【作者】 苏静；

【导师】 王彦君；

【作者基本信息】 吉林大学 ， 临床医学硕士（专业学位）， 2018， 硕士

【摘要】 背景:糖尿病肾病是糖尿病的严重慢性并发症之一,也是目前引起我国慢性肾脏疾病的首要病因。近年来,糖尿病肾病的发病率和死亡率逐年增加,在影响人们的生活水平的同时,给社会的发展也带来了巨大的压力。而现今针对糖尿病肾病的治疗,即便是多因素共同干预,仍不能达到理想的结果。二肽基肽酶-4抑制剂利格列汀自上市以来便颇受关注,近年来的研究发现,利格列汀在控制血糖的同时,能够对肾脏起到保护作用,并且这种作用不单纯依赖于血糖的改善,但目前关于利格列汀保护肾脏的机制尚不十分明确。目的:通过观察利格列汀对糖尿病肾病患者尿蛋白、高迁移率族蛋白B1及晚期糖基化终末产物受体水平的影响,推测其在保护肾脏方面的作用并阐述其可能机制,为糖尿病肾病的治疗提供新的方法和理论依据。方法:1.收集2015.10~2016.02就诊于吉林大学第二医院内分泌科的诊断为2型糖尿病且合并糖尿病肾病(微量白蛋白尿期,即24小时尿白蛋白定量:30~300mg/24h)的患者共160例,经吉林大学第二医院伦理委员会批准并签署知情同意书。入组标准:(1)符合1999年世界卫生组织制定的2型糖尿病诊断(空腹血糖≥7.0mmol/L和/或餐后2小时血糖≥11.1mmol/L)及分型标准,且24小时尿白蛋白定量:30~300mg/24h;(2)糖尿病病程:5~10年,糖化血红蛋白:6.5~10.0%;(3)尿微量白蛋白/肌酐比值:30~300mg/g Cr(半年内复查,3次中至少2次满足),且血肌酐<73mmol/L;(4)肾小球滤过率≥60ml/min/1.73m~2;(5)眼底照相证实合并糖尿病视网膜病变;(6)稳定的胰岛素治疗背景>6个月,可联合应用口服降糖药(除胰高血糖素样肽-1受体激动剂、二肽基肽酶-4抑制剂、钠-葡萄糖协同转运蛋白-2抑制剂);(7)合并高血压,并接受稳定剂量ACEI/ARB类降压药治疗≥4周,可联合应用其他种类降压药。排除标准:(1)其他类型糖尿病;(2)处于妊娠期、哺乳期的女性;(3)合并严重感染;(4)严重心、肝功能不全;(5)合并糖尿病急性并发症;(6)近期(1个月内)服用肾毒性药物;(7)合并泌尿系统疾病。2.入组患者随机分为2组,即利格列汀组(n=80)和对照组(n=80),采集患者一般信息,包括性别、年龄、身高、体重、体重指数、收缩压及舒张压等。留取血样检测入组患者空腹血糖、餐后2小时血糖、糖化血红蛋白、甘油三酯、总胆固醇、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇,采用酶联免疫吸附反应检测各组血清中高迁移率族蛋白B1、晚期糖基化终末产物受体的浓度;留取尿样采用免疫比浊法测定尿微量白蛋白浓度,采用肌氨酸氧化酶法测定尿肌酐浓度,计算两者比值即为尿微量白蛋白/肌酐比值。3.利格列汀组在原有降糖方案的基础上给予利格列汀片(5mg/日)治疗,而对照组继续原有方案,期间根据两组患者血糖、血压水平,及时调整相关药物剂量,同时定期检测肝、肾功等血生化指标。随访第3、6个月再次检测两组患者观察指标,包括:空腹血糖、餐后2小时血糖、糖化血红蛋白、总胆固醇、甘油三酯、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇、尿微量白蛋白/肌酐比值、高迁移率族蛋白B1、晚期糖基化终末产物受体等。结果:1.共纳入研究对象160例,其中利格列汀组80例,男性39例,年龄(57.62±9.51)岁,女性41例,年龄(59.40±10.61)岁;对照组80例,男性42例,年龄(57.45±9.81)岁,女性38例,年龄(60.25±9.02)岁。两组间一般资料、相关治疗背景及观察指标在基线时无统计学差异(P>0.05)。2.随访两组3个月时,与基线相比,利格列汀组空腹血糖、餐后2小时血糖、糖化血红蛋白、尿微量白蛋白/肌酐比值及血清高迁移率族蛋白B1、晚期糖基化终末产物受体浓度显著下降,有统计学意义(P<0.001);对照组观察指标变化无统计学意义(P>0.05)。与对照组相比较,利格列汀组空腹血糖、餐后2小时血糖、糖化血红蛋白、尿微量白蛋白/肌酐比值及血清高迁移率族蛋白B1、晚期糖基化终末产物受体浓度下降,并有统计学意义(P<0.001),其他指标两组对比无统计学意义(P>0.05)。3.随访两组6个月时,与基线相比,利格列汀组空腹血糖、餐后2小时血糖、糖化血红蛋白、尿微量白蛋白/肌酐比值及血清高迁移率族蛋白B1、晚期糖基化终末产物受体浓度显著下降,有统计学意义(P<0.001);对照组尿微量白蛋白/肌酐比值也明显下降,有统计学意义(P<0.001),其他指标较基线无统计学意义(P>0.05)。与随访3个月时相比,利格列汀组空腹血糖、餐后2小时血糖、糖化血红蛋白、尿微量白蛋白/肌酐比值及血清高迁移率族蛋白B1、晚期糖基化终末产物受体浓度明显下降,有统计学意义(P<0.001);对照组尿微量白蛋白/肌酐比值下降,有统计学意义(P<0.001),其他观察指标无统计学意义(P>0.05)。随访6个月时,利格列汀组空腹血糖、餐后2小时血糖、糖化血红蛋白、尿微量白蛋白/肌酐比值及血清高迁移率族蛋白B1、晚期糖基化终末产物受体浓度较对照组下降,有统计学意义(P<0.001)。4.将利格列汀组分别按照收缩压、糖化血红蛋白基线的平均值分为两个亚组,各亚组随访6个月时尿微量白蛋白/肌酐比值较基线均明显下降,有统计学意义(P<0.001),各亚组组间比较无统计学差异(P>0.05)。5.将利格列汀组分别按照随访6个月后收缩压、糖化血红蛋白较基线下降的幅度分为多个亚组,随访6个月时各亚组尿微量白蛋白/肌酐比值较基线明显下降,有统计学意义(P<0.001),各亚组组间比较无统计学差异(P>0.05)。结论:1.在使用肾素-血管紧张素-醛固酮系统抑制剂的基础上,联用利格列汀可以显著降低糖尿病肾病患者尿微量白蛋白/肌酐比值,且不依赖于血糖、血压的水平。2.在使用肾素-血管紧张素-醛固酮系统抑制剂的基础上,联用利格列汀可以显著降低糖尿病肾病患者血清中高迁移率族蛋白B1、晚期糖基化终末产物受体的浓度,推测利格列汀保护肾脏的作用可能与此有关。更多还原

【Abstract】 Background:Diabetic nephropathy is one of the most serious chronic complications of diabetes mellitus,as well as the primary cause of chronic kidney disease in China.With the improvement of living standards,the morbidity and mortality of diabetic nephropathy increased significantly year by year,which had affected the quality of people’s life and exerted tremendous pressure on the development of society.Nowadays,small portion could not achieved the therapeutic goals,even though multi-factor intervention for the therapy of diabetic nephropathy.Linagliptin had drawn much attention since it was listed.It is worth noting that many relative studies have found that linagliptin could protect the kidneys while controlling blood glucose,and this effect was beyond the improvement of blood glucose.However,little is known about the mechanism of linagliptin on protecting the kidney until now.Objective:In the present study,we examined the levels of the urinary albumin-to-creatinine ratio,serum HMGB1 and serum RAGE of the patients with diabetic nephropathy.Aim to observe the role of linagliptin in protecting the kidneys and infer the possible mechanisms,which will offers a new method for the treatment of diabetic nephropathy.Materials and methods:The study collected a total of 160 patients diagnosed with T2DM,as well as combined with diabetic nephropathy from Oct 2015 to Feb 2016,in the Second Hospital of Jilin University.In short,patients whose T2DM duration of 5~10 years combined with microalbuminuria,and whose eGFR was more than 60 ml/min/1.73m~2were eligible for the study.Those who infected with acute complications of diabetes mellitus,or combined with severe heart and liver dysfunction,or women in pregnancy or lactation were excluded.The participants were previously received insulin therapy with one or two hypoglycemic agents for more than 6 months(HbA1c levels of6.5~10.0%at screening),combined with hypertension and had received stable dose of antihypertensive drugs like ACEI/ARB for more than 4 weeks.The eligible patients’general informations and vital signs were collected,including gender,age,height,weight,BMI,SBP and DBP,followed by collecting the blood samples from cubital vein and the spot urine sample in the early morning.The participants were randomly divided into 2 groups,that is the linagliptin group(n=80)and the control group(n=80).The control group continued the background therapy,while the linagliptin group received linagliptin 5mg additionally.The FPG,2hPG,HbA1c,TC,TG,HDL-C,LDL-C,UACR,HMGB1and RAGE were measured per 12weeks.The primary efficacy outcome of our study was the change in UACR,the levels of serum HMGB1and RAGE from baseline to week 24.Results:1.A total of 160 subjects were pooled in the study.Among them,there were 39males with the age(57.62±9.51)years and 41 females with the age(59.40±10.61)years in the linagliptin group(n=80),42 males with the age(57.45±9.81)and 38females with the age(60.25±9.02)in the control group(n=80)(P=0.635).There was no statistical difference between the two groups at the baseline.2.After following up for 3-month,linagliptin group shows a significant reduction in FPG,2hPG,HbA1c,UACR,serum HMGB1 and RAGE compared with the baseline(P<0.001)and the control group(P<0.001),there was no statistical significance in the control group compared with the baseline about the above indexes(P>0.05).3.After following up for 6-month,the linagliptin group decreased significantly in FPG,2hPG,HbA1c,UACR,serum HMGB1 and RAGE compared with the baseline(P<0.001),3-month ago(P<0.001),and the control group(P<0.001),the control group shows a significant reduction in UACR from the baseline(P<0.001)and 3-month ago(P<0.001).4.The linagliptin group was divided into subgroups according to the average value of baseline SBP and baseline HbA1c.Further analysis between the subgroups shows that UACR decreased significantly than baseline when 6-month follow-up in each subgroup(P<0.001),but there was no statistically significant interaction between the subgroups(P>0.05).5.SBP and HbA1c were stratified into categories based on the change from baseline to 6-month follow-up in linagliptin group,further analysis shows that UACR decreased significantly than baseline when 6-month follow-up in each subgroup(P<0.001),but there was no statistically significant interaction between the subgroups(P>0.05).Conclusion:1.Linagliptin administered on top of stable RAAS inhibitors led to a significant reduction in patients with diabetic nephropathy,and its effect on the kidney independent on the control of either blood glucose or blood pressure.2.Linagliptin administered in addition to stable RAAS inhibitors reduced the level of serum HMGB1 and RAGE of the patients with diabetic nephropathy,and its effect of reducing urinary protein maybe relative to this.更多还原