PDF(Pubmed)
Abstract：
Complications of diabetes are often attributed to glucose and reactive dicarbonyl metabolites derived from glycolysis or gluconeogenesis, such as methylglyoxal. However, in the CNS, neurons and endothelial cells use lactate as energy source in addition to glucose, which does not lead to the formation of methylglyoxal and has previously been considered a safer route of energy consumption than glycolysis. Nevertheless, neurons and endothelial cells are hotspots for the cellular pathology underlying neurological complications in diabetes, suggesting a cause that is distinct from other diabetes complications and independent of methylglyoxal. Here, we show that in clinical and experimental diabetes plasma concentrations of dimethylglyoxal are increased. In a mouse model of diabetes, ilvb acetolactate-synthase-like (ILVBL, HACL2) is the enzyme involved in formation of increased amounts of dimethylglyoxal from lactate-derived pyruvate. Dimethylglyoxal reacts with lysine residues, forms Nε-3-hydroxy-2-butanonelysine (HBL) as an adduct, induces oxidative stress more strongly than other dicarbonyls, causes blood-brain barrier disruption, and can mimic mild cognitive impairment in experimental diabetes. These data suggest dimethylglyoxal formation as a pathway leading to neurological complications in diabetes that is distinct from other complications. Importantly, dimethylglyoxal formation can be reduced using genetic, pharmacological and dietary interventions, offering new strategies for preventing CNS dysfunction in diabetes.
摘要：
糖尿病的并发症通常归因于糖酵解或糖异生产生的葡萄糖和反应性二羰基代谢产物。如甲基乙二醛。然而,在中枢神经系统，神经元和内皮细胞使用乳酸作为能量来源，除了葡萄糖，这不会导致甲基乙二醛的形成，并且以前被认为是比糖酵解更安全的能量消耗途径。然而，神经元和内皮细胞是糖尿病神经并发症的细胞病理学热点，提示与其他糖尿病并发症不同的原因，并且独立于甲基乙二醛。这里,我们表明，在临床和实验性糖尿病中，二甲基乙二醛的血浆浓度增加。在糖尿病小鼠模型中，ilvb乙酰乳酸合酶样(ILVBL，HACL2）是参与从乳酸衍生的丙酮酸盐形成增加量的二甲基乙二醛的酶。二甲基乙二醛与赖氨酸残基反应，形成Nε-3-羟基-2-丁赖氨酸（HBL）作为加合物，比其他二羰基化合物更强烈地诱导氧化应激，导致血脑屏障破坏，并且可以模拟实验性糖尿病的轻度认知障碍。这些数据表明，二甲基乙二醛的形成是导致糖尿病神经系统并发症的途径，与其他并发症不同。重要的是,二甲基乙二醛的形成可以通过遗传来减少，药理和饮食干预，提供预防糖尿病中枢神经系统功能障碍的新策略。
