College of Pharmacy, Qatar University, PO Box 2713, Doha, Qatar.
College of Arts and Sciences, Qatar University, PO Box 2713, Doha, Qatar.
Curr Pharm Des. 2018;24(26):3072-3083. doi: 10.2174/1381612824666180903141832.
The incidence and prevalence of diabetes mellitus are increasing globally at alarming rates. Cardiovascular and renal complications are the major cause of morbidity and mortality in patients with diabetes. Methylglyoxal (MG) - a highly reactive dicarbonyl compound - is increased in patients with diabetes and has been implicated to play a detrimental role in the etiology of cardiovascular and renal complications. Derived from glucose, MG binds to arginine and lysine residues in proteins, and the resultant end products serve as surrogate markers of MG generation in vivo. Under normal conditions, MG is detoxified by the enzyme glyoxalase 1 (Glo1), using reduced glutathione as a co-factor. Elevated levels of MG is known to cause endothelial and vascular dysfunction, oxidative stress and atherosclerosis; all of which are risk factors for cardiovascular diseases. Moreover, MG has also been shown to cause pathologic structural alterations and impair kidney function. Conversely, MG scavengers (such as N-acetylcysteine, aminoguanidine or metformin) or Nrf2/Glo1 activators (such as trans-resveratrol / hesperetin) are shown to be useful in preventing MG-induced cardiovascular and renal complications in diabetes. However, clinical evidence supporting the MG lowering properties of these agents are limited and hence, need further investigation.
Reducing MG levels directly using scavengers or indirectly via activation of Nrf2/Glo1 may serve as a novel and potent therapeutic strategy to counter the deleterious effects of MG in diabetic complications.
糖尿病的发病率和患病率正在以惊人的速度在全球范围内上升。心血管和肾脏并发症是糖尿病患者发病率和死亡率的主要原因。甲基乙二醛（MG）-一种高度反应性的二羰基化合物-在糖尿病患者中增加，并被认为在心血管和肾脏并发症的病因中起有害作用。MG 来源于葡萄糖，与蛋白质中的精氨酸和赖氨酸残基结合，其终产物作为体内 MG 生成的替代标志物。在正常情况下，MG 被酶甘油醛 1（Glo1）利用还原型谷胱甘肽作为辅助因子解毒。已知高水平的 MG 会导致内皮和血管功能障碍、氧化应激和动脉粥样硬化；所有这些都是心血管疾病的危险因素。此外，MG 还被证明会导致病理性结构改变和损害肾功能。相反，MG 清除剂（如 N-乙酰半胱氨酸、氨基胍或二甲双胍）或 Nrf2/Glo1 激活剂（如反式白藜芦醇/橙皮苷）被证明可有效预防糖尿病引起的心血管和肾脏并发症。然而，支持这些药物降低 MG 水平的临床证据有限，因此需要进一步研究。
直接使用清除剂或通过激活 Nrf2/Glo1 间接降低 MG 水平可能成为一种新的、有效的治疗策略，以对抗 MG 在糖尿病并发症中的有害影响。
