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通讯作者:

胡本慧,E-mail: hubenhui@njmu.edu.cn

中图分类号:R587.2

文献标识码:A

文章编号:1007-4368(2024)12-1735-10

DOI:10.7655/NYDXBNSN240390

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目录contents

    摘要

    糖尿病神经病变是糖尿病最常见的慢性并发症。当前,传统治疗方法的局限性日益凸显。神经调控技术在糖尿病神经病变的干预中展现出巨大潜力,主要体现在血糖控制与症状缓解等方面。本文总结了神经调控技术在糖尿病神经病变干预中的研究进展,旨在为糖尿病神经病变等慢性并发症的研究和神经调控技术的临床应用提供新的思路。

    Abstract

    Diabetic neuropathy is the most common chronic complication of diabetes. Currently in the intervention of diabetic neuropathy, the limitations of traditional trearnents are becoming increasingly apparent,while neuromodulation technology is gradually showing great potential,particularly in terms of glycaemic control and symptom relief. This article provides a summary of the research progress in the area of neuromodulation technology for the intervention of diabetic neuropathy,aiming to provide new insights for the study of chronic diabetic complications such as diabetic neuropathy and the clinical application of neuroregulation technology.

  • 目前,在“全健康”背景下,人们寻求跨学科、多领域的方法来保证理想的健康状态[1]。糖尿病是一种以高血糖和尿糖为特征的代谢紊乱疾病,可分为 1 型糖尿病(type1 diabetes mellitus,T1DM)、2 型糖尿病(type2 diabetes mellitus,T2DM)、妊娠期糖尿病以及由某些特定病症、病理和/或疾病引起或相关的糖尿病[2]。流行病学证据显示,自上世纪80年代至 2013 年,中国的糖尿病患病率从不到 1%上升到约 11%[3-5]。2013 年,中国糖尿病患者人数居世界首位,用于糖尿病及其并发症公共医疗的支出位居全球第2 [6]。2023年,中国20~79岁人群的糖尿病患病率约为 8.2%[7]。虽然有研究预测 2020—2030 年中国糖尿病患者数量呈下降趋势[8],但糖尿病及其并发症给社会健康带来的不利影响仍需重视。

  • 糖尿病神经病变(diabetic neuropathy,DN)是糖尿病最常见的慢性并发症,常见类型包括糖尿病周围神经病变(diabetic peripheral neuropathy,DPN)和糖尿病自主神经病变(diabetic autonomic neuropathy, DAN),其中DPN是最常见的类型,临床症状包括麻木、疼痛、灼热感、肌无力等[9-10]。15%的糖尿病患者会发生进展性不可逆性足部感觉缺失;2.5%的糖尿病患者易发生肢体溃疡,并且原发溃疡愈合后,溃疡再次发生率(包括但不限于原位溃疡)高达70%; 糖尿病患者中,80%~85%的截肢是由DPN诱发的难以愈合的溃疡所致[11]。最近,一项荟萃分析指出,14 908 例 T2DM 患者中,DAN 占 67.6%,其中重度 DAN占19.3%[12]。DAN和心脏自主神经病变(cardiac autonomic neuropathy,CAN)有着密切的关系[13-14]。高血糖诱导的氧化应激损伤交感、副交感神经元胞体,进而诱发CAN[15]。有研究证实,在T2MD患者体内, CAN进一步导致冠状动脉粥样硬化症状的恶化[16]

  • DN 的干预可分为对因治疗和对症治疗,主要手段包括血糖控制、药物治疗、疼痛管理等[17]。传统疗法如药物控制存在不良反应,如磺脲类药物容易引起发热等,导致安全性较难把控[18]。相比以上疗法,神经调控技术涉及电刺激、超声调控以及光遗传学调控,可以直接刺激神经诱导胰岛素分泌、减少疼痛等,因而近年来在控制血糖及神经痛管理等方面表现出潜在价值。同时,其在治疗糠尿病导致CAN 中的潜在应用价值引起了广泛关注[19]。文章总结神经调控技术在 DN 干预方面的研究进展,并探讨该技术与心血管疾病的联系,旨在为神经调控技术精准干预DN等提供思路和借鉴,同时为DN 慢性并发症、糖尿病及心血管疾病等慢性病的研究提供新的启示和方向。

  • 1 DN的发病机制

  • 1.1 炎症

  • 在糖尿病患者中,慢性高血糖会导致活性氧 (reactive oxygen species,ROS)产生增加,进一步加剧氧化应激,包括线粒体氧化应激等,这些活动会给机体带来更高的炎症水平和慢性炎症反应[20]。研究表明,T2DM 患者的脊髓背根神经中炎症相关基因表达升高[21]。同时,一项关于T1DM的研究表明,伴有DAN的T1DM患者血清白介素(interleukin, IL)-6、肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α) 等炎性细胞因子水平明显升高,提示炎性细胞因子有损伤DM患者外周神经并增加DAN风险的可能[22]

  • 此外,选择素E、趋化因子配体10(C-X-C motif chemokine,CXCL10)等炎症标志物的出现标志着 CAN的发生。慢性高血糖所致的炎性巨噬细胞分化产生以上炎症标志物,并参与神经损伤。其发病机制可能为巨噬细胞介导的吞噬作用导致外周神经脱髓鞘,引起外周神经传导速度和活动性降低,进而使心率变异性(heart rate variability,HRV) 降低[23]

  • 1.2 蛋白激酶C(protein kinase C,PKC)活化

  • 慢性高血糖会使二酰甘油增加,激活下游的 PKC。PKC 过度活化可改变局部小血管的微环境,增加基底膜厚度,改变通透性并导致血管功能障碍[24]。一项研究表明,通过肌酐下调PKC的活化可以减轻DAN所致的疼痛,同样印证了PKC活化与 DAN的发病密切相关[25]

  • 1.3 多元醇途径

  • 在多元醇途径中,醛糖还原酶(aldose reductase, AR)将葡萄糖转化为山梨糖醇,随后通过山梨糖醇脱氢酶将山梨糖醇转化为果糖。糖尿病患者中,葡萄糖水平升高会增强 AR 对葡萄糖的亲和力,导致山梨糖醇的产生增加。山梨糖醇累积降低Na+-K+-ATP酶活性,从而降低神经细胞传导速度。同时,过量的果糖加速糖基化和 NADPH 的消耗,并加剧细胞内氧化应激[26]。二者可能同时对DAN的发生有促进作用。

  • 1.4 氧化应激

  • DAN 患者体内出现 ROS 的积累及抗氧化酶活性的降低,经抗氧化治疗后症状缓解。ROS过多是线粒体的葡萄糖氧化功能受损引起的[27],神经元轴突富含线粒体且无法还原过量的ROS,也不能代偿 ATP产生不足,这使轴突更容易受到ROS介导的高血糖损伤[28]

  • 2 临床表现

  • 2.1 DAN

  • 由于自主神经纤维是薄髓鞘或无髓鞘纤维,所以对于疼痛性躯体神经病变患者,需要怀疑存在自主神经病变的可能。静息性心动过速可能是副交感神经损伤的首发症状或体征,其后出现运动时呼吸困难或胸痛、无症状心肌缺血和直立性头晕。直立性低血压会显著增加跌倒和晕厥的风险[29]

  • 据统计,大约50%的糖尿病患者有泌尿功能障碍。由于支配膀胱壁的感觉神经纤维受损,膀胱充盈的感知能力下降,尿液残留量增加,导致充溢性尿失禁。此外,勃起功能障碍在男性中很常见,发生率为35%~90%,通常作为自主神经病变的首发症状出现[30]。同时,血管内皮细胞功能障碍引起的阳痿需要引起重视,因为这种现象与心血管并发症的风险有关。

  • DAN诱发的其他症状还包括心悸、强光下视力模糊、出汗异常、吞咽困难、便秘和腹泻等。

  • 2.2 DAN诱发的CAN以及心血管结局

  • 糖尿病可诱导自主神经系统的神经元损伤,导致自主神经功能障碍,最初影响副交感神经系统,继而涉及交感神经系统。虽然神经元功能障碍的机制尚不完全清楚,但现已明确高血糖引发的ROS 增加会导致周围神经损伤,影响迷走神经。早在 1980 年,Watkins 等[31] 即提出糖尿病患者持续性心动过速可能是由于迷走神经损伤所致,且心率变异可能是DAN的最早体征。

  • DAN所致CAN的主要临床表现包括HRV下降,静息心动过速,直立性低血压,QT 间期延长等[29]。 HRV降低是亚临床CAN的最早临床表现。在临床 CAN中,静息性心动过速和运动耐量降低可能在早期阶段可见。在早期临床CAN患者中,心率会提高至90~130次/min[32]。此类HRV降低对腺苷/ATP反应不佳,提示重度CAN患者出现了交感神经功能丧失的症状[33]

  • 心脏直立性低血压和交感神经支配功能紊乱是严重CAN的表现[34]。据估计,6%~32%的糖尿病患者存在直立性低血压。除了血压下降≥20 mmHg 等标准外,CAN 还可能出现其他症状,如头晕、晕厥、视力改变、频繁跌倒和夜间高血压,这是交感神经活动反常增加所致[35]

  • 3 神经调控技术

  • 3.1 对因干预

  • 良好的血糖控制是防止和延缓 DN 进展的关键。神经调控技术在 DN 的原发病——糖尿病的干预中崭露头角,提供了全新的治疗途径。其中,神经电刺激调控、神经超声调控和光遗传学调控这 3个方面的研究展示了对糖尿病干预的新思路和潜在机制,为未来DN的干预提供了新的有效治疗策略。

  • 3.1.1 神经电刺激调控

  • 近年来,大量研究证实了颈迷走神经刺激 (cervical vagus nerve stimulation,cVNS)、腹迷走神经刺激、经皮耳迷走神经刺激(transcutaneous auricular vagus nerve stimulation,taVNS)等在血糖调节和糖尿病疼痛干预方面的重要作用,表明迷走神经刺激 (vagus nerve stimulation,VNS)技术具备干预 DN 的潜力。其中,cVNS通常通过在颈部植入神经电极直接向迷走神经发送电脉冲来实现。Horn 等[36] 通过采用基于水凝胶的多接触电极环绕大鼠颈迷走神经,发现cVNS在腹迷走神经中产生神经活动,证明了该选择性cVNS方法在治疗迷走神经调节有关的代谢、炎症、心血管等疾病的潜力。

  • 刺激颈迷走神经可能引起明显的“脱靶效应”,而腹迷走神经位于支配心脏和肺部的迷走神经分支的远端,刺激过程中避开了胸部区域,因此不会对心率、血压和呼吸等产生明显影响。腹迷走神经主干及其肝脏分支、胰腺分支成为调节血糖的潜在刺激靶点。Yin等[37] 在T2DM大鼠模型中,通过在膈下的背侧迷走神经干植入电极实现靶向VNS,发现 5 Hz 低频VNS通过增强迷走神经传出活动和胰高血糖素样肽-1的释放降低血糖,且其降糖效果最显著。Payne 等[38] 在 T2DM 大鼠模型中,评估了多种 VNS 策略对血糖及血糖调节激素的影响,并发现 40 kHz高频VNS可以降低胰高血糖素水平,对治疗 T2DM有潜在的应用价值。而后Payne等[39] 在T2DM 模型中,通过低频(15 Hz)与高频(26 kHz)刺激的组合,实现对腹部迷走神经前干传出神经束的可逆性、选择性刺激,降低了胰高血糖素的分泌,起到了可重复且持续性的降糖作用。Waataja 等[40]在 T2DM 大鼠和猪模型中,首次同时独立调控迷走神经 2 个靶点,通过低频(1 Hz)刺激迷走神经胰腺分支与高频交流电(5 kHz)刺激迷走神经肝分支的组合,增强了对血糖的控制,为T2DM干预提供了一种调控血糖的新方法。在针对 T1DM 的干预中,Dirr 等[41] 在T1DM小鼠模型中提出了识别迷走神经胰腺分支的方法。Dirr等[42] 进一步通过电刺激该分支,发现胰岛直径增加和链脲佐菌素(streptozocin,STZ) 处理的小鼠胰岛素再次升高,为迷走神经胰腺分支电刺激干预 T1DM 提供了可能的技术方案。Guyot 等[43] 则通过电刺激胰腺交感神经,抑制了T细胞向胰岛迁移及促炎因子如IL-2、IL-6的表达,从而延缓 T1DM的进展。因此,可以明确的是,远端迷走神经可以作为神经刺激的靶点,并且可以通过加快VNS 的放电频率以减轻炎症状态和降低血糖水平。但是,有些问题尚未明晰,比如电刺激频率和电刺激时间是否会对促进胰岛素分泌和降糖等刺激效果产生影响?两次电刺激的间隔时间是否会带来差异?这些问题仍需要进一步研究。

  • taVNS 是一种非植入式的新型 VNS 疗法,基于传统VNS及迷走神经解剖特点发展而来,无创无痛且具备更高的安全性[44]。Zhang等[45] 在T2DM大鼠模型中发现taVNS能显著升高糖尿病肥胖大鼠血清胰岛素含量,低强度的taVNS还能显著降低大鼠空腹血糖;临床研究还发现,taVNS可明显降低糖耐量受损患者空腹血糖及糖化血红蛋白,并改善胰岛素抵抗,为 taVNS 调节血糖提供了有力的临床证据。 Yu等[46] 进一步在T2DM大鼠模型中发现taVNS不仅对糖尿病肥胖大鼠有降体重、降血糖的抗糖尿病作用,还可通过抑制其边缘区域 P2X7R 表达,逆转其抑郁样行为。在对健康人群的研究中,Vosseler等[47] 在15例健康男性中通过随机、单盲、交叉研究测试 taVNS 对全身代谢和能量消耗的影响,未发现受试者血糖、胰岛素敏感性和胰岛素分泌的明显变化。然而,Kozorosky等[48] 则发现taVNS 在无热量摄入时可降低血糖水平,在有热量摄入时可升高胰岛素水平,且加速了餐后血浆胃饥饿素水平的下降,提示 taVNS可能通过抑制胃饥饿素的分泌来减少食物摄入,从而间接改善葡萄糖耐量。然而,taVNS对人群的血糖调节作用仍不明确,未来可通过扩大样本量、优化刺激参数、与无创评估自主神经功能结合等进一步展开 taVNS 干预糖尿病的临床实验和长期随访研究,来确定taVNS对糖尿病患者血糖控制的有效性和可行性,以探索其在 DN 改善中的潜在益处。

  • 目前有小鼠实验证明,通过电脉冲精确刺激胰岛β细胞膜上的电压门控钙离子通道 Cav1.2 可以促进胰岛素分泌,快速缓解小鼠的高血糖症状,并且可以在较长时间内控制血糖,同时没有任何低血糖的迹象[49]。此外,一项在丹麦开展的随机双盲临床试验中,对患者应用 tVNS 技术可以改善患者的胃肠道功能,减轻炎症并对血糖有潜在的控制效果,进一步证明了神经刺激对T2DM的潜在治疗应用价值[50]

  • 神经电刺激的目的是通过提高胰岛素的分泌、提高受体敏感性、降低胰高血糖素的分泌以降低血糖,缓解甚至逆转高血糖对外周血管和神经的损伤,以期控制糖尿病并减轻疼痛。针对疼痛和高血糖的始动环节,大直径 Aβ纤维、Aδ纤维的阻滞和网状背侧的神经元,以及神经递质如 5-羟色胺(5-hydroxy tryptamine,5-HT)、去甲肾上腺素 (norepinephrine,NE),都有成为调控靶点的潜力,将会为糖尿病的管理带来新的希望(图1)。

  • 3.1.2 神经超声调控

  • 神经超声调控技术主要通过超声的机械效应、空化作用等调控靶区神经元活动,刺激肝脏、胰腺等与糖代谢相关的核心组织器官,从而有效干预血糖水平[51]。肝脏自主神经在调节糖代谢中起着至关重要的作用,然而支配肝脏的神经解剖结构复杂且功能不同,传出纤维可影响肝脏的血流、胆汁分泌和代谢过程[52],在这种神经分布复杂的部位采用神经电刺激技术往往会产生混合的、相互矛盾的结果。与神经电刺激相比,超声刺激可以聚焦于特定的解剖位置,并通过皮肤无创地应用于深层器官目标,具备无创、穿透性强和分辨率高等优势。

  • Cotero等[52] 利用超声聚焦于脾脏和肝脏内神经支配的特定解剖靶点,调节了脾脏的胆碱能抗炎途径和肝脏的葡萄糖感应神经元。其中,肝脏的超声刺激被证实可以有效调节血糖,并在抑制内毒素引起的高血糖方面与VNS效果相当。而后Cotero等[53] 进一步使用外周聚焦超声刺激(peripheral focused ultrasound stimuli,pFUS)技术在3种T2DM动物模型 (小鼠、大鼠和猪)中探索在肝门区域施加刺激的治疗效果,发现血糖水平显著降低,而这一效果在肝脑通路被物理切断或化学抑制时消失。Chang等[54] 则改变了刺激靶点,通过对 T2DM 大鼠模型腹部 CV12 穴位进行超声刺激,发现刺激 5 min 后血糖显著降低,多次刺激后葡萄糖耐受改善。这说明,适当剂量的无创超声刺激可以产生降糖和提高糖耐量的作用,这为 T2DM 的神经超声调控提供了新思路。

  • 临床研究显示,迷走神经超声诊断还可以作为 DAN的诊断依据[55]。Saab等[56]在之前研究的基础上,利用计算机断层扫描图像技术研究了治疗性超声(therapeutic ultrasound,TUS)对不同身体类型的影响,发现从腹部直接施加 1 MHz、5 W/cm2 的超声可以为胰腺提供最佳压力,从而产生对抗T2DM的效果。Ashe 等[57] 评估了针对肝门的肝脏 pFUS 对 T2DM 受试者空腹血糖、胰岛素等多种糖代谢参数的影响,发现接受 pFUS 后各项指标的变化趋势与临床前研究结果一致,表明了 pFUS 应用于糖尿病非药物辅助治疗的潜力。虽然pFUS等超声神经调控技术在调节血糖和糖尿病干预中的作用已在体外和临床前模型中得到验证,但目前对于其在临床试验中的报告还相对较少,需要更多的研究和验证以确保其在干预糖尿病中的安全性和有效性,以更好地了解pFUS等外周超声神经调控技术在干预DN 方面的潜力(图1)。

  • 3.1.3 光遗传学调控

  • 光遗传学是一个新兴领域,它利用光和分子遗传学,通过表达光敏蛋白来操纵活细胞的生物反应和活性。与电刺激相比,光遗传学能够提供具有毫秒级时间精度的选择性激活。近年来,光遗传学在神经疼痛方面的应用也得到了越来越多的发展。在先前的一项研究中,Wang等[58] 证明了光遗传学在疼痛传导回路中的作用。在另一项研究中,Daou等[59] 使用二元遗传方法,通过将通道视紫红质2(channel rhodopsins 2,ChR2)传递到 Nav1.8-Cre 系转基因小鼠中的外周伤害感受器,证明了光遗传学在疼痛抑制中的作用。

  • 2015 年即有人提出光遗传学刺激可以调节胃肠功能和迷走神经功能[60]。目前认为,光遗传学刺激胆碱能纤维可用于调节胰岛素分泌和血糖。利用光遗传学精准刺激小鼠胰腺,可以在急性葡萄糖升高期间降低小鼠血糖。同时,光遗传学刺激还能增加胰腺血流量[61]

  • 2015 年,Kushibiki 等[62] 研究了光遗传学通过 ChR2 介导胰岛β细胞分泌胰岛素的机制。他们使用纳秒脉冲激光(470 nm)照射ChR2转染的小鼠胰岛素瘤细胞系,揭示了胰岛素分泌是由 ChR2 介导的Ca2+ 直接诱导的。2023年,Kawana等[63] 通过在体实验,利用蓝光刺激小鼠膈下前迷走神经干,增加小鼠胰腺血流量,并且在葡萄糖耐量试验中表现出与对照组小鼠相似的血糖水平。这些研究为光遗传学应用于糖尿病血糖控制和DAN所致的慢性疼痛提供了新思路(图1)。

  • 图1 神经调控技术及其血糖调节机制

  • Figure1 Mechanisms of neuromodulation techniques in blood glucose regulation

  • 3.2 对症干预

  • 3.2.1 糖尿病性神经痛的干预

  • 糖尿病性神经痛,全称是糖尿病性周围神经病理性疼痛(painful diabetic peripheral neuropathy, PDPN),是DN的重要表现之一。PDPN是糖尿病患者最常见的严重并发症,与血糖代谢异常损害外周感觉神经系统有关,常表现为以肢体远端受累为主的对称性周围神经病理性疼痛。

  • 脊髓电刺激(spinal cord stimulation,SCS)是一种微创、可逆的神经调控技术。Zhou 等[64] 率先应用SCS治疗糖尿病足,发现SCS可促进神经功能恢复,减轻患者下肢痛,进一步验证了 SCS 在糖尿病下肢神经病变治疗中的有效性。SCS 也可以通过脊髓传导束激活脑部的疼痛下行抑制系统,从而缓解DPN 患者的疼痛。Xie 等[65] 发现 A-纤维神经元中的孤儿 G 蛋白偶联受体 177 通过 WNT5a 介导的瞬时受体电位香草素受体1离子通道的激活来驱动 PDPN。Galan 等[66] 通过对 26 例试验对象使用硬膜外导联进行刺激或植入永久性10 kHz SCS系统,观察到受试者神经功能有所改善,疼痛的残疾、功能、睡眠、感觉和情感维度均有显著改善,表明 10 kHz SCS可为PDPN患者提供持续的疼痛缓解和残疾改善。Galan 等[67] 还对植入永久性装置的7例受试者进行了为期12个月的随访评估,均未发现神经功能的缺失或恶化,甚至其中5例在感觉测试和/或反射方面有所改善。Petersen 等[68] 通过对216例难治性 PDPN患者进行一项测试10 kHz SCS与常规医疗管理的随机对照试验,发现在 6 个月的 SCS 刺激后, 76%的患者平均疼痛视觉模拟评分降低,进一步支持 10 kHz 脊髓刺激治疗难治性 PDPN 的安全性和有效性。SCS 疗法可显著缓解 PDPN 患者疼痛,然而现有研究仍存在随机对照试验不足、观察性研究居多、样本量小、针对亚洲人群的研究不足等问题,未来仍需更多研究验证 SCS 治疗 PDPN 的广泛适用性。

  • 近年来,随着研究的不断深入,超声在PDPN治疗方面也展现出巨大的潜力。Youn等[69] 通过对由长春新碱诱导的 PDPN 大鼠的 L5 背根神经节应用高强度聚焦超声(high-intensity focused ultrasound, HIFU),发现处理后大鼠L5背根神经节的热阈值和机械阈值均升高,且L5背根神经节出现可在48 h内消退的短暂性细胞水肿,表明 HIFU 可在不损害周围神经的情况下降低 PDPN 大鼠的痛觉敏感性。 Hellman等[70] 则通过对长春新碱诱导的PDPN大鼠的 L5 背根神经节应用低强度聚焦超声(low-intensity focused ultrasound,LIFU),发现其对疼痛的敏感性降低,且未发现神经元变性,这与 Youn 等[69] 使用 HIFU治疗的研究结果类似,可见LIFU和HIFU在改善PDPN 方面均表现出显著优势。在临床上,赵恒侠等[71] 通过对60例PDPN患者进行随机对照试验,发现超声治疗(每日1次,1次20 min,共治疗15 d) 后病变神经在运动和感觉神经传导速度上都优于对照组。林璐璐[72] 则通过对40例PDPN患者进行随机对照试验,发现超声治疗组治疗效果、胫神经等运动神经传导速度、感觉神经传导速度、各症状评分均显著优于对照组,证明低频超声辅助治疗 PDPN 患者,能够缓解疼痛,改善相关症状,加速受损神经功能的恢复。然而,PDPN 的超声治疗主要以基础实验为主,其运用于临床治疗的结果报道较少。

  • 3.2.2 其他症状的干预

  • 除了 PDPN,DN 患者常出现触觉丧失、肌无力等症状,甚至发生毛细血管结构改变,易感性增加而导致糖尿病足的发生[73]

  • 对于 DPN 患者的肌无力症状,研究发现神经肌肉电刺激不仅可以减轻患者的肌肉无力[74],还可辅助力量训练以改善运动[75]。此外,低于感觉阈值 1 μA 的微电流神经电刺激(microcurrent nerve stimulation,MNS)可促进肌肉生长、改善肌肉功能[76-77]。与MNS类似,随机共振的工作范围在感觉阈值以下,大量研究表明,阈下电噪声能够提高患者对触觉和振动刺激的感知,改善平衡和步态行为[78-80]。随着 DN 的发展,患者振动触觉和足底触觉敏感性降低,躯体感觉功能下降[81-82]。早在2006 年,即有研究发现通过振动鞋垫施加到 DN 患者足底的亚感觉机械噪声可改善患者的站立平衡控制,由此引发了大量相关研究。医用振动鞋垫可显著改善患有轻度至中度DPN患者的足部振动感[83-85],有效减轻神经性症状并增强运动表现[86],改善DPN 患者足底侧振动感知阈值[87]

  • 在伤口愈合方面,电刺激不仅可以通过增加血管生成而增加血流量[88],还可以促进伤口中巨噬细胞、成纤维细胞和内皮细胞的迁移,从而促进伤口愈合[89]。近期一项系统性荟萃分析表明,与安慰剂和标准治疗相比,电刺激有利于减少糖尿病相关溃疡[90]

  • 4 总结与展望

  • 神经调控技术在DN的研究中呈现出多元的发展态势。尽管目前仍然存在一些挑战,如临床应用的标准化和长期疗效的验证,但其潜在的治疗优势为未来的糖尿病干预带来了希望。在未来的研究中有以下几个方面需要重点突破:①更全面、深刻地了解DN的发病机制以及神经调控对神经病变的具体影响,更好地理解神经网络,利用神经生理学数据来更好地了解疾病机制和开发有针对性、高效和有效的干预措施;②优化刺激目标和“剂量”,包括刺激的途径、频率、脉宽、持续时间、电流,以及刺激是作为单一治疗还是辅助治疗,是连续提供还是响应性提供,同时考虑神经可塑性的长期变化;③开展临床试验,规范试验范式,建立个性化定制的神经调控处方,加强跨学科交叉研究以促进神经调控技术在临床上的转化应用。总体而言,神经调控技术在DN干预研究方面已经展现了显著潜力。随着神经刺激仪器的不断进步和糖尿病研究的深入,神经调控技术有望成为 DN 干预领域强有力的技术支撑,提高患者的治疗效果和生活质量。

  • 同时,神经调控技术在外周自主神经的刺激效应并不局限于干预糖尿病神经病变。已有研究表明,外周自主神经的电刺激效应可以促进心肌细胞的分化和再生,为心脏病患者的治疗提供了新的路径。未来,神经刺激技术的转化医学需要注意各个器官系统之间的联系,强调关联的同时防止串扰,最大化治疗效果,最小化不良反应,为广大患者提供更理想的治疗与生活质量。

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