Østergaard Leif, Finnerup Nanna B, Terkelsen Astrid J, Olesen Rasmus A, Drasbek Kim R, Knudsen Lone, Jespersen Sune N, Frystyk Jan, Charles Morten, Thomsen Reimar W, Christiansen Jens S, Beck-Nielsen Henning, Jensen Troels S, Andersen Henning
Center of Functionally Integrative Neuroscience and MINDLab, Institute of Clinical Medicine, Aarhus University Hospital, Building 10G, Nørrebrogade 44, DK-8000, Aarhus C, Denmark,
Diabetologia. 2015 Apr;58(4):666-77. doi: 10.1007/s00125-014-3461-z. Epub 2014 Dec 16.
Diabetic neuropathy is associated with disturbances in endoneurial metabolism and microvascular morphology, but the roles of these factors in the aetiopathogenesis of diabetic neuropathy remain unclear. Changes in endoneurial capillary morphology and vascular reactivity apparently predate the development of diabetic neuropathy in humans, and in manifest neuropathy, reductions in nerve conduction velocity correlate with the level of endoneurial hypoxia. The idea that microvascular changes cause diabetic neuropathy is contradicted, however, by reports of elevated endoneurial blood flow in early experimental diabetes, and of unaffected blood flow when early histological signs of neuropathy first develop in humans. We recently showed that disturbances in capillary flow patterns, so-called capillary dysfunction, can reduce the amount of oxygen and glucose that can be extracted by the tissue for a given blood flow. In fact, tissue blood flow must be adjusted to ensure sufficient oxygen extraction as capillary dysfunction becomes more severe, thereby changing the normal relationship between tissue oxygenation and blood flow. This review examines the evidence of capillary dysfunction in diabetic neuropathy, and whether the observed relation between endoneurial blood flow and nerve function is consistent with increasingly disturbed capillary flow patterns. The analysis suggests testable relations between capillary dysfunction, tissue hypoxia, aldose reductase activity, oxidative stress, tissue inflammation and glucose clearance from blood. We discuss the implications of these predictions in relation to the prevention and management of diabetic complications in type 1 and type 2 diabetes, and suggest ways of testing these hypotheses in experimental and clinical settings.
糖尿病性神经病变与神经内膜代谢紊乱及微血管形态改变有关，但这些因素在糖尿病性神经病变发病机制中的作用仍不明确。在人类中，神经内膜毛细血管形态和血管反应性的改变显然早于糖尿病性神经病变的发生，而在明显的神经病变中，神经传导速度的降低与神经内膜缺氧程度相关。然而，早期实验性糖尿病中神经内膜血流增加以及人类神经病变早期组织学征象首次出现时血流未受影响的报道，与微血管变化导致糖尿病性神经病变的观点相矛盾。我们最近发现，毛细血管血流模式紊乱，即所谓的毛细血管功能障碍，会减少组织在给定血流情况下能够摄取的氧气和葡萄糖量。事实上，随着毛细血管功能障碍变得更加严重，必须调整组织血流以确保足够的氧气摄取，从而改变组织氧合与血流之间的正常关系。本综述探讨了糖尿病性神经病变中毛细血管功能障碍的证据，以及观察到的神经内膜血流与神经功能之间的关系是否与日益紊乱的毛细血管血流模式一致。分析表明，毛细血管功能障碍、组织缺氧、醛糖还原酶活性、氧化应激、组织炎症和血液葡萄糖清除之间存在可检验的关系。我们讨论了这些预测对于1型和2型糖尿病并发症预防和管理的意义，并提出了在实验和临床环境中检验这些假设的方法。
