Diabetic peripheral neuropathy is the most common complication of long-standing diabetes mellitus which frequently results in clinically significant morbidities e.g. pain, foot ulcers and amputations. During its natural course it progresses from initial functional changes to late, poorly reversible, structural changes. Various interconnected pathogenetic concepts of diabetic neuropathy have been proposed based on metabolic and vascular factors, mostly derived from long-term hyperglycemia. These pathogenetic mechanisms have been targeted in several experimental and clinical trials. This review summarizes available, mainly morphological data from interventions designed to halt the progression or achieve the reversal of established diabetic neuropathy, which include the recovery of normoglycemia by pancreas or islet transplantation, polyol pathway blockade by aldose reductase inhibitors, mitigation of oxidative stress by the use of antioxidants or correction of abnormalities in essential fatty acid metabolism. Unfortunately, to date, no treatment based on pathogenic considerations has shown clear positive effects and thus early institution of optimal glycemic control remains the only available measure with proven efficacy in preventing or halting progression of diabetic neuropathy. Further experimental and clinical research employing objective reproducible parameters is clearly needed. Novel non-invasive or minimally invasive methods e.g. corneal confocal microscopy or epidermal nerve fiber counts may represent potentially useful instruments for the objective assessment of nerve damage and monitoring of treatment effects.

Diabetes Centre Institute for Clinical and Experimental Medicine Videnska 1958 9 14021 Prague 4 Czech Republic

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Vinik AI, Park TS, Stansberry KB, Pittenger GL. Diabetic neuropathies. Diabetologia. 2000;43:957–973. PubMed

Malik RA, Tesfaye S, Newrick PG, Walker D, Rajbhandari SM, Siddique I, Sharma AK, Boulton AJ, King RH, Thomas PK, Ward JD. Sural nerve pathology in diabetic patients with minimal but progressive neuropathy. Diabetologia. 2005;48:578–585. PubMed

DCCT Research Group. The effect of intensive diabetes therapy on the development and progression of neuropathy. Ann Int Med. 1995;122(8):561–568. PubMed

Yasuda H, Terada M, Maeda K, Kogawa S, Sanada M, Haneda M, Kashiwagi A, Kikkawa R. Diabetic neuropathy and nerve regeneration. Prog Neurobiol. 2003;69(4):229–285. PubMed

Kennedy JM, Zochodne DW. Impaired peripheral nerve regeneration in diabetes mellitus. J Peripher Nerv Syst. 2005;10:144–157. PubMed

Apfel SC. Nerve regeneration in diabetic neuropathy. Diabet Obes Metab. 1999;1:3–11. PubMed

Sima AA. Structure-function interactions in the therapeutic response of diabetic neuropathy. J Diabetes Complications. 1992;6:64–68. PubMed

Sima AA. The reproducibility and sensitivity of sural nerve morphometry in the assessment of diabetic peripheral polyneuropathy. Diabetologia. 1992;35:560–569. PubMed

Stevens MJ, Feldman EL, Thomas T, Greene DA. In: Veves A (ed). Clinical management of diabetic neuropathy. Chapter 2. Humana Press; Totowa, NJ: 1998. Pathogenesis of diabetic neuropathy.

Sheetz MJ, King GL. Molecular understanding of hyperglycemia's adverse effects for diabetic complications. JAMA. 2002;288:2579–2588. PubMed

Sima AA, Sugimoto K. Experimental diabetic neuropathy: an update. Diabetologia. 1999;42:773–788. PubMed

Cameron NE, Eaton SEM, Cotter MA, Tesfaye S. Vascular factors and metabolic interactions in the pathogenesis of diabetic neuropathy. Diabetologia. 2001;44:1973–1988. PubMed

Sima AA, Pierson CR. In: Gries FA, Cameron NE, Low PA, Ziegler D (eds). Textbook of diabetic neuropathy. Thieme; Stuttgart: 2003. Metabolic alterations in experimental models; pp. 96–105.

Terada M, Yasuda H, Kikkawa R. Delayed Wallerian degeneration and increased neurofilament phosphorylation in sciatic nerves of rats with streptozotocin-induced diabetes. J Neurol Sci. 1998;155:23–30. PubMed

Kennedy JM, Zochodne DW. The regenerative deficit of peripheral nerves in experimental diabetes: its extent, timing and possible mechanisms. Brain. 2000;123:2118–2129. PubMed

Vinik AI, Pittenger GL, Barlow P, Mehrabyan A. In: LeRoith D, Taylor SI, Olefsky JM (eds). Diabetes mellitus: a fundamental and clinical text. 3rd Edition. Lippincott, Philadelphia: 2004. Diabetic neuropathies: an overview of clinical aspects, pathogenesis and treatment.

Sima AA, Zhang W, Xu G, Sugimoto K, Guberski D, Yorek MA. A comparison of diabetic polyneuropathy in type II diabetic BBZDR/Wor rats and in type I diabetic BB/wor rats. Diabetologia. 2000;43:786–793. PubMed

Kennedy JM, Zochodne DW. Experimental diabetic neuropathy with spontaneous recovery. Is there irreparable damage? Diabetes. 2005;54:830–837. PubMed

Sima AA, Zhang WX, Tai J, Tze WJ, Nathaniel V. Diabetic neuropathy in STZ-induced diabetic rat and effect of allogenic islet cell transplantation. Morphometric analysis. Diabetes. 1988;37:1129–1136. PubMed

Orloff MJ, Macedo A, Greenleaf GE. Effect of pancreas transplantation on diabetic somatic neuropathy. Surgery. 1988;104:437–444. PubMed

Orloff MJ, Greenleaf GE, Girard B. Reversal of diabetic somatic neuropathy by whole-pancreas transplantation. Surgery. 1990;108:179–189. PubMed

Scott MH, Lee S, D'Silva M, Chang CM, Allen J, Yancey D, Moossa AR. Effect of pancreas allografts on the ultrastructure of sciatic nerves in diabetic rats. Microsurgery. 1990;11:152–161. PubMed

Sima AA, Prashar A, Zhang WX, Chakrabarti S, Greene DA. Preventive effect of long-term aldose reductase inhibition (ponalrestat) on nerve conduction and sural nerve structure in the spontaneously diabetic Bio-Breeding rat. J Clin Invest. 1990;85:1410–1420. PubMed PMC

Yagihashi S, Kamijo M, Ido Y, Mirrlees D. Effects of long-term aldose reductase inhibition on development of experimental diabetic neuropathy: ultrastructural and morphometric studies of sural nerve in streptozotocin-induced diabetic rats. Diabetes. 1990;39:690–696. PubMed

Terada M, Yasuda H, Kikkawa R, Shigeta Y. Tolrestat improves nerve regeneration after crush injury in streptozotocin-induced diabetic rats. Metabolism. 1996;45:1189–1195. PubMed

Kamijo M, Merry AC, Cherian PV, Zkras G, Sima AA. Nerve fibre regeneration following axotomy in the diabetic BB/W-rat. The effect of ARI treatment. J Diabetes Complications. 1996;10:183–191. PubMed

Nagamatsu M, Nickander KK, Schmelzer JD. Lipoic acid improves nerve blood flow, reduces oxidative stress and improves distal nerve conduction in experimental diabetic neuropathy. Diabetes Care. 1995;18:1160–1167. PubMed

Love A, Cotter MA, Cameron NE. Effects of the sulphydryl donor N-acetyl-L-cysteine on nerve conduction, perfusion, maturation and regeneration following freeze damage in diabetic rats. Eur J Clin Invest. 1996;26:698–706. PubMed

Love A, Cotter MA, Cameron NE. Effects of alpha tocopherol on nerve conduction velocity and regeneration following freeze lesion in immature diabetic rats. Naunyn Schmiedebergs Arch Pharmacol. 1997;355:126–130. PubMed

Cameron NE, Cotter MA. Comparison of the effects of ascorbyl gamma-linolenic acid and gamma-linolenic acid in the correction of neurovascular deficits in diabetic rats. Diabetologia. 1996;39:1047–1054. PubMed

Sima AA, Ristic H, Merry A, Kamijo M, Lattimer SA, Stevens MJ, Greene DA. Primary preventive and secondary interventionary effects of acetyl-L-carnitine on diabetic neuropathy in the bio-breeding Worcester rat. J Clin Invest. 1996;97:1900–1907. PubMed PMC

Sima AA. Pathological mechanisms involved in diabetic neuropathy: can we slow the process? Curr Opin Investig Drugs. 2006;7:324–327. PubMed

Sima AA, Zhang W, Sugimoto K, Henry D, Li Z, Wahren J, Grunberger G. C-peptide prevents and improves chronic type 1 diabetic polyneuropathy in the BB/Wor rat. Diabetologia. 2001;44:889–897. PubMed

Brussee V, Cunningham FA, Zochodne DW. Direct insulin signaling of neurons reverses diabetic neuropathy. Diabetes. 2004;53:1824–1830. PubMed

Kennedy WR, Navarro X, Sutherland DE. Neuropathy profile of diabetic patients in a pancreas transplantation program. Neurology. 1995;45:773–780. PubMed

Hathaway DK, Cashion AK, Milstead EJ, Winsett RP, Cowan PA, Wicks MN, Gaber AO. Autonomic dysregulation in patients awaiting kidney transplantation. Am J Kidney Dis. 1998;32:221–229. PubMed

Allen RD, Al-Harbi IS, Morris JG, Clouston PD, O'Connell PJ, Chapman JR, Nankivell BJ. Diabetic neuropathy after pancreas transplantation: determinants of recovery. Transplantation. 1997;63:830–838. PubMed

Navarro X, Sutherland DE, Kennedy WR. Long-term effects of pancreatic transplantation on diabetic neuropathy. Ann Neurol. 1997;42:727–736. PubMed

Ziegler D. In: Gries FA, Cameron NE, Low PA, Ziegler D (eds). Textbook of diabetic neuropathy. Thieme; Stuttgart: 2003. Glycemic control; pp. 91–96.

Boucek P, Saudek F, Adamec M, Janousek L, Koznarova R, Havrdova T, Skibova J. Spectral analysis of heart variation following simultaneous pancreas and kidney transplantation. Transplant Proc. 2003;35:1494–1498. PubMed

Beggs JL, Johnson PC, Olafsen AG, Cleary CP, Watkins CJ, Targovnik JH. Signs of nerve regeneration and repair following pancreas transplantation in an insulin-dependent diabetic with neuropathy. Clin Transplant. 1990;4:133–141.

Kennedy WR, Wendelschafer-Crabb G, Johnson T. Quantitation of epidermal nerves in diabetic neuropathy. Neurology. 1996;47:1042–1048. PubMed

Navarro X, Kennedy WR. In: Gruessner RW, Sutherland DE (eds). Transplantation of the pancreas. Springer; New York: 2004. Effects of pancreas transplantation on secondary complications of diabetes neuropathy; pp. 483–496.

Boucek P, Havrdova T, Voska L, Lodererova A, Hejna A, Saudek F, Lipar K, Janousek L, Adamec M, Sommer C. In: 16th Annual Neurodiab Meeting. Ystad, Sweden: 2006. Epidermal nerve fibre depletion in simultaneous pancreas and kidney transplant patients: no change at follow-up after 18 months of normoglycemia.

Sima AA, Bril V, Nathaniel V, McEwen TA, Brown MB, Lattimer SA, Greene DA. Regeneration and repair of myelinated fibers in sural-nerve biopsy specimens from patients with diabetic neuropathy treated with sorbinil. N Engl J Med. 1988;319:548–555. PubMed

Greene DA, Arezzo JC, Brown MB. Effect of aldose reductase inhibition on nerve conduction and morphometry in diabetic neuropathy. Zenarestat Study Group. Neurology. 1999;53:580–591. PubMed

Greene D. Effects of aldose reductase inhibitors on the progression of nerve fiber damage in diabetic neuropathy. J Diabetes Complications. 1992;6:35–38. PubMed

Ziegler D, Reljanovic N, Mehnert H, Gries FA. alpha-lipoic acid in the treatment of diabetic polyneuropathy in Germany: current evidence from clinical trials. Exp Clin Endocrinol Diabetes. 1999;107:421–430. PubMed

Gamma-Linolenic Acid Multicenter Trial Group. Treatment of diabetic neuropathy with gamma-linolenic acid. Diabetes Care. 1993;16:8–15. PubMed

Ziegler D. In: 16th Annual Neurodiab Meeting. Ystad, Sweden: 2006. Antioxidant treatment in diabetic polyneuropathy - update 2006.

Sima AA, Calvani M, Mehra M, Amato A. Acetyl-L-carnitine improves pain, nerve regeneration, and vibratory perception in patients with chronic diabetic neuropathy: an analysis of two randomized placebo-controlled trials. Acetyl-L-Carnitine Study Group. Diabetes Care. 2005;28(1):89–94. PubMed

Apfel SC, Schwartz S, Adornato BT, Freeman R, Biton V, Rendell M, Vinik A, Giuliani M, Stevens JC, Barbano R, Dyck PJ. Efficacy and safety of recombinant human nerve growth factor in patients with diabetic polyneuropathy. JAMA. 2000;284:2215–2221. PubMed

Wellmer A, Misra VP, Sharief MK, Kopelman PG, Anand P. A double-blind placebo-controlled clinical trial of recombinant human brain-derived neurotrophic factor (rhBDNF) in diabetic polyneuropathy. J Peripher Nerv Syst. 2001;6:204–210. PubMed

Pfeifer MA, Schumer MP. Clinical trials of diabetic neuropathy: past, present, and future. Diabetes. 1995;44:1355–1361. PubMed

Vinik AI, Bril V, Litchy WJ, Price KL, Bastyr EJ. Sural sensory action potential identifies diabetic peripheral neuropathy responders to therapy. MBBQ Study Group. Muscle Nerve. 2005;32:619–625. PubMed

Malik RA, Kallinikos P, Abbott CA, van Schie CH, Morgan P, Efron N, Boulton AJ. Corneal confocal microscopy: a non-invasive surrogate of nerve fibre damage and repair in diabetic patients. Diabetologia. 2003;46:683–688. PubMed

Mehra S, Tavakoli M, Palmer A, Tavakoli A, Pararajasingam R, Parrott NR, Malik R, Augustine T. Early neural regeneration after pancreas transplantation detected by corneal confocal microscopy: a pilot study. Am J Transplant. 2006;82(Suppl 2):A118.

Levy DM, Terenghi G, Gu XH, Abraham RR, Springall DR, Polak JM. Immunohistochemical measurements of nerves and neuropeptides in diabetic skin: relationship to tests of neurological function. Diabetologia. 1992;35:889–897. PubMed

McCarthy BG, Hsieh ST, Stocks A, Hauer P, Macko C, Cornblath DR, Griffin JW, McArthur JC. Cutaneous innervation in sensory neuropathies: evaluation by skin biopsy. Neurology. 1995;45:1848–1855. PubMed

Kennedy WR, Nolano M, Wendelschafer-Crabb G, Johnson T, Tamura E. A skin blister method to study epidermal nerves in peripheral nerve disease. Muscle Nerve. 1999;22:360–371. PubMed

Polydefkis M, Hauer P, Sheth S, Sirdofsky M, Griffin JW, McArthur JC. The time course of epidermal nerve fibre regeneration: studies in normal controls and in people with diabetes, with and without neuropathy. Brain. 2004;127:1606–1615. PubMed

Luft D, Ziegler D. In: Gries FA, Cameron NE, Low PA, Ziegler D (eds). Textbook of diabetic neuropathy. Thieme; Stuttgart: 2003. Evaluation of drug effects; pp. 313–327.

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Preserved Expression of Skin Neurotrophic Factors in Advanced Diabetic Neuropathy Does Not Lead to Neural Regeneration despite Pancreas and Kidney Transplantation