【作者】 王爽；

【导师】 杨萍；

【作者基本信息】 吉林大学 ， 内科学， 2021， 博士

【摘要】 背景:临床证据表明,在得到他汀类药物治疗后,患者低密度脂蛋白胆固醇(LDL-C)降低,心血管疾病(CVD)在一级和二级预防风险显著降低[1]。因此,对于血脂异常的心血管疾病高风险患者,大多数指南建议将LDL-C作为首要治疗目标,他汀类药物作为一线治疗药物[2][3][4]。然而研究发现,尽管通过他汀类药物治疗显著降低了LDL-C水平,心血管疾病患病风险依然很高[5]。人们推测可能由于低密度脂蛋白胆固醇的未降低到治疗标准、高密度脂蛋白胆固醇水平偏低或者甘油三酯水平较高所致。此外,越来越多的证据表明,甘油三酯的水平与动脉粥样硬化风险的关系非常密切。因此,对于目前他汀类药物治疗后,TG水平未得到显著降低的患者,相对于过量使用他汀类药物,联合使用其他降TG的药物可能是一个更好的选择。因此,我们需要更多的努力来探索降低TG的潜在新靶点。氨基酸是蛋白质合成的重要组成部分,在能量产生、炎症、信号传递、胰岛素抵抗、氧化还原等生理过程中起着重要作用[6-9]。在这方面,氨基酸被确定为糖尿病、心血管疾病和肥胖症等慢性疾病的新生物标志物[10-12]。虽然氨基酸和甘油三酯水平异常之间的关系与机制尚未明确,但已有很多研究报道了它们之间存在关联。在研究中,BMI异常患者和非酒精性脂肪肝患者氨基酸代谢分别与其对应健康对照组相比,都发现了明显的改变[13-14]。一些横截面和纵向研究提出,氨基酸水平显著预测了未来儿童高甘油三酸血症[15-16]。为明确血浆氨基酸水平与高甘油三酯血症是否有相关性,对两个独立的临床队列进行了横断面分析,试图发现血浆氨基酸在糖尿病患者人群中是否与他汀药物治疗下的残余高甘油三酯血症相关,并且是否可以作为潜在的新治疗靶点。目的:1)正常TG糖尿病患者与HTG糖尿病患者的氨基酸代谢物是否有差异;2)当LDL-C水平达到治疗标准(LDL-C<2.6mmol/L)时,正常TG糖尿病患者与HTG糖尿病患者的氨基酸代谢物是否有差异;3)有差异的氨基酸代谢物是否与他汀药物治疗下糖尿病患者HTG患病风险有相关性。方法:该研究涉及两个独立的不同医院的患者群体。将辽宁医科大学第一附属医院(LMUFAH,n=146)和大连医科大学第二附属医院(SAHDMU,n=294)两个独立的横断面医院队列纳入分析。高甘油三酯血症定义为甘油三酯≥1.7mmol/L;血脂控制良好的LDL-C定义为<2.6mmol/L。采用Logistic回归方法对高甘油三酯血症循环代谢措施的调整OR(95%CI)进行评估。采用逆方差加权固定效应Meta分析方法,将两个队列中具有相同关联方向的代谢物的集合结果结合起来。在LDL-C的亚组分析中,也获得了高甘油三酯血症患者和非高甘油三酯血症患者的代谢物差异。结果:丙氨酸、天冬酰胺、亮氨酸和缬氨酸的升高都与两个队列中高甘油三酯血症增加呈正相关。在固定效应集合分析中,每增加一个SD,四种氨基酸对应的OR(95%CI)值:丙氨酸为1.71(1.32-2.20),天冬酰胺为1.62(1.20-2.19),亮氨酸为1.64(1.22-2.20),缬氨酸为1.62(1.22-2.13)(所有P值均<0.0018)。当在分析中将C肽作为校正因素进行调整时,Ala,Leu和Val对高甘油三酯血症的作用会减弱。无论低密度脂蛋白胆固醇(LDL-C)是否得到良好控制,这四种氨基酸在正常TG患者与HTG患者之间相比均有显著差异性。结论:丙氨酸、天冬酰胺、亮氨酸和缬氨酸与他汀类药物治疗糖尿病患者高甘油三酯血症残余风险增加呈正相关。更多还原

【Abstract】 Background:Robust clinical evidence demonstrates that statin-induced reductions in low-density lipoprotein cholesterol(LDL-C)lead to substantial reductions in cardiovascular disease(CVD)risk in both the primary and secondary prevention settings.Therefore,in patients at high cardiovascular risk due to dyslipidemia,the majority of current guidelines recommend LDL-C as a primary treatment target,with statins as first-line therapy.Despite significant LDL-C lowering with statin therapy,substantial residual cardiovascular risk often remains.This residual risk is thought to be due,in part,to inadequate reduction of LDL-C for a given level of risk,low levels of high-density lipoprotein cholesterol(HDL-C),and/or high levels of triglycerides(TG).Additionally,there is increasing evidence that triglycerides,may be more strongly associated with atherosclerotic risk than LDL-C alone.So instead of intensive use of statins,combined medication may be a better option for patients with poor response to current statin therapy.Additional efforts are needed to identify these subjects and explore potential new targets for their TG lowering.Amino acids are important components for protein synthesis and play significant roles in a number of physiological processes including energy production,inflammation,signaling,insulin resistance,redox,and so on.In this connection,amino acids were identified as new biomarkers of chronic conditions such as diabetes,CVD,and obesity.Although the relationships between amino acids and triglycerides were yet completely clarified,their associations have been investigated in many studies.Compared with healthy controls,patients with abnormal BMI or non-alcoholic fatty liver disease have profound perturbation of amino acid metabolism.Several cross-sectional and longitudinal studies also showed that amino acid signature significantly predicted future hypertriglyceridemia in children.In order to clarify whether there is a correlation between plasma amino acid levels and hypertriglyceridemia,a cross-sectional analysis of two independent clinical cohorts was carried out in an attempt to find out whether plasma amino acids in diabetic patients are related to residual high triglycerides under statin treatment.Esteremia is related,and whether it can be used as a potential new therapeutic target.Objective:1)Whether there are differences in amino acid metabolites between normal TG diabetes patients and HTG diabetes patients;2)When LDL-C level reached the treatment standard(LDL-C<2.6mmol/L),whether there was a difference in amino acid metabolites between normal TG diabetes patients and HTG diabetes patients;3)Whether the different amino acid metabolites are associated with the risk of HTG in diabetic patients treated with statins.Methods:Two independent cross-sectional hospital based cohorts.Liaoning Medical University First Affiliated Hospital(LMUFAH,n=146)and the Second Affiliated Hospital of Dalian Medical University(SAHDMU,n=294)were included in current analysis.Hypertriglyceridemia was defined as triglyceride ≥ 1.7 mmol/L;well-controlled LDL-C was defined as <2.6 mmol/L.The adjusted ORs(95% CI)of circulating metabolic measures for hypertriglyceridemia were assessed using logistic regression.Pooled results of metabolites with same direction of association in both cohorts were combined using inverse variance-weighted fixed-effect meta-analysis.Difference of identified metabolites in patients with and without hypertriglyceridemia were also obtained in the context of LDL-C.Results:We observed that elevated alanine,asparagine,leucine and valine were consistently associated with increased hypertriglyceridemia in both cohorts.In fixed effect pooled analysis,the OR(95%CI)of per SD increased was 1.71(1.32-2.20)for alanine,1.62(1.20-2.19)for asparagine,1.64(1.22-2.20)for leucine and 1.62(1.22-2.13)for valine(all P value ranged from 0.0018 to <.0001);adjusting for C-peptide attenuated effect sizes of Ala,Leu and Val for hypertriglyceridemia.The difference were robust in groups with well-or bad-controlled LDL-C.Conclusion:Alanine,asparagine,leucine and valine were positively associated with increased residual risk of hypertriglyceridemia in diabetic patients with statins treatment.更多还原