CN101822660B - 大黄酸类化合物或其盐在制备预防和治疗胰岛β细胞功能衰退药物中的应用 - Google Patents
大黄酸类化合物或其盐在制备预防和治疗胰岛β细胞功能衰退药物中的应用 Download PDFInfo
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Abstract
本发明涉及大黄酸类化合物或其盐在制备预防和治疗胰岛β细胞功能衰退药物中的应用。研究表明，口服大黄酸能够非常显著地改善2型糖尿病db/db小鼠葡萄糖耐量，减少胰岛β细胞丢失，保护胰岛β细胞功能，发现并证实了大黄酸对胰岛β细胞的保护作用，能够应用于治疗糖尿病。大黄酸类化合物或其盐能够改善糖尿病状态下糖耐量，保护和修复胰岛β细胞功能，能应用于制备预防和治疗胰岛β细胞功能衰退的药物。
Description
技术领域
本发明涉及大黄酸类化合物或其盐在制备预防和治疗胰岛β细胞功能衰退药物中的应用。
背景技术
胰岛素抵抗和胰岛β细胞功能衰退是2型糖尿病的主要发病机理。英国糖尿病前瞻性研究(UKPDS)的结果表明，初诊2型糖尿病人群的β细胞功能仅及正常人的50％，而且此后以每年4.5％的速率下降。目前临床上缺乏有效的]保护和修复胰岛β细胞功能的治疗。
大黄酸(Rhein)类化合物或其盐是是一种结构确知的化合物，其结构式如下：
其中，M为H、碱金属、碱土金属或有机碱残基，R1、R2各自独立地为H或乙酰基。
目前大黄酸类化合物或其盐的代表有：大黄酸(M、R1、R2均为H)，大黄酸钠盐(M为Na，R1、R2均为H)、钾盐(M为K，R1、R2均为H)、1，8-二乙酰大黄酸(M为H，R1、R2均为乙酰基)、1，8-二乙酰大黄酸钠盐(M为Na，R1、R2均为乙酰基)和1，8-二乙酰大黄酸钾盐(M为K，R1、R2均为乙酰基)。在肠内，1，8-二乙酰大黄酸(1，8-Diacelyrhein)的乙酰基可完全被水解掉，有效物质形式为大黄酸。
发明内容
本发明提供大黄酸类化合物或其盐在制备预防和治疗胰岛β细胞功能衰退药物中的应用。
研究表明，口服大黄酸能够非常显著地改善2型糖尿病db/db小鼠葡萄糖耐量，减少胰岛β细胞丢失，保护胰岛β细胞功能，发现并证实了大黄酸对胰岛β细胞的保护作用，能够应用于治疗糖尿病。
实验表明，大黄酸改善葡萄糖耐量。2型糖尿病db/db小鼠经大黄酸治疗8周后，腹腔葡萄糖耐量试验(IPGTT)结果显示，大黄酸治疗组小鼠糖负荷后0分钟，60分钟和120分钟的血糖水平显著低于未经治疗的对照db/db小鼠(p＜0.05)(表1，图1A)。同时大黄酸治疗组db/db小鼠血浆胰岛素水平在30分钟和60分钟显著升高(图1B)。大黄酸治疗组小鼠血糖曲线下面积(AUC)较未治疗组小鼠显著降低，而胰岛素AUC显著升高，尤其是糖负荷后30分钟差别最为明显(表2)。上述结果表明，大黄酸改善葡萄糖耐量是由于胰岛β细胞功能改善所致。
表1.db/db小鼠经大黄酸治疗8周后的腹腔葡萄糖耐量试验(IPGTT)结果
与db/db小鼠比较，*p＜0.05
表2.腹腔葡萄糖耐量试验(IPGTT)中葡萄糖和胰岛素的曲线下面积(AUC)
AUCINS0-30：0～30分钟胰岛素曲线下面积；与db/db小鼠比较，*p＜0.05
实验表明，大黄酸提高2型糖尿病db/db小鼠第一相胰岛素分泌。胰岛灌流是评价第一相胰岛素分泌的金指标，从分泌时相和分泌数量两个方面对胰岛β细胞的胰岛素分泌功能进行全面评价。16.7mmol/L高糖刺激下，未治疗组db/db小鼠胰岛素水平略有升高，胰岛素峰值水平只有基线水平的三倍。而大黄酸治疗组小鼠的胰岛素水平在高糖刺激1分钟后即显著升高，是基线水平的7倍(图2)，两组有显著性差异。
实验表明，大黄酸增加胰岛β细胞含量。给药8周后，未治疗组db/db胰岛β细胞含量相当低，大黄酸治疗显著减少胰岛β细胞的丢失(图3)。在db/m正常对照组小鼠，胰岛胰岛素染色强而且分布均匀，db/db对照组胰岛呈现出微弱而稀疏的胰岛素表达，其染色强度仅为db/m对照组的50％。与db/db对照组相比，大黄酸治疗显著增强了胰岛内胰岛素表达的强度(图4)。
从上述实验结果证明大黄酸类化合物或其盐能够改善糖尿病状态下糖耐量，保护和修复胰岛β细胞功能，能应用于制备预防和治疗胰岛β细胞功能衰退的药物。
附图说明
图1大黄酸治疗组与对照组IPGTT结果。
图2离体胰岛灌流：大黄酸明显促进糖尿病db/db小鼠第一相胰岛素的分泌。
图3大黄酸干预增加db/db小鼠胰岛β细胞质量。
图4大黄酸治疗组与对照组胰岛细胞的胰岛素染色。
具体实施方式
实施例1大黄酸改善葡萄糖耐量的作用
药品：大黄酸，0.1％纤维素钠溶解。
实验动物给药：取4周龄db/db糖尿病小鼠30，随机分为治疗组和对照组，另取15只4周龄db/m健康小鼠作为正常对照组。其中db/db糖尿病治疗组给予连续8周的大黄酸灌胃干预(120mg/Kg，0.1％纤维素钠溶解)，db/db糖尿病对照组及db/m正常对照组用0.1％纤维素钠灌胃。
实验方法：投药8周后，小鼠行腹腔葡萄糖耐量试验(IPGTT)。隔夜禁食后，腹腔注射给予0.5g/kg体重葡萄糖，于0、30、60和120min时从鼠尾采血，测量全血葡萄糖和胰岛素水平，计算胰岛素曲线下面积(AUC)，0～30分钟胰岛素曲线下面积(AUCINS0-30)按(30分钟胰岛素水平-0分钟胰岛素水平)×15计算，以此评价早期胰岛素分泌能力；
实验结果：大黄酸改善葡萄糖耐量。2型糖尿病db/db小鼠经大黄酸治疗8周后，腹腔葡萄糖耐量试验(IPGTT)结果显示，大黄酸治疗组小鼠糖负荷后0分钟，60分钟和120分钟的血糖水平显著低于未经治疗的对照db/db小鼠(p＜0.05)(表1，图1A)。同时大黄酸治疗组db/db小鼠血浆胰岛素水平在30分钟和60分钟显著升高(图1B)。大黄酸治疗组小鼠血糖曲线下面积(AUC)较未治疗组小鼠显著降低，而胰岛素AUC显著升高，尤其是糖负荷后30分钟差别最为明显(表2)。上述结果表明，大黄酸改善葡萄糖耐量是由于胰岛β细胞功能改善所致。
实施例2大黄酸对2型糖尿病db/db小鼠第一相胰岛素分泌的影响
药品及实验动物同例1
实验方法：投药8周后，每组随机选取5只，分离胰岛行灌流。麻醉后活体夹闭胆总管十二指肠乳头开口，实体显微镜下行胆总管穿刺后注射1mg/ml浓度的IV型胶原酶2ml，逆行进入胰管使胰腺膨大后迅速分离胰腺，将胰腺置于含IV型胶原酶1mg/ml的Hank’s平衡液中消化40分钟，去除胶原成份后多次振荡洗涤，显微镜下成功分离胰岛，50个胰岛一组，于二氧化碳温箱孵育2小时，然后置于专门制作的恒温灌流设备中，使用Harvard微量泵先给予2.8mM葡萄糖饥饿灌流，速度为0.5ml/分钟，30分钟后给予16.7mM高糖灌流，速度为1ml/分钟，每20秒收集灌出液保存，5分钟后改为每分钟收集一次灌出液，留待ELISA法测定胰岛素水平。第一相胰岛素分泌及胰岛素动态分泌水平可从测得的胰岛素水平曲线中反映。
实验结果：实验表明，大黄酸提高2型糖尿病db/db小鼠第一相胰岛素分泌。胰岛灌流是评价第一相胰岛素分泌的金指标，从分泌时相和分泌数量两个方面对胰岛β细胞的胰岛素分泌功能进行全面评价。16.7mmol/L高糖刺激下，未治疗组db/db小鼠胰岛素水平略有升高，胰岛素峰值水平只有基线水平的三倍。而大黄酸治疗组小鼠的胰岛素水平在高糖刺激1分钟后即显著升高，是基线水平的7倍(图2)，两组有显著性差异。
实施例3大黄酸对胰岛β细胞含量的影响
药品及实验动物同例1
实验方法：免疫组织化学测定。小鼠苯巴比妥钠麻醉后，经心脏灌注生理盐水和4％多聚甲醛(pH7.4)固定，剥离胰腺后置4％多聚甲醛4-6h，石蜡包埋，5μm厚度切片。切片经二甲苯脱蜡，不同浓度梯度乙醇再水化后，0.3％过氧化氢室温20min封闭内源性过氧化物酶活性，高压蒸汽121℃持续10min抗原修复，10％山羊血清封闭非特异性抗原，加入兔抗小鼠胰岛素抗体后4℃过夜反应14h加入生物素化山羊抗兔二抗室温反应30min，二氨基联苯胺显色，苏木精染色后脱水包埋。
胰岛测量学分析所有切片用日本尼康E800光学显微镜观察并使用与其连接的日本索尼数码照相机拍照，利用Axiovision 4.3软件获得数字照片后用Image-Pro Plus5.0.1分析，每只小鼠随机选取15张胰岛照片，每组分析至少50张胰岛照片。胰岛β细胞含量测定使用胰岛素染色照片分析，并用下述公式计算：胰岛β细胞含量(mg)＝(胰岛β细胞面积/胰腺面积)×胰腺重量(15张胰腺照片/组。胰岛素染色强度用Scion Image B4.0.3for windows(美国)测定(胰岛30个/组)。
实验结果：大黄酸增加胰岛β细胞含量。给药8周后，未治疗组db/db胰岛β细胞含量相当低，大黄酸治疗显著减少胰岛β细胞的丢失(图3)。在db/m正常对照组小鼠，胰岛胰岛素染色强而且分布均匀，db/db对照组胰岛呈现出微弱而稀疏的胰岛素表达，其染色强度仅为db/m对照组的50％。与db/db糖尿病对照组相比，大黄酸治疗显著增强了胰岛内胰岛素表达的强度(图4)。
Claims (1)
1.大黄酸类化合物或其盐在制备预防和治疗胰岛β细胞功能衰退的药物中的应用，其特征在于所述药物是用0.1％纤维素钠溶解的大黄酸溶液，所述大黄酸类化合物的结构如下所示：
其中，R1、R2均为H，M为H。
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| US12/906,817 US20110281944A1 (en) | 2010-05-13 | 2010-10-18 | Method of a rhein compound for inhibiting pancreatic islet beta-cell dysfunction and preventing or treating a pancreatic islet beta-cell dysfunction related disorder |
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| 刘凯等.大黄酸的药理作用研究述略.《大黄酸的药理作用研究述略》.2004,第22卷(第9期),第1732-1734页. * |
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