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GLP—1受体激动剂对2型糖尿病患者血管病变影响的研究进展

2017-07-31刘晶晶魏丽王建波

中国医药导报 2017年18期
关键词:降糖激动剂心肌细胞

刘晶晶++++++魏丽++++++王建波

[摘要] 2型糖尿病(T2DM)是动脉粥样硬化疾病主要危险因素,因此防治糖尿病血管病变是糖尿病患者除了降糖外另一重要目的。外源性胰高血糖素样肽-1(GLP-1)或GLP-1受体激动剂是一种新型降糖药,其降糖作用已经非常明确,主要是通过与GLP-1受体相结合,從而促进胰岛素分泌来降低血糖。近年来国内外各种研究发现,GLP-1受体激动剂还具有心血管保护作用,其机制可能是通过改善血管内皮细胞功能、抗氧化应激、降低血压、血脂、抑制心肌细胞凋亡等来实现的。GLP-1受体激动剂能否以及是如何改善T2DM患者血管并发症发生发展,仍需要长期大量的研究证实。

[关键词] 胰高血糖素样肽1受体;GLP-1受体激动剂;2型糖尿病;心血管

[中图分类号] R587.1 [文献标识码] A [文章编号] 1673-7210(2017)06(c)-0038-04

[Abstract] Type 2 diabetes is a major risk factor of atherosclerotic disease. Thus, the prevention and treatment of diabetic vascular lesions is another important purpose in addition to hypoglycemic for diabetes patients. Exogenous administration of glucagon-like peptide-1 (GLP-1) or GLP-1 receptor agonist is a new kind of antidiabetic drugs, its hypoglycemic effect has been very clear, mainly through the combination with GLP-1 receptors, thereby promoting insulin secretion to reduce blood glucose. In recent years, domestic and foreign studies have found that GLP-1 receptor agonists also have cardiovascular protection. The mechanism may be achieved by improving the function of vascular endothelial cells, antioxidant stress, lowering blood pressure, lowering blood lipid, inhibiting the apoptosis of myocardial cells and so on. However, whether GLP-1 receptor agonists can improve the development of vascular complications in patients with T2DM remains to be confirmed for a long time.

[Key words] Glucagon-like peptide-1 receptor; GLP-1 receptor agonists; Type 2 diabetes mellitus; Cardiovascular

2型糖尿病(type 2 diabetes mellitus,T2DM)是心脑血管疾病发展的主要危险因素[1],血管并发症更是2型糖尿病患者死亡的首要原因。因此,对于T2DM患者在控制血糖的同时进行血管保护具有十分重要的意义。胰高血糖素样肽1(glucagon-like peptide-1,GLP-1)受体激动剂是一种新型降糖药,近年来国内外各种研究发现除降糖作用之外,其还通过多种机制发挥抗动脉粥样硬化作用,改善T2DM患者血管并发症的发生、发展[2]。本文就GLP-1受体激动剂与糖尿病血管病变的相关性及作用机制予以综述。

1 GLP-1受体生物学作用

GLP-1是由远端小肠和结肠内的L细胞分泌的一种肠促胰素,1932年,LaBarre首次提出了“肠促胰素”这一概念[3]。GLP-1受体属于G蛋白偶联受体,该受体广泛分布于胰腺、胃和小肠黏膜以及心、肺、中枢神经系统[4]。此外,在肌细胞、脂肪细胞和肝脏也发现了GLP-1的结合位点,GLP-1受体分布广泛性决定了其作用多样性[5]。有研究发现,GLP-1与胰腺β细胞表面的GLP-1受体结合后可发挥降糖作用,是通过刺激G蛋白激活腺苷酸环化酶(AC),使细胞内环磷酸腺苷(cAMP)水平升高,再通过下游系列分子机制参与胰岛素分泌过程的调控[6]。随着对GLP-1受体生理功能的深入研究,发现GLP-1与受体结合后,除促进胰岛素分泌之外,还具有保护胰岛、减肥、改善血管内皮功能等作用[7]。

2 GLP-1受体激动剂概述

GLP-1受体激动剂为GLP-1的同源性物质,天然GLP-1在体内被二肽酰肽酶-4(dipeptidyl-peptidase Ⅳ,DPP-4)迅速降解,而GLP-1受体激动剂不会被DPP-4降解,可通过激活GLP-1受体替代生理性GLP-1发挥作用,可使GLP-1浓度达到药理水平[8]。因此,GLP-1受体激动剂具有避免快速被体内DPP-4降解的优点,逐渐代替内源性GLP-1成为研究和治疗糖尿病的热点。目前主要应用于临床的有艾塞那肽、利拉鲁肽等。多项研究表明这些GLP-1受体激动剂不但具有显著降糖疗效,同时还具有不增加体质量(甚至可能轻微地减轻体质量)[9]和较少低血糖风险(尤其是与磺脲类降糖药相比)的优点[10]。

3 GLP-1受体激动剂与血管病变的关系

3.1 GLP-1受体激动剂与改善内皮细胞功能

血管内皮细胞损伤是糖尿病血管病变造成因素及动脉粥样硬化的显著特征。Nystrom等[11]已经证实,在冠状动脉内皮细胞上存在GLP-1受体,使用GLP-1受体激动剂能减少血管损伤后内膜增厚和平滑肌细胞增殖。一项研究表明,艾塞那肽可通过磷酸肌醇激酶3(phosphatidylinositol 3-kinase,PI3K)信号途径调节Bcl-2/Bax蛋白表达来抑制高糖诱导的内皮细胞凋亡[12]。Shiraki等[13]证实,对暴露于肿瘤坏死因子-α(TNF-α)的人脐静脉内皮细胞,利拉鲁肽可通过抑制PKCα、NADPH氧化酶、NF-κB信号传导通路,减轻伴随的内皮细胞功能障碍[14]。以上研究均表明糖尿病患者采用GLP-1受体激动剂进行治疗,可改善血管内皮功能障碍。另一方面,有研究显示,高糖诱导时会产生GLP-1抵抗,使内皮细胞上的GLP-1受体水平降低,并扰乱GLP-1的一般途径,从而可能导致糖尿病血管并发症发生[15]。

3.2 GLP-1受体激动剂与抗氧化应激

Brownlee[16]曾指出,无论糖尿病心脑血管、下肢血管还是微血管并发症,都有一个共同发病机制——氧化应激。因此,糖尿病患者体内氧化应激反应加剧是造成其血管并发症发病率不断攀升的原因之一[17]。研究证实,GLP-1受体激动剂具有抗氧化应激作用[18],其可以通過降糖及降糖外的其他机制来抑制氧化应激。①抑制线粒体氧化磷酸化:高糖状态下葡萄糖经糖酵解途径提供给线粒体呼吸链的供氢体(NADH和FADH2)增多,使氧化自由基(ROS)生成增加[19]。GLP-1受体激动剂可通过调节糖原合成酶激酶3β(GSK-3β)和过氧化物酶体增殖物激活受体γ辅激活因子1α(PGC-1α)两个相互合作的信号通路减少细胞线粒体tau蛋白过度磷酸化,从而抑制氧化应激反应[20]。②减少氧化酶基因的表达:GLP-1受体激动剂可通过与GLP-1受体相结合,减少还原型烟酰胺腺嘌呤二核苷酸磷酸氧化酶gp91phox和氧化酶p67phox、p22phox的基因表达,从而减少超氧化物生成[21]。

3.3 GLP-1受体激动剂与降血压

糖尿病患者的高血压是发生心血管并发症主要驱动因素。一项临床试验表明,在25~41岁的健康人群中,收缩压和舒张压的高低与GLP-1水平有着显著联系,且这种关系会在发生胰岛素抵抗时被减弱[22]。Kim等[23]研究表示,在C57BL/6小鼠模型中,用利拉鲁肽处理的小鼠注入血管紧张素Ⅱ时表现出快速和显著血压下降,并指出利拉鲁肽对血压的作用与增强心房钠尿肽(ANP)分泌有关,且此降压作用可被ANP受体拮抗剂阻断。此外,GLP-1受体激动剂降低血压的另一个机制可能是抑制水钠重吸收,通过增加肠促胰素水平,抑制肾近端小管Na/H交换体的活性,从而抑制肾脏近端小管的Na重吸收,增加尿钠排泄,降低血压[24]。

3.4 GLP-1受体激动剂与降血脂

T2DM可导致脂代谢异常,包括低密度脂蛋白胆固醇、富含三酰甘油的脂蛋白(triglyceride-rich lipoprotein,TRL)、非酯化脂肪酸的增多以及高密度脂蛋白胆固醇的减少等,血脂紊乱与动脉粥样硬化性斑块的形成密切相关[24]。一项临床试验指出,艾塞那肽同时具有调节脂代谢的作用,可降低T2DM患者总胆固醇和三酰甘油水平[25]。GLP-1受体激动剂降血脂机制目前并不明确,概括而言可能与内源性GLP-1受体信号对控制肠道脂蛋白合成和分泌有关,GLP-1可以降低餐后乳糜微粒,减少脂质吸收以及TRL、三酰甘油和apoB-48的水平[26]。载脂蛋白B48(apolipoprotein B-48,apoB-48)参与乳糜微粒的组装和代谢,其分泌过多可致脂代谢异常,进而导致肥胖和动脉粥样硬化等疾病的发生。

3.5 GLP-1受体激动剂与防止心肌损伤

近年研究发现,糖尿病患者体内持续高血糖可导致心肌损伤及心肌传导系统异常等[27]。Lonborg等[28]发现,对ST段抬高型心肌梗死患者行经皮冠状动脉介入治疗时给予GLP-1受体激动剂静脉低剂量输注可以提高心肌细胞存活率和减少梗死面积。关于保护机制有研究表明,利拉鲁肽是通过激活Epac-1/Akt信号途径来防止高糖诱导的心肌细胞凋亡[29]。Yi等[30]认为,GLP-1受体激动剂可以抑制高糖诱导的心肌细胞晚期糖基化终末产物受体(RACE)表达,并通过降低Capase-3的活性减少细胞凋亡,增加心肌细胞活性,从而防止心肌损伤,RACE轴的激活是心肌细胞凋亡的重要机制之一。近期一项研究指出,GLP-1受体激动剂可通过抑制心肌细胞miR-27a表达,发挥抗心肌细胞凋亡的作用[31]。微小RNA(miRNA)是一类保守的内源性非编码单链小分子RNA,其在心血管疾病发生、发展中扮演着重要角色,miR-27a是目前研究较多与细胞凋亡密切相关的miRNA[32]。

4 小结

迄今为止获得的研究结果和一些荟萃分析表明,GLP-1受体激动剂不但具有降低血糖、降低血压、改善血脂的功能,而且表现出改善血管内皮功能、抑制炎性反应、减少心肌梗死缺血等作用,减少动脉粥样硬化的形成,对糖尿病血管病变起到预防和治疗的作用。随着对糖尿病病理生理机制和肠促胰素生理作用研究的深入,GLP-1受体激动剂作为一种基于肠促胰素机制的治疗药物,其广泛的心血管保护作用为治疗带来了新的希望。目前仍需要更多基础及临床研究来明确其长期应用对糖尿病血管并发症的有利影响。

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