2016, Vol. 42引用本文 |
| 茶叶在抵抗Ⅱ型糖尿病中的作用 |  [PDF全文] |
糖尿病(diabetes mellitus,DM)已经是世界上最常见的内分泌紊乱疾病和增长最快的非传染性疾病之一[1]。长期的高血糖症状和代谢紊乱往往会引起一系列并发症,如动脉粥样硬化、酮酸中毒和昏迷。根据美国糖尿病协会(American Diabetes Association,ADA),DM可以分为4种类型：1)Ⅰ型糖尿病(type 1 diabetes mellitus,T1D);2)Ⅱ型糖尿病(type 2 diabetes mellitus,T2D);3)特殊型糖尿病(special diabetes mellitus);4)妊娠型糖尿病(gestational diabetes mellitus)[2]。据国际糖尿病联合会(International Diabetes Federation,IDF)统计的数据表明,2014年,全球DM患者已经有3.87亿人,预计到2035年,患者人数将会增加到5.92亿(www.idf.org/diabetesatlas/)。近30年,随着社会经济的飞速发展和人民生活水平的显著提高,DM患者的数量在中国也不断增多,在目前全球DM数量排名中,中国已位居第二[3]。在DM患者中,T2D占了绝大多数,目前在全球已被诊断的DM成人患者中,90%是T2D[4];而根据中国糖尿病协会(Chinese Diabetes Society,CDS)的统计,T2D在中国已经达到了95%(www.diab.net.cn/index.jsp)。其数量在总DM患者中,已经占据了主导地位。T2D也被称为非胰岛素依赖型糖尿病(non-insulin dependent diabetes),其特点主要是胰岛素抵抗(insulin resistance)伴随着胰岛素分泌相对不足。虽然T2D的发病机制的许多方面不像T1D那样明确,但是目前的普遍共识认为,T2D是在遗传易感的基础上由多种环境因素相互作用而形成的[5]。比如病态肥胖[6],进食过量[5],吸烟[7]和运动量不足[8]等。T2D患者在患病前期,往往都会有胰岛素抵抗的现象,即对胰岛素的敏感性降低,胰岛β-细胞为了缓解这种现象,会通过增加胰岛素分泌来维持血糖,一旦胰岛β-细胞无法产生足够的胰岛素来弥补这一现象时,就产生了T2D[5-6, 9-10]。如果患者持续高血糖而不被正确的治疗,将会导致各种大血管和微脉管的并发症,包括冠状动脉疾病、外周动脉疾病以及糖尿病性肾病、神经病和视网膜病[11]。
将血糖维持在正常的生理学范围内,主要通过口服或注射药物,配合控制饮食,减肥,锻炼等方法[12]。目前治疗DM的主流药物有11种,它们虽然药效强,却会引起一系列的不良反应。其中最常见的就是低血糖,体质量增加和胃肠道功能紊乱[13]。从近几年人体和动物实验表明,许多我们普遍正在消费的食品有很好的降血糖效果[14]。同时,大量的研究发现,平时膳食中的一些组分(可溶性纤维、酚类物质和肽链等)可通过不同的途径起着降血糖的功能,比如抑制一些消化酶;增强一些胰岛素促分泌物的活性以及激活一些糖代谢途径中的相关受体等。虽然它们不如化学合成的药物那样有效,但是这些食品级的天然产物不会带来不良反应。尽管大多数实验是在体外或者动物体内进行的,但根据现有的知识,它们已经可以用于DM的辅助治疗。因此,采用膳食疗法治疗DM已经成为一种趋势。
茶叶(Camellia sinensis)是一种富含可溶性纤维、黄酮类、单宁和多酚的功能性植物,它作为一种天然降血糖材料已经被国内外学者广泛研究,比如通过茶多糖抑制α-葡萄糖苷酶[15-17],茶黄素抑制α-淀粉酶[18],茶多酚抑制蔗糖酶[19]和小肠细胞中吸收葡萄糖的载体蛋白SGLT1(sodium-glucose cotransporter),GLUT2(glucose transporter type 2)和GLUT5(glucose transporter type 5)[20-21]等方法来抵抗T1D,但是其细胞学和分子生物学机制仍然没有完全解开,尤其是抵抗T2D的探究甚为复杂。根据目前的研究成果,可将茶叶抵抗糖尿病的作用机制概括为胰岛素途径、糖代谢途径及其他代谢途径。
1 胰岛素途径提高胰岛素含量与活性等措施会直接影响机体血糖的含量,从而达到治疗T2D的目的,所以这也是目前研究的最主要方向和治疗手段。目前的研究与治疗主要从促进其分泌,增强其活性或敏感性几方面入手。
1.1 促进胰岛素分泌WOLFRAM，等[22]在小鼠实验中用10 mg/(kg·d)的表没食子儿茶素没食子酸酯(epigallocatechin gallate,EGCG)连续填喂2周后发现,小鼠体内血糖浓度明显下降,胰岛素浓度显著上升,同时三酰甘油含量有下降的趋势。在0.5%的EGCG喂养大鼠实验中,也获得了相同的结果。证明了胰岛素分泌现象被EGCG所加强,增强了胰岛素活性及敏感性。
胰岛素抵抗(insulin resistance,IR)往往指的是胰岛素作用的靶器官对胰岛素作用的敏感性下降,即正常剂量的胰岛素产生低于正常生物学效应的一种状态,成因尚未完全清楚。一般认为是人体内胰岛素的接收器出现了问题,所以如果不彻底修复胰岛素的接收器,而单纯刺激胰岛素的分泌,是无法从根本上治疗胰岛素抵抗的。胰岛素敏感性就是描述胰岛素抵抗的程度。胰岛素敏感性越低,单位胰岛素的效果越差,分解糖类的程度越低[23]。T2D的原因一是胰岛素分泌量少;另一原因是胰岛素敏感性低。故在分泌量足够的情况下,提高胰岛素敏感性是很好的治疗T2D的方法。
ANDERSON，等[24]利用大鼠(rats)附睾的脂肪细胞对茶叶增强胰岛素活性进行了体外实验,发现茶水提取物在一定质量浓度范围(4.75~23 μg/mL)内,对胰岛素活性呈显著正相关。进一步分析其成分,发现3.8 mg/mL的绿茶和乌龙茶干茶水提物中EGCG起了主要作用,它使得胰岛素活性上升(17.5±2.3)%。红茶中则是茶单宁、茶黄素和一些未知成分共同起着提升胰岛素活性的作用,其中茶黄素能提升(2.4±0.4)%,茶单宁能提升(5.0±0.2)%,HPLC中保留时间为20~23 min的未知成分则提升4.9%。但是，TANG，等[25]用0.01%的红茶和绿茶提取物进行了小鼠喂养实验,发现到第12周时,2种处理都能显著降低小鼠血糖浓度并且缓解糖耐受不良症状,且绿茶效果较好。同时发现红茶组中小鼠血清胰岛素含量上升,但是绿茶组无明显变化,推测出红茶有促进胰岛素分泌的作用。最后利用稳态模型评估法(homeostatic model assessment,HOMA)分析了红茶和绿茶的降血糖机制,推测绿茶的主要作用机制是降低了胰岛素抵抗。
WU，等[26]在大鼠实验中发现用质量浓度5 mg/mL的绿茶粉喂养了12周后的小鼠与对照相比，血糖、胰岛素、三酰甘油、游离脂肪酸都明显下降。并且在体外脂肪细胞实验中发现0.075%的绿茶多酚能有效提升胰岛素的敏感性。故在胰岛素分泌量足够的情况下,有效提高胰岛素敏感性是很好的治疗T2D的方法。
蛋白酪氨酸磷酸酶(protein tyrosine phosphatases,PTPs)家族包含了一类结构不同的调控蛋白[27]。作为体内重要的信号传导器,PTPs功能的异常将会导致严重的病理反应[28]。许多PTPs已经成为药物开发的靶点,其中比较成熟的就是PTP1B[29]。已有大量的实验证明它与胰岛素抵抗、肥胖以及T2D有关[30-31]。在胰岛素的信号通路中,PTP1B起着负调控的作用,它会使胰岛素受体(insulin receptor,IR)和胰岛素受体的底物IRS-1去磷酸化[32-33]。人类PTP1B基因的数量性状遗传(quantitative trait loci,QTL)和突变分析也表明PTP1B的异常表达会引起DM和肥胖[34-36]。因此,抑制PTP1B的活性能够增强胰岛素的敏感性,改善糖的代谢循环。
MAO，等[37]用乌龙茶、黑茶和绿茶进行了体外半抑制浓度(half maximal inhibitory concentration,IC50)测定实验,发现黑茶抑制PTP1B效果最好(IC50=0.4 g/L),乌龙茶次之(IC50=2 g/L),绿茶最弱(IC50=4 g/L)；进一步实验发现,1 mg/mL绿茶提取物、50 μmol/L EGCG和没食子儿茶素没食子酸酯(gallocatechin gallate,GCG)经过人工氧化后抑制PTP1B的效果上升,证明了茶黄素与茶红素起着主要抑制作用。
1.2 增强肠促胰岛素的作用增强肠促胰岛素作用的方法之一是抑制二肽基肽酶-Ⅳ(dipeptidyl peptidase-Ⅳ,DPP-Ⅳ)。DPP-Ⅳ是DDP(dipeptidyl peptidases)家族中的一员，广泛分布于小肠、肝和肾等上皮组织的细胞膜中[38]。最初它被定义为丝氨酸水解酶,但是后来的研究发现,DPP-Ⅳ可以水解许多不同的功能性多肽,其中最主要的就是GLP-1。据文献记载,由小肠L-细胞分泌的GLP-1有75%在运输到肝的过程中被DPP-Ⅳ所降解[39]。故在血糖控制中,对DPP-Ⅳ的抑制可以减少GLP-1的降解,从而达到治疗T2D的作用。
MARDANYAN，等[40]利用23种植物的提取物对DPP-Ⅳ的抑制效果进行了筛选,发现肉桂、丁香、红茶和绿茶具有较低的IC50值,其中绿茶(干质量)为(5.3±0.4) mg/mL,红茶(干质量)为(6.4±0.5) mg/mL。然而茶叶中具体何种成分起着抑制DPP-Ⅳ的作用仍需要进一步探究。
2 糖代谢途径 2.1 促进葡萄糖分解代谢人体骨骼肌细胞和脂肪细胞是利用葡萄糖的主要场所,其对葡萄糖的分解能力能够被胰岛素所激活[41],因此它们在餐后血糖水平的调控中起着重要的作用。通过该方法治疗T2D一般有2种思路,一是直接模拟胰岛素功能激活受体细胞膜的葡萄糖载体蛋白4(glucose transporter type 4,GLUT4),二是通过激活一些信号通路来间接促进葡萄糖的利用与吸收。UEDA，等[42]用大鼠做了体内实验,发现EGCG在质量分数75 mg/kg时能使其肌细胞中GLUT4的活性被增强。在体外实验中,发现大鼠的L6肌肉细胞在1 nmol/L EGCG处理后GLUT4的活性显著加强。NISHIUMI，等[43]用绿茶和红茶水提取液(20 g/L)分别喂养小鼠,发现14周后,小鼠肌肉组织的葡萄糖吸收能力均显著上升,随后采用Western-blot实验发现了茶叶处理组的小鼠肌细胞膜中GLUT4含量显著增加；WU，等[44]在大鼠实验中也发现用5 mg/mL的绿茶粉溶液喂养12周后,大鼠血压、血糖和血脂都有明显下降,且脂肪细胞的胰岛素受体GLUT4的活性被显著加强；ZHANG，等[45]在L6肌肉细胞体外实验中,发现摩尔浓度20 μmol/L的EGCG除了通过增强GLUT4的活性外,还能通过增强AMPK(AMP-activated protein kinase)途径以及磷脂酰肌醇-3激酶途径(PI3K/Akt pathway)来增强葡萄糖吸收；JUNG，等[46]在体外实验中也发现10 μmol/L的EGCG能使大鼠的L6肌肉细胞的PI3K/Akt途径增强。以上研究共同证明了茶叶中的EGCG既能模拟胰岛素功能直接激活GLUT4,又能通过激活PI3K/Akt和AMPK途径间接促进葡萄糖的利用。
2.2 抑制葡萄糖合成代谢在人类和动物体内,葡萄糖可以通过糖异生(gluconeogenesis,GNG)进行补充,即从丙酮酸、乳酸、丙三醇、糖元氨基酸等非糖类化合物合成葡萄糖。该途径也是维持体内血糖的重要途径之一。对于T2D病人而言,强化此途径可以避免低血糖,抑制该途径可以减少血糖浓度[47]。
WALTNER-LAW，等[48]利用大鼠H4IIE肝癌细胞进行了实验,发现12.5 μmol/L的EGCG能显著减少肝葡萄糖的生成,在25 μmol/L摩尔浓度下能负调控GNG途径中磷酸烯醇式丙酮酸激酶(phosphoenolpyruvate carboxy kinase,PEPCK)的基因,使之转录的mRNA显著减少；WOLFRAM，等[49]在大鼠喂养和填塞实验中也发现了EGCG能下调葡萄糖和脂肪酸、三酰甘油、胆固醇含量。同时H4IIE细胞实验发现100 μmol/L EGCG能使肝癌细胞中PEPCK的mRNA表达量被下调且葡萄糖-6-磷酸激酶(glucose-6-phosphatase,G6Pase)的mRNA表达量被上调；COLLINS，等[50]用小鼠肝细胞进一步实验后发现EGCG能在相对低的摩尔浓度(1 μmol/L)时,通过调节糖异生关键基因(PEPCK和G6Pase)的表达来抑制GNG。并且推测EGCG是通过增强钙调节蛋白激酶β(calmodulin-dependent protein kinase kinase-β,CaMKK-β)的途径来激活AMPK，从而起到对GNG的调控作用。
3 其他途径 3.1 抗氧化目前，有越来越多的实验证明体内持续高血糖,会产生高浓度的游离自由基,使得氧化应激压力增加,进一步加剧后会引发糖尿病的并发症。其中·O2-在引起糖尿病及其并发症过程中危害较大,体内血糖的持续升高会导致糖酵解(glycolysis)的产物增加,线粒体膜氧化磷酸化的负担增加,从而使电子传递链产生的·O2-增多,进一步引起脂质过氧化,动脉粥样硬化和血管收缩,最终导致糖尿病及其并发症[51]。近几年的研究发现,人体的自由基主要通过增强多元醇通路(polyol pathway)及增加晚期糖基化终末产物(advanced glycation end products,AGEs)的形成,增加AGEs受体的表达，增强AGEs受体激动剂的活性，活化蛋白激酶C(protein kinase C,PKC)，超激活己糖胺途径(hexosamine pathway)等，来引起糖尿病的并发症。此外,体内自由基的积累还会直接抑制内皮型一氧化氮合酶(endothelial nitric oxide synthase,eNOS)和环前列腺素合酶(prostacyclin synthase)这2种抗动脉粥样硬化的关键酶[52]。因此，茶叶作为天然抗氧化剂,在抗氧化方面也有防止T2D及其并发症的作用。
YAN，等[53]在小鼠实验中发现，绿茶儿茶素用150 mg/(kg·d)喂养4周后，血糖水平显著降低,糖耐受不良症状也有明显改善。在大鼠实验中绿茶儿茶素用20 mg/(kg·d)喂养45 d也发现了相同的现象。在随后的脂肪细胞实验中,发现0.5 μmol/L的EGCG可以缓解地塞米松(dexamethasone)和肿瘤坏死因子(tumor necrosis factor α,TNF-α)引起的活性氧积累现象。并且，在动物和细胞实验中都发现绿茶儿茶素可以起到清除活性氧的作用,推测绿茶可以通过抗氧化的效果来调节血糖。此外,LEAN，等[54]利用T2D患者做了临床实验,与对照相比,患者在为期2周摄入富含膳食黄酮类的物质(每天400 g洋葱,6杯茶)后,淋巴球的DNA损伤有显著下降的现象。且血浆中除了黄酮类,其余抗氧化物质如维生素C、类胡萝卜素、α-生育酚、尿酸、清蛋白、胆红素等均无明显上升。从中可推测茶叶里的黄酮类物质可以清除自由基来减少T2D引起的DNA损坏现象。
3.2 维持一氧化氮(NO)和内皮素-1(endothelin-1,ET-1)平衡胰岛素能分别通过PI3K和MAPK途径促进内皮细胞分泌NO和ET-1,其中NO会造成血管舒张,ET-1则使得血管紧缩[55]。在健康的人体循环系统中,NO和ET-1处于动态平衡状态,且由于胰岛素的分泌,NO造成的血管舒张现象会略胜一筹。当胰岛素抵抗现象发生时,PI3K(phosphatidyl inositol 3-kinase)途径被破坏,MAP激酶途径被上调,最终导致NO含量下降,ET-1含量上升。NO与ET-1的平衡被打破,就容易引起高血压、T2D、动脉粥样硬化等疾病[56]。
REITER，等[57]利用10 μmol/L的EGCG对牛和人的大动脉内皮细胞进行处理,发现2 h后,ET-1的含量明显下降,8 h后ET-1的浓度和mRNA也明显减少。进一步实验发现,EGCG通过激活Akt和AMPK途径来上调ET-1启动子调节器FOXO1(ET-1 promoter modulator),使得ET-1的表达量下降,从而起到下调ET-1的作用。KIM，等[58]用10 μmol/L的EGCG处理牛内皮细胞15 min后发现eNOS有磷酸化产物出现。随后将摩尔浓度提高到50 μmol/L后,Akt和eNOS均有被磷酸化的现象,而且在15~240 min之间随着处理时间的增加磷酸化现象越明显。随后的压强实验证明了EGCG是通过PI3K途径使得血管扩张而非胰岛素的MAPK途径。因此,EGCG可通过激活PI3K/Akt途径起到增加NO的同时降低ET-1,扮演了NO与ET-1平衡剂的角色,间接缓解了T2D。
3.3 抑制11β羟基类固醇脱氢酶(11beta-hydroxysteroid dehydrogenase type 1,11β-HSD1)在人体肝中,细胞内皮质醇浓度的上升会增加葡萄糖的输出,和脂肪的积累以及胰岛素敏感性的降低，最终导致代谢异常[59]。内皮质醇被11β-HSD1催化生成[60]。故11β-HSD1与胰岛素抵抗、T2D、高血糖、血脂异常和肥胖有关[61-63],它的减弱会改善糖耐受不良，会缓解胰岛素抵抗与减弱糖异生作用[64-66]。
HINTZPETER，等[67]利用不同种类的茶叶及茶多酚和儿茶素，对11β-HSD1的抑制效果进行了体外实验,发现绿茶的效果最好,IC50为3.75 mg/mL干茶水提法,儿茶素中EGCG效果最好,IC50为(57.99±1.99) μmol/L。
4 展望综合上述相关的研究结果,茶叶对Ⅱ型糖尿病的治疗作用途径及机制可以用图 1进行简单阐述。此外,表 1反映了茶叶抵抗T2D的主要物质及其作用场所和对象,可以看出EGCG在抵抗T2D中占了主要地位。
-42-03-358-1.jpg "点击查看原图") |
| AGEs:晚期糖基化终末产物;AGEs-A:晚期糖基化终末产物受体激动剂;AGEs-R:晚期糖基化终末产物受体;PKC:蛋白激酶C;Polyol PW flux:多元醇通路;Hexosamine PW:己糖胺途径；CaMKK β:钙调蛋白激酶β;AMPK;腺苷酸活化蛋白激酶;G6Pase：葡萄糖-6-磷酸激酶;PEPCK:磷酸烯醇丙酮酸羧激酶;GLUT4:葡萄糖运载体4;PI3K:磷脂酰肌醇-3激酶;Akt:蛋白激酶B;11β-HSD1:Ⅰ型11β羟基类固醇脱氢酶；PTP1B:酪氨酸磷酸酶;IR:胰岛素受体;IRS-1:胰岛素受体底物;PPARγ:氧化物酶增生激活受体;DPP-Ⅳ:二肽基肽酶Ⅳ;GLP-1:胰高血糖素样肽-1;eNOS:内皮型一氧化氮合酶;NO:一氧化氮;ET-1:内皮素-1;FOXOL:ET-1启动子调节器;T2D:Ⅱ型糖尿病;↓:正效应;⊥:负效应. AGEs: advanced glycation end products; AGEs-A: advanced glycation end products-agonist; AGEs-R: advanced glycation end products-receptor; PKC: protein kinase C; Polyol PW flux: polyol pathway flux; Hexosamine PW: hexosamine pathway; CaMKK β: calmodulin-dependent protein kinase kinase-β; AMPK: adenosine monophosphate activated protein kinase; G6Pase: glucose-6-phosphatase; PEPCK: phosphoenolpyruvate carboxy kinase; GLUT4: glucose transporter 4; PI3K: phosphatidyl inositol 3-kinase; Akt: protein kinase B; 11β-HSD1: 11beta-hydroxysteroid dehydrogenase type 1; PTP1B: protein tyrosine phosphates 1B; IR: insulin receptor; IRS-1: insulin receptor substrate-1; PPARγ: peroxisome proliferator-activated receptor γ; DPP-Ⅳ: dipeptidyl peptidase-Ⅳ; GLP-1: glucagon-like peptide-1; eNOS: endothelial nitric oxide synthase; NO: nitric oxide; ET-1: endothelin-1; FOXOL: ET-1 promoter modulator; T2D: type 2 diabetes; ↓: positive effects; ⊥: negative effects。 图1 茶叶抵抗T2D的主要物质及其作用部位与对象 Fig. 1 Parts and targets of effective chemicals for anti-T2D by tea |
| 表1 茶叶抵抗T2D的主要物质及其作用部位与对象 Table 1 Parts and targets of effective chemicals for anti-T2D by tea |
-42-03-358-T1.jpg "点击查看表格内容") |
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近年来,已经有许多药品级的化合物被用于治疗DM,这些药物通过针对患者的不同病理、生理性缺陷来控制和改善血糖循环。但是使用药物往往很难摆脱它们所带来的不良反应,因此DM患者迫切需要一系列新的治疗方法来缓解病症。许多流行病学的观察研究已经指出膳食疗法在预防和控制DM中起到主要的作用,通过食用一些特定的食品产物,膳食因子可以降低发病率。而更多的研究证据证明了纤维、黄酮类以及单宁，通过调节各种不同的酶、荷尔蒙和器官起到调节血糖的作用,尽管大多数实验是在体外或者动物体内进行的,但根据现有的知识,它们已经可以用于DM的辅助治疗。
茶叶作为一种天然降血糖材料已经被国内外学者广泛研究,获得许多有益结果。通过前面的综述分析,可看到茶叶在Ⅱ型糖尿病治疗上有明显的效果。主要表现在增加胰岛素分泌，增强胰岛素活性和敏感性，增强肠促胰岛素活性，增强糖酵解和抑制糖异生以及抗氧化等方面入手对T2D进行控制,相关的重要代谢途径有AMPK途径和PI3K/Akt。一是茶叶在治疗Ⅱ型糖尿病方面的细胞学和分子生物学机制仍然没有完全解开；二是不同茶类在茶叶治疗上的差异原因也不清楚，需要我们更进一步的研究。
从以上的机制分析中可看到,许多可能影响糖尿病患者代谢途径的机制并没有完全研究透彻。如茶叶中的茶氨酸(L-theanine)能否在神经系统中通过促进多巴胺(dopamine)来调控胰岛素的活动和脂肪的积累[68-69],茶叶中其他黄酮类能否激活PPARγ[70]，红茶中是何种成分增加了胰岛素活性,又具体是哪种成分抑制了DPP-Ⅳ或者促进了GLP-1等[71]问题，仍然属于未解之谜,需要以后的研究者做进一步解答。
此外,当前的研究已经充分证明了茶叶及其提取物具有胰岛素敏化剂等一系列附属功能。尽管如此,与葡萄糖胺、可可粉、维生素C相比,它们在药物代谢动力学、药效学以及临床研究方面甚少,与现有的抗DM药之间的组合效应也是非常值得研究的。
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