兔血糖、三酰甘油、总胆固醇、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C);应用酶联免疫吸附试验法检测血清AGEs水平;观察主动脉病理形态学改变;免疫组化方法检测主动脉AGEs受体(RAGE)含量,并进行各组间的比较。结果实验12周末,(1)与对照组比较,动脉硬化组兔三酰甘油、总胆固醇、LDL-C、HDL-C均明显增高(均P0.01),血糖无明显变化(P0.05);动脉硬化组的血清AGEs水平[(419±29)mg/L)]、动脉RAGE吸光度(0.88±0.14)及斑块面积[(67.4±5.8)%]均较对照组[分别为(141±11)mg/L、(0.19±0.04)及0%]明显增高(均P0.01);(2)与动脉硬化组相比,吡哆胺小剂量组和吡哆胺大剂量组兔三酰甘油、总胆固醇、LDL-C、HDL-C、血糖均无明显变化(均P0.05);吡哆胺小剂量组的血清AGEs水平[(278±22)mg/L]、动脉RAGE吸光度(0.43±0.06)及斑块面积[(43.2±2.4)%]和吡哆胺大剂量组的血清AGEs水平[(211±18)mg/L]、动脉RAGE吸光度(0.27±0.05)及斑块面积[(27.4±2.8)%]均较动脉硬化组明显减少(均P0.01);(3)吡哆胺大剂量组的血清AGEs水平、动脉RAGE吸光度及斑块面积较吡哆胺小剂量组低(均P0.01)。(4)主动脉病理形态学:显微镜下见动脉硬化组动脉内膜增厚,形成明显的粥样斑块;有大量的泡沫细胞聚集及较多的炎性细胞。吡哆胺小剂量组和吡哆胺大剂量组较动脉硬化组均有不同程度的减轻。结论吡哆胺能够抑制、减缓实验性高脂饮食兔的动脉粥样硬化形成,可抑制血清AGES的生成及动脉RAGE的表达。     

糖基化终末产物与肝病

肝脏是糖基化终末产物的主要代谢部位,肝病时伴随的氧化应激、糖耐量损害以及肝肾功能降低导致糖基化终末产物增加,而糖基化终末产物可通过促进氧应激/脂质过氧化、炎症反应以及纤维化等途径,加重肝脏损伤。     

糖化蛋白终末产物诱发糖尿病患者外周血淋巴细胞分泌TNF—α—IL—6的研究

目的研究糖化蛋白终末产物(advancedglycationendproducts,AGEs)是否可刺激人体淋巴细胞分泌TNF-α、IL-6。探讨正常人与糖尿病患者对同一刺激的反应是否一致。方法取正常对照者及糖尿病患者静脉血2ml,分别与PHA和AGEs培养。24h后取上清液测定细胞因子含量。结果糖尿病患者外周血淋巴细胞对PHA和AGEs刺激反应均较正常对照者敏感。AGEs刺激后TNF-α、IL-6分泌在糖尿病组及正常对照组分别为473.2±66.93pg/mlvs254.62±35.14pg/ml(P＜0.02),2400±399pg/mlvs1983.9±294.9pg/ml(P＞0.05)。糖尿病患者对AGEs刺激反应与病程、血糖、体重及性别等因素无关。结论AGEs确实可刺激人体外周血淋巴细胞分泌细胞因子。这一刺激反应在糖尿病患者身上表现尤为敏感;并未发现这一反应与病程、血糖水平、体重等因素有关。提示这一敏感反应可能是糖尿病并发症发生的独立危险因素之一。体外检测这一反应可能成为预测糖尿病并发症发生的一个指标。     

Advanced glycation end products in senile diabetic and nondiabetic patients with cataract

BackgroundAdvanced glycation end products (AGE) have been reported to contribute to aging and cataract formation in the lens. In the present study, AGE immunoreactivity in human serum samples of normal senile subjects (n=31), senile diabetic patients without cataract (n=33), senile diabetic patients with cataract (n=30), senile nondiabetic with cataract (n=30), and normal young subjects (n=31) was investigated.MethodsA noncompetitive ELISA with polyclonal anti-AGE antibody was performed. The patients were selected on clinical grounds from Eye Ward, Jinnah Postgraduate Medical Centre, Karachi, Pakistan.ResultsFasting blood glucose, glycosylated hemoglobin, and serum fructosamine were estimated. Fasting blood glucose, HbA_1C, and serum fructosamine levels were significantly (P<.001) increased in senile diabetic patients with and without cataract as compared to nondiabetic senile patients with cataract and senile control subjects. However, the serum AGEs were found to be significantly (P<.001) increased in senile diabetic patients with cataract and senile nondiabetic patients with cataract followed by the diabetic patients without cataract as compared to senile control and young control subjects. In contrast to all four senile groups, the serum AGEs were significantly (P<.001) lower in young control subjects.ConclusionsThe AGE distribution in the senile groups corroborates the hypothesis that the advanced glycation process might have a role in cataract formation, which in diabetic patients occurs vigorously as compared with nondiabetic cataract patients.     

Controlling the receptor for advanced glycation end‐products to conquer diabetic vascular complications

Diabetic vascular complications, such as cardiovascular disease, stroke and microangiopathy, lead to high rates of morbidity and mortality in patients with long‐term diabetes. Extensive intracellular and extracellular formation of advanced glycation end‐products (AGE) is considered a causative factor in vascular injuries in diabetes. Receptor‐dependent mechanisms are involved in AGE‐induced cellular dysfunction and tissue damage. The receptor for AGE (RAGE), originally an AGE‐binding receptor, is now recognized as a member of pattern‐recognition receptors and a pro‐inflammatory molecular device that mediates danger signals to the body. Previous animal studies have shown RAGE dependent of diabetic vascular injuries. Prophylactic and therapeutic strategies focusing on RAGE and its ligand axis will be of great importance in conquering diabetic vascular complications. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00191.x, 2012)     

Advanced glycation end products-cytokine-nitric oxide sequence pathway in the development of diabetic nephropathy: aminoguanidine ameliorates the overexpression of tumour necrosis factor-α and inducible nitric oxide synthase in diabetic rat glomeruli

Aims/hypothesis. Advanced glycation end products are believed to contribute to diabetic microvascular complications by inducing glomerular damage but their role has not been fully clarified. In this study, we explain their central role in the induction of inducible nitric oxide synthase and production of nitric oxide (NO) in streptozotocin-induced diabetic rat glomeruli. Methods. Localization of carboxymethyllysine, which is one of the chemical components of advanced glycation end products, glomerular expression of inducible nitric oxide synthase and urinary excretion and glomerular production of NO₂ ^–/NO₃ ^– were examined at 0, 26, 51, and 52 weeks after the induction of diabetes. Therapeutic effects of aminoguanidine were also examined. Results. Carboxymethyllysine was detected in the mesangial area in glomeruli and it progressively accumulated during 52 weeks of observation. Immunohistochemistry and hybridization studies in situ showed that the number of inducible nitric oxide synthase-positive cells was notably increased in diabetic rat glomeruli at 52 weeks. Further, this augmented expression paralleled intraglomerular expression of TNF-α and NO₂ ^–/NO₃ ^– in diabetic rat glomeruli. Treatment with aminoguanidine reduced the expression of TNF-α, inducible nitric oxide synthase and intraglomerular NO₂ ^–/NO₃ ^– production. It also ameliorated proteinuria in diabetic rats. Conclusion/interpretation. This study showed that carboxymethyllysine possibly enhances the expression of inducible nitric oxide synthase by stimulating the expression of TNF-α in diabetic rat glomeruli. The carboxymethyllysine-cytokine-NO sequence pathway could be one of the major mechanisms in the development of diabetic nephropathy. [Diabetologia (1999) 42: 878–886] Received: 11 September 1998 and in revised form: 28 December 1998     

晚期糖基化终产物在糖尿病血管并发症中的作用机制

晚期糖基化终产物（AGEs）是蛋白质或脂质经过糖基化反应的产物。AGEs存在于糖尿病患者的血管中,促进动脉粥样硬化的发展。多种不同的细胞上AGEs的存在和聚集影响着细胞内外的结构和功能。AGEs通过与细胞外基质基底膜上的分子形成交联和与其受体（RAGE）结合引起多种微血管和大血管并发症。RAGE被AGEs激活后导致转录因子NF-κB和它的靶因子的表达。AGEs可诱发糜蛋白酶的表达和糜蛋白酶依赖性血管紧张素Ⅱ的生成,从而作用于糖尿病血管并发症的发展。     

晚期糖化终产物对糖尿病大鼠肾小球改变的影响

目的 探讨晚期糖化终产物（ＡＧＥｓ）与糖尿病肾小球改变的关系。方法 用链脲佐菌素制糖尿病大鼠模型,观察肾小球ＡＧＥｓ、血小板源生长因子－Ａ（ＰＤＧＦ－Ａ）和超微结构的变化。结果 肾小球ＡＧＥｓ从４周起、ＰＤＧＦ－Ａ从８周起增多,１２周时,基膜增厚,系膜增宽。氨基胍能降低ＡＧＥｓ含量,减缓肾小球改变。结论 ＡＧＥｓ是肾小球改变的重要原因,其致病过程可能有ＰＤＧＦ－Ａ参与。