目的: 应用靶向代谢组学方法研究糖尿病肾脏疾病(diabetic kidney disease, DKD)患者与健康对照者血清中苯丙氨酸代谢途径的代谢物的变化,综合分析血清差异代谢物变化规律及其与临床指标的相关性。方法: 选取包头医学院第一附属医院肾内科住院部20例DKD患者作为疾病研究组,20例健康体检者作为正常对照组(NC),收集血液标本。经液相色谱/质谱(LC/MS)检测,采用靶向代谢组学分析苯丙氨酸代谢途径中的血清代谢物的差异性,进行单变量及多变量分析和统计学分析,阐明血清代谢物在DKD中的意义。结果: 与健康对照组相比,DKD患者血清中苯丙氨酸途径的代谢产物苯丙氨酸(L-Phenylalanine)、马尿酸(Hippuric-acid)、D-苯乙酰基-L-谷氨酰胺(Phenlacetyl-L-Glutamine)的含量高于对照组(P<0.05)。对血清代谢物参与的通路富集分析显示,苯丙氨酸代谢通路参与DKD的发展过程。DKD患者苯丙氨酸途径的血清代谢产物苯丙氨酸、马尿酸、D-苯乙酰基-L-谷氨酰胺与临床指标Scr、FBG、HbA1c呈正相关。结论: 苯丙氨酸代谢途径可能参与DKD的发生发展。
Objective: To study the changes of phenylalanine metabolites in serum of diabetic kidney disease (DKD) patients and healthy controls using targeted metabolomics, and to comprehensively analyze the change rule of differential metabolites in serum and its correlation with clinical indicators. Methods: The inpatients in the Department of Nephrology of the First Affiliated Hospital of Baotou Medical College were selected as the research subjects. 20 DKD patients were selected as the study group and 20 healthy subjects as the control group. Blood samples were collected from the two groups. The difference of serum metabolites was analyzed by liquid chromatography/mass spectrometry (LC/MS) and targeted metabolomics. Univariate and multivariate analysis and statistical analysis were performed to analyze the difference of serum metabolites and clarify their significance in DKD. Results: Serum levels of Phenylalanine metabolites (L-phenylalanine, Hippuric acid, D-phenlacetyl-L-glutamine) in DKD patients were significantly higher than those in control group. The enrichment analysis of the pathway involved in serum metabolites showed that phenylalanine metabolism pathway was involved in the progress of DKD. Serum metabolites of phenylalanine metabolism pathway in DKD patients, including L-phenylalanine, Hippuric acid and D-phenlacetyl-L-glutamine, were positively correlated with Scr, FBG and HbA1c. Conclusion: Phenylalanine metabolism pathway may be involved in the occurrence and development of DKD.
[1] 杨敏, 翟光喜. 姜黄素对糖尿病及其并发症的作用及机制研究进展[J]. 中国新药与临床杂志, 2019, 38(2): 65-70.
[2] Cho NH, Shaw JE, Karuranga S, et al. IDF Diabetes Atlas: global estimates of diabetes prevalence for 2017 and projections for 2045[J]. Diabetes Res Clin Pract, 2018, 138: 271-281.
[3] Nicholson JK, Lindon JC, Holmes E. 'Metabonomics': understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data[J]. Xenobiotica, 1999, 29(11): 1181-1189.
[4] Jenkins H, Hardy N, Beckmann M, et al. A proposed framework for the description of plant metabolomics experiments and their results[J]. Nat Biotechnol, 2004, 22(12): 1601-1606.
[5] Patti GJ, Yanes O, Siuzdak G. Innovation: metabolomics: the apogee of the omics trilogy[J]. Nat Rev Mol Cell Biol, 2012, 13(4): 263-269.
[6] 中华医学会糖尿病学分会微血管并发症学组. 中国糖尿病肾脏疾病防治临床指南[J]. 中华糖尿病杂志, 2019, 11(1): 15-28.
[7] Groop PH, Thomas MC, Moran JL, et al. The presence and severity of chronic kidney disease predicts all-cause mortality in type 1 diabetes[J]. Diabetes, 2009, 58(7): 1651-1658.
[8] Soldatos G, Cooper ME. Diabetic nephropathy: important pathophysiologic mechanisms[J]. Diabetes Res Clin Pract, 2008, 82(Suppl 1): S75-S79.
[9] Wild S, Roglic G, Green A, et al. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030[J]. Diabetes Care, 2004, 27(5): 1047-1053.
[10] Skupien J, Warram JH, Niewczas MA, et al. Synergism between circulating tumor necrosis factor receptor 2 and HbA(1c) in determining renal decline during 5-18 years of follow-up in patients with type 1 diabetes and proteinuria[J]. Diabetes Care, 2014, 37(9): 2601-2608.
[11] Weiss RH, Kim K. Metabolomics in the study of kidney diseases[J]. Nat Rev Nephrol, 2011, 8(1): 22-33.
[12] Xiao DF, Zeng LM, Yao K, et al. The glutamine-alpha-ketoglutarate (AKG) metabolism and its nutritional implications[J]. Amino Acids, 2016, 48(9): 2067-2080.
[13] Opara EC, Petro A, Tevrizian A, et al. L-glutamine supplementation of a high fat diet reduces body weight and attenuates hyperglycemia and hyperinsulinemia in C57BL/6J mice[J]. J Nutr, 1996, 126(1): 273-279.
[14] Meijers BKI, Evenepoel P. The gut-kidney axis: indoxyl sulfate, p-cresyl sulfate and CKD progression[J]. Nephrol Dial Transplant, 2011, 26(3): 759-761.