他克莫司诱导糖尿病大鼠和小鼠模型的血清靶向代谢组学研究

Serum metabolomics in tacrolimus-induced diabetic model of rats and mice

目的:采用靶向代谢组学分析他克莫司(taerolimus,TAC)诱导的糖尿病动物模型血清代谢谱的变化,寻找潜在生物标志物和分析代谢通路,并了解它们在TAC诱导的糖尿病发展中的作用。方法:连续10周腹腔注射TAC(3 mg·kg^(-1))构建糖尿病大鼠和小鼠模型,使用液相色谱串联质谱(UPLC-MS/MS)方法分析血清代谢物,采用主成分分析(principal component analysis,PCA)和正交偏最小二乘法判别分析(orthogonal partial least squares discriminant analysis,OPLS-DA)筛选差异代谢物并进行通路富集分析。结果:TAC长期给药可引起大鼠体内51种和小鼠体内24种代谢物的表达变化,这些差异代谢物包括脂肪酸(α-亚麻酸)、氨基酸(L-瓜氨酸和L-天冬氨酸)、胆汁酸(胆酸、脱氧胆酸和牛磺脱氧胆酸)以及氧化三甲胺等,主要影响精氨酸生物合成、α-亚麻酸代谢和丙氨酸、天冬氨酸和谷氨酸代谢等代谢通路。结论:TAC诱导糖尿病动物模型的血清代谢谱发生显著变化,提示精氨酸生物合成和α-亚麻酸代谢等途径与糖代谢异常相关,为TAC诱导糖尿病发生的潜在机制提供新的见解。

OBJECTIVE To employ targeted metabolomics to explore the changes of serum metabolic profiles in tacrolimus(TAC)-induced diabetic animal models,seek potential biomarkers,examine metabolic pathways and understand their roles in the development of TAC-induced diabetes.METHODS Diabetic rat and murine models were constructed by an intraperitoneal injection of TAC(3 mg·kg^(-1))for 10 weeks.Serum metabolites were examined by liquid chromatography-tandem mass spectrometry(UPLC-MS/MS).For screening differential metabolites and perform pathway enrichment analysis,principal component analysis(PCA)and orthogonal partial least squares discriminant analysis(OPLS-DA)were employed.RESULTS After dosing of TAC,the levels of 51 metabolites in rats and 24 metabolites in mice became altered.There were fatty acid(α-linolenic acid),amino acids(L-citrulline&L-aspartic acid),bile acids(cholic acid,deoxycholic acid&taurodeoxycholic acid)and trimethylamine N-oxide.Pathway and enrichment analysis revealed marked impacts on arginine biosynthesis,α-linolenic acid metabolism and alanine,aspartic acid and glutamic acid metabolism.CONCLUSION The serum metabolic profile of TAC-induced diabetic animal models change significantly,suggesting that arginine biosynthesis andα-linolenic acid metabolism are correlated with abnormal glucose metabolism.It provides new insights into the potential mechanism of TAC-induced diabetes.