Associate editor: M.M. Mouradian
Diabetic neuropathy: Mechanisms to management

https://doi.org/10.1016/j.pharmthera.2008.05.005Get rights and content

Abstract

Neuropathy is the most common and debilitating complication of diabetes and results in pain, decreased motility, and amputation. Diabetic neuropathy encompasses a variety of forms whose impact ranges from discomfort to death. Hyperglycemia induces oxidative stress in diabetic neurons and results in activation of multiple biochemical pathways. These activated pathways are a major source of damage and are potential therapeutic targets in diabetic neuropathy. Though therapies are available to alleviate the symptoms of diabetic neuropathy, few options are available to eliminate the root causes. The immense physical, psychological, and economic cost of diabetic neuropathy underscore the need for causally targeted therapies. This review covers the pathology, epidemiology, biochemical pathways, and prevention of diabetic neuropathy, as well as discusses current symptomatic and causal therapies and novel approaches to identify therapeutic targets.

Introduction

Neuropathy is a common and costly complication of both type 1 (T1DM) and type 2 diabetes (T2DM). The prevalence of neuropathy is estimated to be about 8% in newly diagnosed patients and greater than 50% in patients with long-standing disease (Boulton et al., 2005). There is increasing evidence that even pre-diabetic conditions are also associated with some forms of neuropathy (Franklin et al., 1990, Singleton et al., 2003). An estimated 15% of all patients with diabetes will develop foot ulcers (Gordois et al., 2003), and diabetic neuropathy is the leading cause of nontraumatic limb amputation (Thomas, 1999). The annual costs of diabetic neuropathy and its associated morbidities in the US have been estimated to exceed $10.9 billion (Gordois et al., 2003).

In recent years, considerable progress has been made toward understanding the biochemical mechanisms leading to diabetic neuropathy, and as a result, new treatment modalities are being explored. This review will discuss the epidemiology and impact of diabetic neuropathy and the current understanding of its pathogenesis. This will be followed by a discussion of the diagnosis and evaluation of diabetic neuropathy, and conclude with an examination of current treatment options and anticipated new therapeutic approaches.

Diabetic neuropathy is a descriptive term that encompasses a spectrum of clinical and subclinical syndromes with differing anatomical distributions, clinical courses, and possibly differing underlying pathogenetic mechanisms. Each is characterized by diffuse or focal damage to peripheral somatic or autonomic nerve fibers resulting from diabetes mellitus, although indistinguishable syndromes may occur idiopathically or in association with other disorders in nondiabetic individuals. Table 1 lists the most common clinical syndromes comprising diabetic neuropathy.

The syndromes may be grouped under two general headings: diffuse and focal neuropathies. The diffuse neuropathies, i.e., distal symmetrical sensorimotor polyneuropathy (DPN) and diabetic autonomic neuropathy (DAN) are common, usually chronic, and often progressive. The focal neuropathies are less common, usually acute in onset, and often self-limited.

In DPN, sensory deficits usually overshadow motor nerve dysfunction and appear first in the distal portions of the extremities and progress proximally in a “stocking-glove” distribution with increasing duration or severity of diabetes (Fig. 1). The signs and symptoms of DPN vary depending on fiber type involved, with large fiber disease impairing proprioception and light touch. Small fiber disease impairs pain and temperature perception, leading to paresthesias, dysesthesias, and/or neuropathic pain. Distal weakness occurs only in the most severe cases. Diminished or absent deep-tendon reflexes, particularly the Achilles tendon reflex, often indicates mild and otherwise asymptomatic DPN. More advanced asymptomatic neuropathy may first present with late complications such as ulceration or neuroarthropathy (Charcot's joints) of the foot.

Diabetic autonomic neuropathy (DAN) is the other form of diffuse diabetic neuropathy. DAN often accompanies DPN and, as detailed in Table 2, can impair any sympathetic or parasympathetic autonomic function. Although DAN is highly prevalent and associated with a markedly reduced quality of life and increased mortality, it is among the least recognized and most poorly understood complications of diabetes (Freeman, 2005). Further, many of the clinical symptoms of DAN are common and may be due to causes other than diabetic neuropathy. Therefore, as will be discussed in a subsequent section on diagnosis and treatment, it is important to rule out nondiabetes related etiologies for the specific symptom(s) a diabetic patient is experiencing before making a final diagnosis.

The focal forms of diabetic neuropathy reflect damage to single (mononeuropathy) or multiple peripheral nerves (mononeuropathy multiplex), cranial nerves, regions of the brachial or lumbosacral plexuses (plexopathy), or the nerve roots (radiculopathy). The most common peripheral nerve mononeuropathies, medial and ulnar neuropathy, are essentially indistinguishable from entrapment neuropathies in nondiabetic subjects, suggesting that the diabetic nerve has increased susceptibility to compression. Indeed, carpal tunnel syndrome can be demonstrated electrophysiologically in 20 to 30% of diabetic patients, and presents as a clinically relevant problem in 5 to 10% of patients with diabetes (Dyck et al., 1993). Except for these mononeuropathies, the focal diabetic neuropathies are relatively uncommon, acute in onset, self-limiting, and tend to occur in older patients. The most common cranial neuropathy affects the third nerve, producing unilateral headache, diplopia, and ptosis with pupillary sparing (diabetic ophthalmoplegia) (Vinik & Mehrabyan, 2004). Both lumbosacral plexopathy and polyradiculopathy, sometimes referred to as diabetic amyotrophy, occur in diabetic patients, particularly elderly males with T2DM. These conditions usually present with pain, particularly of one thigh, involve L2 through L4 innervated muscles and self-resolve over time. Thoracic radiculopathy produces unilateral band like or abdominal pain that may be misdiagnosed as an acute intrathoracic or intra-abdominal emergency.

In summary, DPN and DAN are very common, generally diffuse, and progressive. The focal neuropathies, with the exception of median and ulnar neuropathies, are generally rare, sudden in onset, often self-limited, and tend to occur in older patients. The remainder of this module will focus on DPN and DAN. The reader is referred to a review by Vinik et al. (2004) for an extensive discussion of the focal neuropathies.

Section snippets

Diabetic polyneuropathy (DPN)

Estimating the prevalence, incidence, and risk of DPN depends on the criteria employed to identify the syndrome. The American Academy of Neurology, the American Association of Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation published a consensus definition in 2005. Important points in the case definition include: 1) the combination of neuropathic symptoms, signs and abnormal electrodiagnostic studies is the strongest predictor of DPN, 2) symptoms

Clinical evaluation of diabetic neuropathy

A consensus statement from the San Antonio Conference on Diabetic Neuropathy recommended that the diagnosis and classification of DPN for research and clinical trials be based on at least one standardized measure from each of the following categories: clinical symptoms, clinical examination, EDX, QST, and AFT (Ziegler et al., 1993). Many currently-used techniques are based on methods developed by Dyck et al. (1992) at the Mayo Clinic. In the absence of neurological symptoms or clinically

Pathogenesis of diabetic neuropathy

There may be multiple etiologies which account for the various neuropathic syndromes seen in patients with diabetes. Hyperglycemia clearly plays a key role in the development and progression of diabetic neuropathy as well as the other microvascular complications of diabetes. Understandably, then, investigations into the molecular and biochemical pathophysiology of diabetic neuropathy have focused on glucose metabolic pathways. Over the past 25 years animal experiments and in vitro studies have

Glycemic control

Therapies for DPN and DAN may be divided into treatments that target the underlying pathogenetic mechanisms (Boulton, 2004, Boulton et al., 2004b, Trotta et al., 2004, Singh et al., 2005) and those aiming to relieve symptoms (Adriaensen et al., 2005). In the latter category there are numerous established approaches; in the former, the only proven method currently available to prevent DPN and DAN or slow progression is strict glycemic control (Tesfaye et al., 2005).

The search for novel therapeutic targets

While this review has discussed the fusion of over 30 years of research in diabetic neuropathy, glucose control alone still remains the only disease-modifying therapy for diabetic neuropathy (Leinninger et al., 2006b, Little et al., 2007, Vincent et al., 2008). This lack of progress, despite intense research, suggests that a new paradigm is needed. We contend that a “discovery approach” using informatics to analyze genomic and proteomic data from animal models and patients with DPN may provide

Summary

Neuropathy is one of the most prevalent, devastating and costly complications of diabetes. Distal symmetrical sensorimotor polyneuropathy (DPN) is the leading cause of nontraumatic limb amputation. Diabetic autonomic neuropathy (DAN) can affect virtually any body system and is associated with greatly increased morbidity and mortality and can have a profound influence on quality of life. Several biochemical mechanisms of nerve and neurovascular damage have been identified and excessive

Acknowledgments

We would like to thank Ms. Julie Erwin for her expert secretarial assistance. This work was supported by NIH T32 D07245, the Juvenile Diabetes Research Foundation Center for the Study of Complications in Diabetes and the Program for Neurological Research and Development (PNRD).

References (417)

  • CalcuttN.A. et al.

    Reduced ciliary neuronotrophic factor-like activity in nerves from diabetic or galactose-fed rats

    Brain Res

    (1992)
  • CalcuttN.A. et al.

    Effects of diabetes on tissue content and evoked release of calcitonin gene-related peptide-like immunoreactivity from rat sensory nerves

    Neurosci Lett

    (1998)
  • ChenW.P. et al.

    Resveratrol enhances insulin secretion by blocking K(ATP) and K(V) channels of beta cells

    Eur J Pharmacol

    (2007)
  • ChristiansonJ.A. et al.

    Beneficial actions of neurotrophin treatment on diabetes-induced hypoalgesia in mice

    J Pain

    (2003)
  • ChristiansonJ.A. et al.

    Neurotrophic modulation of myelinated cutaneous innervation and mechanical sensory loss in diabetic mice

    Neuroscience

    (2007)
  • ChudlerE.H. et al.

    Nerve growth factor depletion by autoimmunization produces thermal hypoalgesia in adult rats

    Brain Res

    (1997)
  • ChylackL.T. et al.

    Efficacy of Alrestatin, an aldose reductase inhibitor, in human diabetic and nondiabetic lenses

    Ophthalmology

    (1979)
  • CollinsS.L. et al.

    Antidepressants and anticonvulsants for diabetic neuropathy and postherpetic neuralgia: a quantitative systematic review

    J Pain Symp Manag

    (2000)
  • ContiG. et al.

    Macrophage infiltration and death in the nerve during the early phases of experimental diabetic neuropathy: a process concomitant with endoneurial induction of IL-1beta and p75NTR

    J Neurol Sci

    (2002)
  • CoppiniD.V. et al.

    Showing neuropathy is related to increased mortality in diabetic patients — a survival analysis using an accelerated failure time model

    J Clin Epidemiol

    (2000)
  • CotterM.A. et al.

    Effect of the NAD(P)H oxidase inhibitor, apocynin, on peripheral nerve perfusion and function in diabetic rats

    Life Sci

    (2003)
  • CoughlanM.T. et al.

    Role of the AGE crosslink breaker, alagebrium, as a renoprotective agent in diabetes

    Kidney Int

    (2007)
  • DallocchioC. et al.

    Gabapentin vs. amitriptyline in painful diabetic neuropathy: an open-label pilot study

    J Pain Symp Manag

    (2000)
  • Das EvcimenN. et al.

    The role of protein kinase C activation and the vascular complications of diabetes

    Pharmacol Res

    (2007)
  • DelcroixJ.D. et al.

    Diabetes and axotomy-induced deficits in retrograde axonal transport of nerve growth factor correlate with decreased levels of p75LNTR protein in lumbar dorsal root ganglia

    Brain Res Mol Brain Res

    (1997)
  • DidangelosT.P. et al.

    Effect of quinapril or losartan alone and in combination on left ventricular systolic and diastolic functions in asymptomatic patients with diabetic autonomic neuropathy

    J Diabetes Its Complicat

    (2006)
  • DiemelL.T. et al.

    Expression of neuropeptides in experimental diabetes; effects of treatment with nerve growth factor or brain-derived neurotrophic factor

    Brain Res Mol Brain Res

    (1994)
  • DograS. et al.

    Oxcarbazepine in painful diabetic neuropathy: a randomized, placebo-controlled study

    Eur J Pain (Lond, Engl)

    (2005)
  • AdlerA.I. et al.

    Risk factors for diabetic peripheral sensory neuropathy. Results of the Seattle prospective diabetic foot study

    Diabetes Care

    (1997)
  • AdministrationF.a.D.

    New drug application for Trovan (trovafloxacin) to the FDA. [Application Number: 020759/020760]

    Cent Drug Eval Res

    (1997)
  • AdriaensenH. et al.

    Critical review of oral drug treatments for diabetic neuropathic pain-clinical outcomes based on efficacy and safety data from placebo-controlled and direct comparative studies

    Diabetes/Metab Res Rev

    (2005)
  • AielloL.P. et al.

    Inhibition of PKC beta by oral administration of ruboxistaurin is well tolerated and ameliorates diabetes-induced retinal hemodynamic abnormalities in patients

    Investig Ophthalmol Vis Sci

    (2006)
  • AndersonP.C. et al.

    New phosphodiesterase inhibitors in the treatment of erectile dysfunction

    Expert Opin Pharmacother

    (2004)
  • AnjaneyuluM. et al.

    Quercetin attenuates thermal hyperalgesia and cold allodynia in STZ-induced diabetic rats

    Indian J Exp Biol

    (2004)
  • ArezzoJ. et al.

    Zopolrestat phase II neuropathy study group: efficacy and safety results of a phase II multicenter study of the aldose reductase inhibitor zopolrestat in patients with peripheral symmetrical diabetic polyneuropathy

    Diabetes Care

    (1996)
  • ArikawaE. et al.

    Effects of insulin replacements, inhibitors of angiotensin, and PKCbeta's actions to normalize cardiac gene expression and fuel metabolism in diabetic rats

    Diabetes

    (2007)
  • ArrietaO. et al.

    Retinoic acid increases tissue and plasma contents of nerve growth factor and prevents neuropathy in diabetic mice

    Eur J Clin Investig

    (2005)
  • AsburyA.K. et al.

    Report and recommnedations of the San Antoio conference on diabetic neuropathy

    Diabetes

    (1988)
  • AshburnerM. et al.

    Gene ontology: tool for the unification of biology. The gene ontology consortium

    Nat Genet

    (2000)
  • AssociationA.D.

    Clinical practice recommendations 2004

    (2004)
  • AtliA. et al.

    Zonisamide in the treatment of painful diabetic neuropathy: a randomized, double-blind, placebo-controlled pilot study

    Pain Med (Malden, Mass)

    (2005)
  • AverillS. et al.

    Immunocytochemical localization of trkA receptors in chemically identified subgroups of adult rat sensory neurons

    Eur J Neurosci

    (1995)
  • BackonjaM. et al.

    Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial [see comments]

    J Am Med Assoc

    (1998)
  • BarbacidM.

    The Trk family of neurotrophin receptors

    J Neurobiol

    (1994)
  • BarbanoR.L. et al.

    Effectiveness, tolerability, and impact on quality of life of the 5% lidocaine patch in diabetic polyneuropathy

    Arch Neurol

    (2004)
  • BarnettP.A. et al.

    The effect of oxidation on sorbitol pathway kinetics

    Diabetes

    (1986)
  • BarrettA.M. et al.

    Epidemiology, public health burden, and treatment of diabetic peripheral neuropathic pain: a review

    Pain Med

    (2007)
  • BaxG. et al.

    Reproducibility of Michigan Neuropathy Screening Instrument (MNSI). A comparison with tests using the vibratory and thermal perception thresholds

    Diabetes Care

    (1996)
  • BeckmanJ.A. et al.

    Inhibition of protein kinase Cbeta prevents impaired endothelium-dependent vasodilation caused by hyperglycemia in humans

    Circ Res

    (2002)
  • BeydounA. et al.

    Oxcarbazepine in painful diabetic neuropathy: results of a dose-ranging study

    Acta Neurol Scand

    (2006)
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