Rajchgot Trevor, Thomas Sini Christine, Wang Jo-Chiao, Ahmadi Maryam, Balood Mohammad, Crosson Théo, Dias Jenny Pena, Couture Réjean, Claing Audrey, Talbot Sébastien
Département de Pharmacologie et Physiologie, Faculté de Médecine, Université de Montréal, Montréal, QC, Canada.
Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Front Neurosci. 2019 Jan 31;13:25. doi: 10.3389/fnins.2019.00025. eCollection 2019.
Diabetes is a common condition characterized by persistent hyperglycemia. High blood sugar primarily affects cells that have a limited capacity to regulate their glucose intake. These cells include capillary endothelial cells in the retina, mesangial cells in the renal glomerulus, Schwann cells, and neurons of the peripheral and central nervous systems. As a result, hyperglycemia leads to largely intractable complications such as retinopathy, nephropathy, hypertension, and neuropathy. Diabetic pain neuropathy is a complex and multifactorial disease that has been associated with poor glycemic control, longer diabetes duration, hypertension, advanced age, smoking status, hypoinsulinemia, and dyslipidemia. While many of the driving factors involved in diabetic pain are still being investigated, they can be broadly classified as either neuron -intrinsic or -extrinsic. In neurons, hyperglycemia impairs the polyol pathway, leading to an overproduction of reactive oxygen species and reactive nitrogen species, an enhanced formation of advanced glycation end products, and a disruption in Na/K ATPase pump function. In terms of the extrinsic pathway, hyperglycemia leads to the generation of both overactive microglia and microangiopathy. The former incites a feed-forward inflammatory loop that hypersensitizes nociceptor neurons, as observed at the onset of diabetic pain neuropathy. The latter reduces neurons' access to oxygen, glucose and nutrients, prompting reductions in nociceptor terminal expression and losses in sensation, as observed in the later stages of diabetic pain neuropathy. Overall, microglia can be seen as potent and long-lasting amplifiers of nociceptor neuron activity, and may therefore constitute a potential therapeutic target in the treatment of diabetic pain neuropathy.
糖尿病是一种以持续性高血糖为特征的常见病症。高血糖主要影响那些调节葡萄糖摄取能力有限的细胞。这些细胞包括视网膜中的毛细血管内皮细胞、肾小球中的系膜细胞、施万细胞以及外周和中枢神经系统的神经元。因此，高血糖会引发诸如视网膜病变、肾病、高血压和神经病变等基本上难以治疗的并发症。糖尿病性疼痛性神经病变是一种复杂的多因素疾病，与血糖控制不佳、糖尿病病程较长、高血压、高龄、吸烟状况、低胰岛素血症和血脂异常有关。虽然许多与糖尿病性疼痛相关的驱动因素仍在研究中，但它们大致可分为神经元内在因素或外在因素。在神经元中，高血糖会损害多元醇途径，导致活性氧和活性氮的过度产生、晚期糖基化终产物的形成增加以及钠/钾ATP酶泵功能的破坏。在外在途径方面，高血糖会导致过度活跃的小胶质细胞和微血管病变的产生。前者引发一种前馈性炎症循环，使伤害感受神经元超敏，这在糖尿病性疼痛性神经病变发作时可以观察到。后者减少神经元对氧气、葡萄糖和营养物质的获取，促使伤害感受器终末表达减少和感觉丧失，这在糖尿病性疼痛性神经病变后期可以观察到。总体而言，小胶质细胞可被视为伤害感受神经元活动的强效且持久的放大器，因此可能构成治疗糖尿病性疼痛性神经病变的潜在治疗靶点。
