Diabetic neuropathy and nerve regeneration

https://doi.org/10.1016/S0301-0082(03)00034-0Get rights and content

Abstract

Diabetic neuropathy is the most common peripheral neuropathy in western countries. Although every effort has been made to clarify the pathogenic mechanism of diabetic neuropathy, thereby devising its ideal therapeutic drugs, neither convinced hypotheses nor unequivocally effective drugs have been established. In view of the pathologic basis for the treatment of diabetic neuropathy, it is important to enhance nerve regeneration as well as prevent nerve degeneration. Nerve regeneration or sprouting in diabetes may occur not only in the nerve trunk but also in the dermis and around dorsal root ganglion neurons, thereby being implicated in the generation of pain sensation. Thus, inadequate nerve regeneration unequivocally contributes to the pathophysiologic mechanism of diabetic neuropathy. In this context, the research on nerve regeneration in diabetes should be more accelerated. Indeed, nerve regenerative capacity has been shown to be decreased in diabetic patients as well as in diabetic animals. Disturbed nerve regeneration in diabetes has been ascribed at least in part to all or some of decreased levels of neurotrophic factors, decreased expression of their receptors, altered cellular signal pathways and/or abnormal expression of cell adhesion molecules, although the mechanisms of their changes remain almost unclear. In addition to their steady-state changes in diabetes, nerve injury induces injury-specific changes in individual neurotrophic factors, their receptors and their intracellular signal pathways, which are closely linked with altered neuronal function, varying from neuronal survival and neurite extension/nerve regeneration to apoptosis. Although it is essential to clarify those changes for understanding the mechanism of disturbed nerve regeneration in diabetes, very few data are now available. Rationally accepted replacement therapy with neurotrophic factors has not provided any success in treating diabetic neuropathy. Aside from adverse effects of those factors, more rigorous consideration for their delivery system may be needed for any possible success. Although conventional therapeutic drugs like aldose reductase (AR) inhibitors and vasodilators have been shown to enhance nerve regeneration, their efficacy should be strictly evaluated with respect to nerve regenerative capacity. For this purpose, especially clinically, skin biopsy, by which cutaneous nerve pathology including nerve regeneration can be morphometrically evaluated, might be a safe and useful examination.

Section snippets

Introduction: aims and scope of review

Diabetic polyneuropathy, the most common of the peripheral neuropathies, occurs widely in western countries. It most often develops in the midst of complications observed in diabetes. The putative pathogenesis of diabetic neuropathy includes increased polyol pathway activity leading to the accumulation of sorbitol and fructose (Gabby et al., 1966, Gabby and O’Sullivan, 1968) and imbalances in nicotinamide adenine dinucleotide phosphate/nicotinamide adenine dinucleotide, reduced form (Williamson

Growth-associated protein-43 (GAP-43)

The synthesis and axonal transport of GAP-43/B-50 are induced in the process of axonal elongation. GAP-43 is a major constituent of the axonal growth cone (Fig. 2), where it is localized exclusively in the membrane skeleton. GAP-43 is never induced in injured neurons of the central nervous system (CNS), where nerve regeneration does not occur under physiological conditions. By contrast, the protein is dramatically induced after nerve injury in the PNS (Vanselow et al., 1994). In steady state,

Relevance of examining nerve regeneration in experimental diabetic models

From the morphological standpoint of view, pathological findings reported in diabetic patients include axonal atrophy, demyelination, loss of nerve fibers, and blunted regeneration of nerve fibers (Sima et al., 1988a, Sima et al., 1988b; Dyck and Giannini, 1996). The progressive nerve fiber loss found in human diabetic neuropathy may be due, in part, to an impaired ability of the diabetic nerve to regenerate in response to the degenerative process. Number of nerve fibers of the peripheral nerve

Pathological findings suggesting nerve regeneration in diabetic nerves

Diabetic polyneuropathy is characterized by a variety of neuropathologic findings, including axonal degeneration and segmental demyelination (Dyck and Giannini, 1996, Gianni and Dyck, 1999). It has not been completely established whether the primary site of involvement is the axon or the Schwann cell. Although earlier investigators rather favored a hypothesis that Schwann cells or myelin are primarily involved in the pathogenesis of diabetic neuropathy (Bischoff, 1967, Ballin and Thomas, 1968,

Regenerating nerve fibers with special reference to pain generation

Diabetic patients can experience a variety of different pain syndromes (Thomas, 1999). However, the mechanism by which such sensory disturbance develops remains unclear. Although neurophysiological abnormalities including dysfunction of ion channels may contribute to the generation of pain in diabetic state (Hirade et al., 1999), it has been suggested that regenerating peripheral afferent neurons are implicated in painful symptoms (Asbury and Fields, 1984). Indeed, nerve biopsies from patients

Evaluation of nerve pathology including regeneration by skin biopsy

Since skin biopsy is a convenient and safe method, it is often used for the diagnosis and evaluation of certain diseases in which cutaneous vascular and nervous tissues are systematically involved. The diagnosis for certain neurological diseases by skin biopsy is usually made on the qualitative basis; lysosomal storage diseases and other degenerative neurological disorders are good candidates (Martin et al., 1977, Martin et al., 1979, Aresenio-Nunes et al., 1981). Specific ultrastructures

Neuronal cell death

The pathological characteristics of MNFs in diabetic patients include axonal degeneration and segmental demyelination. Although loss of neuronal cells including DRG neurons and anterior horn cells was previously described in diabetic patients (Dolman, 1963, Greenbaum et al., 1964), extensive morphometric analysis has not been done. Ohnishi et al. reported that there was no evidence of a decrease in the number of cell bodies in L5 DRG and in their diameters, although the results were obtained

Conclusion

In spite of much effort to introduce ideal therapeutic drugs for diabetic neuropathy, ARIs, whose effects have been best investigated both clinically and experimentally and have been shown to be mediated through multifactorial mechanisms including amelioration of neurotrophic support, are still the most established compounds among potent drugs. However, although experimental data on ARIs have been very promising, a reality is that their clinical efficacy seems limited even for mild degrees of

References (558)

  • M.A. Bisby et al.

    Delayed Wallerian degeneration in sciatic nerves of C57BL/Ola mice is associated with impaired regeneration of sensory axons

    Brain Res.

    (1990)
  • M.S. Bitar et al.

    Diabetes-induced suppression of IGF-1 and its receptor mRNA levels in rat superior cervical ganglia

    Diabetes Res. Clin. Pract.

    (1997)
  • M.M. Black et al.

    Slowing of the rate of axonal regeneration during growth and maturation

    Exp. Neurol.

    (1979)
  • M. Bondoux-Jahan et al.

    Conditioning lesion effects on rat sciatic nerve regeneration are influenced by electrical stimulation delivered to denervated muscles

    Brain Res.

    (1989)
  • O. Bourde et al.

    Quantification of interleukin-6 mRNA in Wallerian degeneration by competitive reverse transcription polymerase chain reaction

    J. Neuroimmunol.

    (1996)
  • W.J. Brewster et al.

    Changes in nerve growth factor and preprotachykinin messenger RNA levels in the iris and trigeminal ganglion in diabetic rats effects of treatment with insulin or NGF

    Mol. Brain Res.

    (1995)
  • S.T. Britland et al.

    Acute and remitting painful diabetic polyneuropathy: a comparison of peripheral nerve fibre pathology

    Pain

    (1992)
  • M.C. Brown et al.

    Macrophage dependence of peripheral sensory nerve regeneration: possible involvement of nerve growth factor

    Neuron

    (1991)
  • F. Cai et al.

    Elevated expression of neurotrophin-3 mRNA in sensory nerve of streptozotocin-diabetic rats

    Neurosci. Lett.

    (1999)
  • N.A. Calcutt et al.

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

    Brain Res.

    (1992)
  • B.D. Carter et al.

    Neurotrophins live or let die: does p75NTR decide?

    Neuron

    (1997)
  • Y.S. Chen et al.

    Facial nerve regeneration in the silicone chamber: the influence of nerve growth factor

    Exp. Neurol.

    (1989)
  • H.-L. Cheng et al.

    Bi-directional regulation of p38 kinase and c-Jun N-terminal protein kinase by insulin-like growth factor-I

    J. Biol. Chem.

    (1998)
  • K. Chung et al.

    The receptive part of the primary afferent axon is most vulnerable to systemic capsaicin in adult rats

    Brain Res.

    (1990)
  • M. Cobb et al.

    How MAP kinases are regulated

    J. Biol. Chem.

    (1995)
  • E.J. Coulson et al.

    p75 neurotrophin receptor-mediated neuronal death in promoted by Bcl-2 and prevented by Bcl-xL

    J. Biol. Chem.

    (1999)
  • C. Crowley et al.

    Mice lacking nerve growth factor display perinatal loss of sensory and sympathetic neurons yet develop basal forebrain cholinergic neurons

    Cell

    (1994)
  • R.J. Davis

    MAPKs: new JNK expands the group

    Trends Biochem. Sci.

    (1994)
  • T.M. De Chiara et al.

    Mice lacking the CNTF receptor, unlike mice lacking CNTF, exhibit profound motor neuron deficits at birth

    Cell

    (1995)
  • J. Delcroix 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

    Mol. Brain Res.

    (1997)
  • S.M. de Waegh et al.

    Local modulation of neurofilament phosphorylation, axonal caliber, and slow axonal transport by myelinating Schwann cells

    Cell

    (1992)
  • D. Alok et al.

    Cyclic AMP and ethanol interact to control apoptosis and differentiation in hypothalamic β-endorphin neurons

    J. Biol. Chem.

    (1994)
  • P. Anand et al.

    The role of endogenous nerve growth factor in human diabetic neuropathy

    Nat. Med.

    (1996)
  • S.C. Apfel et al.

    Recombinant human nerve growth factor in the treatment of diabetic polyneuropathy

    Neurology

    (1998)
  • S.C. Apfel et al.

    Efficacy and safety of recombinant human nerve growth factor in patients with diabetic polyneuropathy

    J. Am. Med. Assoc.

    (2000)
  • Y. Arakawa et al.

    Survival effect of ciliary neurotrophic factor (CNTF) on chick embryonic motoneurons in culture: comparison with other neurotrophic factors and cytokines

    J. Neurosci.

    (1990)
  • A.G. Archer et al.

    The natural history of acute painful neuropathy in diabetes mellitus

    J. Neurol. Neurosurg. Psychiatry

    (1983)
  • M.L. Aresenio-Nunes et al.

    An ultramicroscopic study of skin and conjunctival biopsies in chronic neurological disorders of childhood

    Ann. Neurol.

    (1981)
  • A.K. Asbury et al.

    Pain due to peripheral nerve damage: a hypothesis

    Neurology

    (1984)
  • Asbury, A.K., Thomas, P.K., 1978. Basic pathologic mechanisms. In: Pathology of Peripheral Nerve. Saunders,...
  • S. Averill et al.

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

    Eur. J. Neurosci.

    (1995)
  • L.A. Bach et al.

    Insulin-like growth factors and diabetes

    Diabetes Metab. Rev.

    (1992)
  • P.F. Baker et al.

    Depolarization and calcium entry in squid giant axon

    J. Physiol.

    (1971)
  • R.H.M. Ballin et al.

    Hypertrophic changes in diabetic neuropathy

    Acta Neuropathol.

    (1968)
  • J.A. Batch et al.

    Abnormal regulation of insulin-like growth factor binding protein in adolescents with insulin-dependent diabetes

    J. Clin. Endocrinol. Metab.

    (1991)
  • R.C. Baxter

    Characterization of the acid-labile subunit of the growth hormone-dependent insulin-like growth factor binding protein complex

    J. Clin. Endocrinol. Metab.

    (1988)
  • R.C. Baxter et al.

    Radioimmunoassay of growth hormone-dependent insulin-like growth factor binding protein in human plasma

    J. Clin. Invest.

    (1986)
  • J.W. Baynes

    Role of oxidative stress in the development of complications in diabetes

    Diabetes

    (1991)
  • F. Bellavere et al.

    Prolonged QT period in diabetic autonomic neuropathy: a possible role in sudden cardiac death?

    Br. Heart J.

    (1988)
  • D.L.H. Bennett et al.

    Postnatal changes in the expression of the TrkA high-affinity NGF receptor in primary sensory neurons

    Eur. J. Neurosci.

    (1996)
  • Cited by (212)

    View all citing articles on Scopus
    View full text