DPP4抑制劑對糖尿病的作用：遠(yuǎn)遠(yuǎn)超過控制血糖

朱路 李華榮

糖尿病的患病人數(shù)在全世界持續(xù)上升，且有低齡化的趨勢。糖尿病是一種以高血糖為特征的代謝性疾病，它的發(fā)病機(jī)制與遺傳因素和免疫功能紊亂等因素有關(guān)。2型糖尿病與胰島素抵抗相關(guān)，患者的胰島素信號受損。另一方面，糖尿病會增加相關(guān)心血管疾病(CVD)和慢性腎臟疾病(CKD)發(fā)生的風(fēng)險,會引起心腎性代謝綜合征(CRS，指心臟和腎臟其中一個作為原發(fā)性受損器官均可影響另一器官的功能的臨床綜合征)[1-6]。傳統(tǒng)藥物不能針對糖尿病的全部發(fā)病機(jī)制發(fā)揮療效，而近年上市的二肽基肽酶 4(DPP4)抑制劑為治療糖尿病開辟了新途徑。目前已有深入研究并已應(yīng)用于臨床的DPP4抑制劑有西格列汀(Sitagliptin)、沙格列汀(Saxagliptin)、維格列汀(Vildagliptin)、阿格列汀(Alogliptin)和利格列汀(linagliptin)。本文將通過分析胰島素抵抗、免疫功能、CRS之間的關(guān)聯(lián)，來闡明DPP4抑制劑治療糖尿病的機(jī)制，其不僅僅能控制血糖，并能改善胰島素代謝信號和胰島素抵抗，還能保護(hù)心血管，改善CRS，降低血壓。

一、胰島素抵抗、免疫功能、CRS之間的關(guān)聯(lián)

早期研究已經(jīng)發(fā)現(xiàn)，胰島素抵抗會引起心血管疾病和腎損傷[5-7]。胰島素抵抗對心臟功能有著深遠(yuǎn)的影響，尤其是在心臟舒張期功能上，且胰島素抵抗可能有助于發(fā)現(xiàn)血管內(nèi)皮功能障礙、心血管疾病、早期慢性腎病[4-5]。

心血管、腎臟疾病與胰島素代謝信號受損相關(guān)。胰島素信號通路主要有磷脂酰肌醇3激酶(PI3-K)/蛋白激酶B(PKB)信號通路及促蛋白激酶(MAPK)信號通路[6]。 導(dǎo)致胰島素抵抗發(fā)生主要的點(diǎn)是蛋白質(zhì)胰島素受體底物1(IRS-1) 。研究發(fā)現(xiàn)，游離脂肪酸(FFA)可增加IRS-1的絲氨酸磷酸化，抑制胰島素代謝信號，引發(fā)2型糖尿病。胰島素代謝信號受損會使心臟舒張功能受損、鈣處理受損、基質(zhì)代謝改變、線粒體功能障礙、炎癥和氧化應(yīng)激，導(dǎo)致心肌纖維化和減少肌漿網(wǎng)的鈣吸收[7-10]。另外，胰島素抵抗會使內(nèi)皮細(xì)胞基質(zhì)釋放減少、代謝不靈活，引起心臟纖維化。胰島素信號受損也可導(dǎo)致腎小球和腎小管功能障礙[8-10]。

先天和適應(yīng)性免疫對胰島素代謝和心血管、腎臟疾病有影響。肥胖的人類和老鼠脂肪組織中的浸潤單核細(xì)胞和巨噬細(xì)胞數(shù)目增多。巨噬細(xì)胞被認(rèn)為是導(dǎo)致慢性炎癥、胰島素抵抗、和心血管功能障礙的關(guān)鍵因素[11-15]。另外, 除了巨噬細(xì)胞，T細(xì)胞也會在糖尿病肥胖脂肪組織中積聚[16-17]。Th1細(xì)胞因子會促進(jìn)胰島素抵抗的發(fā)生，Th2細(xì)胞因子誘導(dǎo)巨噬細(xì)胞分化為具有免疫抑制和抗炎特性的表型[14-15]。有研究顯示，糖尿病小鼠脂肪組織中的CD4+、CD25+、調(diào)控T細(xì)胞(Tregs)數(shù)量減少，這種不平衡可能會導(dǎo)致胰島素抵抗和糖尿病心血管并發(fā)癥的發(fā)生。另有研究發(fā)現(xiàn)，巨噬細(xì)胞和Tregs存在交叉調(diào)控[18-23]。

近來的研究已經(jīng)發(fā)現(xiàn)免疫系統(tǒng)在調(diào)節(jié)血管緊張素Ⅱ(AngⅡ)和醛固酮誘導(dǎo)心臟功能障礙、血管損傷、高血壓方面的作用。例如CD4+、CD25+、 Tregs的過繼轉(zhuǎn)移通過限制炎癥反應(yīng)可預(yù)防AngⅡ誘導(dǎo)心血管損傷和腎功能障礙。研究發(fā)現(xiàn)Th17細(xì)胞產(chǎn)生的某一促炎細(xì)胞因子有對抗Tregs的作用，長期攝入AngⅡ和醛固酮會導(dǎo)致IL-17生成增加和Tregs累積減少[23]。我們認(rèn)為，Th17細(xì)胞因子和Treg之間的不平衡可能是導(dǎo)致胰島素抵抗和CRS發(fā)生的關(guān)鍵因素[22]。

二、DPP4抑制劑的作用

1.控制血糖、抑制胰高糖素樣肽-1(GLP-1)降解和降血壓

通過強(qiáng)化胰島素分泌和抑制胰高糖素釋放，源自腸道的腸促胰島素GLP-1和葡萄糖依賴性促胰島素釋放肽(GIP)在維持餐后血糖以及長期的血糖穩(wěn)態(tài)中扮演著關(guān)鍵角色[24]。循環(huán)中的GLP-1和GIP迅速被DPP4酶降解，而DPP4抑制劑可減少其降解，從而發(fā)揮治療2型糖尿病的作用。

早期的心力衰竭和心肌梗死實(shí)驗(yàn)?zāi)Ｐ惋@示，DPP4抑制劑不僅能控制血糖，還因能減少GLP的降解而具有保護(hù)心血管的作用[26-27]。DPP4酶不是特定作用于GLP-1，其還能在其他范圍發(fā)揮多種多樣的作用[28]。DPP4底物包括有趨化因子,被稱為基質(zhì)細(xì)胞衍生因子-1α(SDF -1α)[29]。來源于骨髓的內(nèi)皮祖細(xì)胞(EPC)可以促進(jìn)血管修復(fù)和新血管形成，SDF -1α是EPC的調(diào)控者，可刺激EPC的啟動，由于SDF-1α是DPP4底物，抑制DPP4會增加SDF1-α的濃度，潛在地加強(qiáng)了EPC促進(jìn)受損血管修復(fù)的作用[30]。

已有研究證明，西格列汀可以降低高血壓患者和高血壓糖尿病老鼠的血壓，利格列汀對血管的舒張作用最強(qiáng)[25，29]。利格列汀和阿格列汀的舒張血管作用與NO/cGMP路徑有關(guān)。AngⅡ與DPP4/GLP-1信號的相互關(guān)聯(lián)，可以作為DPP4抑制劑降低血壓的一個理論機(jī)礎(chǔ)[31-34]。DPP4抑制劑也可以減少近端小管NHE3和鈉的攝取來降低血壓[34]。

2.通過免疫調(diào)節(jié)作用改善組織和系統(tǒng)的胰島素代謝信號

DPP4抑制劑在心血管炎癥中的免疫調(diào)節(jié)作用的相關(guān)研究較少。由于DPP4酶在T細(xì)胞和巨噬細(xì)胞中廣泛表達(dá)，DPP4抑制劑調(diào)節(jié)免疫系統(tǒng)的研究成為重要的新興研究領(lǐng)域[36-39]。接受DPP4抑制劑治療者的炎癥巨噬細(xì)胞M1減少、M2增加[35-41]。巨噬細(xì)胞極化減弱(M1減少)可改善炎癥反應(yīng)。肥胖者血清和組織中DPP4酶活動顯著增加，因此使用DPP4抑制劑是抑制炎癥和相關(guān)的胰島素抵抗的新策略[29，35]。 近期研究表明，巨噬細(xì)胞M2誘導(dǎo)了Tregs的感應(yīng)，而DPP4抑制劑增強(qiáng)了M2的極化，因此認(rèn)為，DPP4抑制劑療法改善了心臟和冠狀動脈的胰島素代謝信號，以及能改善相關(guān)的心臟和冠狀動脈的舒張功能損害和腎損傷，且有益于調(diào)節(jié)CRS的免疫反應(yīng)[40-44]。另外，聯(lián)合DPP4抑制劑和Ang受體/鹽皮質(zhì)激素受體阻斷劑來改善胰島素抵抗和心血管和腎臟的功能能獲得較好療效，可以促進(jìn)胰島細(xì)胞再生，也可改善糖尿病腎病[45-46]。也有報(bào)道示，聯(lián)合使用DPP4抑制劑與Tregs過繼轉(zhuǎn)移可以進(jìn)一步增加胰島素的敏感性[47-48]。

綜上所述，DPP4抑制劑不僅能控制血糖，還具有改善胰島素抵抗，保護(hù)心血管，降低血壓的作用，其已經(jīng)成為治療糖尿病的一種新選擇，DPP4抑制劑和Ang受體阻斷劑的聯(lián)合使用已經(jīng)在胰島細(xì)胞再生和治療糖尿病腎病方面顯現(xiàn)出良好的作用[45-46]。

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