Grapov Dmitry, Fahrmann Johannes, Hwang Jessica, Poudel Ananta, Jo Junghyo, Periwal Vipul, Fiehn Oliver, Hara Manami
NIH West Coast Metabolomics Center, University of California Davis, Davis, California.
Department of Medicine, The University of Chicago, Chicago, Illinois.
Metabolomics. 2015 Apr;11(2):425-437. doi: 10.1007/s11306-014-0706-2.
Non-obese diabetic (NOD) mice are a widely-used model oftype1 diabetes (T1D). However, not all animals develop overt diabetes. This study examined the circulating metabolomic profiles of NOD mice progressing or not progressing to T1D. Total beta-cell mass was quantified in the intact pancreas using transgenic NOD mice expressinggreen fluorescent protein under the control of mouse insulin I promoter.While both progressor and non-progressor animals displayed lymphocyte infiltration and endoplasmic reticulum stress in the pancreas tissue;overt T1D did not develop until animals lost ~70% of the total beta-cell mass.Gas chromatography time of flight mass spectrometry (GC-TOF) was used to measure >470 circulating metabolites in male and female progressor and non-progressor animals (n=76) across a wide range of ages (neonates to >40-wk).Statistical and multivariate analyses were used to identify age and sex independent metabolic markers which best differentiated progressor and non-progressor animals' metabolic profiles. Key T1D-associated perturbations were related with: (1) increased plasma glucose and reduced 1,5-anhydroglucitol markers of glycemic control; (2) increased allantoin, gluconic acid and nitric oxide-derived saccharic acid markers of oxidative stress; (3) reduced lysine, an insulin secretagogue; (4) increased branched-chain amino acids, isoleucine and valine; (5) reduced unsaturated fatty acids including arachidonic acid; and (6)perturbations in urea cycle intermediates suggesting increased arginine-dependent NO synthesis. Together these findings highlight the strength of the unique approach of comparing progressor and non-progressor NOD mice to identify metabolic perturbations involved in T1D progression.
非肥胖糖尿病（NOD）小鼠是广泛应用的1型糖尿病（T1D）模型。然而，并非所有动物都会发展为显性糖尿病。本研究检测了进展为或未进展为T1D的NOD小鼠的循环代谢组学谱。使用在小鼠胰岛素I启动子控制下表达绿色荧光蛋白的转基因NOD小鼠，对完整胰腺中的总β细胞质量进行定量。虽然进展型和非进展型动物在胰腺组织中均表现出淋巴细胞浸润和内质网应激，但直到动物失去约70%的总β细胞质量时才会发展为显性T1D。采用气相色谱飞行时间质谱法（GC-TOF）测量了不同年龄（从新生儿到40周以上）的雄性和雌性进展型及非进展型动物（n = 76）体内470多种循环代谢物。运用统计和多变量分析来确定与年龄和性别无关的代谢标志物，这些标志物能最佳地区分进展型和非进展型动物的代谢谱。与T1D相关的关键扰动涉及：（1）血糖控制的血浆葡萄糖升高和1,5-脱水葡萄糖醇降低；（2）氧化应激的尿囊素、葡萄糖酸和一氧化氮衍生的糖酸升高；（3）胰岛素分泌促进剂赖氨酸降低；（4）支链氨基酸异亮氨酸和缬氨酸升高；（5）包括花生四烯酸在内的不饱和脂肪酸降低；（6）尿素循环中间体的扰动表明精氨酸依赖性一氧化氮合成增加。这些发现共同凸显了比较进展型和非进展型NOD小鼠以识别T1D进展中涉及的代谢扰动这一独特方法的优势。
