Vascular factors and metabolic interactions in the pathogenesis of diabetic neuropathy

Abstract

Diabetes mellitus is a major cause of peripheral neuropathy, commonly manifested as distal symmetrical polyneuropathy. This review examines evidence for the importance of vascular factors and their metabolic substrate from human and animal studies. Diabetic neuropathy is associated with risk factors for macrovascular disease and with other microvascular complications such as poor metabolic control, dyslipidaemia, body mass index, smoking, microalbuminuria and retinopathy. Studies in human and animal models have shown reduced nerve perfusion and endoneurial hypoxia. Investigations on biopsy material from patients with mild to severe neuropathy show graded structural changes in nerve microvasculature including basement membrane thickening, pericyte degeneration and endothelial cell hyperplasia. Arterio-venous shunting also contributes to reduced endoneurial perfusion. These vascular changes strongly correlate with clinical defects and nerve pathology. Vasodilator treatment in patients and animals improves nerve function. Early vasa nervorum functional changes are caused by the metabolic insults of diabetes, the balance between vasodilation and vasoconstriction is altered. Vascular endothelium is particularly vulnerable, with deficits in the major endothelial vasodilators, nitric oxide, endothelium-derived hyperpolarising factor and prostacyclin. Hyperglycaemia and dyslipidaemia driven oxidative stress is a major contributor, enhanced by advanced glycation end product formation and polyol pathway activation. These are coupled to protein kinase C activation and omega-6 essential fatty acid dysmetabolism. Together, this complex of interacting metabolic factors accounts for endothelial dysfunction, reduced nerve perfusion and function. Thus, the evidence emphasises the importance of vascular dysfunction, driven by metabolic change, as a cause of diabetic neuropathy, and highlights potential therapeutic approaches.

Enhancement of endothelial nitric oxide synthase production reverses vascular dysfunction and inflammation in the hindlimbs of a rat model of diabetes

“…Therefore we analysed the peripheral production of nitrotyrosine and iNOS as well as the lipid peroxidation activity, all known to be activated under diabetic conditions and to contribute to vascular damage [31]. As expected, and previously described, all measured indices of oxidative stress were markedly enhanced in untreated STZ rats in our model [32][33][34]. Whereas diabetes-induced increased nitrotyrosine and iNOS production were both attenuated nearly to levels in normoglycaemic conditions because of pharmacological enhancement of eNOS by AVE3085, the lipid peroxidation activity was not significantly reduced by the treatment, suggesting that vascular protection against hyperglycaemia by eNOS enhancement is at least in part mediated by attenuation of iNOS and nitrotyrosine overproduction.…”

Cognitive efficiency declines over time in adults with Type 1 diabetes: effects of micro- and macrovascular complications

“…Distal symmetric polyneuropathy has also been found to predict the degree of cognitive slowing in adults with Type 1 diabetes [5], and like both retinopathy and nephropathy, this neurological complication is now thought to be largely vascular in origin [42]. If the effects of these microvascular complications on the central nervous system (CNS) are additive or synergistic, one might expect to see a relationship between the number of complications and the magnitude of cognitive change.…”

Schwann cell interactions with axons and microvessels in diabetic neuropathy

“…The morphology and function of microvessels is altered in nerve biopsy samples from patients with diabetic neuropathy 118,119 (FIG. 1); these microvascular changes are particularly severe in endoneurial capillaries, and include capillary basement membrane thickening, loss of pericyte coverage, and endothelial hyperplasia 120 .…”

“…1); these microvascular changes are particularly severe in endoneurial capillaries, and include capillary basement membrane thickening, loss of pericyte coverage, and endothelial hyperplasia 120 . 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 .…”