Systemic alterations in the metabolome of diabetic NOD mice delineate increased oxidative stress accompanied by reduced inflammation and hypertriglyceremia
Systemic alterations in the metabolome of diabetic NOD mice delineate increased oxidative stress accompanied by reduced inflammation and hypertriglyceremia
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DOI：
10.1152/ajpendo.00019.2015
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发表时间：
2015-06-01
影响因子：
5.1
通讯作者：
Hara, Manami
中科院分区：
文献类型：
--
作者：
Fahrmann, Johannes;Grapov, Dmitry;Hara, Manami
1例糖尿病（T1 D）。然而，并非所有的动物都会发展明显的糖尿病，尽管经历了类似的自身免疫性损伤。在本研究中，使用综合代谢组学方法（包括气相色谱飞行时间（GC-TOF）质谱（MS）、超高效液相色谱-精确质量四重飞行时间（UHPLC-qTOF）MS和基于靶向UHPLC-串联质谱的方法）捕获进展或未进展为T1 D的NOD小鼠血浆代谢组和脂质组的代谢改变。使用这种多平台方法，我们在雄性和雌性进展者和非进展者动物（n = 71）中鉴定了> 1，000种循环脂质和代谢物。统计和多变量分析用于确定年龄和性别无关的代谢标志物，最好区分进展者和非进展者的代谢谱。关键的T1 D相关扰动与1）氧化产物β-δ-内酯和半乳糖酸增加以及半胱氨酸、蛋氨酸和苏糖酸减少有关，表明氧化应激增加; 2）循环多不饱和脂肪酸和脂质信号传导介质减少，最明显的是花生四烯酸（AA）和AA衍生的类花生酸，表明全身炎症状态受损; 3）反映高胆固醇血症的循环三酰甘油升高;和4）主要结构脂质，最显著的是溶血磷脂酰胆碱和磷脂酰胆碱减少。总之，我们的研究结果强调了伴随血糖控制丧失和明显T1 D发展的全身性扰动。
1 diabetes (T1D). However, not all animals will develop overt diabetes despite undergoing similar autoimmune insult. In this study, a comprehensive metabolomic approach, consisting of gas chromatography time-of-flight (GC-TOF) mass spectrometry (MS), ultra-high-performance liquid chromatography-accurate mass quadruple time-of-flight (UHPLC-qTOF) MS and targeted UHPLC-tandem mass spectrometry-based methodologies, was used to capture metabolic alterations in the metabolome and lipidome of plasma from NOD mice progressing or not progressing to T1D. Using this multi-platform approach, we identified >1,000 circulating lipids and metabolites in male and female progressor and nonprogressor animals (n = 71). Statistical and multivariate analyses were used to identify age-and sex-independent metabolic markers, which best differentiated metabolic profiles of progressors and nonprogressors. Key T1D-associated perturbations were related with 1) increases in oxidation products glucono-delta-lactone and galactonic acid and reductions in cysteine, methionine and threonic acid, suggesting increased oxidative stress; 2) reductions in circulating polyunsaturated fatty acids and lipid signaling mediators, most notably arachidonic acid (AA) and AA-derived eicosanoids, implying impaired states of systemic inflammation; 3) elevations in circulating triacylglyercides reflective of hypertriglyceridemia; and 4) reductions in major structural lipids, most notably lysophosphatidylcholines and phosphatidylcholines. Taken together, our results highlight the systemic perturbations that accompany a loss of glycemic control and development of overt T1D.