Review
Pathogenesis of diabetic neuropathy: Focus on neurovascular mechanisms

https://doi.org/10.1016/j.ejphar.2013.07.017Get rights and content

Abstract

Neuropathies of the peripheral and autonomic nervous systems affect up to half of all people with diabetes, and are major risk factors for foot ulceration and amputation. The aetiology is multifactorial: metabolic changes in diabetes may directly affect neural tissue, but importantly, neurodegenerative changes are precipitated by compromised nerve vascular supply. Experiments in animal models of diabetic neuropathy suggest that similar metabolic sequelae affect neurons and vasa nervorum endothelium. These include elevated polyol pathway activity, oxidative stress, the formation of advanced glycation and lipoxidation end products, and various pro-inflammatory changes such as elevated protein kinase C, nuclear factor κB and p38 mitogen activated protein kinase signalling. These mechanisms do not work in isolation but strongly interact in a mutually facilitatory fashion. Nitrosative stress and the induction of the enzyme poly (ADP-ribose) polymerase form one important link between physiological stressors such as reactive oxygen species and the pro-inflammatory mechanisms. Recently, evidence points to endoplasmic stress and the unfolded protein response as forming another crucial link. This review focuses on the aetiopathogenesis of neurovascular changes in diabetic neuropathy, elucidated in animal studies, and on putative therapeutic targets the majority of which have yet to be tested for efficacy in clinical trials.

Introduction

Peripheral neuropathies affect up to 50% of people with diabetes. The diffuse neuropathies, distal symmetrical sensori-motor polyneuropathy (DPN) and autonomic neuropathy (DAN) are common. They constitute major risk factors for foot ulceration and amputation (Boulton, 2005). All nerve fibre types are adversely affected by diabetes; autonomic, motor and sensory, myelinated and unmyelinated.

DPN gives rise to a “stocking-glove” pattern of sensory loss progressing proximally with increasing diabetes duration. DAN causes dysfunction of major organ systems including cardiac, gastrointestinal and urogenital (Vinik et al., 2003). Both DPN and DAN markedly reduce quality of life and increase mortality. To date no satisfactory treatment targeting the causes of neuropathy exists except for good metabolic control, which slows but does not prevent progression (Cameron et al., 2001).

The aetiologies of DPN and DAN are multi-factorial. Studies by the Eurodiab group on type 1 diabetes complications showed that in addition to glycaemic control and duration of diabetes, conventional markers of macro- and micro-vascular disease are strongly associated with DPN (Tesfaye et al., 2005). Similar correlations have been observed for DPN in type 2 diabetes (Papanus and Ziegler, 2012, Ziegler et al., 2008) and for cardiac DAN (Witte et al., 2005). Thus, while the metabolic insult of diabetes may directly affect neural tissue, it is likely that neurodegenerative changes are precipitated by compromised nerve vascular supply. This is in line with earlier work that showed pathological changes in vasa nervorum epi/perineurial and endoneurial vessels (Fagerberg, 1957) and established good correlations between vascular parameters, nerve structural damage and measures of function such as nerve conduction velocity, vibration perception thresholds and thermal discrimination (Giannini and Dyck, 1995, Malik et al., 1989, Malik et al., 1994). These vascular changes occur early, when nerve pathology and neuropathy is minimal (Malik et al., 2005). Physiological measurements of sural nerve oxygen tension and blood flow in patients show that the endoneurium is hypo-perfused and hypoxic with diabetes, and that this is exacerbated in subjects with neuropathy (Ibrahim et al., 1999, Newrick et al., 1986, Tesfaye et al., 1993). An important contributory factor, revealed by photography of epi/perineurial vessels, was an increase of arterio-venous shunting in patients with neuropathy, bypassing the nutritive endoneurial circulation (Tesfaye et al., 1993). Other morphological studies showed denervation of perineurial vessels, suggesting that DAN could potentially contribute to the impaired control of nerve perfusion in diabetes (Beggs et al., 1992). Whether the resultant hypoxic stress on nerve fibres is sufficient to account for diabetic neuropathy or whether it acts in concert with direct metabolic stress on nerve fibres resulting from the diabetic milieu cannot be answered by the limited number of investigations carried out to date in patients. However, data from animal models provides further insight into the pathogenetic mechanisms underlying DPN, and pharmacological intervention studies have revealed numerous potential therapeutic targets, a small number of which have advanced to clinical trials.The aim of this review is to provide an update on the putative mechanisms leading to DPN/DAN in diabetes mellitus, with a focus on neurovascular dysfunction.

Section snippets

Vasa nervorum changes and endoneurial ischaemia in experimental diabetes

It is generally agreed that nerve blood flow is reduced by diabetes. In chemically-induced animal models such as the streptozotocin (STZ)-treated rat, this occurs within the first few days of diabetes induction, preceding changes in nerve electrophysiology such as reduced conduction velocity (Cameron et al., 1991, Coppey et al., 2000, Wright and Nukada, 1994). The perfusion deficit causes endoneurial hypoxia sufficient to compromise nerve function and initiate neurodegenerative processes (Tuck

Metabolic alterations in diabetes and the pathogenesis of neuropathy

Some of the major metabolic changes in diabetes thought to contribute to DPN and DAN are schematised in Fig. 1. These include elevated polyol pathway activity, oxidative stress, the formation of advanced glycation end products, and various proinflammatory changes such as elevated nuclear factor κB (NFκB) and p38 mitogen activated protein kinase (MAPK) signalling. These mechanisms do not work in isolation but strongly interact in a mutually facilitatory fashion. Other mechanisms include

Conclusions

Neuropathy is a common complication of diabetes, reducing the quality of life and increasing mortality. Available treatments to date consist of improved metabolic control and a focus on symptoms but do not concentrate on fundamental mechanisms in the pathogenesis of neuropathy. Current research has revealed a multifactorial aetiology of interlinked pathways dependent on oxidative/nitrosative stress, advanced glycation/lipoxidation, PARP activity and E–R stress that activate pro-inflammatory

References (113)

  • M.M Jack et al.

    Protection from diabetes-induced peripheral sensory neuropathy—a role for elevated glyoxalase I?

    Exp. Neurol.

    (2012)
  • A. Kumar et al.

    Suppression of NF-κB and NF-κB regulated oxidative stress and neuroinflammation by BAY 11-7082 (IκB phosphorylation inbibitor) in experimental diabetic neuropathy

    Biochimie

    (2012)
  • S. Lupachyk et al.

    PARP inhibition alleviates diabetes-induced systemic oxidative stress and neural tissue 4-hydroxynonenal adduct accumulation: correlation with peripheral nerve function

    Free Rad. Biol. Med.

    (2011)
  • R.A. Malik et al.

    Transperineurial capillary abnormalities in the sural nerve of patients with diabetic neuropathy

    Microvasc. Res.

    (1994)
  • R.A. Malik et al.

    Effects of angiotensin-converting-enzyme (ACE) inhibitor trandolapril on human diabetic neuropathy: randomized double-blind controlled trial

    Lancet

    (1998)
  • S.M. Manschot et al.

    Angiotensin converting enzyme inhibition partially prevents deficits in water maze performance, hippocampal synaptic plasticity and cerebral blood flow in streptozotocin-diabetic rats

    Brain Res.

    (2003)
  • E.K. Maxfield et al.

    Effect of diabetes on reactivity of sciatic vasa nervorum in rats

    J. Diabetes Complications

    (1997)
  • J. Nakamura et al.

    Physiological and morphometric analyses of neuropathy in sucrose-fed OLETF rats

    Diabetes Res. Clin. Pract

    (2001)
  • M.R. Nangle et al.

    Effects of the peroxynitrite decomposition catalyst, FeTMPyP, on function of corpus cavernosum from diabetic mice

    Eur. J. Pharmacol.

    (2004)
  • M.R. Nangle et al.

    IkB kinase 2 inhibition corrects defective nitrergic erectile mechanisms in diabetic mouse corpus cavernosum

    Urology

    (2006)
  • M.R. Nangle et al.

    Poly(ADP-ribose) polymerase inhibition reverses nitrergic neurovascular dysfunctions in penile erectile tissue from streptozotocin-diabetic mice

    J. Sex. Med.

    (2010)
  • I.G. Obrosova

    Diabetes and the peripheral nerve

    Biochim. Biophys. Acta

    (2009)
  • I.G. Obrosova et al.

    Different roles of 12/15-lipoxygenase in diabetic large and small fiber peripheral and autonomic neuropathies

    Am. J. Pathol.

    (2010)
  • R.E. Schmidt et al.

    A potent sorbitol dehydrogenase inhibitor exacerbates sympathetic autonomic neuropathy in rats with streptozotocin-induced diabetes

    Exp. Neurol.

    (2005)
  • R. Stavniichuk et al.

    Interplay of sorbitol pathway of glucose metabolism, 12/15-lipoxygenase, and mitogen-activated protein kinases in the pathogenesis of diabetic peripheral neuropathy

    Biochem. Pharmacol.

    (2012)
  • S.M Sweitzer et al.

    Antinociceptive action of a p38α MAPK inhibitor, SD-282, in a diabetic neuropathy model

    Pain

    (2004)
  • B. Basha et al.

    Endothelial dysfunction in diabetes mellitus: possible involvement of endoplasmic reticulum stress?

    Exp. Diabetes Res

    (2012)
  • J. Beggs et al.

    Innervation of the vasa nervorum: changes in human diabetics

    J. Neuropathol. Exp. Neurol.

    (1992)
  • A.J.M. Boulton

    Management of diabetic peripheral neuropathy

    Clin. Diabetes

    (2005)
  • V. Brill et al.

    Ranirestat for the management of diabetic polyneuropathy

    Diabetes Care

    (2009)
  • N.E. Cameron

    Role of endoplasmic reticulum stress in diabetic neuropathy

    Diabetes

    (2013)
  • N.E. Cameron et al.

    Neurovascular deficits in diabetic rats: potential contribution of autoxidation and free radicals examined using transition metal chelating agents

    J. Clin. Invest

    (1995)
  • N.E. Cameron et al.

    Effects of an extracellular transition metal chelator, hydroxyethyl starch-deferoxamine, on neurovascular function in diabetic rats

    Diabetologia

    (2001)
  • N.E. Cameron et al.

    Effects of protein kinase C beta inhibition on neurovascular dysfunction in diabetic rats: interaction with oxidative stress and essential fatty acid dysmetabolism

    Diabetes Metab. Res. Rev

    (2002)
  • N.E. Cameron et al.

    Pro-inflammatory mechanisms in diabetic neuropathy: focus on the nuclear factor kappa B pathway

    Curr. Drug Targets

    (2008)
  • N.E. Cameron et al.

    Nerve blood flow in early experimental diabetes in rats: relation to conduction deficits

    Am. J. Physiol.

    (1991)
  • N.E. Cameron et al.

    Anti-oxidant and pro-oxidant effects on nerve conduction velocity and endoneurial blood flow and oxygen tensions in non-diabetic and streptozotocin-diabetic rats

    Diabetologia

    (1994)
  • N.E. Cameron et al.

    Aldose reductase inhibition, nerve perfusion, oxygenation and function in streptozotocin–diabetic rats: dose-response considerations and independence from a myo-inositol mechanism

    Diabetologia

    (1994)
  • N.E. Cameron et al.

    Comparison of the effects of inhibitors of aldose reductase and sorbitol dehydrogenase on neurovascular function, nerve conduction and tissue polyol pathway metabolites in streptozotocin-diabetic rats

    Diabetologia

    (1997)
  • N.E. Cameron et al.

    Protein kinase C effects on nerve function, perfusion and Na+,K+-ATPase activity and glutathione content in diabetic rats

    Diabetologia

    (1999)
  • N.E. Cameron et al.

    Vascular factors and metabolic interactions in the pathogenesis of diabetic neuropathy

    Diabetologia

    (2001)
  • N.E. Cameron et al.

    Inhibitors of advanced glycation end product formation and neurovascular dysfunction in experimental diabetes

    Ann. NY Acad. Sci

    (2005)
  • C.M. Casellini et al.

    A 6-month, randomized, double-masked, placebo-controlled study evaluating the effects of the protein kinase C-β inhibitor ruboxistaurin on skin microvascular blood flow and other measures of diabetic peripheral neuropathy

    Diabetes Care

    (2007)
  • H.T. Cheng et al.

    p38 mediates mechanical allodynia in a mouse model of type 2 diabetes

    Mol. Pain

    (2010)
  • L.J. Coppey et al.

    Slowing of motor nerve conduction velocity in streptozotocin-induced diabetic rats is preceded by impaired vasodilation in arterioles that overlie the sciatic nerve

    Int. J. Exp. Diabetes Res.

    (2000)
  • L.J. Coppey et al.

    Mediation of vascular relaxation in epineurial arterioles of the sciatic nerve: Effects of diabetes in type 1 and type 2 diabetic rat models

    Endothelium

    (2003)
  • M.A. Cotter et al.

    Effects of the protein kinase C β-isoform inhibitor, LY333531, on neural and vascular function in streptozotocin-diabetic rats

    Clin. Sci.

    (2002)
  • E.P. Davidson et al.

    Diet-induced obesity in Sprague-Dawley rats causes microvascular and neural dysfunction

    Diabetes Metab. Res. Rev.

    (2010)
  • X. Du et al.

    Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycaemic damage in endothelial cells

    J. Clin. Invest.

    (2003)
  • S.E. Fagerberg

    Studies in the pathogenesis of diabetic neuropathy. IV Angiopathia diabetic vasae nervorum

    Acta Med. Scand.

    (1957)
  • Cited by (132)

    • Diabetic neuropathy: Molecular approach a treatment opportunity

      2022, Vascular Pharmacology
      Citation Excerpt :

      Additionally, CRP and poly-ADP ribose polymerase (PARP) are associated with the regulation of gene expression through NF-κB, activator protein-1 and p53, thus modulating the activity of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, endothelin-1 and various inflammatory genes [41]. PARP is induced in response to damage to single-stranded DNA caused by peroxynitrite [42] . The risk of coronary atherosclerosis reportedly increases in the presence of the low-grade inflammation (i.e., an elevated level of CRP, fibrinogen, the erythrocyte sedimentation rate and the white blood cell count) characteristic of T1D and T2D, and also with a high level of HbA1c in non-diabetic individuals.

    View all citing articles on Scopus
    View full text