郭莉霞,刘建辉,殷菲
(重庆工商大学药物化学与化学生物学研究中心,重庆400067)
高血糖素样肽1(9-36)NH2的生理学功能
郭莉霞,刘建辉,殷菲
(重庆工商大学药物化学与化学生物学研究中心,重庆400067)
许多研究表明,高血糖素样肽1(9-36)NH2〔GLP-1(9-36)NH2〕是GLP-1(7-36)NH2被二肽基肽酶快速降解后的主要体内存在形式,具有许多的生理学功能。GLP-1(9-36)NH2中除了具有非依赖于胃排空和胰岛素分泌所致的降低餐后血糖的作用外,GLP-1(9-36)NH2更多的是直接对外周器官的保护作用,包括快速逆转心力衰竭、改善舒张末期压、快速刺激心肌葡萄糖摄取及减少缺血再灌注对心脏的损伤;以及它具有不依赖于GLP-1受体的血管系统的抗氧化作用和抑制肝脏糖原异生、促进肝糖原的合成。因此,可以说明GLP-1(9-36)NH2在体内是一个具有重要生理功能的活性肽,而不仅仅是GLP-1(7-36)NH2的代谢产物。GLP-1(9-36)NH2对糖尿病及其包括胰岛素抵抗、心血管疾病、肝脏脂肪变性等并发症的治疗将会起到非常重要的作用。
高血糖素样肽1(9-36)NH2;生理功能;心血管系统;肝
高血糖素样肽1(glucagon-like peptide-1,GLP-1)是肠上皮内分泌L细胞所分泌的一种肽类物质,作用于体内的胰腺β细胞和α细胞、胃肠道、中枢神经系统及心脏等,它能够通过促进胰岛素分泌[1]、刺激胰岛β细胞增生[2]、阻止胰岛β细胞凋亡[3]、抑制高血糖素的释放[4]、延迟胃排空、产生饱胀感和食欲下降等多重途径来控制血糖。最重要的是,GLP-1具有葡萄糖浓度依赖性效应[5-6],降糖过程中可有效减少低血糖的发生。
体内的GLP-1进入到循环系统时很快地被二肽基肽酶Ⅳ(dipeptidyl peptidaseⅣ,DPP-Ⅳ)降解(t1/2=1~2 min),降解产物主要为GLP-1(9-37)和GLP-1(9-36)NH2,占总GLP-1的80%~90%[7]。很多研究都证明GLP-1(9-37)或GLP-1(9-36)NH2是较弱的GLP-1受体(GLP-1R)的激动剂,促胰岛素分泌活性远不及GLP-1[8],而且不能改善胰腺β细胞的生长及功能,长时间孵育还可致GLP-1R脱敏[9]。自发现GLP-1功能以来[10],人们在关注GLP-1所带来的欣喜之时,却忽视它的代谢产物本来的生理功能,直到2005年Nikolaidis等[11]发现GLP-1(9-36)NH2对心脏的保护作用,才渐渐重视了GLP-1(9-36)NH2的研究。虽然,2005年前已对GLP-1(9-36)NH2的生理功能进行了探讨,但都没有发现其功能[12-13]。本文从GLP-1的产生和分泌着手,综述GLP-1(9-36)NH2在心脏、血管系统及肝的生理功能,为研究GLP-1及其类似物治疗糖尿病和其并发症理清思路以及提供理论依据。
胰腺、肠道和脑中均表达高血糖素原mRNA,但在不同器官中翻译为不同产物。在肠中,高血糖素原被位点选择性蛋白酶1/3作用形成无活性的高血糖素、有活性的GLP-1(7-36)NH2和GLP-2(图1)。进食后,在营养物(特别是碳水化合物)的刺激下,GLP-1(7-36)NH2从肠上皮内分泌L细胞分泌出来,通过基膜被毛细血管吸收,此时,GLP-1(7-36)NH2就开始被DPP-Ⅳ降解成GLP-1(9-36)NH2,只剩余约25%的未被降解的GLP-1(7-36)NH2进入到门静脉循环;到达肝后,未降解的GLP-1(7-36)NH2又有40%~50%GLP-1(7-36)NH2被降解,所以最后进入体循环系统的GLP-1(7-36)NH2只有最初含量的10%~15%可到达胰腺、脑等部位发挥作用(有可能血浆中的DPP-Ⅳ再降解GLP-1使得存在的量会更少)[14]。GLP-1(9-36)NH2又进一步被中性肽链内切酶(neutral endopeptidase,NEP)24.11分别降解成2个短肽即9肽〔GLP-1(28-36)NH2〕和5肽〔GLP-1(32-36)NH2〕[15]。
研究表明,体内GLP-1的主要存在形式是GLP-1(9-36)NH2(80%~90%)[7],而且具有较弱的促进胰岛素分泌的功能[8]。从进化的角度来讲,这些结果说明两个问题:①GLP-1(9-36)NH2承接了GLP-1(7-36)NH2的功能,可以缓解餐后血糖过高;②它本身可能具有其他的、不同于GLP-1(7-36)NH2的重要的生理学功能。
图1 肠中高血糖素样肽1(GLP-1)的生成及降解过程[15].Fig.1 Generation and degradation process ofglucagon-like peptide-1(GLP-1)in guts[15].
GLP-1(7-36)NH2的重要生理作用就是延迟胃排空、促胰岛素分泌及类胰岛素作用[1];然而GLP-1(9-36)NH2的这些作用还不是很确定。Elahi等[16]研究发现,肥胖患者在注射葡萄糖和GLP-1(9-36)NH2后,血浆胰岛素水平快速显著升高。但也有研究表明,GLP-1(9-36)NH2具有降血糖的作用,但并不依赖于胃排空和胰岛素的分泌[17-18]。同样,对ob/ob小鼠连续14 d注射GLP-1(9-36)NH2并不影响血浆胰岛素及葡萄糖的动态平衡[19]。
Nikolaidis等[11]首先发现GLP-1(9-36)NH2对心脏的有直接作用并建立了实验性扩张型心肌病(dilated cardiomyopathy,DCM)的狗模型,此模型表现出左心室或双心室扩张并伴心室收缩功能受损的进行性充血性心力衰竭,直接灌注GLP-1(9-36)NH2后,快速地逆转心力衰竭,改善舒张末期压以及显著地刺激心肌葡萄糖摄取,并且此过程中并没有改变血浆胰岛素的水平,说明GLP-1(9-36)NH2的作用是直接增加了糖酵解,即葡萄糖氧化的过程。GLP-1(9-36)NH2对心脏的保护作用还在分离出的小鼠的缺血再灌注损伤的心脏实验中得到验证[20],它能改善心功能,增加血管舒张和冠状动脉血流,减少缺血诱导的心肌损伤。另外,一些研究也显示,GLP-1(9-36)NH2的心脏保护功能不依赖于GLP-1R[20-23]。在敲除GLP-1R的小鼠心脏中,GLP-1(9-36)NH2依然发挥心脏保护功能[23];同样,在分离出的大鼠的缺血再灌注损伤的心脏中分别给予激动肽4和GLP-1(9-36)NH2,都能够恢复左心室的功能,而此效应只部分地被GLP-1R的拮抗剂激动肽(9-39)所抑制[22]。
探讨作用机制的研究发现,随着GLP-1(9-36)NH2对心脏的保护作用的发生,心肌cGMP的量、NO合酶的活性及NO的产率都有所增加,活性氧含量减少,说明GLP-1(9-36)NH2可能具有抗氧化的作用[20]。
Green等[24]研究发现,不仅GLP-1(7-36)NH2及其长效类似物激动肽4,还有GLP-1(9-36)NH2和GLP-1R拮抗剂激动肽(9-39)都对分离出的大鼠血管有舒张的作用。这些作用部分经由cAMP,开放ATP敏感的K+通道。但是,也有研究表明,在分离出来的大鼠股动脉血管环体外实验中,GLP-1(7-36)NH2和GLP-1(9-36)NH2有显著的血管舒张的作用,而激动肽4并未表现出明显的作用[25]。众所周知,GLP-1(7-36)NH2和激动肽4是GLP-1R的强效激动剂,GLP-1(9-36)NH2只能部分地激活GLP-1R[8],如同GLP-1(9-36)NH2对心脏的作用一样,血管舒张的作用可能是GLP-1R非依赖性的,而且,GLP-1(7-36)NH2对血管舒张的作用是因为其被DPP-Ⅳ快速降解为GLP-1(9-36)NH2而发挥作用的,无论是先天遗传的还是利用化学试剂来抑制DPP-Ⅳ的活性都不能改善心血管系统的功能[26]。另外,由于是分离出来的股动脉血管,排除了由于GLP-1(7-36)NH2和激动肽4具有的促胰岛素释放而间接发挥的作用[24]。
Elahi等在肥胖所致的胰岛素抵抗的糖尿病患者身上证明了GLP-1(9-36)NH2的作用。在给这些患者注射GLP-1(9-36)NH2的15~20 min后,肝糖原异生就快速减少了50%,但是对体瘦的、胰岛素敏感的患者并未起作用。有研究也证实,对正常的、胰岛素敏感的人注射GLP-1(9-36)NH2后,既不影响胰岛素的释放,也不影响葡萄糖的代谢[12]。由此可以看出,GLP-1(9-36)NH2不影响人体内正常的葡萄糖代谢,但是一旦糖尿病患者体内的糖代谢紊乱,GLP-1(9-36)NH2短时间就会作出反应,这可能可以解释体内GLP-1(9-36)NH2存在的主要原因。
最近,Tomas等[27]发现,GLP-1(9-36)NH2能抑制分离的肝实质细胞的葡萄糖异生,并且此效应不依赖于GLP-1R和其类胰岛素活性。另外,除了GLP-1(9-36)NH2直接作用到肝实质细胞外,有实验证明在肝门静脉迷走神经传入末梢表达有GLP-1R。经门静脉灌注给予大鼠[28]和狗[29]GLP-1后,增加了肝葡萄糖摄取及肝糖原的储存,而且这个作用可以被GLP-1R的拮抗剂激动肽(9-39)所抑制。然而有不同的研究结果,Naishizawa等[30]就发现,经门静脉灌注给予激动肽4后对肝并没有作用,而且激动肽(9-39)也没有阻断GLP-1刺激迷走神经传入末梢的作用。而且对于弱的GLP-1受体激动剂GLP-1(9-36)NH2来说,也有减少肝糖原异生的作用[16]。另外,GLP-1经肝动脉灌注也能达到门静脉灌注的增加葡萄糖摄取的相同效果[31]。所有这些结果都说明了肝门静脉的GLP-1R有可能只参与了部分肝葡萄糖代谢的功能,也就是说GLP-1R对于肝葡萄糖代谢不是必需的[31]。
GLP-1(9-36)NH2是DPP-Ⅳ降解GLP-1的主要的体内代谢存在形式,越来越多的研究发现,GLP-1(9-36)NH2不仅仅是一个代谢产物,它具有恢复心脏功能,改善心血管系统,调节肝糖原异生的重要的生理学作用。如果打破了生理状态下的GLP-1(9-36)NH2在体内的平衡,有可能会增加心脏、肝及血管系统的损伤风险。这是值得进一步研究的。
虽然血流动力学研究结果表明GLP-1(9-36)NH2在心血管系统不具有保护作用[32],但从目前的研究结果看,不能忽视GLP-1(9-36)NH2的生理作用。对GLP-1(9-36)NH2的进一步深入研究,将成为GLP-1类似物治疗糖尿病研究过程中不可避免的一个重要环节。
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Physiological functions of glucagon-like peptide-1(9-36)NH2
GUO Li-xia,LIU Jian-hui,YIN Fei
(Research Center of Pharmaceutical Chemistry and Chemibiology,Chongqing Technology and Business University,Chongqing 400067,China)
Many findings demonstrate that glucagon-like peptide-1(9-36)NH2〔GLP-1(9-36)NH2〕,mostly a cleavage product of GLP-1(7-36)NH2,has a lot of physiological functions.GLP-1(9-36)NH2can reduce postprandial glycemia independently of gastric emptying and insulin secretion,rapidly reverse heart failure,improve end diastolic pressure,markedly stimulate myocardial glucose uptake,exert antioxidant cardioprotective actions,reduce oxidative stress in vasculature tissues independently of GLP-1 receptor,suppress hepatic glucose production,and promote glycogen stores.Thus,GLP-1(9-36)NH2is an active peptide with important physiological functions,and it will play an important role in treating obesity and accompanying manifestations of metabolic syndrome,including insulin resistance,cardiovascular disease,and hepatic steatosis.
glucagon-like peptide-1(9-36)NH2;physiological functions;cardiovascular system;liver
The project supported by National Natural Science Foundation of China(30973576);Key project of Chongqing Science and Technology Committee(CSTC2009BA5069);Innovative Research Team Development Program in University of Chongqing(KJTD201020);and Project of Chongqing Municipal Education Committee(KJ090710)
GUO Li-xia,E-mail:mglx5794@ctbu.edu.cn,Tel:(023)62768056
Q493
A
1000-3002(2011)05-0483-04
10.3867/j.issn.1000-3002.2011.05.013
国家自然科学基金项目(30973576);重庆市科委重点项目(CSTC2009BA5069);重庆市科技创新团队项目(KJTD201020);重庆市教委项目(KJ090710)
郭莉霞,(1979-),女,博士研究生,主要从事中药有效成分的药理学研究。
郭莉霞,E-mail:mglx5794@ctbu.edu.cn,Tel:(023)62768056
2010-12-30接受日期:2011-05-05)
(本文编辑:乔虹)