Diabetologia $2001) 44: 1973±1988 Ó Springer-Verlag 2001 Vascular factors and metabolic interactions in the pathogenesis of diabetic neuropathy N. E.Cameron1, S.E.M.Eaton2, M.A.Cotter1, S.Tesfaye2 1 Department of Biomedical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, Scotland, United Kingdom 2 Diabetes Centre, Royal Hallamshire Hospital, Glossop Road, Sheffield, United Kingdom Abstract betes, the balance between vasodilation and vasocon- striction is altered. Vascular endothelium is particu- Diabetes mellitus is a major cause of peripheral neu- larly vulnerable, with deficits in the major endothelial ropathy, commonly manifested as distal symmetrical vasodilators, nitric oxide, endothelium-derived hy- polyneuropathy. This review examines evidence for perpolarising factor and prostacyclin. Hyperglycae- the importance of vascular factors and their metabol- mia and dyslipidaemia driven oxidative stress is a ma- ic substrate from human and animal studies. Diabetic jor contributor, enhanced by advanced glycation end neuropathy is associated with risk factors for macro- product formation and polyol pathway activation. vascular disease and with other microvascular com- These are coupled to protein kinase C activation and plications such as poor metabolic control, dyslip- w-6 essential fatty acid dysmetabolism. Together, idaemia, body mass index, smoking, microalbumin- this complex of interacting metabolic factors ac- uria and retinopathy. Studies in human and animal counts for endothelial dysfunction, reduced nerve models have shown reduced nerve perfusion and en- perfusion and function. Thus, the evidence emphasis- doneurial hypoxia. Investigations on biopsy material es the importance of vascular dysfunction, driven by from patients with mild to severe neuropathy show metabolic change, as a cause of diabetic neuropathy, graded structural changes in nerve microvasculature and highlights potential therapeutic approaches. including basement membrane thickening, pericyte [Diabetologia $2001) 44: 1973±1988] degeneration and endothelial cell hyperplasia. Arte- rio-venous shunting also contributes to reduced en- Keywords Diabetic neuropathy, nerve conduction, doneurial perfusion. These vascular changes strongly nerve pathology, blood flow, ischaemia, microangio- correlate with clinical defects and nerve pathology. pathy, vascular endothelium, nitric oxide, oxidative Vasodilator treatment in patients and animals im- stress, protein kinase C, advanced glycation, aldose proves nerve function. Early vasa nervorum function- reductase. al changes are caused by the metabolic insults of dia- Hyperglycaemia is a fundamental metabolic insult in Received: 19 March 2001 and in revised form: 15 June 2001 diabetes mellitus, due to either a relative or absolute Corresponding author: N.Cameron, Department of Biomedi- deficiency of insulin. However, hyperglycaemia alone cal Sciences, Institute of Medical Sciences, Institute of Medical cannot completely explain the complications of dia- Sciences, University of Aberdeen, Foresterhill, Aberdeen betes. Intensive blood glucose control dramatically AB25 2ZD reduces microvascular complications but does not Abbreviations: ACE, angiotensin converting enzyme; AGE, prevent them altogether [1, 2]. The current optimal advanced glycation end product; ARI, aldose reductase inhibi- management of microvascular disease can only at- tor; DSP, distal symmetrical polyneuropathy; eDHF, endothe- lium derived hyperpolarising factor; NCV, nerve conduction tempt to control glycaemia and then to deal with the velocity; NO, nitric oxide; PG, prostaglandin; PKC, protein ki- complications when they occur. Consequently, pa- nase C tients continue to go blind, develop renal failure and 1974 N. E.Cameron et al.: vascular factors in diabetic neuropathy undergo lower extremity amputations making a whether metabolic or vascular factors were more im- greater understanding of the pathogenesis of mi- portant. However, current opinion focuses on the ex- crovascular disease to enhance the development of istence of complex interactions between the two at rational therapies urgent. all stages of disease. Indeed, microvascular reactivity Distal symmetrical polyneuropathy $DSP) is prob- is impaired and agonist-stimulated endothelium-de- ably the most common but least understood of the mi- pendent vasodilation can be compromised before crovascular complications of diabetes [3]. This review the onset of frank hyperglycaemia in those at risk of will discuss the pathogenesis of DSP and the complex developing Type II $non-insulin-dependent) diabetes vascular and metabolic interactions involved. mellitus [19, 20]. The association of DSP with macro- vascular and other microvascular diseases highlights the role of vascular factors. Diabetic distal symmetrical polyneuropathy Neuropathy and risk factors for macrovascular dis- Diabetes mellitus can predispose to a variety of neu- ease. Several studies have shown the association of rological syndromes, DSP being the most common DSP with risk factors that predict the development [4±6]. DSP is a length-dependent sensory and motor of macrovascular disease. Hypertension has been im- neuropathy, with sensory loss starting in the toes and plicated as a strong risk factor for DSP [14, 21, 22]. In spreading into the legs and hands in a ªstocking and the United Kingdom Prospective Diabetes Study gloveº distribution. Sensory symptoms and signs pre- $UKPDS), control of hypertension not only markedly dominate, usually sensory loss and numbness. How- improved macrovascular outcomes but also reduced ever, some patients also suffer painful or ªpositiveº microvascular complications. Furthermore, two small symptoms, which can be extremely distressing and trials with angiotensin converting enzyme $ACE) in- difficult to treat [7, 8]. The involvement of the motor hibitors and one using another vasodilator, the 5HT2 system is usually sub-clinical in the early stages of antagonist sarpogrelate, have shown nerve conduc- DSP although it is easily detectable by neurophysio- tion velocity $NCV) improvements in DSP [23±25]. logical testing and can become disabling as the dis- Other important risk factors for DSP include ciga- ease progresses [9]. Autonomic dysfunction also is rette smoking, dyslipidaemia, microalbuminuria and usually present and can be manifested in a variety of BMI [14, 26]. Many of these factors are already treat- ways including postural hypotension, gastrointestinal ed aggressively in diabetes and this could conse- dysmotility or erectile dysfunction [6]. Progressive quently also benefit peripheral nerve. However, evi- axon degeneration affects all fibre types and teased dence from a recent trial on the effects of aggressive fibre studies show demyelination [10, 11], indicating risk factor control showed benefits for nephropathy, a combined insult on axons and Schwann cells. retinopathy and autonomic neuropathy but not pe- Diabetes mellitus is the leading cause of peripher- ripheral neuropathy [27]. al neuropathy in the western world [12]. In the past, there have been wide variations in reported preva- Association with other microvascular disease. There is lence rates of DSP [13], however, with improved con- a clear vascular aetiology for retinopathy and neph- sensus as to the definition of DSP and better stan- ropathy. The strong association between these com- dardisation of neurophysiological tests, several re- plications and DSP indicate a common pathogenic cent large epidemiological studies have consistently mechanism [14]. The retina allows direct visualiza- reported rates around 30% [14, 15]. The most impor- tion of the vasculature and has therefore been studied tant clinical sequalae of sensory loss is foot ulcer- extensively. It used to be thought that retinal blood ation, the most common cause of hospital admission flow is increased initially, followed by hypoperfusion in diabetic patients and the leading cause of non-trau- and hypoxia, all occurring before any effect on retinal matic lower limb amputations [12, 16]. Consequently, function is evident [28]. However, more recent stud- DSP is important not just on clinical grounds but also ies, backed by data from animal models, show that on economic grounds, particularly because the preva- the very earliest insult is a fall in retinal perfusion lence of diabetes continues to increase dramatically [29]. Subsequently, there are maladaptive interac- [17, 18]. To understand the pathogenesis of DSP tions with trophic factors such as vascular endothelial more clearly, to allow the development of effective growth factor and poor metabolic control, which treatments to prevent, slow, or even reverse the dis- eventually cause proliferation of unstable vessels ease process is therefore more and more important. and the development of potentially sight-threatening diseases [30, 31]. Studies of renal perfusion have also shown that blood flow initially increases before any Pathogenesis of distal symmetrical polyneuropathy functional defect is apparent [32]. This is followed by a gradual decline in glomerular perfusion and conse- An understanding of the pathogenesis of DSP has quently filtration and renal function. It is still not been obfuscated in the past by polarised views as to completely clear whether hyperperfusion precedes N. E.Cameron et al.: vascular factors in diabetic neuropathy 1975 blood flow reductions in the peripheral nerve, al- [44]. Furthermore, peripheral neuropathy can devel- though the majority of experimental evidence