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学科主题: 内科学
题名:
血清miR-1181在糖尿病分型诊断中的 作用及与胰岛自身抗体的关系
作者: 张保振
答辩日期: 2016-05-18
导师: 纪立农
专业: 内科学
授予单位: 北京大学
授予地点: 北京大学第二临床医学院
学位: 博士
关键词: 1型糖尿病 ; 2型糖尿病 ; 鉴别诊断 ; 谷氨酸脱羧酶抗体 ; 血清miR-1181
其他题名: The Application of Serum miR-1181 in Differential Diagnosis of Diabetes and its Relationship with Pancreatic Autoantibodies
分类号: R587.1
摘要:

背景及目的1型糖尿病(T1DM)和2型糖尿病鉴别诊断的传统指标已受到越来越多的挑战。当前迫切需要寻找新的早期协助糖尿病分型诊断的生物标志物,指导临床诊治。本中心早期的一项研究发现, miR-1181在1型糖尿病患者、新诊断2型糖尿病患者血清中的相对表达水平比糖代谢正常人群存在显著下调,且新诊断2型糖尿病患者血清miR-1181表达水平与1型糖尿病患者相比也存在差异。有文献报道miR-1181能够直接抑制靶基因STAT3基因表达,而STAT3基因突变与DM等多种自身免疫疾病的发病有关。故本研究进一步扩大样本量,验证miR-1181是否可作为糖尿病分型诊断的生物标志物。研究对象1.2012-2015年我院出院诊断为1型糖尿病的患者57人(M%,40%;平均年龄44.7±17.9岁); 2.年龄、性别与1组匹配的T2DM 患者共56人(M%,43%;平均年龄46.2±16.2岁); 3.糖代谢正常人群对照41人(M%,44%;平均年龄42.1±16.4岁)。研究方法 采用实时定量PCR(qRT-PCR)Taqman探针法测定以上各组血清miR-1181的相对表达水平。运用线性回归及logistic回归分析血清miR-1181与血糖、胰岛β细胞功能及胰岛自身抗体等临床指标之间的相关性。研究结果1.各组受试者血清miR-1181结果及比较:1型糖尿病患者和2型糖尿病患者血清miR-1181表达水平较正常对照组显著下调(P<0.01);1型糖尿病患者血清miR-1181表达水平较2型糖尿病未达到显著统计学差异(P=0.161)。2.GAD抗体阳性患者和GAD抗体阴性患者组间血清miR-1181表达水平有所下调,但未达到显著统计学差异(P=0.11);3. logistic回归分析显示:血清miR-1181与空腹血糖呈显著负相关。研究结论 血清miR-1181在糖尿病患者中表达水平较正常对照组明显下调;血清miR-1181在T1DM患者中的表达水平与T2DM患者差异不显著。血清miR-1181与空腹血糖呈独立负相关关系而与GAD抗体和空腹C肽之间无显著相关。血清miR-1181与糖尿病相关性是否存在因果关系及相关机制尚有待进一步研究

英文摘要:

Background and aims:  In recent years, with the rapid increase in the incidence of obesity, the prevalence of early-onset T2DM is increasing significantly. The role of body mass index and age of onset as traditional differential diagnostic biomarkers for T1DM and T2DM has been challenged. Some studies suggest that fasting C-peptide levels at early stage of diabetes can be used to classify the type of diabetes, namly T1DM and T2DM, but so far there is still no internationally accepted diagnostic cut-off point for C-peptide. Moreover, once the fasting C-peptide level become significantly lower,βcell function has already been seriousely damaged, thus can not meet the purpose of early prevention and βcell function prevention.Therefore, there is an urgent need to find new differential diagnostic biomarker for diabetes. An earlier study of our group found that the expression level of serum microRNA1181 in newly onset type 2 diabetic patients (NOT2DM)is significantly downregulated compared with control group of normal glucose tolerance(NGT). When compare the expression level of serum miR-1181 beteewn T1DM and NOT2DM patients, the fomer has a much lower miR-1181 expression level than the later. MicroRNA has also been reported to participate in the autoimmune related diseases (such as T1DM, RA and SLE). Therefore, this study further expand the sample size of T1DM patients, T2DM patients and NGT control group, and detection for expression levels of miR-1181 in serum was conducted with the Taqman-rtPCR technology in order to confirm our previous foundings and verify wether serum miR-1181 can be used as a differential diagnostic biomarkers for diabetes classification.

Objective  Fifty-seven inhospital type 1 diabetic patients(M%,40%;mean age 44.7±17.9) and fifty-six age and gender-matched type 2 diabetic patients were enrolled from year 2012 to 2015(M%,40%;mean age 44.7±17.9), fourty-one NGT people were enrolled as normal control group.

Methods  1. Clinical information and serum sample were collected,serum sample were stored in -80℃condition.Clinical information include sex, age,disease duration, BMI, blood pressure, fasting blood glucose,postprandial blood glucose,fasting C peptide, postprandial C peptide,TC,HDL-c,LDL-c,TG,uric acid,creatine,and diabetic complications. 2. Serum miRNA levels were determined by Taqman-tab real-time polymerase chain reaction(RT-PCR)and the expression levels were calculated with ΔΔCt method. Comparisons of miR-1181 expression level were conducted among the three groups. 3. Glutamic acid decarboxylase antibodies were measured in T1DM group with the GADA ELISA kit(RSR Limited), clinical features and miR-1181 level were compared beteewn GADA positive T1DM patients and GADA negative T1DM patients.4. Linear regeression were made to analyse the relationship beteewn miR-1181 expression level and some clinical features including GADA,fasting plasma glucose,fasting C peptide et al.

Results  Expression levels of miR-1181 in two diabetic patients groups were significantly downregulated compared with the NGT control group(P<0.05, respectively);when compare between the two diabetic groups, expression levels of serum miR-1181 in T1DM patients were lower than that of T2DM patients,but not reach a significant level(P>0.05) . For type 1 diabetic patients, there was no significant difference between expression levels of miR-1181 between GADA(+)T1DM patients and GAD(-) T1DM patients(P>0.05). Linear and logistic regression analysis were conducted to determine the reason for the different expression patterns of miR-1181 between diabetic patients and the NGT control group, and the result showed that fasting blood glucose,but not C peptide and GADA, may be an indipendent factor for the expression level of miR-1181 in serum.

Conclusion  

Expression levels of miR-1181 in diabetic patients are significantly downregulated compared with the normal controls, and the reason may mainly due to the difference in blood gluose which was confirmed by the logistic regression analysis.miR-1181 may not be a qualified candidate biomarker for the differential diagnosis of type 1 diabetes and type 2 diabetes.There is no relationship seen between serum miR-1181 and GAD-Ab.

Key words   Type 1 diabetes mellitus; Type 2 diabetes; Serum miR-1181; Glutamic acid decarboxylase antibody; Differential diagnosis

语种: 中文
相关网址: 查看原文
内容类型: 学位论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/124606
Appears in Collections:北京大学第二临床医学院_学位论文

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作者单位: 北京大学第二临床医学院

Recommended Citation:
张保振. 血清miR-1181在糖尿病分型诊断中的 作用及与胰岛自身抗体的关系[D]. 北京大学第二临床医学院. 北京大学. 2016.
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