The effects of capillary dysfunction on oxygen and glucose extraction in diabetic neuropathy

Abstract

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.

Cardiac vagal tone, a non‐invasive measure of parasympathetic tone, is a clinically relevant tool in Type 1 diabetes mellitus

“…The presence of diabetic sensory peripheral neuropathy, irrespective of age, predicted a lower CVT, confirming the hypothesis of the study that CAN and peripheral neuropathy have a shared pathogenesis, resulting in both peripheral and autonomic impairment of neuronal function [17]. In those with concomitant diabetic sensory peripheral neuropathy, CVT correlated with established measures derived from HRV.…”

Schwann cell interactions with axons and microvessels in diabetic neuropathy

“…Furthermore, microangiopathy can precede development of diabetic neuropathy 120,121 , and the degree of microvascular changes correlates with the clinical severity of diabetic neuropathy 119,120 . Microvascular changes have been thought to elicit nerve damage by limiting nerve blood supply (ischaemia), but evidence now shows that endoneurial hypoxia can be caused by inefficient oxygen extraction alone via capillary dysfunction 122 . Tissue hypoxia, in turn, can activate the same cellular signalling pathways that inflammation activates 123 .…”

“…Glucose breakdown via the polyol pathway -despite its detrimental long-term effects -is an efficient source of ATP in these conditions. As a result, aldose reductase inhibitors could be detrimental in nerve fibres with severely affected microvessels, as they will limit this alternative source of energy 122 .…”

Laminar microvascular transit time distribution in the mouse somatosensory cortex revealed by Dynamic Contrast Optical Coherence Tomography

“…Moreover, it was shown that the transit time distribution, rather than mean transit time (MTT) alone, most directly determines the maximum oxygen extraction that a capillary bed can support [12]. Recent theoretical work has implicated pathological transit time heterogeneity in a number of diseases including stroke [13], ischemia [14], Alzheimer’s disease [15], traumatic brain injury [16], and diabetic nephropathy [17], leading to renewed interest in this subject. In spite of these theoretical studies highlighting the importance of transit time distribution, efficient and robust experimental methods that quantify this distribution at the capillary level have been lacking.…”