Glucoselysine (GL) is an unique advanced glycation end-product derived from fructose. The main source of fructose is the polyol pathway, and an increase in its activity leads to diabetic complications. Here, we aimed to demonstrate that GL can serve as an indicator of the polyol pathway activity. Additionally, we propose a novel approach for detecting GL in peripheral blood samples using liquid chromatography-tandem mass spectrometry and evaluate its clinical usefulness. We successfully circumvent interference from fructoselysine, which shares the same molecular weight as GL, by performing ultrafiltration and hydrolysis without reduction, successfully generating adequate peaks for quantification in serum. Furthermore, using immortalized aldose reductase KO mouse Schwann cells, we demonstrate that GL reflects the downstream activity of the polyol pathway and that GL produced intracellularly is released into the extracellular space. Clinical studies reveal that GL levels in patients with type 2 diabetes are significantly higher than those in healthy participants, while -(5-hydro-5-methyl-4-imidazolon-2-yl)ornithine (MG-H1) levels are significantly lower. Both GL and MG-H1 show higher values among patients with vascular complications; however, GL varies more markedly than MG-H1 as well as hemoglobin A1c, fasting plasma glucose, and estimated glomerular filtration rate. Furthermore, GL remains consistently stable under various existing drug treatments for type 2 diabetes, whereas MG-H1 is impacted. To the best of our knowledge, we provide important insights in predicting diabetic complications caused by enhanced polyol pathway activity assessment of GL levels in peripheral blood samples from patients.

中文翻译：

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葡萄糖赖氨酸，多元醇途径的一种独特的晚期糖基化终产物及其与 2 型糖尿病血管并发症的关系


葡萄糖赖氨酸 (GL) 是一种源自果糖的独特的高级糖基化终产物。果糖的主要来源是多元醇途径，其活性增加会导致糖尿病并发症。在这里，我们的目的是证明 GL 可以作为多元醇途径活性的指标。此外，我们提出了一种使用液相色谱-串联质谱法检测外周血样本中 GL 的新方法，并评估其临床实用性。我们通过进行超滤和不还原水解，成功地规避了与 GL 具有相同分子量的果糖赖氨酸的干扰，成功地产生了足够的峰用于血清中的定量。此外，使用永生化醛糖还原酶KO小鼠雪旺细胞，我们证明GL反映了多元醇途径的下游活性，并且细胞内产生的GL被释放到细胞外空间。临床研究表明，2型糖尿病患者的GL水平显着高于健康参与者，而-(5-氢-5-甲基-4-咪唑啉-2-基)鸟氨酸(MG-H1)水平显着较低。 GL 和 MG-H1 在有血管并发症的患者中均表现出较高的值；然而，GL 的变化比 MG-H1 以及糖化血红蛋白、空腹血糖和估计肾小球滤过率的变化更显着。此外，GL 在各种现有的 2 型糖尿病药物治疗下始终保持稳定，而 MG-H1 则受到影响。据我们所知，我们通过增强对患者外周血样本中 GL 水平的多元醇途径活性评估，为预测糖尿病并发症提供了重要的见解。