Menaquinone-7 Supplementation Increases Multiple Advanced Glycation End-products and Oxidation Markers in Zucker Diabetic Fatty Rats

Background: Dicarbonyls and advanced glycation end-products (AGEs) contribute to oxidative stress, inflammation, and complications in type 2 diabetes mellitus (T2DM). Menaquinone-7 (MK-7), a vitamin K2 subtype, has shown benefits for glucose tolerance and vascular health in some studies. We evaluated the impact of MK-7 on dicarbonyls, free AGEs, and protein nitration/oxidation adducts in a rat model of T2DM.
Methods: Male heterozygous (fa/+, control) and homozygous (fa/fa, diabetic) Zucker Diabetic Fatty rats were fed a diabetogenic diet without or with MK-7 for 12 weeks. After sacrifice, plasma dicarbonyls as well as plasma and urinary levels of free AGEs, and protein nitration/oxidation adducts were quantified by isotope dilution tandem mass spectrometry.
Results: Diabetic rats showed significantly increased plasma glyoxal, 3-deoxyglucosone, and fructosyl-lysine with non-significant trends toward increased methylglyoxal-derived hydroimidazolone and methionine sulfoxide, and reductions in methylglyoxal and dityrosine. Urinary carboxyethyl-lysine, carboxymethyl-lysine, fructosyl-lysine (all significant), and dityrosine (non-significant) were elevated in diabetic rats, glucosepane (non-significant) was reduced.
MK-7 supplementation reduced no measured parameter but was associated with non-significant further increases in plasma glyoxal-derived hydroimidazolone, carboxyethyl-lysine, carboxymethyl-lysine, fructosyl-lysine, 3-nitrotyrosine, and methionine sulfoxide as well as in urinary glyoxal-derived hydroimidazolone, carboxyethyl-lysine, fructosyl-lysine, and 3-nitrotyrosine in diabetic rats. Correlation analysis revealed significant associations between glucose, dicarbonyls, AGEs and oxidative markers.
Conclusion: High-dose MK-7 did not improve dicarbonyl stress, AGE burden, or protein nitration/oxidation, indicating limited systemic efficacy in modulating glycation and oxidative pathways under T2DM conditions. Correlation analysis suggested a glycemia-driven amplification of glycation and oxidative stress.

背景：二羰基化合物与晚期糖基化终末产物（advanced glycation end-products, AGEs）可诱发2型糖尿病（type 2 diabetes mellitus, T2DM）患者出现氧化应激、炎症反应及并发症。甲基萘醌-7（Menaquinone-7, MK-7）作为维生素K2的亚型，在多项研究中被证实可改善葡萄糖耐量与血管健康。本研究旨在评估MK-7对2型糖尿病大鼠模型中二羰基化合物、游离晚期糖基化终末产物以及蛋白质硝化/氧化加合物的影响。
方法：将雄性杂合型（fa/+，对照组）与纯合型（fa/fa，糖尿病模型组）Zucker糖尿病肥胖大鼠（Zucker Diabetic Fatty rats）饲喂致糖尿病饲料，分别添加与不添加MK-7，持续12周。大鼠处死后，采用同位素稀释串联质谱法对血浆中二羰基化合物、血浆与尿液中的游离晚期糖基化终末产物以及蛋白质硝化/氧化加合物进行定量检测。
结果：糖尿病模型组大鼠的血浆乙二醛、3-脱氧葡萄糖醛酮与果糖基赖氨酸水平显著升高；甲基乙二醛衍生的咪唑啉酮与蛋氨酸亚砜水平呈升高趋势，但差异无统计学意义，而血浆甲基乙二醛与二酪氨酸水平则呈降低趋势。糖尿病模型组大鼠尿液中的羧乙基赖氨酸、羧甲基赖氨酸、果糖基赖氨酸（均差异有统计学意义）与二酪氨酸（差异无统计学意义）水平升高，而葡萄糖烷（glucosepane）水平则呈降低趋势（差异无统计学意义）。
补充MK-7未对本研究检测的任何参数产生改善作用，但在糖尿病模型组大鼠中，血浆乙二醛衍生的咪唑啉酮、羧乙基赖氨酸、羧甲基赖氨酸、果糖基赖氨酸、3-硝基酪氨酸与蛋氨酸亚砜，以及尿液中乙二醛衍生的咪唑啉酮、羧乙基赖氨酸、果糖基赖氨酸与3-硝基酪氨酸的水平均呈非显著性进一步升高。相关性分析显示，血糖、二羰基化合物、晚期糖基化终末产物与氧化应激标志物之间存在显著关联。
结论：高剂量MK-7未能改善二羰基应激、晚期糖基化终末产物负荷或蛋白质硝化/氧化状态，提示在2型糖尿病状态下，MK-7在调节糖基化与氧化通路方面的全身疗效有限。相关性分析表明，血糖可驱动糖基化与氧化应激的放大效应。