CN111909998B - TN的抑制剂在制备改善β细胞功能、预防和/或治疗糖尿病的药物中的应用 - Google Patents
TN的抑制剂在制备改善β细胞功能、预防和/或治疗糖尿病的药物中的应用 Download PDFInfo
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Abstract
本发明涉及生物技术领域，特别涉及TN的抑制剂在制备改善β细胞功能、预防和/或治疗糖尿病的药物中的应用。本发明的研究发现，TN在肥胖和糖尿病患者和小鼠血清中均升高。此外，敲除TN基因可改善小鼠糖耐量，而急性给予TN补充加剧小鼠的葡萄糖不耐受。还通过Binding实验发现TN与人和小鼠胰岛组织有高亲和力的结合。TN处理胰岛β细胞会减弱了β细胞葡萄糖刺激胰岛素分泌(GSIS)能力。结果证实，TN是一种新型脂肪因子，在肥胖诱导的β细胞功能障碍中起重要作用。因此，靶向TN信号通路可能会是一种改善β细胞功能和治疗糖尿病的有效治疗方法。
Description
本申请要求于2020年06月09日提交中国专利局、申请号为202010518534.9、发明名称为“TN的抑制剂在制备改善β细胞功能、预防和/或治疗糖尿病的药物中的应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及生物技术领域，特别涉及TN的抑制剂在制备改善β细胞功能、预防和/或治疗糖尿病的药物中的应用。
背景技术
GSIS是胰岛β细胞维持代谢平衡的关键之一。胰岛素分泌受损是2型糖尿病(T2D)的一个特征，可能是由于β细胞质量缺乏(代偿性增殖不足)或β细胞功能障碍(葡萄糖依赖的胰岛素释放受损)造成的。在正常生理条件下，胰岛β细胞分泌有两个时相。葡萄糖通过高米氏常数(Km)并且低亲和力葡萄糖转运蛋白2(GLUT2)进入β细胞，通过糖酵解和Krebs循环代谢，导致β细胞ATP/ADP比值增加，ATP敏感性钾通道(KATP)关闭。KATP通道的闭合导致β细胞膜去极化，引起电压依赖性的Ca2+通道(VDCC)开放，随后Ca2+进入细胞，是诱导胰岛素分泌颗粒外吐不可缺少的触发信号。上述过程被称为葡萄糖诱导的胰岛素分泌的触发途径(也称为KATP依赖途径)。除了葡萄糖之外，胰岛β细胞的胰岛素分泌也受到许多其他因素的调节，如钙、代谢物和分泌肽/蛋白质，这些因素介导β细胞和其他细胞之间的相互作用，从而维持系统的能量平衡。一些分泌分子，如脂肪因子、胃肠激素、肌肉因子和骨源性分泌因子已被证明通过增强或抑制胰岛素释放或通过影响细胞存活来影响细胞功能。
TN是C型凝集素超家族的同源三聚体粘附分子。小鼠TN蛋白与人类TN蛋白氨基酸同源性达87％。TN在脂肪组织中高度表达，健康成年人血清TN水平约为10-12ug/mL。TN通过其C末端结构域与纤溶酶原结合，这种结合涉及纤溶和蛋白水解过程。TN也被发现在成骨和骨骼矿化中起作用。然而，TN在糖尿病中的作用以及TN对T1D和T2D的贡献机制尚不清楚。
发明内容
有鉴于此，本发明提供了TN的抑制剂在制备改善β细胞功能、预防和/或治疗糖尿病的药物中的应用。
为了实现上述发明目的，本发明提供以下技术方案：
本发明提供了TN作为β细胞功能障碍的关键负调节因子中的应用。
本发明提供了TN的抑制剂在制备预防和/或治疗β细胞功能障碍的药物中的应用。
本发明提供了TN的抑制剂在制备改善动物糖耐量中的应用。
本发明提供了TN的抑制剂或TN所在信号通路的阻断剂在制备改善β细胞功能、预防和/或治疗糖尿病的药物中的应用。
在本发明的一些具体实施方案中，所述TN的抑制剂包括减少TN的表达、抑制TN的分泌、TN基因的敲除和/或下调、中和TN的功能。
在本发明的一些具体实施方案中，TN能够特异性结合人和/或小鼠的胰岛组织。
在本发明的一些具体实施方案中，TN抑制人和/或小鼠胰岛的GSIS能力。
在本发明的一些具体实施方案中，TN作为脂肪因子，与肥胖诱导的β细胞功能障碍具有相关性。
在本发明的一些具体实施方案中，TN负调节葡萄糖代谢；或TN直接与胰岛细胞相互作用，参与代谢平衡。
在本发明的一些具体实施方案中，TN作用于ATP依赖性钾离子通道的下游位点；或TN在线粒体氧化功能中不起作用。
本发明的研究发现，TN在肥胖和糖尿病患者和小鼠血清中均升高。此外，敲除TN基因可改善小鼠糖耐量，而急性给予TN补充加剧小鼠的葡萄糖不耐受。还通过Binding实验发现TN与人和小鼠胰岛组织有高亲和力的结合。TN处理胰岛β细胞会减弱了β细胞GSIS能力。结果证实，TN是一种新型脂肪因子，在肥胖诱导的β细胞功能障碍中起重要作用。因此，靶向TN信号通路可能会时一种改善β细胞功能和治疗糖尿病的有效治疗方法。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍。
图1示效果例1的实验结果；其中，(A)和(B)Western blot分析正常、肥胖和T2D患者的TN表达，以IgG作为内参(正常n＝24；肥胖n＝24；T2D n＝24)；(C)患者血清TN水平与BMI的相关性；用Spearman秩相关法计算血清TN水平与HbA1c状态相关性的P、R值；(D)-(I)TN蛋白在HFD(D和E)、STZ(F和G)和fasted(H和I)鼠模型(n＝6)血清中的表达水平，其表达量以均数±SEM表示，*p<0.05，**p<0.01，***p<0.001；
图2示效果例2的实验结果；其中，(A)定量PCR(qPCR)分析小鼠不同组织中TN的表达水平(n＝3)；(B)Western blot分析不同小鼠组织中TN的表达，数据代表三个独立的实验；(C)在不同浓度的葡萄糖刺激48小时后，脂肪细胞TN表达水平，数据代表三个独立实验；(D)在1mM棕榈酸(PA)下刺激48小时后，脂肪细胞TN表达水平，数据代表三个独立实验；值用均数±SEM表示，*p<0.05，**p<0.01，***p<0.001；
图3示效果例3的实验结果；其中，人(A)和小鼠(B)胰腺冰冻切片的TN结合试验；(C)在过量重组HIS或HIS-TN的情况下，SEAP-TN与小鼠胰腺切片结合；数据代表了三个独立的实验；
图4示效果例4的实验结果；其中，(A)和(B)GTT分别在HFD雄性TN-/-小鼠(n＝12)和年龄匹配的WT小鼠(n＝12)中进行；(C)和(D)在HFD喂养条件下，TN-/-小鼠和对照组进行ITT试验(WT n＝11；TN-/-n＝11)；(E)和(F)第一次注射STZ后60天，每隔一天监测随机血糖水平(WT n＝12；TN-/-n＝12)；黑色箭头表示注射STZ的天数(前5天)；(G)及(H)第8天进行GTT(WTn＝7；TN-/-n＝7)；(I)STZ治疗后生存率(WT n＝11；TN-/-n＝11)；(J)重组TN可在注射后12小时的小鼠血清中检测到；(K)和(L)用ND喂养WT小鼠，经单次腹腔注射HIS或哺乳动物表达HIS-TN(10mg/kg)后进行GTT(n＝5或者6)；(N)和(M)用ND喂养WT小鼠，单次腹腔注射HIS或哺乳动物表达的HIS-TN(10mg/kg)后进行ITT(n＝5或6)；(O)和(P)用HFD喂养WT小鼠，在小鼠腹腔注射HIS或哺乳动物表达HIS-TN(10mg/kg)后进行GTT(n＝6)；(Q)和(R)用HFD喂养WT小鼠，小鼠腹腔注射HIS或哺乳动物表达HIS-TN(10mg/kg)后进行ITT；数值以平均值±SEM表示，*p<0.05，**p<0.01，***p<0.001；
图5示效果例5的实验结果；其中，(A)和(B)WT和TN-/-小鼠高糖钳夹时的血糖水平(WT n＝4；TN-/-n＝4)；(C)和(D)WT和TN-/-小鼠高糖钳夹时的胰岛素水平(WT n＝4；TN-/-n＝4)；在体外GSIS试验中，从WT小鼠身上分离出新鲜的人(E)(n＝4)和小鼠(F)胰岛(n＝3)，分别用16.7mM葡萄糖含或不含TN(10mg/L)处理，并在30分钟收集培养基以测量胰岛素水平；(G)体外胰岛素分泌试验：取WT小鼠新鲜胰岛，加入或不加入TN(10mg/L)后用30mM KCl处理，于30分钟收集培养液，测定胰岛素水平(n＝5)；TN处理人(H)(n＝4)和小鼠(I)(n＝4)胰岛灌流试验的胰岛素释放曲线图；值用均数±SEM表示，*p<0.05，**p<0.01，***p<0.001；
图6示对图1的补充结果；其中，(A)对纯化后的His-TN蛋白进行SDS-PAGE分析和银染色，以确定其纯度水平；(B)His-TN纯化后的总离子色谱图；(C)质谱分析片段和pubmed数据库中TN蛋白氨基酸序列的比对。
具体实施方式
本发明公开了TN的抑制剂在制备改善β细胞功能、预防和/或治疗糖尿病的药物中的应用，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明的方法及应用已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。
不可逆转的β细胞衰竭导致的高血糖仍然是T1D和T2D治疗的主要挑战。然而，糖尿病最有效的治疗方法是给病人注射胰岛素，但这种治疗有一些副作用，如体重增加，低血糖发作的风险，以及长期强化胰岛素治疗后可能增加癌症风险。最近的研究表明，胰高血糖素样肽-1类似物(GLP-1)和二肽基肽酶IV(DPP IV)抑制剂是有效的胰岛素增敏剂，可以减轻糖尿病，但也发现它们与T2D成年人胆管癌增加有关。因此，确定改善糖尿病细胞功能的新靶点并了解其作用机制，对于开发更有效的糖尿病治疗方法具有重要意义。
在本发明中，申请人确定TN(一种脂肪因子)，其血清水平在肥胖和T2D人和小鼠中血清中升高(图1和图2)，是β细胞功能障碍的关键负调节因子。以前发现，TN在T1D患者中增加，在糖尿病进展过程中更加明显。然而，其在糖尿病中的功能作用及其作用机制尚不清楚。我们发现TN与人和小鼠的胰岛组织有很高的亲和力(图3)。此外，敲除TN基因可提高小鼠的葡萄糖耐量(图4A-4I)，而急性给予TN可降低小鼠的葡萄糖耐量(图4K、4L、4O和4P)。我们的研究还表明，TN抑制人和小鼠胰岛的GSIS能力(图5)。这些发现非常重要，因为人类和啮齿动物的胰岛在结构和生理上有明显的差异。由于TN是一种肥胖诱导的循环因子，抑制TN的表达和/或中和其功能可能成为治疗糖尿病的一种有前途的治疗策略。
自从20年前在β细胞表面发现瘦素受体以来，已经有人提出存在一个脂肪-胰岛轴，介导脂肪细胞和β细胞之间的内分泌联系。据报道，一些脂肪因子通过促进β细胞胰岛素分泌(促胰岛素性脂肪因子)或抑制胰岛素分泌(调节性脂肪因子)影响细胞功能。脂联素，是一种在肥胖和T2D期间循环中减少的物质，已经发现在体外和体内都能增强β细胞GSIS的能力。另一方面，瘦素在体内、体外都可以抑制小鼠、大鼠和人胰岛的胰岛素分泌。我们的发现揭示了TN是另一种负向调节β细胞功能的脂肪因子。据我们所知，这是第一个证明TN在人类和小鼠β细胞功能障碍中的作用的研究。研究这些脂肪因子影响β细胞功能的机制，以及脂肪因子、营养素和其他激素(如GLP-1和胰高血糖素)的组合如何相互作用以协调胰岛素分泌，将是未来的主要挑战。
总之，本发明的研究确定TN是一种肥胖诱导的脂肪因子，它损害人类和小鼠β细胞的功能。这项研究揭示了肥胖加剧人类T2D的新机制。TN靶向β细胞的发现也揭示了脂肪组织与β细胞之间的一个关键性的节点，提示减少TN的表达、抑制其分泌和/或下调其功能可能是一条有希望的抗糖尿病治疗途径，以挽救β细胞衰竭。
本发明提供的TN的抑制剂在制备改善β细胞功能、预防和/或治疗糖尿病的药物中的应用中所用原料及试剂均可由市场购得。
下面结合实施例，进一步阐述本发明：
实施例1人血清和人胰岛研究
收集年龄和性别匹配的成人血清样本，包括正常受试者24人；肥胖患者24人；T2D患者24人。肥胖和T2D的诊断是根据世界卫生组织(WHO)的标准诊断的。所有受试者按体重指数(BMI)、腰围、臀围和生化指标进行分组。所有参与者的排除标准为:经常使用消炎药或皮质类固醇类药物；1型糖尿病(T1D)；继发性糖尿病；炎症、传染病或其他自身免疫性疾病；怀孕；和恶性疾病。正常对照组和肥胖组排除了患有T2D、高血压和高脂血症病史的患者。
人胰腺来自中南大学湘雅第二医院泌尿器官/肝移植组从非糖尿病死亡供体获得。根据下述步骤进行处理，用胶原酶P消化胰腺(sigma公司)分离胰岛。仔细清除周围的脂肪组织、淋巴结、血管和筋膜后，对人体胰腺进行了修整。用5毫升注射器和含1毫克/毫升胶原酶P的Hanks平衡盐溶液通过胰管注入胰腺并使其膨胀。每1mg胰腺使用2mL胶原酶溶液。胶原酶溶液的量相当于胰腺重量的两倍。取下胰腺，在37℃下50毫升离心管中震荡摇晃约20-30分钟，以便完全消化。将离心管置于4℃的冰浴中，加入Hanks平衡盐溶液，用Hanks平衡盐溶液冲洗胰腺三次，停止消化。在体视显微镜下用移液枪收集胰岛，在37℃细胞培养箱中用CMRL培养基(Gibco)培养，CMRL培养基加入了FBS(Gibco,10％，vol./vol.)、谷氨酰胺(Gibco,2mmol/L)和青霉素-链霉素(Gibco,100U/mL,0.1mg/mL)。人血清和胰岛的使用获得了CSU湘雅第二医院伦理委员会的批准(MSRC2016LF协议)。
实施例2动物实验研究
雄性TN基因敲除小鼠(TN-/-)和野生型小鼠(WT)控制被安置在中南大学湘雅二医院或圣安东尼奥德克萨斯大学健康(UTHSA)的实验动物中心屏障中，该屏障是一个特定的无菌环境并保持12小时光照/黑暗周期。小鼠均为C57BL/6背景，在喂养过程中可自由获取食物和水。在正常饮食喂养(ND)实验中，小鼠分别被喂食含有19％蛋白质、5％脂肪和5％纤维的正常饲料(思莱克京达实验动物有限公司，中国)。在高脂(HFD)喂养实验中，小鼠出生后6周开始摄入含有20％蛋白质、60％的脂肪和20％碳水化合物的高职饲料(D12492,Research Inc.)。所有动物使用程序均按照中南大学湘雅二医院动物伦理委员会或UTHSA动物伦理委员会的规定执行。
实施例3链脲佐菌素(STZ)给药
对于STZ给药处理，向8周龄的小鼠腹膜内(IP)注射新鲜制备的45mg/kg用0.1M柠檬酸盐缓冲液(Ph 4.5)配置的链脲佐菌素(STZ，Sigma S0130)或等体积的柠檬酸盐缓冲液，小剂量连续注射5天。最后一次注射后3天，将小鼠禁食过夜并进行GTT。为了确定对STZ治疗的早期反应，在第9天通过脱颈处死一组小鼠(每组12只)，收集小鼠组织用于免疫荧光分析。为了进行高血糖测量，每隔一天监测另一组小鼠的随机血糖水平，直到第60天为止。糖尿病的发展的特征是连续两次血糖读数超过250mg/dL。通过脱颈处死小鼠，并在第60天收集组织用于组织形态学分析。
实施例4体重和身体成分
从第6周开始，在每周的同一时间点，测量接受HFD喂养小鼠的体重和食物摄入量，持续时间12-16周的。通过MQ Minispec 7.5HZ活鼠分析仪(MinispecLF50；BRUKER OptikGmbH；德国)检测小鼠身体成分(脂肪质量，瘦肉质量，体液质量和脂肪百分比)。
实施例5TN结合测定
构建表达分泌型碱性磷酸酶(SEAP)和TN蛋白的SEAP融合蛋白(SEAP-TN)质粒并转染HEK293T细胞。24小时后，将细胞培养基再换成无血清培养基培养2天，然后收集培养基。将冷冻的组织切片与含有SEAP或SEAP-TN的培养基在室温下孵育1-2小时，接着用含有0.1％Tween-20的PBS洗涤四次。将切片用含有20mM HEPES(pH 7.4)，60％丙酮和3％甲醛的溶液中固定15秒钟。在65℃水浴锅中孵育1小时，将内源性碱性磷酸酶灭活。将样品置于SEAP或SEAP-TN培基中室温孵育1～2小时。最后使用NBT/BCIP底物(Sigma)检测融合蛋白的酶活性。在竞争结合实验中，将冷冻的组织切片与20mg/mL的His-GFP或His-TN中预先孵育1h，然后在室温下与SEAP或SEAP-TN培养基中孵育1～2h。
实施例6重组TN和GFP蛋白表达
通过PCR从白色脂肪组织(WAT)中分离出人和小鼠TN蛋白的cDNA，然后将其克隆到pcDNA 3.1/myc-His B载体中。将该质粒转染到HEK293T细胞中，并收集含有分泌的His-TN蛋白的细胞培养基。His-TN蛋白通过HisTrap excel色谱柱(GE Healthcare)进行第一步纯化。彻底清洗色谱柱以除去污染蛋白后，使用250mM咪唑缓冲液从色谱柱上洗脱His-TN。接着使用分子筛色谱法通过用PBS平衡后的分析柱Superdex200(GE Healthcare)进第二步纯化重组蛋白。从质粒文库获得His标记的GFP蛋白作为对照蛋白。TN蛋白来自SinoBiological Inc(纯度>95.9％)公司并且包括自制的TN蛋白。对自制的纯化TN蛋白进行SDS-PAGE分析，并通过银染和质谱法确定蛋白的纯度(图2A-图2C)。所有实验中使用的自制His-TN蛋白纯度均>90％。
实施例7 GTT，ITT和GSIS
通过将葡萄糖(2g/kg体重)腹腔注射禁食过夜的小鼠中进行葡萄糖耐量试验(GTT)。葡萄糖给药后0、15、30、60和120分钟从尾静脉抽血。胰岛素耐受性测试(ITT)是通过将人胰岛素(0.75单位/kg体重)腹腔注射禁食4小时的小鼠中进行的。胰岛素注射后0、15、30、60和90分钟从尾静脉抽血。使用血糖仪(One Touch；Bionime Corp)测定血清葡萄糖水平。通过胰岛素超敏酶免疫测定法(Alpco Diagnostics，Slemm，NH)测定血清胰岛素水平。对于某些实验，在GTT和ITT实验之前，将单剂量的重组TN蛋白(100mg/kg)腹腔注射到禁食16小时的小鼠中。
为了进行GSIS离体测试，将新鲜分离的人或小鼠胰岛在含有10％FBS(Gibco)和100U/mL青霉素-链霉素(Gibco)的RPMI-1640培养基(Gibco)中于细胞培养箱中37℃孵育过夜。然后将胰岛转移至KRBH缓冲液(Ph 7.4)中，该缓冲液包含115mM NaCl，5mM KCl，2.5mMCaCl2、1mM MgCl2、24mM NaHCO3、25mM HEPES，1mg/mL BSA和2.8mM葡萄糖，室温孵育2小时后，将胰岛(5个胰岛/孔)分为4组，并在含有2.8或16.7mM葡萄糖的KRBH缓冲液中孵育30分钟，有或没有重组TN蛋白作用下收集胰岛孵育上清
为了测量胰岛中的胰岛素含量，手工挑选胰岛并在0.5mL乙酸-乙醇(在100mL70％乙醇中的1.5mL HCl)中溶解。根据制造商的说明，使用小鼠/大鼠胰岛素ELISA试剂盒(Alpco Diagnostics，Slemm，NH)确定上清液中的胰岛素水平。
实施例8高糖钳夹
将小鼠禁食过夜并通过腹腔注射氯胺酮(100mg/kg体重)和甲苯噻嗪(10mg/kg体重)麻醉。钳夹实验前4-5天，将一根留置导管插入右颈内静脉。将小鼠关在单独的笼子中，并监测术后恢复情况和体重增加。禁食过夜后，在有意识的小鼠中进行2小时的高血糖钳制实验输注可变的10％葡萄糖以将血浆葡萄糖浓度维持在350-400mg/dL。每隔5到10分钟收集一次血样(20μL)，以测量血浆葡萄糖和胰岛素水平。
实施例9胰岛灌流实验
胰岛灌流之前，分别用含2.8mM、16.7mM葡萄糖及30mM KCl的KRBH缓冲液灌流整个装置，调整流速，保证整个装置无气泡，温度稳定在37℃。将约100个胰岛安装滤纸-凝胶柱-胰岛-凝胶柱的顺序铺在灌流小室内，并将小室安装在加热棒上，用含2.8mM葡萄糖的KRBH缓冲液平衡20min。低糖(2.8mM)KRBH缓冲液灌流30min，高糖(16.7mM)KRBH缓冲液灌流30min,接着(2.8mM)KRBH缓冲液灌流20min，30mM KCl灌流20min。以1min为单位，收集每分钟流出来的液体，用ELISA检测每分钟流出液中胰岛素含量,绘制小鼠胰岛灌流曲线。
实施例10实时定量PCR
用Trizol(生命技术公司)处理过的细胞和组织中分离出总RNA。使用SYBR混合物(Bimake)进行定量PCR反应，并使用Applied Biosystems 7900HT序列检测系统进行定量。将每个样品的重复孔用β-Actin标准化以确定相对表达水平。
实施例11蛋白检测western blot实验
用自制的小鼠抗TN单克隆抗体(1:1000)Western blot法测定血清和组织中的TN蛋白水平。TN-/-小鼠组织中TN信号的消失证实了自制抗体的特异性(图2B)。在免疫印迹实验使用的其他抗体anti-β-Actin(Sigma,A38541:5000)anti-Rabbit免疫球蛋白抗体(Promega,W401B 1:5000)和anti-Mouse免疫球蛋白抗体(Promega,W402B 1:5000)。
效果例1 TN在肥胖糖尿病人和小鼠血清中均有上调
为了阐明肥胖引起的代谢性疾病的分子机制，我们对健康人和有中心性肥胖、高血糖、高脂血症等不同症状的代谢综合征(MS)患者的血清进行了深层次的蛋白质组学研究。通过蛋白质组学分析，我们鉴定出223种蛋白质，其表达水平在正常人和MS患者之间存在显著差异(p<0.05)。我们从这个分析中鉴定出一个蛋白TN，在与正常人相比时，其血清水平在T2D患者(p＝0.0159)中显著升高(图1A和1B)但在肥胖患者无明显变化(p＝0.8038)。并且有趣的是血清TN水平与HbA1c呈正相关(R＝0.3452,P＝0.0034)(图1C)。在HFD(图1D和图1E)和STZ(图1F和图1G)诱导的两种糖尿病小鼠模型血清TN水平也显著升高。另一方面，小鼠隔夜禁食后血清TN浓度显著降低(图1H和1I)。这些结果表明TN与糖代谢存在一定的相关性。
表1.图1B数据
表2.图1C数据
表3.图1D数据
| ND | HFD |
| 0.86015 | 1.376628 |
| 0.845555 | 1.127769 |
| 0.999664 | 1.359594 |
| 1.15576 | |
| 0.902296 | 1.160444 |
表4.图1E数据
表5.图1I数据
| Adlib.fed | fasted |
| 1.106454 | 0.7528 |
| 1.816536 | 0.980921 |
| 0.609017 | 0.300962 |
| 1.69597 | 0.665321 |
效果例2 TN是一种脂肪细胞因子
通过定量PCR(qPCR)分析，我们发现小鼠脂肪组织中TN的mRNA的表达水平很丰富(图2A)。而蛋白水平在小鼠腹股沟白色脂肪组织(iWAT)和附睾白色脂肪组织(eWAT)和褐色脂肪组织(BAT)中表达最多。有趣的是，葡萄糖和PA处理能显著刺激已分化小鼠脂肪细胞表达和分泌更多的TN蛋白(图2C和2D)，提示TN可能在调节葡萄糖代谢中发挥作用。
表6.图2A数据
| H | 1 | 1 | 1 |
| Li | 0.008 | 2.399 | 0.045 |
| S | 0.006 | 5.16 | 0.077 |
| L | 1.018 | 0.273 | 1.327 |
| K | 0.142 | 0.794 | 0.833 |
| P | 0.002 | 1.066 | 0.038 |
| B | 0.055 | 0.502 | 0.116 |
| M | 1.559 | 0.026 | 0.147 |
| EWAT | 5.9 | 4.9 | |
| SWAT | 7 | 6.646 | 5.3 |
| BAT | 4.6 | 5.74 | 1.8 |
效果例3 TN与人和小鼠的胰岛组织具有很高的结合力
为了鉴定TN的靶组织，我们研究了人胰腺组织和小鼠各组织冷冻切片上SEAP-TN的结合情况。在人胰腺切片中检测到较强的SEAP-TN结合信号(图3A)。在脑、肝、胰等组织中也检测到SEAP-TN结合信号(图3B)。通过重组His-TN竞争性地阻断SEAP-TN与胰腺组织切片的结合，证实了TN与胰腺胰岛组织结合的特异性。
效果例4 TN影响小鼠葡萄糖耐量
为了探讨TN在体内的生理作用，我们对ND或HFD喂养的TN-/-和WT小鼠的代谢表型进行了分析。TN-/-和WT小鼠在体重、食物摄入量、脂肪量、瘦肉量等方面无显著差异。在正常饲料喂养下，TN-/-小鼠与WT小鼠之间的葡萄糖耐量(GTT)相同。但是，在HFD喂养条件下，TN-/-雄性小鼠的葡萄糖耐量(GTT)明显高于WT小鼠(图4A和4B)，而TN-/-和WT对照小鼠(f图4C和图4D)的胰岛素敏感性没有显著差异。
我们还监测了小剂量STZ注射后诱导的糖尿病小鼠模型随时间的血糖水平和葡萄糖耐量变化。STZ治疗后，WT小鼠出现了更严重的糖尿病，我们的研究持续了10天，在自由采食期间WT小鼠平均血糖水平超过了400mg/dl(图4E和4F)。与野生型WT小鼠相比，TN-/-小鼠的糖尿病症状有所减轻，糖耐量有所改善，对STZ刺激的血糖控制和生存率明显提高(图4E-4I)。
为了进一步研究TN在体内的潜在作用，我们同时给ND和HFD正常小鼠注射了实施例6制得的重组TN蛋白。增加血清中TN蛋白的水平，如Western blot所示(图4J)，导致ND和HFD喂养小鼠的葡萄糖明显不耐受(图4K，4L，4O和4P)。与TN基因敲除对小鼠胰岛素耐受无明显影响的结果一致(图4C)，TN注射后对小鼠胰岛素敏感性无明显影响(图4N，4M，4Q和图4R)。总之，这些结果强烈提示TN可能直接与胰岛细胞相互作用，参与代谢平衡。
表7.图4A数据
表8.图4B数据
表9.图4C数据
表10.图4D数据
表11.图4E数据
表12.图4F数据
表13.图4G数据
表14.图4H数据
表15.图4I数据
表16.图4K数据
表17.图4L数据
表18.图4N数据
表19.图4M数据
表20.图4O数据
表21.图4P数据
表22.图4Q数据
表23.图4R数据
效果例5 TN抑制葡萄糖刺激的人和小鼠β细胞胰岛素的释放
为了证实TN在小鼠胰岛中的作用，我们对TN-/-小鼠进行了高糖钳夹实验，发现TN-/-小鼠的葡萄糖输注率(GIR)显著高于野生型小鼠(图5A和图5B)。而TN-/-小鼠的胰岛素分泌率也显著高于野生型小鼠(图5C和图5D)。
为了确定TN体外调节胰岛β细胞功能的机制，我们检测了离体人和小鼠胰岛的葡萄糖刺激胰岛素分泌能力(GSIS)。在分离的人(图5E)和小鼠(图5F)胰岛中，TN减少30％-50％的高葡萄糖刺激胰岛素分泌。当与ATP依赖性K+通道的抑制剂KCl共同处理时，TN处理也损害了KCl刺激的胰岛素分泌(图5G)。此外，在胰岛灌流实验中，TN(与高糖和KCl一起)抑制了人和C57小鼠胰岛的胰岛素分泌(图5H和5I)，表明TN可能作用于ATP依赖性钾离子通道的下游位点。
为了探讨TN抑制β细胞功能的可能机制，我们对β细胞进行了形态学观察。TN-/-小鼠与野生型对照小鼠在胰岛形态学上无显著性差异。TN-/-小鼠的β细胞质量与对照组小鼠相比也没有差异。对照组小鼠和TN-/-组小鼠胰岛细胞中Ki67+胰岛素+细胞和Ngn3+胰岛素+细胞数量也无明显差异，提示敲除TN对β细胞质量、增殖和分化没有显著影响。TN基因敲除对丙酮酸羧化酶(Pcx)和葡萄糖激酶(Gck)mRNA水平没有显著影响,提示TN在线粒体氧化功能中不起作用。
表24.图5A数据
表25.图5B数据
表26.图5C数据
表27.图5D数据
表28.图5E数据
表29.图5F数据
表30.图5G数据
表31.图5H数据
表32.图5I数据
图6(C)中序列如下所示：
1.基因名：Clec3B种属：小鼠
基因CDS序列:如SEQ ID No.1所示
蛋白氨基酸序列：如SEQ ID No.2所示
2.基因名：Clce3B，种属：人
基因CDS序列1(isoform X1)：如SEQ ID No.3所示；
蛋白氨基酸序列(isoform X1)：如SEQ ID No.4所示；
基因CDS序列2(isoform X2):如SEQ ID No.5所示；
蛋白氨基酸序列(isoform X2)：如SEQ ID No.6所示；
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
序列表
<110> 中南大学湘雅二医院
<120> TN的抑制剂在制备改善β细胞功能、预防和/或治疗糖尿病的药物中的应用
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1.敲除TN基因的试剂在制备治疗2型糖尿病的药物中的应用。
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