CN113981074A - 一种与2型糖尿病相关的microRNA及其应用 - Google Patents
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Abstract
本发明提供了一种与2型糖尿病相关的microRNA及其应用,属于体外诊断和生物医药技术领域,所述microRNA的核苷酸序列如SEQ ID NO.1所示。本发明的microRNA在肥胖和糖尿病个体的血清样本中显著高表达,并且该microRNA的表达与受试个体的空腹血糖显著正相关。本发明能够通过检测患者循环microRNA的表达量,能够提前预测出患者罹患2型糖尿病的风险以及早期诊断2型糖尿病。本发明在体外培养人肝癌细胞系HepG2细胞、人肝细胞L02以及小鼠前脂肪细胞3T3‑L1的基础上,转染microRNA‑Xmimic或inhibitor后观察对细胞葡萄糖代谢能力的影响。
Description
技术领域
本发明属于体外诊断和生物医药技术领域,具体涉及一种与2型糖尿病相关的microRNA及其应用。
背景技术
2型糖尿病(diabetes mellitus type 2,T2DM),旧称非胰岛素依赖型糖尿病(noninsulin-dependent diabetes mellitus,NIDDM)或成人发病型糖尿病(adult-onsetdiabetes),是一种慢性代谢疾病,多在35~40岁之后发病,占糖尿病患者90%以上。2型糖尿病的早期症状包括饥饿、口渴、尿频、皮肤瘙痒、代谢异常和疲劳虚弱等。但是2型糖尿病病情隐匿,其发病早期一般都比较缓和、隐蔽,病程较长,典型的糖尿病症状(三多一少等)较少出现。因而,2型糖尿病的早期诊断可以使患者尽早得到适当的治疗,从而并减少并发症的风险。
microRNA是一类由内源基因编码的长度约为22个核苷酸的非编码单链RNA分子,它们在动植物中参与转录后基因表达调控。体内大部分循环外泌体microRNAs来源于脂肪组织并通过血液循环到达靶组织器官,影响其糖、脂代谢关键基因的表达,导致脂肪肝、动脉粥样硬化、癌症以及糖尿病等疾病的发生。目前,对于治疗肥胖及其相关慢性疾病,microRNAs表现出了非常大的潜力,可作为诊断和治疗肥胖及其相关慢性疾病的靶点。但是,目前还没有以microRNA作为2型糖尿病早期诊断的靶点的报道。
发明内容
有鉴于此,本发明的目的在于提供一种与2型糖尿病相关的microRNA及其应用,本发明的microRNA与空腹血糖显著正相关,能够作为靶点用于2型糖尿病早期诊断。
本发明提供了一种与2型糖尿病相关的microRNA,核苷酸序列如SEQ ID NO.1所示。
本发明还提供了检测上述方案所述microRNA表达量的试剂在制备2型糖尿病早期诊断试剂或试剂盒中的应用。
本发明还提供了检测上述方案所述microRNA表达量的试剂在制备预测2型糖尿病患病风险的试剂或试剂盒中的应用。
本发明还提供了一种用于PCR检测上述方案所述microRNA表达量的引物组,包括上游引物和下游引物,所述上游引物的核苷酸序列如SEQ ID NO.2所示;所述下游引物的核苷酸序列如SEQ ID NO.3所示。
本发明还提供了一种用于PCR检测上述方案所述microRNA表达量的试剂或试剂盒,包括上述方案所述的引物组和PCR扩增用试剂。
本发明还提供了上述方案所述microRNA的表达抑制剂在制备治疗2型糖尿病和/或肥胖的药物中的应用。
本发明还提供了一种上述方案所述microRNA的表达抑制剂,核苷酸序列如SEQ IDNO.4所示的。
本发明还提供了一种治疗2型糖尿病和/或肥胖的药物,包括表达上述方案所述表达抑制剂的重组病毒表达系统。
优选的,所述重组病毒表达系统包括重组腺病毒。
优选的,所述药物的剂型包括注射剂。
本发明提供了一种与2型糖尿病相关的microRNA,核苷酸序列如SEQ ID NO.1所示;在本发明中,命名为:microRNA-X。本发明的microRNA在肥胖和糖尿病个体的血清样本中显著高表达,并且该microRNA的表达与受试个体的空腹血糖显著正相关。本发明能够通过检测患者血清中microRNA的表达量,和正常人相比,归一化之后有统计学意义,差异显著,则患2型糖尿病患病风险高或者患有2型糖尿病。本发明的方案能够提前预测出患者罹患2型糖尿病的风险以及早期诊断2型糖尿病。
本发明在体外培养人肝癌细胞系HepG2细胞、人肝细胞L02以及小鼠前脂肪细胞3T3-L1的基础上,转染microRNA-X模拟物(microRNA-Xmimic,人工合成的本发明的microRNA-X,核苷酸序列如SEQ ID NO.1所示)或microRNA-X抑制剂(microRNA-Xinhibitor)(SEQ ID NO.1所示的核苷酸序列的互补序列,如SEQ ID NO.4所示,具体为:AGCAAAAUCCACAAUUACUUUU)后观察对细胞葡萄糖代谢能力的影响。结果显示,microRNA-X模拟物可抑制细胞葡萄糖代谢能力。
本发明还提供了microRNA表达抑制剂在制备治疗2型糖尿病和/或肥胖的药物中的应用。本发明通过腺病毒介导的microRNA-X inhibitor sponge表达下调了高脂饮食诱导的肥胖C57BL/6小鼠体内的microRNA-X。同样地,普通饮食喂养的小鼠通过腹腔注射腺病毒介导的microRNA-X模拟物上调microRNA-X表达。体内实验结果表明,microRNA-X的抑制显著改善饮食诱导肥胖小鼠的葡萄糖耐量和胰岛素敏感性,同时降低肥胖小鼠血清的甘油三酯和血糖水平。由此提示,microRNA-X抑制剂可作为治疗2型糖尿病的潜在靶标。
附图说明
图1表示microRNA-X在正常、肥胖和糖尿病个体血清内的表达水平,正常血清样本36例,肥胖血清样本36例,糖尿病血清样本12例,microRNA-X的表达水平;秩和检验,*P<0.05差异具有统计学意义;
图2表示microRNA-X mimic转染24h后HepG2、L02细胞和3T3-L1葡萄糖利用率,与NC组相比,t检验,**P<0.01,***P<0.001,差异具有统计学意义;
图3表示microRNA-X inhibitor转染24h后HepG2、L02细胞和3T3-L1葡萄糖利用率,与NC组相比,t检验,*P<0.05,**P<0.01,***P<0.001,差异具有统计学意义;
图4为体内过表达/抑制miR-X(microRNA-X),C57BL/6小鼠大体图;
图5为体内过表达/抑制miR-X,小鼠体重;
图6为体内过表达/抑制miR-X,腹腔注射前后小鼠体重比较;
图7为体内过表达/抑制miR-X,小鼠各组织重量;
图8为体内过表达miR-X小鼠的空腹血糖水平;
图9为体内过表达miR-X小鼠的GTT;
图10为体内过表达miR-X小鼠的GTT曲线下面积;
图11为体内过表达miR-X小鼠的ITT;
图12为体内过表达miR-X小鼠的ITT曲线下面积;
图13为体内过表达miR-X小鼠的血清TG水平;
图14为体内过表达miR-X小鼠的血清TC水平;
图15为体内过表达miR-X小鼠的血清FFA水平;
图16为体内过表达miR-X小鼠的血清HDL-C水平;
图17为体内过表达miR-X小鼠的血清LDL-C水平;
图18为体内抑制miR-X小鼠的空腹血糖水平;
图19为体内抑制miR-X小鼠的GTT;
图20为体内抑制miR-X小鼠的GTT曲线下面积;
图21为体内抑制miR-X小鼠的ITT;
图22为体内抑制miR-X小鼠的ITT曲线下面积;
图23为体内抑制miR-X小鼠的血清TG水平;
图24为体内抑制miR-X小鼠的血清TC水平;
图25为体内抑制miR-X小鼠的血清FFA水平;
图26为体内抑制miR-X小鼠的血清HDL-C水平;
图27为体内抑制miR-X小鼠的血清LDL-C水平;
图4~7中n=10,图8~27中n=8,秩和检验,*P<0.05,**P<0.01,***P<0.001表示差异具有统计学意义。
具体实施方式
本发明提供了一种与2型糖尿病相关的microRNA,核苷酸序列如SEQ ID NO.1所示,具体为:AAAAGUAAUUGUGGAUUUUGCU。
本发明还提供了检测上述方案所述microRNA表达量的试剂在制备2型糖尿病早期诊断试剂盒中的应用。
本发明通过收集562名维吾尔族个体血清,运用Illumina Infinium GlobalScreening Array-24 v1.0(GSA)Bead Chip技术进行分析,发现上述方案所述microRNA与空腹血糖显著正相关。本发明的microRNA能够显著降低细胞葡萄糖消耗能力。
本发明还提供了检测上述方案所述microRNA表达量的试剂在制备预测2型糖尿病患病风险的试剂或试剂盒中的应用。和正常人相比,归一化之后有统计学意义,差异显著,则患2型糖尿病患病风险高或者患有2型糖尿病。
在本发明中,检测上述方案所述microRNA表达量的试剂包括检测所述microRNA的表达量的引物组,优选的还包括PCR扩增用试剂。
本发明还提供了一种用于PCR检测上述方案所述microRNA的表达量的引物组,包括上游引物和下游引物,所述上游引物;所述上游引物的核苷酸序列如SEQ ID NO.2所示,具体为:5’-AAAAGUAAUUGUGGAUUUUGCU-3’;所述下游引物的核苷酸序列如SEQ ID NO.3所示,具体为:5’-CAAAAUCCACAAUUACUUUUUU-3’。
本发明还提供了一种用于PCR检测上述方案所述microRNA的表达量的试剂或试剂盒,包括上述方案所述的引物组和PCR扩增用试剂;所述PCR扩增用试剂优选为qRT-PCR扩增用试剂。在本发明中,所述qRT-PCR扩增用试剂优选的包括2×miRcute Plus miRNA Premix和无酶水;所述2×miRcute Plus miRNAPremix中含有染料;所述染料优选为SYBR或ROX。
在本发明中,检测上述方案所述microRNA的表达量的方法优选的包括以下步骤:
1)提取待测患者血清的miRNA,所述miRNA反转录为cDNA;
2)以所述cDNA为模板,采用上述方案所述的引物组进行qRT-PCR扩增,得到Ct值。
与健康个体Ct值比较,归一化之后有统计学意义,差异显著,则患2型糖尿病患病风险高或者患有2型糖尿病。
本发明还提供了上述方案所述microRNA的表达抑制剂在制备治疗2型糖尿病和/或肥胖的药物中的应用。
本发明还提供了一种上述方案所述microRNA的表达抑制剂,核苷酸序列如SEQ IDNO.4所示,具体为:5’-AGCAAAAUCCACAAUUACUUUU-3’。本发明的microRNA的表达抑制剂能够显著促进细胞对葡萄糖的利用。
本发明的microRNA的表达抑制剂还能够降低肥胖小鼠体重,显著降低肥胖小鼠的肝脏及不同类型的脂肪组织(如附睾白色脂肪组织、内脏脂肪组织、肾周白色脂肪组织以及皮下白色脂肪组织)的重量;同时降低肥胖小鼠血清甘油三酯和血糖水平,改善饮食诱导肥胖小鼠的葡萄糖耐量和胰岛素敏感性,低水平的microRNA介导肥胖小鼠有益代谢表型的产生。
本发明还提供了一种治疗2型糖尿病和/或肥胖的药物,包括表达上述方案所述表达抑制剂的重组病毒表达系统。
在本发明中,所述重组病毒表达系统优选的包括重组腺病毒。
在本发明中,所述药物的剂型优选的包括注射剂;所述注射剂重组腺病毒的滴度优选为1×1012PFU/mL。
下面将结合本发明中的实施例,对本发明中的技术方案进行清楚、完整地描述。
实施例1
1.人体样本收集:
(1)样本分组及来源:2016年12月~2018年12月,分别在新疆维吾尔自治区喀什地区、伊犁地区以及石河子地区,收集正常个体血清样本36例,肥胖个体血清样本36例,糖尿病个体血清样本12例。
(2)样本的纳入和排除标准:正常组:40岁<年龄<50岁;体质指数(BMI)<24kg/m2;空腹血糖<6.1mmol/l;甘油三酯(TG)<1.7mmol/l;总胆固醇(TC)<5.17mmol/l;性别:1:1配对;肥胖组:40岁<年龄<50岁;BMI≥28kg/m2;空腹血糖<6.1mmol/l;性别:1:1配对;T2DM组:38岁<年龄<50岁;空腹血糖≥7.0mmol/l;性别:1:1配对。
(3)血液样本的收集和保存:样本自收集后,室温4000rpm离心5min,吸取上层血清至1.5ml RNase-Free EP管中,置于-80℃冰箱保存。
(4)血液标本中microRNA的提取方法:
1)样品处理:每200μL血清或血浆中加入900μL裂解液MZA,振荡器振荡混匀30sec至完全匀浆,颠倒混匀;
2)室温放置5min,使得核酸蛋白复合物完全分离;
3)加入200μL氯仿,盖好管盖,剧烈振荡15sec,室温放置5min;
4)12000rpm,4℃,离心15min,样品会分为3层:黄色的有机相,白色的中间层和无色的水相,RNA主要在水相中,把水相转移到新管中,进行下一步操作;
5)量取转移液的体积,缓慢加入转移液2倍体积的无水乙醇,混匀,将得到的溶液和沉淀一起转入吸附柱miRelute,室温放置2min,室温12000rpm离心30sec,离心后弃掉流出液,保留吸附柱miRelute;
6)向吸附柱miRelute中加入700μL去蛋白液MRD,室温静置2min,室温12000rpm离心30sec,弃废液;
7)向吸附柱miRelute中加入500μL漂洗液RW,室温静置2min,室温12000rpm离心30sec,弃废液;
8)重复步骤7)一次;
9)室温12000rpm离心2min,弃收集管;
10)将吸附柱miRelute转入一个新的RNase-Free 1.5ml离心管中,向吸附膜中心位置加15-30μL RNase-Free ddH2O,室温放置2min,室温12000离心2min。
(5)体外扩增的反应体系和条件:
1)qRT-PCR反应体系如表1所示:
表1 qRT-PCR反应体系
2)实时定量PCR扩增程序如表2所示:
表2实时定量PCR扩增程序
2.在体外培养人肝癌细胞系HepG2、人肝细胞L02、小鼠前脂肪细胞3T3-L1的基础上,运用microRNA-X模拟物序列(AAAAGUAAUUGUGGAUUUUGCU,SEQ ID NO.1)和抑制剂inhibitor序列(AGCAAAAUCCACAAUUACUUUU,SEQ ID NO.4),上/下调microRNA-X后观察对细胞糖代谢能力的影响:
1)人肝癌细胞系HepG2体外培养:细胞由中国科学院上海细胞库购入,DMED培养基,10%FBS(胎牛血清),青霉素(100单位/mL)和链霉素(100ug/mL),常规培养于37℃含5%CO2培养箱内。
2)mimic模拟物序列的合成:模拟物合成序列购自吉玛基因,
F:5’-AAAAGUAAUUGUGGAUUUUGCU-3’(SEQ ID NO.2所示)
R:5’-CAAAAUCCACAAUUACUUUUUU-3’(SEQ ID NO.3所示)
(1)细胞糖代谢能力的检测方法:
细胞糖消耗实验:
1)正常培养基培养12h后更换无糖培养基剥夺葡萄糖12h;
2)利用无糖DMEM和lipo 2000将模拟物转染至细胞内;
3)4h后更换高糖DMEM含血清培养基,检测0h和24h培养基中葡萄糖含量。
(2)小鼠糖耐量和胰岛素耐量实验
1)腹腔注射葡萄糖耐量实验:用生理盐水和D-Glucose(cat#G6125,Sigma-Aldrich)配置20%的葡萄糖溶液。小鼠禁食不禁水16h后,尾部采血测定空腹血糖,测定值记为0min的血糖值。每只小鼠腹腔注射剂量为2g/Kg的葡萄糖溶液。在15min、30min、60min、90min、120min测定每只小鼠的血糖。
2)腹腔注射胰岛素耐量实验:小鼠胰岛素耐受实验的胰岛素用量为0.5U/Kg,胰岛素(诺和灵30R)用生理盐水稀释,配制浓度0.5U/ml。小鼠禁食4-6h,正常饮水。注射胰岛素前测血糖,注射胰岛素后在在15min、30min、60min、90min、120min测定每只小鼠的血糖。
(3)血清生化指标检测
血清游离脂肪酸、甘油三酯、总胆固醇、高密度脂蛋白和低密度脂蛋白检测试剂盒均购自中国南京建成生物工程研究所。小鼠血糖检测使用罗氏血糖试纸和配套的罗氏血糖仪(中国上海罗氏血糖健康医护公司)。
3.统计学方法:检测结果数据用均值±标准差(x±s)表示,应用SPSS 25.0软件进行数据统计分析。数据分析采用t检验和秩和检验,多组间比较采用单因素方差分析,数据相关性分析采用Pearson和Spearman相关性分析,P<0.05认为有统计学意义。
试验结果:
1.miR-X在肥胖和2型糖尿病个体体内显著高表达
在36例正常,36例肥胖和12例T2DM个体血清中对microRNA-X(AAAAGUAAUUGUGGAUUUUGCU,如SEQ ID NO.1所示)的拷贝数进行验证,结果参见图1。结果显示与正常组相比,该序列在肥胖组和T2DM组中的拷贝数显著升高(P<0.05),提示microRNA-X可能与2型糖尿病的发生发展密切相关。
2.miR-X的表达与糖代谢显著正相关
SPSS 25.0分析miR-X与糖脂代谢相关指标的相关性,Spearman相关性分析结果显示miR-X与空腹血糖显著相关。
表3 miR-X与糖脂代谢相关指标的相关性分析
Spearman相关性分析,*P<0.05,相关性具有统计学意义。
3.miR-X降低细胞葡萄糖消耗能力,抑制miR-X显著促进细胞葡萄糖消耗
将miR-X mimic或inhibitor转染至HepG2、L02和3T3-L1中24小时检测细胞培养上清液内葡萄糖含量,microRNA-X mimic转染24h后HepG2、L02细胞和3T3-L1葡萄糖利用率参见图2。microRNA-X inhibitor转染24h后HepG2、L02细胞和3T3-L1葡萄糖利用率参见图3。结果提示:转染了miR-X的细胞葡萄糖消耗能力显著降低,相反miR-X的抑制显著促进细胞对葡萄糖的利用。
4.抑制miR-X可降低小鼠体重,改善葡萄糖耐量和系统胰岛素敏感性。
腹腔注射microRNA-X过表达/抑制剂腺病毒载体,小鼠体重及组织重量变化参见图4~图7。腹腔注射microRNA-X过表达腺病毒载体,小鼠葡萄糖耐量、胰岛素敏感性及血清生化指标检测结果参见图8~图17。腹腔注射microRNA-X抑制剂腺病毒载体,小鼠葡萄糖耐量、胰岛素敏感性及血清生化指标检测结果参见图18~图27。结果显示,抑制microRNA-X表达能够降低肥胖小鼠体重,与体重降低相一致的是,肥胖小鼠的肝脏及不同类型的脂肪组织(如附睾白色脂肪组织、内脏脂肪组织、肾周白色脂肪组织以及皮下白色脂肪组织)重量均显著降低;同时降低了肥胖小鼠血清甘油三酯和血糖水平,改善饮食诱导肥胖小鼠的葡萄糖耐量和胰岛素敏感性,体内实验结果提示低水平的miR-X介导肥胖小鼠有益代谢表型的产生。
尽管上述实施例对本发明做出了详尽的描述,但它仅仅是本发明一部分实施例而不是全部实施例,人们还可以根据本实施例在不经创造性前提下获得其他实施例,这些实施例都属于本发明保护范围。
序列表
<110> 石河子大学
<120> 一种与2型糖尿病相关的microRNA及其应用
<160> 4
<170> SIPOSequenceListing 1.0
<210> 1
<211> 22
<212> RNA
<213> 人工序列(Artificial Sequence)
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<211> 22
<212> RNA
<213> 人工序列(Artificial Sequence)
<400> 2
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<210> 3
<211> 22
<212> RNA
<213> 人工序列(Artificial Sequence)
<400> 3
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<210> 4
<211> 22
<212> RNA
<213> 人工序列(Artificial Sequence)
<400> 4
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Claims (10)
1.一种与2型糖尿病相关的microRNA,核苷酸序列如SEQ ID NO.1所示。
2.检测权利要求1所述microRNA表达量的试剂在制备2型糖尿病早期诊断试剂或试剂盒中的应用。
3.检测权利要求1所述microRNA表达量的试剂在制备预测2型糖尿病患病风险的试剂或试剂盒中的应用。
4.一种用于PCR检测权利要求1所述microRNA表达量的引物组,包括上游引物和下游引物,所述上游引物的核苷酸序列如SEQ ID NO.2所示;所述下游引物的核苷酸序列如SEQ IDNO.3所示。
5.一种用于PCR检测权利要求1所述microRNA表达量的试剂或试剂盒,包括权利要求4所述的引物组和PCR扩增用试剂。
6.权利要求1所述microRNA的表达抑制剂在制备治疗2型糖尿病和/或肥胖的药物中的应用。
7.一种权利要求1所述microRNA的表达抑制剂,核苷酸序列如SEQ ID NO.4所示的。
8.一种治疗2型糖尿病和/或肥胖的药物,包括表达权利要求7所述表达抑制剂的重组病毒表达系统。
9.根据权利要求8所述的药物,其特征在于,所述重组病毒表达系统包括重组腺病毒。
10.根据权利要求8或9所述的药物,其特征在于,所述药物的剂型包括注射剂。
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