CN114831971A - 雪松醇用于预防或治疗糖尿病的应用 - Google Patents
雪松醇用于预防或治疗糖尿病的应用 Download PDFInfo
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- CN114831971A CN114831971A CN202210545786.XA CN202210545786A CN114831971A CN 114831971 A CN114831971 A CN 114831971A CN 202210545786 A CN202210545786 A CN 202210545786A CN 114831971 A CN114831971 A CN 114831971A
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Abstract
本发明涉及糖尿病领域，提供了雪松醇用于预防或治疗糖尿病的应用。雪松醇或包含雪松醇的组合物能够显著降低有风险患有或患有糖尿病的受试者的空腹血糖，明显改善葡萄糖耐受、胰岛素耐受和丙酮酸耐受，有效抑制肝脏糖异生过程。
Description
技术领域
本发明涉及糖尿病领域，具体地涉及雪松醇用于预防或治疗糖尿病的应用。
背景技术
糖尿病是一种由胰岛素分泌不足或胰岛素敏感性降低引起的以高血糖为特征的慢性代谢性疾病，主要分为1型糖尿病和2型糖尿病。近年来，全球糖尿病患病人数急剧上升，已经成为影响全球人类健康的最大的非传染性疾病之一，严重威胁公共卫生安全，对各国卫生系统造成严重的财政影响。糖尿病的治疗是一个复杂的、多方面的过程，其中膳食干预在糖尿病的防治过程中发挥重要的作用。因此，从食品等天然产物中寻找安全有效的降糖化合物是当前的研究热点，具有重要的临床应用价值。
发明内容
本发明旨在至少在一定程度上解决相关技术中的技术问题之一。
为此，一方面，本发明的实施例提出了雪松醇在制备用于预防或治疗糖尿病的药物中的应用。
根据本发明实施例，雪松醇能够显著降低有风险患有或患有糖尿病的受试者的空腹血糖，明显改善葡萄糖耐受、胰岛素耐受和丙酮酸耐受，有效抑制肝脏糖异生过程。
在一些实施例中，所述雪松醇的有效量为100至500mg/kg/天、优选150至300mg/kg/天，更优选200mg/kg/天。
在一些实施例中，所述雪松醇抑制有风险患有或患有糖尿病的受试者的肝脏糖异生，其中所述糖尿病为肝脏糖异生紊乱引起的。
在一些实施例中，所述雪松醇降低有风险患有或患有糖尿病的受试者的血糖水平。
在一些实施例中，所述雪松醇改善有风险患有或患有糖尿病的受试者的葡萄糖耐受。
在一些实施例中，所述雪松醇改善有风险患有或患有糖尿病的受试者的胰岛素耐受。
在一些实施例中，所述雪松醇改善有风险患有或患有糖尿病的受试者的丙酮酸耐受。
在一些实施例中，所述有风险患有或患有糖尿病的受试者是哺乳动物。
在一些实施例中，所述哺乳动物是人或非人动物。
另一方面，本发明的实施例提出了用于预防或治疗糖尿病的组合物。所述组合物包含：如上述任一实施例中所述的雪松醇；和药学上或食品学上可接受的载体。
在一些实施例中，所述组合物为药物组合物或食品组合物的形式。
在一些实施例中，所述药物组合物还包含另一种治疗糖尿病的药剂。
在一些实施例中，所述药物组合物为散剂、颗粒剂、片剂、丸剂、糖衣钉剂、胶囊剂、液体剂、凝胶剂、糖浆剂、混悬剂或注射剂。
在一些实施例中，所述食品组合物还包含食品添加剂。
在一些实施例中，所述食品组合物为饮料，例如茶、果汁、碳酸饮料或离子饮料；加工乳，例如乳和酸乳、口香糖；食品，例如年糕、甜点、面包、糕点糖果或面条；或保健功能食品制剂，如片剂、胶囊剂、丸剂、颗粒剂、液体剂、散剂、薄片剂、糊剂、糖浆剂、凝胶剂、果冻剂或棒剂。
根据本发明实施例，包含雪松醇的组合物能够显著降低有风险患有或患有糖尿病的受试者的空腹血糖，明显改善葡萄糖耐受、胰岛素耐受和丙酮酸耐受，有效抑制肝脏糖异生过程。
附图说明
图1是根据本发明实施例的示例性流程图。
图2是本发明实施例中各个实验组小鼠的日摄食量的结果图。其中，****表示与普通饲料组小鼠相比，p<0.0001；ns表示与高脂饮食组小鼠相比无统计学差异。每个实验组各8只老鼠。
图3是本发明实施例中雪松醇对高脂饮食模型小鼠体重的影响的结果图。其中，****表示与普通饲料组小鼠相比，p<0.0001；####表示与高脂饮食组小鼠相比，p<0.0001。每个实验组各8只老鼠。
图4是在本发明实施例中雪松醇对高脂饮食模型小鼠空腹血糖的影响的结果图。其中，****表示与普通饲料组小鼠相比，p<0.0001；##表示与高脂饮食组小鼠相比，p<0.01。每个实验组各8只老鼠。
图5是在本发明实施例中雪松醇对高脂饮食模型小鼠葡萄糖耐受的影响的结果图。左图为葡萄糖耐受实验结果，右图为经计算的曲线下面积。其中，****表示与普通饲料组小鼠相比，p<0.0001；#表示与高脂饮食组小鼠相比，p<0.05。每个实验组各8只老鼠。
图6是在本发明实施例中雪松醇对高脂饮食模型小鼠胰岛素耐受的影响的结果图。左图为胰岛素耐受实验结果，右图为经计算的曲线下面积。其中，*表示与普通饲料组小鼠相比，p<0.05；#表示与高脂饮食组小鼠相比，p<0.05。每个实验组各8只老鼠。
图7是在本发明实施例中雪松醇对高脂饮食模型小鼠丙酮酸耐受的影响的结果图。左图为丙酮酸耐受实验结果，右图为经计算的曲线下面积。其中，***表示与普通饲料组小鼠相比，p<0.001；#表示与高脂饮食组小鼠相比，p<0.05。每个实验组各8只老鼠。
具体实施方式
下面详细描述本发明的实施例，所述实施例的示例在附图中示出。下面通过参考附图描述的实施例是示例性的，旨在用于解释本发明，而不能理解为对本发明的限制。
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。
术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
术语“防止”或“预防”指获病或障碍的风险的减少(即：使疾病的至少一种临床症状在受试者内停止发展，该受试者可能面对或预先倾向面对这种疾病，但还没有经历或表现出疾病的症状)。
术语“治疗”任何疾病或病症，在其中一些实施方案中指改善疾病或病症(即减缓或阻止或减轻疾病或其至少一种临床症状的发展)。在另一些实施方案中，“治疗”指缓和或改善至少一种身体参数，包括可能不为受试者所察觉的身体参数。在另一些实施方案中，“治疗”指从身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。在另一些实施方案中，“治疗”指预防或延迟疾病或病症的发作、发生或恶化。
术语“有效量”是指当施用于受试者来治疗疾病时，化合物的分量足够对这种疾病的治疗起效。“有效量”可以随着疾病的严重程度，以及有待治疗的受试者的身体条件，年龄，体重，性别等而改变。
术语“受试者”是指人或非人动物。典型地所述非人动物是哺乳动物。受试者，例如也指灵长类动物(例如人类，男性或女性)、牛、绵羊、山羊、马、犬、猫、兔、大鼠、小鼠、鱼、鸟等。在某些实施方案中，所述受试者是灵长类动物。在其他实施方案中，所述受试者是人。
术语“药学上或食品学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者受试者无毒副作用的任何制剂或载体介质。代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。
术语“药物组合物”表示一种或多种本文所述化合物或者其生理学上/药学上可以接受的盐或前体药物与其他化学组分的混合物，其他组分例如生理学上/药学上可以接受的载体、赋形剂、稀释剂、辅剂、媒介物，以及抗糖尿病试剂的附加治疗剂。药物组合物的目的是促进化合物对生物体的给药。
本发明的药物组合物可以通过本领域已知的常规方法根据施用途径制备成口服剂型或肠胃外剂型，包含活性成分和药学上可接受的载体。这里，施用途径可以是任何合适的途径，包括局部途径、口服途径、静脉内途径或肌肉内途径，并且可以组合使用两种或更多种途径。两种或更多种途径的组合的实例是根据施用途径组合两种或更多种药物制剂的情况。例如，一种药物首先施用而另一种药物相继施用。
当本发明的药物组合物制备成口服剂型时，该药物组合物可以根据本领域已知的方法与合适的载体一起制备成制剂，例如散剂、颗粒剂、片剂、丸剂、糖衣钉剂、胶囊剂、液体剂、凝胶剂、糖浆剂、混悬剂、圆片等。合适的载体的实例包括糖，例如乳糖、葡萄糖、蔗糖、右旋糖、山梨糖醇、甘露醇或木糖醇，淀粉，例如玉米淀粉、马铃薯淀粉或小麦淀粉，纤维素，例如甲基纤维素、乙基纤维素、羧甲基纤维素钠，或羟丙基甲基纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、硬脂酸镁、矿物油、麦芽、明胶、滑石粉、多元醇、植物油、乙醇、甘油等。配制时，适当的粘合剂、润滑剂、崩解剂、着色剂、稀释剂等可以根据需要包括在内。合适的粘合剂的实例可以包括淀粉、硅酸铝镁、淀粉糊、明胶、甲基纤维素、羧甲基纤维素钠、聚乙烯吡咯烷酮、葡萄糖、玉米甜味剂、海藻酸钠、聚乙二醇、蜡等，润滑剂的实例可以包括油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠、二氧化硅、滑石、硬脂酸、其镁盐和钙盐以及聚乙二醇，崩解剂的实例可以包括淀粉、甲基纤维素、琼脂(agar)、膨润土、黄原胶、淀粉、海藻酸或其钠盐。此外，稀释剂的实例可包括乳糖、右旋糖、蔗糖、甘露醇、山梨糖醇、纤维素、甘氨酸等。
当本发明的药物组合物制备成用于肠胃外使用的制剂时，该药物组合物可以根据本领域已知的方法与合适的载体一起配制为例如注射剂的形式。当本发明的药物组合物配制成注射剂时，可以使用等渗水溶液或混悬液作为合适的载体，并且具体地，可使用包含三乙醇胺的磷酸盐缓冲盐水(phosphate buffered saline,PBS)、无菌注射用水或等渗溶液，例如5％右旋糖。
本发明的食品组合物可以制备成任何形式，包括例如：饮料，例如茶、果汁、碳酸饮料或离子饮料；加工乳，例如乳和酸乳、口香糖；食品，例如年糕、甜点、面包、糕点糖果或面条；或保健功能食品制剂，如片剂、胶囊剂、丸剂、颗粒剂、液体剂、散剂、薄片剂、糊剂、糖浆剂、凝胶剂、果冻剂或棒剂。
本发明的食品组合物除了其活性成分之外还可以包含食品添加剂。食品添加剂一般可以理解为在食品制造、加工或保存过程中与食品混合或渗透的物质。由于食品添加剂每天都在食用，并且与食物一起食用很长时间，因此必须确保其安全性。食品添加剂按成分分为化学合成产品、天然添加剂和混合制剂，并且这些食品添加剂是按功能分为甜味剂、调味剂、防腐剂、乳化剂、酸味剂、增稠剂等。
雪松醇(C15H26O)
为一种倍半萜醇，可由柏木油制得，具有温和的杉木芳香，已被批准作为调味剂或佐剂应用于化妆品、食品、医药、香精等领域。目前对于雪松醇生物活性的研究主要集中于其抗菌、抗肿瘤、抗焦虑、促进毛发生长及抗脱发以及抗炎镇痛能力。现有研究表明，雪松醇在体外具有显著的抑菌活性，对金黄色葡萄球菌、沙门氏菌、大肠杆菌、枯草芽孢杆菌、伤寒沙门氏菌等都具有明显的抑制作用，表明雪松醇具有被开发为抗菌药物的可能；雪松醇对黑色素瘤C32细胞、肾细胞腺癌细胞、胶质母细胞瘤、人慢性髓原白血病细胞K562细胞、人结肠癌细胞HT29细胞、A594肺癌细胞、NCI-H460人肺癌细胞具有显著抑制作用，表明其具有被开发为抗癌药物的可能；此外，体内研究表明雪松醇具有显著的抗焦虑能力，能够升高小鼠5-羟色胺水平，降低多巴胺水平，并具有镇静作用；雪松醇还具有促进小鼠毛发生长作用，有效缩短毛发进入生长期的时间，并促进毛囊生长，预防脱发、促进毛发再生，表明雪松醇具有被开发为抗脱发药物的可能。雪松醇具有良好的镇痛抗炎作用，已被证明可应用于制备关节炎和镇痛药物。然而，目前雪松醇对糖尿病等慢性代谢性疾病的防治作用尚未见报道。
根据本发明的实施例，发明人首次发现雪松醇或包含雪松醇的组合物能够显著降低有风险患有或患有糖尿病的受试者的空腹血糖，明显改善葡萄糖耐受、胰岛素耐受和丙酮酸耐受，有效抑制肝脏糖异生过程。
下面将结合实施例对本发明的方案进行解释。本领域技术人员将会理解，下面的实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
实施例1动物模型建立、分组、干预及处理
本研究中7周龄C57BL/6J雄性小鼠在用普通饲料预养3周后，将小鼠随机分为普通饲料对照组、高脂饮食模型组和高脂饮食+0.2％雪松醇干预组，进行19周的分组饲养。饲料在每天下午17时至18时之间与水一起供应。实验过程中所有动物随意获取食物和水。喂养期间，测定小鼠体重(每周一次)和摄食量(每天一次)。实验结束后，将小鼠禁食6小时，之后取血液并摘取肝脏组织及其他脏器。将组织保存在-80℃冰箱或10％多聚甲醛中以待后续分析。将血液样品在室温静置一段时间，离心15分钟后取上层血清。
经换算，如图2所示，高脂饮食+0.2％雪松醇干预组小鼠每日平均摄入雪松醇的量为100至500mg/kg/天、优选150至300mg/kg/天，更优选200mg/kg/天。
如图3所示，高脂饮食+0.2％雪松醇干预组小鼠与高脂饮食模型组相比，明显缓解了由高脂饮食引起的体重增加。
实施例2空腹血糖测定
喂养第13周结束时，于早上8:00禁食不禁水，并于14:00以剪尾尖的方式测定每只小鼠的空腹血糖值。实验完毕后，正常饲喂小鼠，用Graphpad Prism软件分析实验结果。
如图4所示，结果清楚地证明了雪松醇能够降低高脂饮食小鼠的血糖水平。
实施例3葡萄糖耐受实验
喂养第15周时，进行葡萄糖耐受实验。实验前称量每只小鼠的体重，然后禁食不禁水6小时。禁食结束后，首先测定空腹血糖，记为0分钟的血糖值。待小鼠适应30分钟后，按照2g/kg B.W.剂量灌胃生理盐水配置的葡萄糖溶液。从灌胃完毕一刻起，开始计时，并于15分钟、30分钟、60分钟、90分钟、120分钟的节点测定每只小鼠的血糖值。实验完毕后，正常饲喂小鼠，用Graphpad Prism软件分析实验结果。
如图5所示，结果清楚地表明了雪松醇能够明显改善高脂饮食小鼠的葡萄糖耐受。
实施例4胰岛素耐受实验
喂养第16周时，进行胰岛素耐受实验。实验前称量每只小鼠的体重，然后禁食不禁水6小时。禁食结束后，首先测定空腹血糖，记为0分钟的血糖值。待小鼠适应30分钟后，按照0.75U/kg B.W.剂量腹腔注射0.01U/mL胰岛素溶液。从灌胃完毕一刻起，开始计时，并于15分钟、30分钟、60分钟、90分钟、120分钟的节点测定每只小鼠的血糖值。实验完毕后，正常饲喂小鼠，用Graphpad Prism软件分析实验结果。
如图6所示，结果清楚地表明了雪松醇能够明显改善高脂饮食小鼠的胰岛素耐受。
实施例5丙酮酸耐受实验
喂养第17周时，进行丙酮酸耐受实验。实验前称量每只小鼠的体重，然后禁食不禁水16小时。禁食结束后，首先测定空腹血糖，记为0分钟的血糖值。待小鼠适应30分钟后，按照1g/kg B.W.剂量腹腔注射40％丙酮酸钠溶液。从灌胃完毕一刻起，开始计时，并于15分钟、30分钟、60分钟、90分钟、120分钟的节点测定每只小鼠的血糖值。实验完毕后，正常饲喂小鼠，用Graphpad Prism软件分析实验结果。
如图7所示，结果清楚地表明了雪松醇能够明显改善高脂饮食小鼠的丙酮酸耐受，抑制肝脏糖异生过程。
本发明人的上述药效学试验表明：在高脂饮食诱导的高血糖小鼠模型中发现，以0.2％的添加量补充雪松醇19周能够显著降低高血糖小鼠的空腹血糖、改善小鼠的葡萄糖耐受、胰岛素耐受和丙酮酸耐受、抑制肝脏糖异生过程。已有证据表明，肝脏糖异生的增加直接引起机体血糖水平的升高，且该过程贯穿于糖尿病的整个病程，因此，抑制肝脏糖异生过程可有效治疗糖尿病。试验结果表明，雪松醇抑制肝脏糖异生过程，发挥防治高血糖、葡萄糖抵抗和胰岛素抵抗的作用。根据上述研究，本发明提供了雪松醇在制备具有抑制肝脏糖异生、预防高血糖的相关食品及药物方面的新用途。
如上所述，本发明的雪松醇在制备抑制肝脏糖异生、预防高血糖产品中的用途，具有以下有益效果：发明人发现了雪松醇抑制肝脏糖异生、降低高血糖的功能，为糖尿病的预防奠定新的理论基础。
在本发明中，术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。
Claims (10)
1.雪松醇在制备用于预防或治疗糖尿病的药物中的应用。
2.根据权利要求1所述的应用，其特征在于，所述雪松醇的有效量为100至500mg/kg/天、优选150至300mg/kg/天，更优选200mg/kg/天。
3.根据权利要求1所述的应用，其特征在于，所述雪松醇抑制有风险患有或患有糖尿病的受试者的肝脏糖异生，其中所述糖尿病为肝脏糖异生紊乱引起的。
4.根据权利要求3所述的应用，其特征在于，所述雪松醇降低有风险患有或患有糖尿病的受试者的血糖水平。
5.根据权利要求3所述的应用，其特征在于，所述雪松醇改善有风险患有或患有糖尿病的受试者的葡萄糖耐受。
6.根据权利要求3所述的应用，其特征在于，所述雪松醇改善有风险患有或患有糖尿病的受试者的胰岛素耐受。
7.根据权利要求3所述的应用，其特征在于，所述雪松醇改善有风险患有或患有糖尿病的受试者的丙酮酸耐受。
8.根据权利要求3至7中任一项所述的应用，其特征在于，所述有风险患有或患有糖尿病的受试者是哺乳动物。
9.根据权利要求8所述的应用，其特征在于，所述哺乳动物是人或非人动物。
10.一种用于预防或治疗糖尿病的组合物，其特征在于，所述组合物包含：如权利要求1至9中任一项所定义的雪松醇；和药学上或食品学上可接受的载体。
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