DPP4抑制剂对糖尿病的作用：远远超过控制血糖

朱路 李华荣

糖尿病的患病人数在全世界持续上升，且有低龄化的趋势。糖尿病是一种以高血糖为特征的代谢性疾病，它的发病机制与遗传因素和免疫功能紊乱等因素有关。2型糖尿病与胰岛素抵抗相关，患者的胰岛素信号受损。另一方面，糖尿病会增加相关心血管疾病(CVD)和慢性肾脏疾病(CKD)发生的风险,会引起心肾性代谢综合征(CRS，指心脏和肾脏其中一个作为原发性受损器官均可影响另一器官的功能的临床综合征)[1-6]。传统药物不能针对糖尿病的全部发病机制发挥疗效，而近年上市的二肽基肽酶 4(DPP4)抑制剂为治疗糖尿病开辟了新途径。目前已有深入研究并已应用于临床的DPP4抑制剂有西格列汀(Sitagliptin)、沙格列汀(Saxagliptin)、维格列汀(Vildagliptin)、阿格列汀(Alogliptin)和利格列汀(linagliptin)。本文将通过分析胰岛素抵抗、免疫功能、CRS之间的关联，来阐明DPP4抑制剂治疗糖尿病的机制，其不仅仅能控制血糖，并能改善胰岛素代谢信号和胰岛素抵抗，还能保护心血管，改善CRS，降低血压。

一、胰岛素抵抗、免疫功能、CRS之间的关联

早期研究已经发现，胰岛素抵抗会引起心血管疾病和肾损伤[5-7]。胰岛素抵抗对心脏功能有着深远的影响，尤其是在心脏舒张期功能上，且胰岛素抵抗可能有助于发现血管内皮功能障碍、心血管疾病、早期慢性肾病[4-5]。

心血管、肾脏疾病与胰岛素代谢信号受损相关。胰岛素信号通路主要有磷脂酰肌醇3激酶(PI3-K)/蛋白激酶B(PKB)信号通路及促蛋白激酶(MAPK)信号通路[6]。 导致胰岛素抵抗发生主要的点是蛋白质胰岛素受体底物1(IRS-1) 。研究发现，游离脂肪酸(FFA)可增加IRS-1的丝氨酸磷酸化，抑制胰岛素代谢信号，引发2型糖尿病。胰岛素代谢信号受损会使心脏舒张功能受损、钙处理受损、基质代谢改变、线粒体功能障碍、炎症和氧化应激，导致心肌纤维化和减少肌浆网的钙吸收[7-10]。另外，胰岛素抵抗会使内皮细胞基质释放减少、代谢不灵活，引起心脏纤维化。胰岛素信号受损也可导致肾小球和肾小管功能障碍[8-10]。

先天和适应性免疫对胰岛素代谢和心血管、肾脏疾病有影响。肥胖的人类和老鼠脂肪组织中的浸润单核细胞和巨噬细胞数目增多。巨噬细胞被认为是导致慢性炎症、胰岛素抵抗、和心血管功能障碍的关键因素[11-15]。另外, 除了巨噬细胞，T细胞也会在糖尿病肥胖脂肪组织中积聚[16-17]。Th1细胞因子会促进胰岛素抵抗的发生，Th2细胞因子诱导巨噬细胞分化为具有免疫抑制和抗炎特性的表型[14-15]。有研究显示，糖尿病小鼠脂肪组织中的CD4+、CD25+、调控T细胞(Tregs)数量减少，这种不平衡可能会导致胰岛素抵抗和糖尿病心血管并发症的发生。另有研究发现，巨噬细胞和Tregs存在交叉调控[18-23]。

近来的研究已经发现免疫系统在调节血管紧张素Ⅱ(AngⅡ)和醛固酮诱导心脏功能障碍、血管损伤、高血压方面的作用。例如CD4+、CD25+、 Tregs的过继转移通过限制炎症反应可预防AngⅡ诱导心血管损伤和肾功能障碍。研究发现Th17细胞产生的某一促炎细胞因子有对抗Tregs的作用，长期摄入AngⅡ和醛固酮会导致IL-17生成增加和Tregs累积减少[23]。我们认为，Th17细胞因子和Treg之间的不平衡可能是导致胰岛素抵抗和CRS发生的关键因素[22]。

二、DPP4抑制剂的作用

1.控制血糖、抑制胰高糖素样肽-1(GLP-1)降解和降血压

通过强化胰岛素分泌和抑制胰高糖素释放，源自肠道的肠促胰岛素GLP-1和葡萄糖依赖性促胰岛素释放肽(GIP)在维持餐后血糖以及长期的血糖稳态中扮演着关键角色[24]。循环中的GLP-1和GIP迅速被DPP4酶降解，而DPP4抑制剂可减少其降解，从而发挥治疗2型糖尿病的作用。

早期的心力衰竭和心肌梗死实验模型显示，DPP4抑制剂不仅能控制血糖，还因能减少GLP的降解而具有保护心血管的作用[26-27]。DPP4酶不是特定作用于GLP-1，其还能在其他范围发挥多种多样的作用[28]。DPP4底物包括有趋化因子,被称为基质细胞衍生因子-1α(SDF -1α)[29]。来源于骨髓的内皮祖细胞(EPC)可以促进血管修复和新血管形成，SDF -1α是EPC的调控者，可刺激EPC的启动，由于SDF-1α是DPP4底物，抑制DPP4会增加SDF1-α的浓度，潜在地加强了EPC促进受损血管修复的作用[30]。

已有研究证明，西格列汀可以降低高血压患者和高血压糖尿病老鼠的血压，利格列汀对血管的舒张作用最强[25，29]。利格列汀和阿格列汀的舒张血管作用与NO/cGMP路径有关。AngⅡ与DPP4/GLP-1信号的相互关联，可以作为DPP4抑制剂降低血压的一个理论机础[31-34]。DPP4抑制剂也可以减少近端小管NHE3和钠的摄取来降低血压[34]。

2.通过免疫调节作用改善组织和系统的胰岛素代谢信号

DPP4抑制剂在心血管炎症中的免疫调节作用的相关研究较少。由于DPP4酶在T细胞和巨噬细胞中广泛表达，DPP4抑制剂调节免疫系统的研究成为重要的新兴研究领域[36-39]。接受DPP4抑制剂治疗者的炎症巨噬细胞M1减少、M2增加[35-41]。巨噬细胞极化减弱(M1减少)可改善炎症反应。肥胖者血清和组织中DPP4酶活动显著增加，因此使用DPP4抑制剂是抑制炎症和相关的胰岛素抵抗的新策略[29，35]。 近期研究表明，巨噬细胞M2诱导了Tregs的感应，而DPP4抑制剂增强了M2的极化，因此认为，DPP4抑制剂疗法改善了心脏和冠状动脉的胰岛素代谢信号，以及能改善相关的心脏和冠状动脉的舒张功能损害和肾损伤，且有益于调节CRS的免疫反应[40-44]。另外，联合DPP4抑制剂和Ang受体/盐皮质激素受体阻断剂来改善胰岛素抵抗和心血管和肾脏的功能能获得较好疗效，可以促进胰岛细胞再生，也可改善糖尿病肾病[45-46]。也有报道示，联合使用DPP4抑制剂与Tregs过继转移可以进一步增加胰岛素的敏感性[47-48]。

综上所述，DPP4抑制剂不仅能控制血糖，还具有改善胰岛素抵抗，保护心血管，降低血压的作用，其已经成为治疗糖尿病的一种新选择，DPP4抑制剂和Ang受体阻断剂的联合使用已经在胰岛细胞再生和治疗糖尿病肾病方面显现出良好的作用[45-46]。

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