CN103813723B - 可食用组合物 - Google Patents
可食用组合物 Download PDFInfo
- Publication number
- CN103813723B CN103813723B CN201280027352.5A CN201280027352A CN103813723B CN 103813723 B CN103813723 B CN 103813723B CN 201280027352 A CN201280027352 A CN 201280027352A CN 103813723 B CN103813723 B CN 103813723B
- Authority
- CN
- China
- Prior art keywords
- flavonoid
- glucosides
- glucoside
- glucose
- aglucon
- 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.)
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- 239000000203 mixture Substances 0.000 title claims abstract description 22
- 229930182478 glucoside Natural products 0.000 claims abstract description 107
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- 229930003935 flavonoid Natural products 0.000 claims abstract description 58
- 235000017173 flavonoids Nutrition 0.000 claims abstract description 58
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- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 claims abstract description 25
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- ZCOLJUOHXJRHDI-CMWLGVBASA-N genistein 7-O-beta-D-glucoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=C2C(=O)C(C=3C=CC(O)=CC=3)=COC2=C1 ZCOLJUOHXJRHDI-CMWLGVBASA-N 0.000 claims description 4
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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。反复的高餐后血糖“峰值”与提高的发生II型糖尿病的危险相关联。不受调节的血糖偏移是不合意的,餐后血糖浓度的任何降低或“钝化”可能有益。本发明涉及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。因此在本发明的第一方面中,提供可食用组合物,所述组合物包含至少5干重量%的至少一种类黄酮糖苷配基和至少5干重量%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%,且其中所述类黄酮糖苷配基是GLUT 2抑制剂,且所述类黄酮葡糖苷是SGLT 1抑制剂。
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等人所述(Cardiovascular diabetology, 8, 23 (2009)),反复的高餐后血糖“峰值”与提高的发生II型糖尿病的危险相关联。不受调节的血糖偏移(glycemic excursion)是不合意的,餐后血糖浓度的任何降低或“钝化”可能有益。本发明涉及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。
发明概述
在本发明的第一方面中,提供可食用组合物,所述组合物包含至少5干重量%的至少一种类黄酮糖苷配基(flavonoid aglycone)和至少5干重量%的至少一种类黄酮单葡糖苷,其中所述类黄酮单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 %,且其中所述类黄酮糖苷配基是GLUT 2抑制剂,所述类黄酮单葡糖苷是SGLT 1抑制剂。
乳糖酶根皮苷水解酶(LPH)——一种β-半乳糖苷酶,是在小肠中发现的参与二糖乳糖水解成其成分半乳糖和葡萄糖单体的酶。特别地,该酶水解D-乳糖中的β-糖苷键。这种酶的缺乏造成乳糖不耐受。LPH也具有葡糖苷酶活性。因此,类黄酮葡糖苷必须表现出一定程度的对小肠中的LPH水解的抗性,在小肠中经由葡萄糖转运体发生葡萄糖吸收。
术语“对LPH水解的抗性比槲皮素-4-葡糖苷高至少20%”是指被LPH水解的比率比槲皮素-4’-葡糖苷低至少20 %。因此,如果对LPH水解的抗性比槲皮素-4-葡糖苷高100%,该比率为0。
术语“类黄酮糖苷配基”是指未糖基化的类黄酮。术语“类黄酮单葡糖苷”是指连接到单葡萄糖单元上的类黄酮。术语“GLUT 2抑制剂”是指抑制被称作被动葡萄糖转运体2的跨膜载体蛋白的化合物。术语“SGLT1抑制剂”是指抑制被称作钠葡萄糖共转运体1的跨膜载体蛋白的化合物。
类黄酮糖苷配基可选自黄酮糖苷配基、黄烷醇糖苷配基、黄烷酮糖苷配基、异黄酮糖苷配基及其混合物。因此术语“黄酮糖苷配基”、“黄烷醇糖苷配基”、“黄烷酮糖苷配基”和“异黄酮糖苷配基”分别是指未糖基化的黄酮、黄烷醇、黄烷酮和异黄酮。类黄酮糖苷配基特别可选自芹菜苷配基(apigenin)、木犀草素(luteolin)、槲皮素(quercetin)、山奈黄素(kaempferol)、杨梅黄酮(myricetin)、柚皮素(naringenin)、生松素(pinocembrin)、橙皮素(hesperetin)、染料木黄酮(genistein)及其混合物。
类黄酮单葡糖苷可选自木犀草素-7-葡糖苷、芹菜苷配基-8-C-葡糖苷、山奈黄素-7-O-葡糖苷、山奈黄素-3-O-葡糖苷、柚皮素(naringenoin)-7-O-葡糖苷、大豆糖苷配基-8-葡糖苷、矢车菊苷元-3-葡糖苷、槲皮素-3-葡糖苷、天竺葵色素-3-葡糖苷、锦葵色素-3-葡糖苷、飞燕草色素-3-葡糖苷及其混合物。
类黄酮糖苷配基与类黄酮单葡糖苷的摩尔比的范围可以为4:1至1:4,优选3:1至1:3,最优选2:1至1:2。
该组合物可包含按重量计不多于50 %,优选不多于10 %,最优选不多于2 %的类黄酮糖苷配基,和按重量计分别不多于50 %,优选不多于10 %,最优选不多于2 %的类黄酮单葡糖苷。因此,在不多于2重量%的类黄酮糖苷配基水平下,该组合物必须包含水以使该组合物包含至少5干重量%的至少一种类黄酮糖苷配基。
该组合物优选为日剂量形式,该日剂量包含至少50微摩尔,优选至少100微摩尔,最优选至少250微摩尔的类黄酮糖苷配基和至少50微摩尔,优选至少100微摩尔,最优选至少250微摩尔的类黄酮单葡糖苷。
本发明的组合物可以是包含不多于99.95 % w/w水的包装饮料形式。其也可以是装在小袋中的干粉形式,该干粉适合添加到膳食中。
在本发明的第二方面中,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,所述方法包括步骤:
(a) 由非糖尿病人口服根据本发明的第一方面的组合物;和
(b) 由非糖尿病人口服糖类;
其中步骤(a)与步骤(b)同时、提前0至90,优选0至60分钟或延后0至30分钟,且其中所述糖类包含葡萄糖或是葡萄糖。
在本发明的第三方面中,提供治疗需要其的人的2型糖尿病的方法,所述方法包括步骤:
(a) 由需要其的人口服根据本发明的第一方面的组合物;和
(b) 由需要其的人口服糖类;
其中步骤(a)与步骤(b)同时、提前0至90,优选0至60分钟或延后0至30分钟,且其中所述糖类包含葡萄糖或是葡萄糖。
该糖类可选自多糖、寡糖、二糖、单糖及其混合物。
在本发明的第四方面中,提供根据本发明的第一方面的组合物,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中,提供根据本发明的第一方面的组合物,其用于治疗2型糖尿病。
在本发明的第六方面中,提供根据本发明的第一方面的组合物用于制造降低非糖尿病人的餐后血糖峰值幅度或血糖反应的药剂的用途。
在本发明的第七方面中,提供根据本发明的第一方面的组合物用于制造治疗2型糖尿病的药剂的用途。
附图简述
参照附图阐述本发明,其显示:
图1 餐中葡萄糖浓度时间轴模型;
图2 前15分钟在5 mM D-葡萄糖中在存在或不存在SGLT1抑制剂(300 µM根皮苷(Pz))的情况下和随后剩余45分钟在25 mM D-葡萄糖中在存在或不存在GLUT2抑制剂(125µM根皮素(Pt))的情况下,跨过分化Caco-2单层的总累积葡萄糖转运(µM)(NC = 媒介物阴性对照);
图3 前15分钟在5 mM D-葡萄糖中在存在或不存在SGLT1抑制剂(300 µM木犀草素-7-葡糖苷(L7G))的情况下和随后剩余45分钟在25 mM D-葡萄糖中在存在或不存在GLUT2抑制剂(50 µM染料木黄酮(G))的情况下,跨过分化Caco-2单层的总累积葡萄糖转运(µM)(NC = 媒介物阴性对照);
图4 前15分钟在5 mM D-葡萄糖中在存在或不存在SGLT1抑制剂(300 µM芹菜苷配基-8-C-葡糖苷(A8G))的情况下和随后剩余45分钟在25 mM D-葡萄糖中在存在或不存在GLUT2抑制剂(50 µM染料木黄酮(G))的情况下,跨过分化Caco-2单层的总累积葡萄糖转运(µM)(NC = 媒介物阴性对照);
图5 前15分钟在5 mM D-葡萄糖中在存在或不存在SGLT1抑制剂(300 µM槲皮素-3-葡糖苷(Q3G))的情况下和随后剩余45分钟在25 mM D-葡萄糖中在存在或不存在GLUT2抑制剂(100 µM橙皮素(H))的情况下,跨过分化Caco-2单层的总累积葡萄糖转运(µM)(NC =媒介物阴性对照);
图6 前15分钟在5 mM D-葡萄糖中在存在或不存在SGLT1抑制剂(300 µM槲皮素-3-葡糖苷(Q3G))的情况下和随后剩余45分钟在25 mM D-葡萄糖中在存在或不存在GLUT2抑制剂(50 µM木犀草素(L))的情况下,跨过分化Caco-2单层的总累积葡萄糖转运(µM)(NC =媒介物阴性对照);
图7 前15分钟在5 mM D-葡萄糖中在存在或不存在SGLT1抑制剂(300 µM山奈黄素-3-葡糖苷(K3G))的情况下和随后剩余45分钟在25 mM D-葡萄糖中在存在或不存在GLUT2抑制剂(50 µM橙皮素(H))的情况下,跨过分化Caco-2单层的总累积葡萄糖转运(µM)(NC = 媒介物阴性对照);
图8 前15分钟在5 mM D-葡萄糖中在存在或不存在SGLT1抑制剂(300 µM槲皮素-3-葡糖苷(Q3G))的情况下和随后剩余45分钟在25 mM D-葡萄糖中在存在或不存在GLUT2抑制剂(50 µM柚皮素(N))的情况下,跨过分化Caco-2单层的总累积葡萄糖转运(µM)(NC = 媒介物阴性对照);
图9 前15分钟在5 mM D-葡萄糖中在存在或不存在SGLT1抑制剂(300 µM柚皮素-7-葡糖苷(N7G))的情况下和随后剩余45分钟在25 mM D-葡萄糖中在存在或不存在GLUT2抑制剂(50 µM芹菜苷配基(A))的情况下,跨过分化Caco-2单层的总累积葡萄糖转运(µM)(NC= 媒介物阴性对照);和
图10 前15分钟在5 mM D-葡萄糖中在存在或不存在SGLT1抑制剂(300 µM飞燕草色素-3-葡糖苷(D3G))的情况下和随后剩余45分钟在25 mM D-葡萄糖中在存在或不存在GLUT2抑制剂(50 µM染料木黄酮(G))的情况下,跨过分化Caco-2单层的总累积葡萄糖转运(µM)(NC = 媒介物阴性对照)。
发明详述
实施例1:SGLT1和GLUT2抑制剂的鉴定
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’s modified Eagle's培养基(含有Glutamax-1, 4.5 g/L D-葡萄糖和25 mM 4-(2-羟乙基)-1-哌嗪乙磺酸(Hepes) (Invitrogen))、10% 胎牛血清(Sigma)、1%非必需氨基酸(Invitrogen)和1 mM丙酮酸钠(Sigma)构成的生长培养基中培养。使用TrypLE™ Express Stable Trypsin-Like Enzyme (Invitrogen)使细胞以大约80%汇合度照惯例传代以剥离细胞,并以大约114个细胞/平方毫米接种在新鲜组织培养烧瓶中。只有传代数为45至49之间的细胞用于实验。
分化Caco-2细胞单层的制备
Corning® HTS Transwell® 96孔可透插入载体(insert support)(Sigma)在室温下在无菌条件下用40微升在0.02 M乙酸中的50微克/毫升I型大鼠尾胶原(BDBiosciences)包被胶原1小时。该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9.6 x 105个细胞/毫升(75微升/插件)接种到插件中并将30毫升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,细胞在37℃, 5 % CO2下用含有MITO+™ Serum Extender溶液的BD Entero-STIM™ Enterocyte分化培养基(都是BDBiosciences)培养(每插件75微升,30毫升在给料板中)另外48小时。
葡萄糖转运抑制剂细胞筛选检测
分化细胞单层在含有CaCl2和MgCl2的Dulbecco's磷酸盐缓冲盐水(PBS(+)(Invitrogen))中温和洗涤并将插件转移到新的Corning® HTS Transwell®-96孔接收板(Sigma)中。细胞在37℃, 5 % CO2下用新鲜PBS(+)(75微升/插件和225微升/孔)培养60分钟。一式三份地,轻轻抽出PBS(+)并换成75微升/插件的5 mM D-葡萄糖(Sigma) ± 测试活性剂或25 mM D-葡萄糖 ± 测试活性剂,并将225微升/孔的PBS(+)快速添加到各孔中。5mM葡萄糖孔和25 mM葡萄糖孔在37℃, 5 % CO2下分别培养15分钟和30分钟。所有测试活性剂的细节可见于表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100微升的100 μM Lucifer Yellow (Sigma)溶液以证实该单层的完整性。将225微升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SpectramaxGemini EM荧光酶标仪上在485纳米(激发)和530纳米(发射)下测量样品荧光来检查该膜的Lucifer Yellow可透性。
葡萄糖检测
使用基于Invitrogen’s Amplex Red葡萄糖/葡萄糖氧化酶检测试剂盒的葡萄糖检测测量跨过细胞单层转运的葡萄糖量。简言之,将50微升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100微升反应缓冲液(0.5微升10 mM AmplifluRed、1微升10U/ml辣根过氧化物酶、1微升100U/ml葡萄糖氧化酶和97.5微升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530纳米(激发)和590纳米(发射)下测量样品荧光并由标准曲线外推葡萄糖浓度。
表1显示各测试活性剂对跨过分化Caco-2细胞单层的葡萄糖转运的抑制百分比。在5 mM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。在较高D-葡萄糖浓度下,SGLT1转运体变饱和,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。上述方法中详述的筛选细胞模型被设计用来利用各转运体的最佳条件的这些差异鉴定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,而在基底外侧膜中也表达GLUT2,在此其对于将葡萄糖转运到细胞外是必要的。因此,GLUT2特异性抑制剂不仅在高D-葡萄糖浓度(25 mM)下阻断顶端靶向的转运体,它们还进入细胞并在低D-葡萄糖浓度(5 mM)下阻止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之间的抑制,各活性剂在5 mM D-葡萄糖下测试15分钟和在25 mM D-葡萄糖下测试30分钟。如果活性剂表现出在5 mM D-葡萄糖下至少20%的葡萄糖转运抑制和在25 mM D-葡萄糖下相应的不多于20%的抑制,活性剂被归类为SGLT1抑制剂。在这两种条件下都能抑制至少20%葡萄糖转运的活性剂被归类为GLUT2特异性抑制剂。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)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))描述并由被设计用来模拟在富含碳水化合物的膳食摄入过程中小肠中的葡萄糖浓度局部变化的图1图解。餐前,肠腔中的游离葡萄糖浓度低(<5 mM),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(5-10 mM)并被SGLT1从肠腔转运出来并随后经由GLUT2转运到全身循环中。由于跨过肠上皮细胞的这种初始葡萄糖转运,动员GLUT2的细胞内储备并靶向顶端膜。餐后不久,由于该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(25-100 mM)。在这些高葡萄糖水平下,高亲和力、低容量转运体SGLT1变饱和且跨过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,如通过木犀草素-7-葡糖苷、芹菜苷配基-7-葡糖苷、芹菜苷配基-8-c-葡糖苷、山奈黄素-3-葡糖苷、山奈黄素-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、圣草酚-7-葡糖苷、大豆糖苷配基-8-c-葡糖苷、大豆糖苷配基-7-葡糖苷、矢车菊苷元-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-葡糖苷证实,需要类黄酮单葡糖苷。实际上,如槲皮素-3,4’-二葡糖苷所示,该化学结构上的额外葡萄糖部分的存在破坏这种抑制作用。通过其它测试类黄酮糖苷,包括矢车菊苷元-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该葡糖苷分子中的类黄酮结构的重要性。Welsch等人(J. of Nutrition, 119, 11, 1698-704(1989))宣称是葡萄糖转运体抑制剂的其它非类黄酮葡糖苷,如氯原酸、咖啡酸和迷迭香酸(咖啡酸的酯)在SGLT1或GLUT2抑制的这种细胞模型中没有表现出抑制活性。表1还表明,除花色素类外的来自所选各类黄酮类别的所有测试糖苷配基都被证实是GLUT2抑制剂。
实施例2:SGLT1和GLUT2抑制剂之间的协同作用
分化Caco-2细胞单层的制备
Caco-2细胞如实施例1中所述培养和照惯例传代。将Caco-2细胞在生长培养基中以2.5 x 105个细胞/毫升(500微升/插件)接种到BioCoat HTS Fibrillar CollagenMultiwell Inserts (BD Biosciences)中并将30毫升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,细胞在37℃, 5 % CO2下用含有MITO+™ Serum Extender溶液的BD Entero-STIM™Enterocyte分化培养基(都是BD Biosciences)培养(每插件500微升,30毫升在给料板中)另外48小时。
表1:分别使用5 mM D-葡萄糖15分钟和25 mM D-葡萄糖30分钟,测试Caco-2细胞中的SGLT1和GLUT2抑制活性用的活性剂。各活性剂抑制的转运体的指定种类基于具有在5mM D-葡萄糖下≥ 20 %的葡萄糖转运体抑制和在25 mM D-葡萄糖下≤ 20 %抑制的SGLT1抑制剂,和在5 mM和25 mM D-葡萄糖水平下都具有≥ 20 %抑制的GLUT2抑制剂。ND = 未检出;Nt = 未测试。
葡萄糖转运细胞模型
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。细胞在37℃ 5 % CO2下用新鲜PBS(+)(500微升/插件和1毫升/孔)培养30分钟。轻轻抽出PBS(+)并换成250微升/插件的5 mM D-葡萄糖 ± 测试活性剂,并将1毫升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。在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250微升的45 mM D-葡萄糖 ± 测试活性剂(以使葡萄糖最终浓度为25 mM)并再将1毫升PBS(+)添加到孔中。在另外15分钟后,再将插件转移到新的24孔板中,这次仅向下方孔中加入新鲜PBS(+)。在另外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500微升的100 μM LuciferYellow (Sigma)溶液以证实该单层的完整性。将1毫升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485纳米(激发)和530纳米(发射)下测量样品荧光来检查该膜的Lucifer Yellow可透性。
葡萄糖检测
在最后一次培养后,如实施例1中所述检测来自各步骤(即在15、30、45和60分钟)的所有残留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(5 mM 15分钟)、接着立即用高水平D-葡萄糖持续培养(25 mM的最终浓度45分钟),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。
表2绘制前15分钟在5 mM D-葡萄糖中在存在或不存在SGLT1抑制剂的情况下和随后剩余45分钟在25 mM D-葡萄糖中在存在或不存在GLUT2抑制剂的情况下,跨过分化Caco-2单层的总累积葡萄糖转运。为了验证这一细胞系统,分别使用根皮苷(Pz)和根皮素(Pt)作为SGLT1和GLUT2的广泛认可的特异性抑制剂。SGLT1特异性抑制剂根皮苷(Pz)当从该细胞系统一开始就添加时表现出总累积葡萄糖转运(tCGT)的降低(Pz NC - 水平条纹条),表明抑制SGLT1(其是低葡萄糖水平下的主导活性转运体)。但是,当随后在高D-葡萄糖浓度下添加时,Pz没有表现出对tCGT的抑制(NC Pz – 虚线条),因为SGLT1转运体现在饱和且葡萄糖转运现在依赖于高容量GLUT2转运体。如预期,GLUT2特异性抑制剂根皮素(Pt)当在高D-葡萄糖浓度下添加时表现出显著的(p ≤ 0.05)tCGT降低(NC Pt – 斜条纹条)。但是,在低葡萄糖浓度下300 uM Pz、接着在高葡萄糖浓度下125 uM Pt的组合看起来显著(p ≤ 0.01)和协同抑制tCGT。这种协同效应利用在高容量GLUT2可靶向顶端膜之前先通过SGLT1将葡萄糖转运到肠上皮细胞中的要求。联合使用的SGLT1和GLUT抑制剂可协同抑制从肠腔局部摄取葡萄糖,因此降低与2型糖尿病的发病相关的高餐后血糖“峰值”。
因此,实施例1中被鉴定为特异性SGLT1抑制剂的任何类黄酮单葡糖苷可以与实施例1中被鉴定为特异性GLUT2抑制剂的任何类黄酮糖苷配基组合,以表现出如上文对Pz和Pt的组合详述的跨过分化Caco-2细胞单层的葡萄糖转运的协同抑制。这通过将黄酮单葡糖苷:木犀草素-7-葡糖苷(L7G)和芹菜苷配基-8-C-葡糖苷(A8G)与异黄酮糖苷配基:染料木黄酮组合而证实(分别为图3和4)。类似地,如图5、6、7和8中所示,黄酮醇单葡糖苷:槲皮素-3-葡糖苷(Q3G)和山奈黄素-3-葡糖苷(K3G)可以与黄酮糖苷配基:木犀草素和黄烷酮糖苷配基:橙皮素和柚皮素组合以表现出协同效应。此外,黄烷酮单葡糖苷:柚皮素-7-葡糖苷(N7G)在与黄酮糖苷配基:芹菜苷配基组合时表现出协同葡萄糖转运抑制(图9)。最后,图10显示花色素苷:飞燕草色素-3-葡糖苷(D3G)和异黄酮糖苷配基:染料木黄酮表现出的协同葡萄糖转运抑制。
实施例3:类黄酮葡糖苷对人乳糖酶根皮苷水解酶(hLPH)降解的抗性
人乳糖酶根皮苷水解酶(LPH)提取物的制备
人上皮结直肠腺癌(Caco-2)细胞获自American Type Culture Collection(ATCC)并在Dulbecco’s modified eagle培养基(DMEM)(含有GlutaMAX™ I、4500 mg/L D-葡萄糖、25 mM HEPES, Invitrogen)+ 10%胎牛血清(FCS)(Sigma)、MEM非必需氨基酸(Fisher Scientific UK Ltd)和1.0 mM丙酮酸钠(SIGMA)中在汇合下培养21天,接着用Novagen ProteoExtractTM跨膜Protein Extraction试剂盒使用“Reagent A”(用于回收脆弱蛋白质复合体的温和提取试剂)和蛋白酶抑制剂混合物(包括在试剂盒中)提取。由各T175cm2烧瓶生成200微升提取物。提取物以50微升等分试样储存在-80 ℃下。在使用前,通过经过小G-25 Sephadex 50-100 μl旋转柱(Roche或ThermoFisher Scientific)将提取物半提纯,以除去低分子量干扰组分。
hLPH酶检测
将10微升半提纯的LPH提取物添加到在0.1 M马来酸盐(Sigma)缓冲液, pH 6.0中的90微升葡糖苷(1.0 mM最终浓度)中并在37 ℃下培养60分钟。通过添加200 μl 2M Tris(Sigma), pH 8.0,终止反应。对于各葡糖苷(1.0 mM),在37 ℃下同时运行空白试验60分钟——其添加Tris 2 M,然后仅在结束时添加LPH提取物。200微升所得反应混合物经过用(HPLC级甲醇(VWR)和马来酸盐缓冲液)准备的小C-18柱(Sep-Pak® Light C18药筒 55-105 µm, Waters Ltd.)x5次以除去可能的干扰性疏水LPH提取物、底物(葡糖苷)和反应产物(糖苷配基)组分。这能够充分回收葡萄糖,所述葡萄糖使用Amplex® Red 葡萄糖/葡萄糖氧化酶检测法测量。简言之,将100 微升反应试剂(0.5 % 10 mM Ampliflu Red;1.0 %10 U/ml辣根过氧化物酶和1.0 % 100 U/ml葡萄糖氧化酶在磷酸盐缓冲盐水(PBS)中,所有试剂来自SIGMA)添加到50微升样品中并在回旋振荡器上在室温下培养20分钟。在SpectraMax Gemini EM SN酶标仪(Molecular Devices)(激发530纳米,发射590纳米)上读取荧光。
表2: 葡糖苷被LPH水解,和相对于Q4G的抗性。在37 ℃下将葡糖苷(1.0 mM)与10% LPH提取物(Caco2细胞系)混合1小时。通过使用Amplex® Red葡萄糖/葡萄糖氧化酶检测法测量葡萄糖反应产物,评估LPH水解程度。该表列举表现出比Q4G高的抗LPH水解性的那些葡糖苷。
表2显示hLPH对不同类黄酮葡糖苷的降解率的变化。Q4G表现出最高的被hLPH降解程度,而Q3G看起来在这一检测中对hLPH的抗性比Q4G高大约95%。类似地,其它八种葡糖苷都表现出比Q4G提高的对hLPH的抗性,范围为从N7G的49.5 %至K3G的92.8 %。因此,这些葡糖苷在就餐中较不容易被肠中的hLPH水解,因此可能延长其作为SGLT1抑制剂的活性。因此,选择对hLPH的抗性比Q4G高至少20%的类黄酮葡糖苷有益于延长体内的任何葡糖苷特异性活性。
实施例4: 瓶装水
将包含200毫克槲皮素-3-葡糖苷/克和125毫克木犀草素/克以及还包含香料的干粉以每升水2克干粉的水平添加到水中。将该制剂分配到250毫升瓶中并密封。各瓶标记为“1天1瓶(1-a-day)”或类似的话。各瓶因此提供100毫克槲皮素-3-葡糖苷和62.5毫克木犀草素的日剂量。
实施例5: 添加到膳食中的小袋
将包含100毫克木犀草素-7-葡糖苷/克和60毫克染料木黄酮/克并还包含香料的干粉以每袋1克的水平分配到小袋中并密封。各袋标记为“1天1袋(1-a-day)”或类似的话。
Claims (20)
1.可食用组合物在制备用于抑制GLUT 2和SGLT 1的产品中的用途,其中所述可食用组合物包含至少5 干重量%的至少一种类黄酮糖苷配基和至少5干重量%的至少一种类黄酮单葡糖苷,其中所述类黄酮单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 %,且其中所述类黄酮糖苷配基是GLUT 2抑制剂,且所述类黄酮单葡糖苷是SGLT1抑制剂,其中类黄酮糖苷配基与类黄酮单葡糖苷的摩尔比的范围为4:1至1:4,且其中所述类黄酮单葡糖苷选自木犀草素-7-葡糖苷、芹菜苷配基-8-C-葡糖苷、山奈黄素-7-O-葡糖苷、山奈黄素-3-O-葡糖苷、柚皮素-7-O-葡糖苷、大豆糖苷配基-8-葡糖苷、矢车菊苷元-3-葡糖苷、天竺葵色素-3-葡糖苷、锦葵色素-3-葡糖苷、飞燕草色素-3-葡糖苷及其混合物。
2.根据权利要求1的用途,其中所述可食用组合物包含至少10 干重量%的至少一种类黄酮糖苷配基。
3.根据权利要求1的用途,其中所述可食用组合物包含至少10 干重量%的至少一种类黄酮单葡糖苷。
4.根据权利要求1的用途,其中所述类黄酮单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40 %。
5.根据权利要求1的用途,其中所述类黄酮单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60 %。
6.根据权利要求1的用途,其中所述类黄酮糖苷配基选自黄酮糖苷配基、黄烷醇糖苷配基、黄烷酮糖苷配基、异黄酮糖苷配基及其混合物。
7.根据权利要求6的用途,其中所述类黄酮糖苷配基选自芹菜苷配基、木犀草素、槲皮素、山奈黄素、杨梅黄酮、柚皮素、生松素、橙皮素、染料木黄酮及其混合物。
8.根据权利要求1的用途,其中类黄酮糖苷配基与类黄酮单葡糖苷的摩尔比的范围为3:1至1:3。
9.根据权利要求8的用途,其中类黄酮糖苷配基与类黄酮单葡糖苷的摩尔比的范围为2:1至1:2。
10.根据权利要求1的用途,其中所述组合物包含按重量计不多于50 %的类黄酮糖苷配基。
11.根据权利要求1的用途,其中所述组合物包含按重量计不多于50 %的类黄酮单葡糖苷。
12.根据权利要求1的用途,其中所述组合物为日剂量形式,所述日剂量包含至少50微摩尔的类黄酮糖苷配基和至少50微摩尔的类黄酮单葡糖苷。
13.根据权利要求12的用途,其中所述日剂量包含至少100微摩尔的类黄酮糖苷配基。
14.根据权利要求12的用途,其中所述日剂量包含至少250微摩尔的类黄酮糖苷配基。
15.根据权利要求12的用途,其中所述日剂量包含至少100微摩尔的类黄酮单葡糖苷。
16.根据权利要求12的用途,其中所述日剂量包含至少250微摩尔的类黄酮单葡糖苷。
17.根据权利要求1至16任一项的用途,其中所述产品用于降低非糖尿病人的餐后血糖峰值幅度或血糖反应。
18.根据权利要求1至16任一项的用途,其中所述产品用于治疗2型糖尿病。
19.根据权利要求1至16任一项的用途,其中所述产品为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剂。
20.根据权利要求1至16任一项的用途,其中所述产品为用于治疗2型糖尿病的药剂。
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