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Diabetes:经典降糖药DPP-4抑制剂竟然还是糖尿病足的克星

2018-01-07 应雨妍 奇点网

每一款药物的诞生都带着自己的“使命”,有自己的适应症,但是在实验过程中,研究人员时不时能收获一些意料之外的惊喜。

每一款药物的诞生都带着自己的“使命”,有自己的适应症,但是在实验过程中,研究人员时不时能收获一些意料之外的惊喜。比如“神药”二甲双胍,除了本职工作降糖外,还有不少研究显示它可能有延缓衰老、抗癌和减重方面的效果。又或者像抗炎药物卡纳单抗,能降低心血管肺癌的发生风险。最近,这个“一药多用”的行列里又多了一个新成员——二肽基肽酶-4抑制剂,也就是DPP-4抑制剂。

DPP-4抑制剂也是一款经典的口服降糖药,这一次,陆军军医大学新桥医院郑宏庭教授的团队发现,这款经典降糖药还可以加速糖尿病患者的溃疡伤口愈合,治疗糖尿病足,他们不仅确定了其中机制,还在67名患者中进行了临床试验。研究结果发表在了美国糖尿病学会会刊《Diabetes》上。

糖尿病患者长期的高血糖水平会损害神经、肾、眼睛和血管,降低机体抗感染的能力。糖尿病足的发展具有综合性的原因,一方面糖尿病引起的周围神经功能障碍会让患者感受疼痛的能力下降,这意味着平时不太关注的部位即使有轻微的伤也难以被发现。再加上血管和免疫系统受损,创口不能按照正常速度痊愈,暴露在外容易发生细菌感染,创口不断扩大,严重的患者可能需要截肢才能终止病情的发展。


在人的角化细胞细胞系中,研究人员发现,与对照组相比,5种不同的DPP-4抑制剂(西格列汀、维格列汀、沙格列汀、阿格列汀和利格列汀)都能使细胞的损伤区域减小。接下来,研究人员以沙格列汀为代表,在化学物质诱导的2型糖尿病模型小鼠中也观察到了同样的效果。服用了DPP-4抑制剂的小鼠11天后伤口几乎完全愈合了,而对照组的小鼠还有20%尚未愈合。



紫色:DPP-4抑制剂(沙格列汀)组小鼠;黑色:对照组小鼠

观察到了效果还得再问一句为什么。以前的研究发现,DPP-4抑制剂可以激活NRF2,而NRF2通路在糖尿病导致的溃疡形成中起着保护作用,研究人员猜想,DPP-4抑制剂的效果也可能与这一通路有关。可是事实并没有这么简单,当研究人员敲低了NRF2之后,DPP-4抑制剂仍然加速了小鼠创口的愈合,和未敲低前保持了差不多的效果。这样看来,NRF2并不是DPP-4抑制剂起效的途径,或者说,至少不是主要途径。

通过对过去研究的总结,研究人员决定将重点放在角化细胞和成纤维细胞上,因为它们两个是伤口愈合过程中关键的参与者,也是皮肤中DPP-4的主要来源。研究人员观察到,在伤口愈合过程中,DPP-4抑制剂促进了角化细胞的迁移,而且有意思的是,这些角化细胞呈现出上皮间充质转化(EMT)的形态改变。

EMT与损伤修复有关,通过产生纤维细胞以修复由创伤和炎症造成的组织损伤,5种不同的DPP-4抑制剂都观察到了这种现象。此外研究人员还观察到了E-钙粘蛋白表达的减少和波形蛋白表达的增加,这与过去已经发现的EMT发生的特征是一致的。

那么又是什么“力量”推动了EMT的发生呢?这就和成纤维细胞有关系了。虽然DPP-4抑制剂并没有影响它的增殖和迁移,但是却促使它更多地分泌了一种参与皮肤伤口愈合的细胞因子——基质细胞衍生因子-1α(SDF-1α)。使用SDF-1α治疗的小鼠的角化细胞确实出现了上皮形态向成纤维形态转化的改变,说明伤口的部分在慢慢愈合,同时,E-钙粘蛋白和波形蛋白的水平也都相应的发生了变化。

也就是说,DPP-4抑制剂发挥作用靠的是促进成纤维细胞中SDF-1α的产生,间接推动了角化细胞的上皮间充质转化这个损伤修复途径,从而促进了伤口的愈合。后来的正向推导实验也证明了这个“闭环”,小鼠服用了DPP-4抑制剂之后出现了一系列的SDDF-1α表达量增加、角化细胞EMT等现象。

DPP-4抑制剂的使用不仅能够加速伤口的愈合,还可以减少疤痕的形成,这一作用是通过减少细胞外基质(ECM)合成实现的,ECM是由细胞合成并分泌到胞外,分布在细胞表面和细胞间的多糖和蛋白,起到连接组织结构、调节细胞功能的作用,过多的ECM就会形成疤痕了。



在问题都研究清楚了之后,就该进行临床试验的“重头戏”了。研究人员招募了67名2型糖尿病且糖尿病足达到III期或IV期的患者进行了安慰剂对照试验,结果显示,服用了DPP-4抑制剂(沙格列汀)的患者溃疡痊愈率达到87.5%(28/32),而安慰剂组只有51.42%(18/35),而且沙格列汀组的伤口愈合时间也比安慰剂组要快上15天。统计学分析显示,在不同的时间点上,沙格列汀组患者的伤口愈合速率普遍是快于安慰剂组的。



紫色:沙格列汀组;黑色:安慰剂组

与临床前实验相似,沙格列汀组患者的检查结果也显示了SDF-1α的高表达,以及大量处于EMT过程的角化细胞。这些表现都验证了DPP-4抑制剂作为治疗糖尿病足药物的潜力。

最后,研究人员指出,过往的药物研究很少有针对糖尿病的溃疡并发症,糖尿病足患者主要还是依靠抗生素和手术,因此DPP-4抑制剂这个“意外”的功效可能会有很大的用途。但是DPP-4抑制剂有它本身的局限,研究发现它会增加癌症转移和心衰的风险,所以,研究人员建议,癌症和心衰患者如果要使用DPP-4抑制剂应该经过严格的评估,未来也还需要更大型的临床研究来进一步评判DPP-4抑制剂作为治疗糖尿病足等溃疡并发症的效果和限制。

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    2018-03-20 jklm09
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    2018-01-12 半夏微凉

    学习了谢谢分享

    0

  7. 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    2018-01-09 gaoxiaoe
  10. 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    2018-01-08 wzb521zf

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