The Role of Oxidative Stress in the Pathogenesis of Type 2 Diabetes Mellitus Micro- and Macrovascular Complications: Avenues for a Mechanistic-Based Therapeutic Approach
The Role of Oxidative Stress in the Pathogenesis of Type 2 Diabetes Mellitus Micro- and Macrovascular Complications: Avenues for a Mechanistic-Based Therapeutic Approach
复制标题
DOI：
10.2174/157339911797415585
复制
发表时间：
2011-01-01
影响因子：
3.3
通讯作者：
Muscogiuri, Giovanna
中科院分区：
文献类型：
--
作者：
Folli, Franco;Corradi, Domenico;Muscogiuri, Giovanna
越来越多的证据表明，氧化应激在糖尿病微血管和大血管并发症的发病机制中起着关键作用。2型糖尿病受试者的氧化应激增加是几种异常的结果，包括高血糖症、胰岛素抵抗、高胰岛素血症和血脂异常，每种异常都导致大血管和小血管以及心肌的内皮细胞中线粒体超氧化物过量产生。糖尿病并发症的统一病理生理学机制可以通过以下途径增加活性氧（ROS）的产生来解释：（1）多元醇途径通量，（2）晚期糖基化终产物（AGEs）的形成增加，（3）AGEs受体表达增加，（4）蛋白激酶C亚型活化，（5）己糖胺途径过度活性。此外，氧化应激对2型糖尿病患者的影响因两种关键的抗动脉粥样硬化酶（内皮一氧化氮合酶和前列环素合酶）的失活而加剧。值得注意的是，在2型糖尿病患者中进行的临床试验结果显示，对代谢综合征的所有组分（高血糖症、高胆固醇血症和原发性高血压）进行强化管理（分别使用对血糖、血脂浓度和血压产生有益影响的药物）的不良心血管终点降低。本综述的目的是（1）检查2型糖尿病受试者中氧化应激与微血管和大血管并发症之间的联系机制，（2）考虑目前使用的具有抗氧化特性的治疗药物以及新的潜在抗氧化物质所提供的治疗机会。
A growing body of evidence suggests that oxidative stress plays a key role in the pathogenesis of micro- and macrovascular diabetic complications. The increased oxidative stress in subjects with type 2 diabetes is a consequence of several abnormalities, including hyperglycemia, insulin resistance, hyperinsulinemia, and dyslipidemia, each of which contributes to mitochondrial superoxide overproduction in endothelial cells of large and small vessels as well as the myocardium. The unifying pathophysiological mechanism that underlies diabetic complications could be explained by increased production of reactive oxygen species (ROS) via: (1) the polyol pathway flux, (2) increased formation of advanced glycation end products (AGEs), (3) increased expression of the receptor for AGEs, (4) activation of protein kinase C isoforms, and (5) overactivity of the hexosamine pathway. Furthermore, the effects of oxidative stress in individuals with type 2 diabetes are compounded by the inactivation of two critical anti-atherosclerotic enzymes: endothelial nitric oxide synthase and prostacyclin synthase. Of interest, the results of clinical trials in patients with type 2 diabetes in whom intensive management of all the components of the metabolic syndrome (hyperglycemia, hypercholesterolemia, and essential hypertension) was attempted (with agents that exert a beneficial effect on serum glucose, serum lipid concentrations, and blood pressure, respectively) showed a decrease in adverse cardiovascular end points. The purpose of this review is (1) to examine the mechanisms that link oxidative stress to micro- and macrovascular complications in subjects with type 2 diabetes and (2) to consider the therapeutic opportunities that are presented by currently used therapeutic agents which possess antioxidant properties as well as new potential antioxidant substances.