CN107920578A - 可食用组合物 - Google Patents
可食用组合物 Download PDFInfo
- Publication number
- CN107920578A CN107920578A CN201680051065.6A CN201680051065A CN107920578A CN 107920578 A CN107920578 A CN 107920578A CN 201680051065 A CN201680051065 A CN 201680051065A CN 107920578 A CN107920578 A CN 107920578A
- Authority
- CN
- China
- Prior art keywords
- glucose
- edible composition
- homoisoflavone
- glucoside
- glucosides
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 46
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims abstract description 80
- 239000008103 glucose Substances 0.000 claims abstract description 71
- 229930182478 glucoside Natural products 0.000 claims abstract description 70
- 229930003935 flavonoid Natural products 0.000 claims abstract description 40
- 235000017173 flavonoids Nutrition 0.000 claims abstract description 40
- 150000002215 flavonoids Chemical class 0.000 claims abstract description 36
- 150000008131 glucosides Chemical class 0.000 claims abstract description 35
- 230000000291 postprandial effect Effects 0.000 claims abstract description 23
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- 238000000034 method Methods 0.000 claims description 19
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
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Abstract
富含可利用的碳水化合物如蔗糖或淀粉的食物或膳食提高餐后血糖浓度。根据Node等人(Cardiovascular diabetology,8,23(2009)),反复的高餐后血糖“峰值”与提高的II型糖尿病发生风险相关。不受调节的血糖偏移是不期望的,并且餐后血糖浓度的任何降低或“钝化”可能是有益的。本发明涉及可食用组合物,其通过协同抑制活性钠葡萄糖共转运体1(SGLT1)和被动葡萄糖转运体2(GLUT2)而延迟肠道葡萄糖摄取以使餐后血糖峰值趋平或钝化。因此,在本发明的第一方面,提供可食用组合物,其以一个或多个单位剂量的单份形式提供,其包含2‑200mg至少一种高异黄酮与20‑2000mg至少一种类黄酮单葡糖苷及其盐的组合。
Description
富含可利用的碳水化合物如蔗糖或淀粉的食物或膳食提高餐后血糖浓度。根据Node等人(Cardiovascular diabetology,8,23(2009)),反复的高餐后血糖“峰值”与提高的II型糖尿病发生风险相关。不受调节的血糖偏移(glycemic excursion)是不期望的,并且餐后血糖浓度的任何降低或“钝化”可能是有益的。本发明涉及可食用组合物,其通过协同抑制活性钠葡萄糖共转运体1(SGLT1)和被动葡萄糖转运体2(GLUT2)而延迟肠道葡萄糖摄取以使餐后血糖峰值趋平或钝化。
WO 2012/168108(Unilever等)公开了通过协同抑制活性钠葡萄糖共转运体1(SGLT1)和被动葡萄糖转运体2(GLUT2)而延迟肠道葡萄糖摄取以使餐后血糖峰值趋平或钝化的可食用组合物。特别地,提供了可食用组合物,其包含以干重计至少5%的至少一种类黄酮苷元和以干重计至少5%的至少一种类黄酮葡糖苷,其中所述类黄酮葡糖苷对乳糖酶根皮苷水解酶水解的抗性比槲皮素-4-葡糖苷高至少20%,优选至少40%,最优选至少60%,并且其中所述类黄酮苷元为GLUT2抑制剂,而所述类黄酮葡糖苷为SGLT1抑制剂。
WO 2014/086632(Unilever等)公开了通过协同抑制活性钠葡萄糖共转运体1(SGLT1)和被动葡萄糖转运体2(GLUT2)而延迟肠道葡萄糖摄取以使餐后血糖峰值趋平或钝化的可食用组合物。特别地,提供了可食用组合物,其为一个或多个单位剂量的单份形式,其中所述可食用组合物包含20-2000,优选30-1000,最优选40-500mg的3,5-二羟基-反式-茋,和10-2000,优选20-1000,最优选40-500mg的类黄酮单葡糖苷或二氢查耳酮单葡糖苷。
Zhang等人(J.Nat.Prod.,73,548-552(2010))报道了发现玉竹(Polygonatumodoratum)须根的90%甲醇提取物的乙酸乙酯可溶部分在分化3T3-L1脂肪细胞中加强胰岛素刺激的葡萄糖摄取。活性追踪分离(bioassay-guided fractionation)得到九种高异黄酮(homoisoflavonoid)以及一种异黄酮糖苷和一种黄烷酮糖苷。高异黄酮包括5,7-二羟基-3-(4’-羟基苄基)-6-甲基-8-甲氧基色烷-4-酮(EA2)和5,7-二羟基-3-(4’-羟基苄基)-6,8-二甲基色烷-4-酮(EA3),其中异黄酮糖苷为鸢尾苷。结果显示高异黄酮可能是良好的胰岛素增敏剂。
发明内容
在基于Caco-2细胞(异质人上皮结直肠腺癌细胞)的葡萄糖转运细胞模型中,观察到用高异黄酮(GLUT2抑制剂)和类黄酮单葡糖苷(SGLT1抑制剂)选择性混合物处理后,与单独使用任一化合物处理或者与它们的名义加和性能相比,存在统计学显著性的跨细胞葡萄糖转运的协同下调。
因此,在本发明的第一方面,提供可食用组合物,其以一个或多个单位剂量的单份形式提供,所述可食用组合物包含2-200mg至少一种高异黄酮与20-2000mg至少一种类黄酮单葡糖苷及其盐的组合。这些水平的至少一种高异黄酮和至少一种类黄酮单葡糖苷及其盐是如此以产生餐后血糖峰值幅度或血糖反应的协同降低。
根据Lin等人(Planta Med,80,1053-1066(2014)),高异黄酮是在自然界罕有发现的类黄酮亚类。它们主要发现于豆科(Fabacae)和天门冬科(Asparagacae)中。它们可分为五种亚类:苏木素(sappanin)型、绵枣儿素(scillascillin)型、巴西木素(brazilin)型、云实素(caesalpin)型和原苏木素(protosappanin)型。
在本发明的第二方面,提供降低非糖尿病人的餐后血糖峰值幅度或血糖反应的方法,所述方法包括以下步骤:
(a)向所述非糖尿病人口服给药本发明第一方面的可食用组合物;和
(b)向所述非糖尿病人口服给药糖类;
其中步骤(a)与步骤(b)同时进行,步骤(a)比步骤(b)提前0至90,优选0至60分钟,或者步骤(a)比步骤(b)延后0至30分钟,且
其中所述糖类包含葡萄糖或者是葡萄糖。
在本发明的第三方面,提供治疗患有2型糖尿病的人的方法,所述方法包括以下步骤:
(a)向有此需要的人口服给药本发明第一方面的可食用组合物;和
(b)向所述有此需要的人口服给药糖类;
其中步骤(a)与步骤(b)同时进行,步骤(a)比步骤(b)提前0至90,优选0至60分钟,或者步骤(a)比步骤(b)延后0至30分钟,且
其中所述糖类包含葡萄糖或者是葡萄糖。
在本发明的第四方面,提供本发明第一方面的可食用组合物,其用于降低非糖尿病人的餐后血糖峰值幅度或血糖反应。
在本发明的第五方面,提供本发明第一方面的可食用组合物,其用于治疗2型糖尿病。
在本发明的第六方面,提供本发明第一方面的可食用组合物在制备用于降低非糖尿病人的餐后血糖峰值幅度或血糖反应的药物中的用途。
在本发明的第七方面,提供本发明第一方面的可食用组合物在制备用于治疗2型糖尿病的药物中的用途。
附图说明
参照以下附图阐述本发明:
图1,其示出餐中葡萄糖浓度时间轴模型。
具体实施方式
在本发明的第一方面,提供可食用组合物,其以一个或多个单位剂量的单份形式提供,所述可食用组合物包含2-200mg至少一种高异黄酮与20-2000mg至少一种类黄酮单葡糖苷及其盐的组合。这些水平的至少一种高异黄酮和至少一种类黄酮单葡糖苷及其盐是如此以产生餐后血糖峰值幅度或血糖反应的协同降低。
优选地,可食用组合物包含至少5mg,更优选至少10mg,仍更优选至少15mg,且优选至多100mg,更优选至多50mg,仍更优选至多25mg至少一种高异黄酮。
优选地,可食用组合物包含至少50mg,更优选至少100mg,仍更优选至少150mg,且优选至多1000mg,更优选至多500mg,仍更优选至多250mg至少一种类黄酮单葡糖苷。
优选地,至少一种高异黄酮为苏木素型高异黄酮。优选地,苏木素型高异黄酮为3-苄基色烷-4-酮型高异黄酮。优选地,高异黄酮具有以下结构I:
其中R1为-H或-Me;且
其中R2为-OH、-OMe或-O-CH2-O-(C3’)。
优选地,高异黄酮选自5,7-二羟基-3-(4’-羟基苄基)-6-甲基色烷-4-酮(EA1)、5,7-二羟基-3-(4’-羟基苄基)-6-甲基-8-甲氧基色烷-4-酮(EA2)、5,7-二羟基-3-(4’-羟基苄基)-6,8-二甲基色烷-4-酮(EA3)、甲基麦冬黄烷酮A(MOA)和甲基麦冬黄烷酮B(MOB)。
5,7-二羟基-3-(4’-羟基苄基)-6-甲基色烷-4-酮(EA1)
5,7-二羟基-3-(4’-羟基苄基)-6-甲基-8-甲氧基色烷-4-酮(EA2)
5,7-二羟基-3-(4’-羟基苄基)-6,8-二甲基色烷-4-酮(EA3)
甲基麦冬黄烷酮A(MOA)
甲基麦冬黄烷酮B(MOB)
优选地,至少一种类黄酮单葡糖苷及其盐选自黄酮单葡糖苷、黄酮醇单葡糖苷、黄烷酮单葡糖苷、异黄酮单葡糖苷和花色苷,及其盐。优选地,至少一种类黄酮单葡糖苷及其盐选自木犀草素-7-葡糖苷、鸢尾苷、氯化飞燕草色素-3-O-葡糖苷(氯化飞燕草素葡萄糖苷(myrtillin chloride))、山柰酚-3-葡糖苷、柚皮素-7-O-葡糖苷和芹菜素-8-C-葡糖苷。
优选地,类黄酮单葡糖苷及其盐与高异黄酮的摩尔比为至少1,优选至少5,最优选至少10。
在本发明的第二方面,提供降低非糖尿病人的餐后血糖峰值幅度或血糖反应的方法,所述方法包括以下步骤:
(a)向所述非糖尿病人口服给药本发明第一方面的可食用组合物;和
(b)向所述非糖尿病人口服给药糖类;
其中步骤(a)与步骤(b)同时进行,步骤(a)比步骤(b)提前0至90,优选0至60分钟,或者步骤(a)比步骤(b)延后0至30分钟,且
其中所述糖类包含葡萄糖或者是葡萄糖。
优选地,糖类可选自多糖、寡糖、二糖、单糖及其混合物。
在本发明的第三方面,提供治疗患有2型糖尿病的人的方法,所述方法包括以下步骤:
(a)向有此需要的人口服给药本发明第一方面的可食用组合物;和
(b)向所述有此需要的人口服给药糖类;
其中步骤(a)与步骤(b)同时进行,步骤(a)比步骤(b)提前0至90,优选0至60分钟,或者步骤(a)比步骤(b)延后0至30分钟,且
其中所述糖类包含葡萄糖或者是葡萄糖。
在本发明的第四方面,提供本发明第一方面的可食用组合物,其用于降低非糖尿病人的餐后血糖峰值幅度或血糖反应。
在本发明的第五方面,提供本发明第一方面的可食用组合物,其用于治疗2型糖尿病。
在本发明的第六方面,提供本发明第一方面的可食用组合物在制备用于降低非糖尿病人的餐后血糖峰值幅度或血糖反应的药物中的用途。
在本发明的第七方面,提供本发明第一方面的可食用组合物在制备用于治疗2型糖尿病的药物中的用途。
实施例1:SGLT1和GLUT2抑制剂的鉴定
方法
常规细胞培养
人上皮结直肠腺癌(Caco-2)细胞获自American Type Culture Collection(ATCC)并在由Dulbecco氏改良的Eagle氏培养基(含有Glutamax-1,4.5g/L D-葡萄糖和25mM 4-(2-羟基乙基)-1-哌嗪乙磺酸(Hepes)(Invitrogen))、10%胎牛血清(Sigma)、1%非必需氨基酸(Invitrogen)和1mM丙酮酸钠(Sigma)组成的生长培养基中培养。使用TrypLETMExpress Stable Trypsin-Like Enzyme(Invitrogen)使细胞以约80%汇合度常规地传代以剥离细胞,并以约114个细胞/mm2接种在新鲜组织培养烧瓶中。只有传代数为45至49的细胞用于实验。
分化Caco-2细胞单层的准备
将HTS96孔通透性插件载体(insert support)(Sigma)在室温和无菌条件下用40μl在0.02M乙酸中的50mg/ml I型大鼠尾胶原(BD Biosciences)包被胶原1小时。插件在磷酸盐缓冲盐水(PBS(Invitrogen))中洗涤两次并将Caco-2细胞在生长培养基中以1.0x 105个细胞/ml(每插件75μl)接种到插件中并将30ml生长培养基添加到下方给料板中。在37℃,5%CO2下使细胞附着到胶原基质上并经48小时形成单层。插件和给料板都在PBS中洗涤,并且将细胞在37℃,5%CO2下用含有MITO+TMSerum Extender溶液的BDEntero-STIMTM肠上皮细胞分化培养基(都是BD Biosciences)培养(每插件75μl,30ml在给料板中)另外48小时。
葡萄糖转运抑制剂细胞筛选测定
将分化细胞单层在含有CaCl2和MgCl2的Dulbecco氏磷酸盐缓冲盐水(PBS(+)(Invitrogen))中温和洗涤并将插件转移到新的HTS-96孔接收板(Sigma)中。将细胞在37℃,5%CO2下用新鲜PBS(+)(每插件75μl和每孔225μl)培养60分钟。一式三份地,轻轻抽出PBS(+)并换成75μl/插件的5mM D-葡萄糖(Sigma)±测试化合物或25mM D-葡萄糖±测试化合物,并将225μl/孔的PBS(+)快速添加到各孔中。将5mM葡萄糖孔和25mM葡萄糖孔在37℃,5%CO2下分别培养15分钟和30分钟。所有测试化合物的细节可见于表1。将细胞插件转移到新接收板中,从细胞中轻轻抽出上清液并换成100μl的100μMLucifer Yellow(Sigma)溶液以证实单层的完整性。将225μl PBS(+)添加到各孔中并在37℃,5%CO2下培养1小时。然后弃去细胞插件并通过在Spectramax Gemini EM荧光酶标仪上在485nm(激发)和530nm(发射)下测量样品荧光来检查膜的Lucifer Yellow通透性。
葡萄糖测定
使用基于Invitrogen’s Amplex Red葡萄糖/葡萄糖氧化酶测定试剂盒的葡萄糖测定测量跨细胞单层转运的葡萄糖量。简言之,将50μl各测试样品转移到黑面/透明底96孔板(Greiner Bio-One)中,向其中加入100μl反应缓冲液(0.5μl的10mM Ampliflu Red、1μl的10U/ml辣根过氧化物酶、1μl的100U/ml葡萄糖氧化酶和97.5μl PBS(都为Sigma))。在室温下培养10分钟后,在Spectramax Gemini EM荧光酶标仪上在530nm(激发)和590nm(发射)下测量样品荧光并由标准曲线外推葡萄糖浓度。
结果
表1显示各测试化合物对跨分化Caco-2细胞单层的葡萄糖转运的抑制百分比。在5mM的较低D-葡萄糖浓度下,跨细胞单层的早期葡萄糖转运主要通过顶端表达的高亲和力、低容量SGLT1葡萄糖转运体进行。在较高D-葡萄糖浓度下,SGLT1转运体变饱和,并且因此跨单层的葡萄糖转运大部分由仅在最初的SGLT1-依赖性葡萄糖转运后靶向顶端膜的低亲和力、高容量GLUT2转运体驱动。设计上述方法中详述的筛选细胞模型以利用各转运体的最佳条件的这些差异来鉴定SGLT1和GLUT2特异性抑制剂。顶端膜上的SGLT1和GLUT2都将葡萄糖转运到肠上皮细胞中,而GLUT2在基底外侧膜中也表达,在此其对于将葡萄糖转运到细胞外是必需的。因此,GLUT2特异性抑制剂不仅会在高D-葡萄糖浓度(25mM)下阻断顶端靶向的转运体,它们还会进入细胞并在低D-葡萄糖浓度(5mM)下阻断葡萄糖从肠上皮细胞中离开。因此,为了区分顶端和基底外侧转运体的抑制,各化合物在5mM D-葡萄糖下测试15分钟并在25mM D-葡萄糖下测试30分钟。如果化合物表现出在5mM D-葡萄糖下至少20%的葡萄糖转运抑制和在25mM D-葡萄糖下相应的不多于20%的抑制,则它们被归类为SGLT1抑制剂。在两种条件下都能抑制葡萄糖转运至少20%的化合物被归类为GLUT2特异性抑制剂。通过使用SGLT1和GLUT2的广泛认可的特异性抑制剂(即分别为根皮苷和根皮素)来验证这种方法。
上述葡萄糖转运细胞模型由Kellett等人(Diabetes,54,10,3056-62(2005))描述并被设计用来模拟在富含碳水化合物膳食的摄入过程中小肠中的葡萄糖浓度局部变化,参考图1。餐前,肠腔中的游离葡萄糖浓度低(<5mM),并且顶端表达的SGLT1转运体积极地将任何可利用的葡萄糖转运到肠上皮细胞中。GLUT2转运体也在肠上皮细胞的基底外侧膜上活跃,如果需要,将葡萄糖从血液转运到细胞中以维持细胞代谢。餐中,葡萄糖局部浓度开始提高(5-10mM)并被SGLT1从肠腔转运出来并随后经由GLUT2转运到全身循环中。由于跨肠上皮细胞的这种初始葡萄糖转运,GLUT2的细胞内储备得到动员并靶向顶端膜。餐后不久,由于膳食的碳水化合物含量被位于顶端肠上皮细胞膜上的α-葡糖苷酶分解成单糖,出现葡萄糖的极高局部浓度(25-100mM)。在这些高葡萄糖水平下,高亲和力、低容量转运体SGLT1变饱和并且跨肠上皮细胞的大部分葡萄糖转运归因于如今存在于顶端膜中的低亲和力、高容量GLUT2转运体。
表1显示,为了抑制SGLT1,如通过根皮苷、鸢尾苷、氯化飞燕草色素-3-O-葡糖苷(氯化飞燕草素葡萄糖苷)证实的,需要类黄酮单葡糖苷或二氢查耳酮单葡糖苷。
WO 2014/086632(Unilever等)的表1公开了SGLT1抑制剂的进一步实例,所述抑制剂均为类黄酮单葡糖苷,如木犀草素-7-葡糖苷、芹菜素-7-葡糖苷、芹菜素-8-C-葡糖苷、山柰酚-3-葡糖苷、山柰酚-7-葡糖苷、槲皮素-3-葡糖苷、槲皮素-4-葡糖苷、柚皮素-7-葡糖苷、圣草素-7-葡糖苷、大豆素-8-C-葡糖苷、大豆素-7-葡糖苷、花青色素-3-葡糖苷、锦葵色素-3-O-葡糖苷、飞燕草色素-3-葡糖苷和天竺葵色素-3-葡糖苷。实际上,如槲皮素-3,4’-二葡糖苷所示,化学结构上的额外葡萄糖部分的存在破坏这种抑制作用。通过所测试的其他类黄酮糖苷(包括花青色素-3-芸香糖苷和锦葵色素-3-O-半乳糖苷)不存在SGLT1抑制活性证实了对葡糖苷的特异性。此外,氢醌单葡糖苷熊果苷表现出的SGLT1抑制活性的欠缺加强了葡糖苷分子中的类黄酮和二氢查耳酮结构的重要性。
表1还显示显示全部五种高异黄酮,EA1、EA2、EA3、MOA和MOB均为GLUT2抑制剂。
表1:分别使用5mM D-葡萄糖15分钟和25mM D-葡萄糖30分钟测试的化合物在Caco-2细胞中的SGLT1和GLUT2抑制活性。各化合物抑制的转运体的指定种类基于SGLT1抑制剂在5mM D-葡萄糖下具有≥20%的葡萄糖转运抑制和在25mM D-葡萄糖下≤20%的抑制,GLUT2抑制剂在5mM和25mM D-葡萄糖水平下都具有≥20%的抑制。葡萄糖转运体抑制百分比为一式三份的平均值。
*所有化合物均在300μM下测试;根皮苷为SGLT1抑制剂的阳性对照。
#基于SGLT1抑制剂在5mM D-葡萄糖下具有≥20%的抑制和在25mM D-葡萄糖下≤20%的抑制,并且GLUT2抑制剂在5mM和25mM D-葡萄糖下都具有≥20%的抑制。
结论
使用Caco-2细胞测定鉴定鸢尾苷和氯化飞燕草色素-3-O-葡糖苷(氯化飞燕草素葡萄糖苷)为SGLT1抑制剂。使用Caco-2细胞测定鉴定高异黄酮EA1、EA2、EA3、MOA和MOB为GLUT2抑制剂。
实施例2:从玉竹(Polygonatum odoratum,Fragrant Solomonseal))提取和分离化合物
方法
将玉竹的干燥根部(1.0kg)用95%的乙醇水溶液提取2小时,固液重量比为1:4。然后将残余植物根用70%的乙醇水溶液提取2小时,固液重量比为1:3。然后将两个乙醇水提取液合并、浓缩并真空干燥,得到333.1g玉竹的乙醇水提取物(收率33.3%)。
将干燥的提取物溶于水,并依次用石油醚、乙酸乙酯和1-丁醇进行分配,得到21.0g石油醚提取物(收率6.3%)、4.33g乙酸乙酯提取物(收率1.3%)、29.3g 1-丁醇提取物(收率8.8%)和216.5g水提取物(收率65.0%)。
使用配备YMC-Pack-C18柱(250mm×10mm,5μm)的LC3000半制备HPLC系统进一步纯化乙酸乙酯提取物,用等度溶剂系统(含有约60%乙腈和约40%水,有0.18%甲酸)洗脱,在280nm下监测,流速为6ml/分钟,提供38.3mg 5,7-二羟基-3-(4’-羟基苄基)-6-甲基色烷-4-酮(EA1)(收率0.885%)、59.0mg 5,7-二羟基-3-(4’-羟基苄基)-6-甲基-8-甲氧基色烷-4-酮(EA2)(收率1.362%)、93.8mg 5,7-二羟基-3-(4’-羟基苄基)-6,8-二甲基色烷-4-酮(EA3)(收率2.167%)。
结论
发现玉竹干燥根部的乙醇水提取物的乙酸乙酯提取物包含5,7-二羟基-3-(4’-羟基苄基)-6-甲基色烷-4-酮(EA1)、5,7-二羟基-3-(4’-羟基苄基)-6-甲基-8-甲氧基色烷-4-酮(EA2)、5,7-二羟基-3-(4’-羟基苄基)-6,8-二甲基色烷-4-酮(EA3)。鸢尾苷未鉴定为提取产物。
实施例3:SGLT1抑制剂与高异黄酮的协同作用
材料
5,7-二羟基-3-(4’-羟基苄基)-6-甲基色烷-4-酮(EA1)(来自实施例2)
5,7-二羟基-3-(4’-羟基苄基)-6-甲基-8-甲氧基色烷-4-酮(EA2)(来自实施例2)
5,7-二羟基-3-(4’-羟基苄基)-6,8-二甲基色烷-4-酮(EA3)(来自实施例2)
甲基麦冬黄烷酮A(MOA)(上海纯优生物科技有限公司)
甲基麦冬黄烷酮B(MOB)(上海纯优生物科技有限公司)
方法
分化Caco-2细胞单层的准备
如实施例1中所述将Caco-2细胞培养和常规地传代。将Caco-2细胞在生长培养基中以2.5x 105个细胞/ml(每插件500μl)接种到BioCoat HTS Fibrillar CollagenMultiwell Inserts(BD Biosciences)中并将30ml生长培养基添加到下方给料板中。在37℃,5%CO2下使细胞附着到胶原基质上并经24小时形成单层。插件和给料板都在PBS中洗涤,并且将细胞在37℃,5%CO2下用含有MITO+TMSerum Extender溶液的BD Entero-STIMTM肠上皮细胞分化培养基(都是BD Biosciences)培养(每插件500μl,30ml在给料板中)另外48小时。
葡萄糖转运细胞模型
将分化细胞单层在PBS(+)中温和洗涤并将插件转移到新的标准组织培养24孔板中。将细胞在37℃,5%CO2下用新鲜PBS(+)(每插件500μl和每孔1ml)培养30分钟。轻轻抽出PBS(+)并换成250μl/插件的5mM D-葡萄糖±测试化合物,并将1ml PBS(+)快速添加到下方各孔中,然后在培养器中在37℃5%CO2下更换细胞。15分钟后,将细胞插件转移到新的24孔板中并向各插件中加入另外250μl的45mM D-葡萄糖±测试化合物(以使葡萄糖最终浓度为25mM)并再将1ml PBS(+)添加到孔中。另外15分钟后,再次将插件转移到新的24孔板中,并且这次仅向下方孔中加入新鲜PBS(+)。另外15分钟后重复这一步骤。将细胞插件转移到新的24孔板中,从细胞中轻轻抽出上清液并换成500μl的100μM Lucifer Yellow(Sigma)溶液以证实单层的完整性。将1ml PBS(+)添加到各孔中并在37℃,5%CO2下培养1小时。然后弃去细胞插件并通过在Spectramax Gemini EM荧光酶标仪上在485nm(激发)和530nm(发射)下测量样品荧光来检查膜的Lucifer Yellow通透性。
葡萄糖测定
在最后一次培养后,如实施例1中所述测定来自各步骤(即在15、30、45和60分钟)的所有保留的PBS(+)的葡萄糖水平,并计算总累积葡萄糖转运。通过最初用低水平D-葡萄糖短时间培养分化Caco-2细胞(5mM 15分钟)、接着立即用高水平D-葡萄糖持续培养(25mM的最终浓度45分钟)来体外模拟如实施例1中描述和例示的腔葡萄糖浓度的局部变化。
结果
表2总结了使用以所选高异黄酮与SGLT1抑制剂(多种类黄酮单葡糖苷)的组合进行的上述Caco-2测定的结果,并清楚地表明组合使用SGLT1抑制剂和高异黄酮可协同抑制从肠腔局部摄取葡萄糖,并因此降低与2型糖尿病的发病相关的高餐后血糖“峰值”。
表2:组合使用已知的SGLT1抑制剂和所选的高异黄酮(5,7-二羟基-3-(4’-羟基苄基)-6-甲基色烷-4-酮(EA1);5,7-二羟基-3-(4’-羟基苄基)-6-甲基-8-甲氧基色烷-4-酮(EA2);5,7-二羟基-3-(4’-羟基苄基)-6,8-二甲基色烷-4-酮(EA3);甲基麦冬黄烷酮A(MOA);甲基麦冬黄烷酮B(MOB))的累积葡萄糖转运和标准差(一式两份)。
在上表中,每一高异黄酮(HIF)和类黄酮单葡糖苷(FM)测试对报告了5个值:
1.无化合物(NC)+NC
2.NC+HIF(数据未用于计算协同作用)
3.NC+HIF
4.FM+NC
5.FM+HIF
第1对提供基线。
第3对显示HIF单独产生的抑制。
第4对显示FM单独产生的抑制。
第5对显示HIF与FM组合产生的抑制。
当HIF与FM组合产生的抑制大于HIF单独产生的抑制与FM单独产生的抑制之和时,实现协同作用。
会注意到,对于鸢尾苷(T,300μM)和EA1(10μM)这一对,没有观察到协同效果。这是因为高水平的EA1(10μM)引起抑制饱和。因此在低水平EA1(5μM)下重复这一对,并由此在未因EA1导致抑制饱和的情况下观察到了协同效果。
类似地,会注意到,对于木犀草素-7-葡糖苷(L7G,300μM)和EA1(10μM)这一对,没有观察到协同效果。这同样是因为高水平的EA1(10μM)引起抑制饱和。因此在低水平EA1(2.5μM)下重复这一对,并由此在未因EA1导致抑制饱和的情况下观察到了协同效果。
结论
SGLT1抑制剂和高异黄酮协同抑制从肠腔局部摄取葡萄糖,并因此降低与2型糖尿病的发病相关的高餐后血糖“峰值”。
SGLT1抑制剂为类黄酮单葡糖苷,其基于类黄酮的五种亚类,即一种异黄酮、两种黄酮、一种花色苷、一种黄烷酮和一种黄酮醇。所选的高异黄酮为5,7-二羟基-3-(4’-羟基苄基)-6-甲基色烷-4-酮(EA1);5,7-二羟基-3-(4’-羟基苄基)-6-甲基-8-甲氧基色烷-4-酮(EA2);5,7-二羟基-3-(4’-羟基苄基)-6,8-二甲基色烷-4-酮(EA3);甲基麦冬黄烷酮A(MOA);甲基麦冬黄烷酮B(MOB)。
Claims (15)
1.可食用组合物,其以一个或多个单位剂量的单份形式提供,其包含2-200mg至少一种高异黄酮与20-2000mg至少一种类黄酮单葡糖苷及其盐的组合。
2.权利要求1的可食用组合物,其中所述至少一种高异黄酮为苏木素型高异黄酮。
3.权利要求2的可食用组合物,其中所述苏木素型高异黄酮为3-苄基色烷-4-酮型高异黄酮。
4.权利要求3的可食用组合物,其中所述高异黄酮具有以下结构I:
其中R1为-H或-Me;且
其中R2为-OH、-OMe或-O-CH2-O-(C3’)。
5.权利要求4的可食用组合物,其中所述高异黄酮选自5,7-二羟基-3-(4’-羟基苄基)-6-甲基色烷-4-酮(EA1)、5,7-二羟基-3-(4’-羟基苄基)-6-甲基-8-甲氧基色烷-4-酮(EA2)、5,7-二羟基-3-(4’-羟基苄基)-6,8-二甲基色烷-4-酮(EA3)、甲基麦冬黄烷酮A(MOA)和甲基麦冬黄烷酮B(MOB)。
6.权利要求1至5中任一项的可食用组合物,其中所述至少一种类黄酮单葡糖苷及其盐选自黄酮单葡糖苷、黄酮醇单葡糖苷、黄烷酮单葡糖苷、异黄酮单葡糖苷和花色苷,及其盐。
7.权利要求6的可食用组合物,其中所述至少一种类黄酮单葡糖苷及其盐选自木犀草素-7-葡糖苷、鸢尾苷、氯化飞燕草色素-3-O-葡糖苷(氯化飞燕草素葡萄糖苷)、山柰酚-3-葡糖苷、柚皮素-7-O-葡糖苷和芹菜素-8-C-葡糖苷。
8.权利要求1至7中任一项的可食用组合物,其中类黄酮单葡糖苷及其盐与高异黄酮的摩尔比为至少1,优选至少5,最优选至少10。
9.降低非糖尿病人的餐后血糖峰值幅度或血糖反应的方法,所述方法包括以下步骤:
(a)向所述非糖尿病人口服给药权利要求1至8中任一项的可食用组合物;和
(b)向所述非糖尿病人口服给药糖类;
其中步骤(a)与步骤(b)同时进行,步骤(a)比步骤(b)提前0至90,优选0至60分钟,或者步骤(a)比步骤(b)延后0至30分钟,且
其中所述糖类包含葡萄糖或者是葡萄糖。
10.治疗患有2型糖尿病的人的方法,所述方法包括以下步骤:
(a)向有此需要的人口服给药权利要求1至8中任一项的可食用组合物;和
(b)向所述有此需要的人口服给药糖类;
其中步骤(a)与步骤(b)同时进行,步骤(a)比步骤(b)提前0至90,优选0至60分钟,或者步骤(a)比步骤(b)延后0至30分钟,且
其中所述糖类包含葡萄糖或者是葡萄糖。
11.权利要求9或10的方法,其中所述糖类可选自多糖、寡糖、二糖、单糖及其混合物。
12.权利要求1至8中任一项的可食用组合物,其用于降低非糖尿病人的餐后血糖峰值幅度或血糖反应。
13.权利要求1至8中任一项的可食用组合物,其用于治疗2型糖尿病。
14.权利要求1至8中任一项的可食用组合物在制备用于降低非糖尿病人的餐后血糖峰值幅度或血糖反应的药物中的用途。
15.权利要求1至8中任一项的可食用组合物在制备用于治疗2型糖尿病的药物中的用途。
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PCT/EP2016/070118 WO2017036926A1 (en) | 2015-09-03 | 2016-08-25 | Edible composition |
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EA201890213A1 (ru) | 2018-09-28 |
EP3344070A1 (en) | 2018-07-11 |
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