CNS Drugs

, Volume 21, Supplement 1, pp 13–23 | Cite as

Acetyl-L-Carnitine in Diabetic Polyneuropathy

Experimental and Clinical Data
Review Article


Diabetic polyneuropathy (DPN) is the most common late complication of diabetes mellitus. The underlying pathogenesis is multifaceted, with partly interrelated mechanisms that display a dynamic course. The mechanisms underlying DPN in type 1 and type 2 diabetes mellitus show overlaps or may differ. The differences are mainly due to insulin deficiency in type 1 diabetes which exacerbates the abnormalities caused by hyperglycaemia.

Experimental DPN in rat models have identified early metabolic abnormalities with consequences for nerve conduction velocities and endoneurial blood flow. When corrected, the early functional deficits are usually normalised. On the other hand, if not corrected, they lead to abnormalities in lipid peroxidation and expression of neurotrophic factors which in turn result in axonal, nodal and paranodal degenerative changes with worsening of nerve function. As the structural changes progress, they become increasingly less amendable to metabolic interventions.

In the past several years, experimental drugs — such as aldose reductase inhibitors, antioxidants and protein kinase C inhibitors — have undergone clinical trials, with disappointing outcomes. These drugs, targeting a single underlying pathogenetic factor, have in most cases been initiated at the advanced stage of DPN. In contrast, substitution of acetyl-L-carnitine (ALC) or C-peptide in type 1 DPN target a multitude of underlying mechanisms and are therefore more likely to be effective on a broader spectrum of the underlying pathogenesis.

Clinical trials utilising ALC have shown beneficial effects on nerve conduction slowing, neuropathic pain, axonal degenerative changes and nerve fibre regeneration, despite relatively late initiation in the natural history of DPN. Owing to the good safety profile of ALC, early initiation of ALC therapy would be justified, with potentially greater benefits.


Nerve Growth Factor Neuropathic Pain Nerve Conduction Velocity Dorsal Root Ganglion Cell Diabetic Polyneuropathy 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Dr Anders Sima is a paid consultant to Sigma-Tau Research Inc., Gaithersburg, MD, USA. He has no financial interest in the company.


  1. 1.
    Sima AAF, Bril V, Greene DA. Pathogenetic heterogeneity in human diabetic neuropathy. Pediatr Adoles Endocrin 1989; 18: 56–62Google Scholar
  2. 2.
    Sima AAF, Nathaniel V, Bril V, et al. Histopathological heterogeneity of neuropathy in insulin-dependent and non-insulin-dependent diabetes, and demonstration of axo-glial dysjunction in human diabetic neuropathy. J Clin Invest 1988; 81: 349–64PubMedCrossRefGoogle Scholar
  3. 3.
    Sima AAF. Diabetic neuropathy differs in type 1 and type 2 diabetes. Ann N Y Acad Sci 2006; 1084: 235–49PubMedCrossRefGoogle Scholar
  4. 4.
    Vinik AI, Liuzze FJ, Holland MT, et al. Diabetic neuropathies. Diabetes Care 1992; 15: 1926–75PubMedCrossRefGoogle Scholar
  5. 5.
    Greene DA, Lattimer SA, Sima AAF. Sorbitol, phosphoinositides and sodium-potassium ATPase in the pathogenesis of diabetic complications. N Engl J Med 1987; 316: 599–606PubMedCrossRefGoogle Scholar
  6. 6.
    Sima AAF. New insights into the metabolic and molecular basis for diabetic neuropathy. Cell Mol Life Sci 2003; 60: 2445–64PubMedCrossRefGoogle Scholar
  7. 7.
    Tomlinson DR, Fernyhough P. Neurotrophism in diabetic neuropathy. In:Sima AAF, editor. Chronic complications in diabetes. Amsterdam: Harwood Academic Publishers, 2000: 167–182Google Scholar
  8. 8.
    Zochodne DW, Verge VMK, Cheng C, et al. Does diabetes target ganglion neurons?. Progressive sensory neuron involvement in long-term experimental diabetes. Brain 2001; 124: 2319–34Google Scholar
  9. 9.
    Sugimoto K, Murakawa Y, Sima AAF. Diabetic neuropathy: a continuing enigma. Diab/Metab Res Rev 2000; 16(6): 408–33CrossRefGoogle Scholar
  10. 10.
    Kamiya H, Zhang W, Sima AAF. Degeneration of Golgi and neuronal loss in DRGs in diabetic BB/Wor-rats. Diabetologia 2006; 49: 2763–74PubMedCrossRefGoogle Scholar
  11. 11.
    Sugimoto K, Sima AAF. Experimental diabetic neuropathy: an update. Diabetologia 1999; 42: 773–88PubMedCrossRefGoogle Scholar
  12. 12.
    Sima AAF. Pathological mechanisms involved in diabetic neuropathy: can we slow the process? Curr Opin Drug Develop 2006; 7: 324–37Google Scholar
  13. 13.
    Ward JO, Bowes CG, Fisher J, et al. Improvement in nerve conduction following treatment in newly diagnosed diabetes. Lancet 1971; 1: 428–30PubMedCrossRefGoogle Scholar
  14. 14.
    Tze WJ, Sima AAF, Tai J. Effect of endocrine pancreas allotransplantation on diabetic nerve dysfunction. Metabolism 1985; 34: 721–31PubMedCrossRefGoogle Scholar
  15. 15.
    Sima AAF, Bril V, Nathaniel V, et al. Regeneration and repair of myelinated fibers in sural nerve biopsies from patients with diabetic neuropathy treated with an aldose reductase inhibitor. N Eng J Med 1988; 319: 548–55CrossRefGoogle Scholar
  16. 16.
    Sima AAF. C-peptide and diabetic neuropathy. Expert Opin Investig Drugs 2003; 12: 1471–88PubMedCrossRefGoogle Scholar
  17. 17.
    Pierson CR, Zhang W, Murakawa Y, et al. Early gene responses of trophic factors differ in nerve regeneration in type 1 and type 2 diabetic neuropathy. J Neuropath Exp Neurol 2002; 61: 857–71PubMedGoogle Scholar
  18. 18.
    Sima AAF, Zhang W, Xu G, et al. A comparison of diabetic polyneuropathy in type-2 diabetic BBZDR/Wor-rat and in type 1 diabetic BB/Wor-rat. Diabetologia 2000; 43: 786–93PubMedCrossRefGoogle Scholar
  19. 19.
    Sima AAF, Zhang W, Li Z-G, et al. Molecular alterations underlie nodal and paranodal degeneration in type 1 diabetic neuropathy and are prevented by C-peptide. Diabetes 2004; 53: 1556–63PubMedCrossRefGoogle Scholar
  20. 20.
    Stevens MJ, Feldman EL, Thomas TP, et al. The pathogenesis of diabetic neuropathy. In: Veves A, Corn PMC, editors. Clinical management of diabetic neuropathy. Totowa (NJ): Humana, 1997: 13–47Google Scholar
  21. 21.
    Dvornik D. Hyperglycemia in the pathogenesis of diabetic complications. In: Porte D, editor. Aldose reductase inhibition. New York: Biomedical Information Corp., 1987: 69–151Google Scholar
  22. 22.
    Cameron N, Cotter M, Basso M, 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; 40: 271–81PubMedCrossRefGoogle Scholar
  23. 23.
    Forst T, Kunt T, Pohlmann T, et al. Biological activity of C-peptide on the skin microcirculation in patients with insulin dependent diabetes mellitus. J Clin Invest 1998; 101: 2036–41PubMedCrossRefGoogle Scholar
  24. 24.
    Jensen ME, Messina EJ. C-peptide induces a concentration-dependent dilatation of skeletal muscle arterioles only in the presence of insulin. Am J Physiol 1999, H1228Google Scholar
  25. 25.
    Stevens MJ, Zhang W, Li F, et al. C-peptide corrects endoneurial blood flow but not oxidative stress in type 1 BB/Wor-rats. Am J Physiol 2004; 287: E497–505Google Scholar
  26. 26.
    Brismar T, Sima AAF. Changes in nodal function in nerve fibres of the spontaneously diabetic BB-Wistar rat. Potential clamp analysis. Acta Physiol Scand 1981; 113: 499–506Google Scholar
  27. 27.
    Sima AAF, Brismar T. Reversible diabetic nerve dysfunction: structural correlates to electrophysiological abnormalities. Ann Neurol 1985; 18: 21–9PubMedCrossRefGoogle Scholar
  28. 28.
    Hirade M, Yasuda H, Omatsu-Kaube M, et al. Tetrodotoxin-resistant sodium channels of dorsal root ganglion neurons are readily activated in diabetic rats. Neuroscience 1999; 90: 933–9PubMedCrossRefGoogle Scholar
  29. 29.
    Lee YH, Ryn TG, Park SJ, et al. Alpha-1 adrenoreceptor involvement in painful diabetic neuropathy: a role in allodynia. Neuroreport 2000; 11: 1417–20PubMedCrossRefGoogle Scholar
  30. 30.
    Woolf CJ, Shortland P, Reynolds H, et al. Reorganization of central terminals of myelinated primary afferents in rat dorsal horn following primary axotomy. J Comp Neurol 1995; 360: 121–34PubMedCrossRefGoogle Scholar
  31. 31.
    Zhang W, Murakawa Y, Wozniak KH, et al. The preventive and therapeutic effects of GCPIII (NAALADase) inhibition on nociceptive and sensory neuropathy. J Neurol Sci 2006; 247: 217–23PubMedCrossRefGoogle Scholar
  32. 32.
    Sugimoto K, Murakawa Y, Sima AAF. Expression and localization of insulin receptor in rat dorsal root ganglion and spinal cord. JPNS 2002; 7: 44–53PubMedCrossRefGoogle Scholar
  33. 33.
    Kamiya H, Murakawa Y, Zhang W, et al. Unmyelinated fiber sensory neuropathy differs in type 1 and type 2 diabetes. Diab Metab Res Rev 2005; 21: 448–58CrossRefGoogle Scholar
  34. 34.
    Brismar T, Sima AAF, Greene DA. Reversible and irreversible nodal dysfunction in diabetic neuropathy. Ann Neurol 1987; 21: 504–7PubMedCrossRefGoogle Scholar
  35. 35.
    Sima AAF, Lorusso AC, Thibert P. Distal symmetric polyneuropathy in the spontaneously diabetic BB-Wistar rat: an ultrastructural and teased fiber study. Acta Neuropath (Berl.) 1982; 58: 39–47CrossRefGoogle Scholar
  36. 36.
    Scott JN, Clark AW, Zochodne DW. Neurofilament and gene expression in progressive experimental diabetes: failure of synthesis and export by sensory neurons. Brain 1999; 122: 2109–18PubMedCrossRefGoogle Scholar
  37. 37.
    Xu G, Murakawa Y, Pierson CR, et al. Altered β-tubulin and neurofilament expression and impaired axonal growth in diabetic nerve regeneration. J Neuropath Exp Neurol 2002; 61: 164–75PubMedGoogle Scholar
  38. 38.
    Fernyhough P, Gallagher A, Averill SA, et al. Aberrant neurofilament phosphorylation in sensory neurons of rats with diabetic neuropathy. Diabetes 1999; 48: 881–9PubMedCrossRefGoogle Scholar
  39. 39.
    Sima AAF, Bouchier M, Christensen H. Axonal atrophy in sensory nerves of the diabetic BB-Wistar rat, a possible early correlate of human diabetic neuropathy. Ann Neurol 1983; 13: 264–72PubMedCrossRefGoogle Scholar
  40. 40.
    Sima AAF, Lattimer SA, Yagihashi S, et al. “Axo-glial dysjunction”: a novel structural lesion that accounts for poorly reversible slowing of nerve conduction in the spontaneously diabetic BB-rat. J Clin Invest 1986; 77: 474–84PubMedCrossRefGoogle Scholar
  41. 41.
    Murakawa Y, Zhang W, Pierson CR, et al. Impaired glucose tolerance and insulinopenia in the GK-rat causes peripheral neuropathy. Diab Metab Res Rev 2002; 18: 473–83CrossRefGoogle Scholar
  42. 42.
    Novella SP, Inzucchi SE, Goldstein JM. The frequency of undiagnosed diabetes and impaired glucose tolerance in patients with idiopathic sensory neuropathy. Muscle Nerve 2001; 24: 1229–31PubMedCrossRefGoogle Scholar
  43. 43.
    Singleton JR, Smith AG, Bromberg MB. Increased prevalence of impaired glucose tolerance in patients with painful sensory neuropathy. Diabetes Care 2001; 24: 1448–53PubMedCrossRefGoogle Scholar
  44. 44.
    Kamiya H, Zhang W, Sima AAF. C-Peptide prevents nociceptive sensory neuropathy in type 1 diabetes. Ann Neurol 2004; 56: 827–35PubMedCrossRefGoogle Scholar
  45. 45.
    Sima AAF. Pathological mechanisms involved in diabetic neuropathy: can we slow the process? Curr Opin Invest Drugs 2006; 7: 324–37Google Scholar
  46. 46.
    Pfeifer MA, Shumer MP, Gelber DA. Aldose reductase inhibitors: the end of an era or the need for different trial design. Diabetes 1997; 46: 582–9Google Scholar
  47. 47.
    Oates PJ, Mylori BL. Aldose reductase inhibitors: therapeutic implications for diabetic complications. Exp Opin Invest Drugs 1999; 8: 2095–119CrossRefGoogle Scholar
  48. 48.
    Ziegler D, Hanefeld M, Ruhnau K-J, et al. Treatment of sympathetic diabetic polyneuropathy with antioxidant β-lipoic acid. Diabetes Care 1999; 22: 1296–301PubMedCrossRefGoogle Scholar
  49. 49.
    Vinik AI. Treatment of diabetic polyneuropathy (DPN) with recombinant human nerve growth factor (rhNGF). Diabetes 1999; 48: A54–5Google Scholar
  50. 50.
    Apfel SC, Schwarz S, Adornato BT, et al. Efficacy and safety of recombinant human nerve growth factor in patients with diabetic polyneuropathy. JAMA 2000; 284: 2215–21PubMedCrossRefGoogle Scholar
  51. 51.
    The Diabetes Control and Complication Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329: 977–86CrossRefGoogle Scholar
  52. 52.
    Prospective Diabetes Study UK (UKPDS) Group. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPD533). Lancet 1998; 352: 837–53CrossRefGoogle Scholar
  53. 53.
    Ekberg K, Brismar T, Johansson B-L, et al. Amelioration of sensory nerve dysfunction by C-peptide in patients with type 1 diabetes. Diabetes 2003; 52: 536–41PubMedCrossRefGoogle Scholar
  54. 54.
    Sima AAF. C-Peptide and diabetic neuropathy. Expert Opin Investig Drugs 2003; 12: 1471–88PubMedCrossRefGoogle Scholar
  55. 55.
    Sima AAF. Kamiya H. Insulin, C-peptide and diabetic neuropathy. Science Med 2004; 10: 308–19Google Scholar
  56. 56.
    Zhang W, Kamiya H, Ekberg K, et al. C-peptide improves neuropathy in type 1 diabetic BB/Wor-rats. Diabetes Metab Res Rev 2007; 23(1): 63–70PubMedCrossRefGoogle Scholar
  57. 57.
    Kamiya H, Zhang W, Ekberg K, et al. C-peptide reverses nociceptive neuropathy in type 1 diabetes. Diabetes 2006 Dec; 55(12): 3581–7PubMedCrossRefGoogle Scholar
  58. 58.
    Brecher P. Interaction of long-chain acyl CoA with membranes. Mol Cell Biochem 1983; 57: 3–15PubMedCrossRefGoogle Scholar
  59. 59.
    Williamson JR, Arrigoni-Martelli E. The roles of glucose-induced metabolic hypoxia and imbalances in carnitine metabolism in mediating diabetes-induced vascular dysfunction. Int J Clin Pharmacol Res 1992; 12: 247–52PubMedGoogle Scholar
  60. 60.
    Stevens MJ, Lattimer SA, Feldman EL, et al. Acetyl-L-carnitine deficiency as a cause of altered nerve myo-inositol content, Na+ K+-ATPase activity and motor conduction velocity in the streptozotocin diabetic rat. Metabolism 1996; 45: 865–72PubMedCrossRefGoogle Scholar
  61. 61.
    Scarpini E, Doneda P, Pizzul S, et al. L-Carnitine and acetyl-L-carnitine in human nerves from normal and diabetic subjects. J Peripher New Syst 1996; 1: 157–63Google Scholar
  62. 62.
    Stevens MJ, Lattimer SA, Kamijo M, et al. Osmotically induced nerve taurine depletion and the compatible osmolyte hypothesis in experimental diabetic neuropathy in the rat. Diabetologia 1993; 36: 608–14PubMedCrossRefGoogle Scholar
  63. 63.
    Pop-Busui R, Marinescu V, Van Huysen C, et al. Dissection of metabolic, vascular, and nerve conduction interrelationships in experimental diabetic neuropathy by cyclooxygenase inhibition and acetyl-L-carnitine administration. Diabetes 2002; 51: 2619–28PubMedCrossRefGoogle Scholar
  64. 64.
    Stevens MS, Lattimer S, Feldman EL, et al. Correction of nerve conduction slowing, nerve myoinositol but not sorbitol by acetyl-L-carnitine in streptozotocin-diabetic rat [abstract]. Diabetes 1995; 44Suppl. 1: 66aGoogle Scholar
  65. 65.
    Sima AAF, Ristic H, Merry A, et al. The primary preventional and secondary interventative effects of acetyl-L-carnitine on diabetic neuropathy in the BB/W-rat. J Clin Invest 1996; 97: 1900–7PubMedCrossRefGoogle Scholar
  66. 66.
    Stevens MJ, Lattimer SA, Feldman EL, et al. Acetyl-L-carnitine deficiency as a course of altered nerve myo-inositol content, Na+ K+-ATPase activity and motor conduction velocity in the streptozotocin diabetic rat. Metabolism 1996; 45: 865–72PubMedCrossRefGoogle Scholar
  67. 67.
    Cameron NE, Cotter MA. The relationship of vascular changes to metabolic factors in diabetes mellitus and their role in the development of peripheral nerve complications. Diab Metab Rev 1994; 10: 189–224CrossRefGoogle Scholar
  68. 68.
    Sonobe M, Yasuda H, Hisanaga T, et al. Amelioration of nerve Na+/K+-ATPase activity independently of myoinositol level by PGE1 analogue OP-1206 α-CD in streptozotocin-induced diabetic rats. Diabetes 1991; 40: 726–30PubMedCrossRefGoogle Scholar
  69. 69.
    Lee BJ. The prostaglandins. In: Williams RH, editor. Textbook of endocrinology. Philadelphia (PA): WB Saunders, 1981: 1047–63Google Scholar
  70. 70.
    Pop-Busui R, Sima AAF, Stevens M. Oxidative stress and diabetic neuropathy. Diab Metab Res Rev 2006; 22: 257–73CrossRefGoogle Scholar
  71. 71.
    Lowitt S, Malone JI, Salem AF, et al. Acetyl-L-carnitine corrects altered peripheral nerve function of experimental diabetes. Metabolism 1995; 44: 677–80PubMedCrossRefGoogle Scholar
  72. 72.
    DiGiulio AM, Lessna E, Gorio A. Diabetic neuropathy in the rat: 1. Alcar augments the reduced levels and axoplasmic transport of substance P. J Neurosci Res 1995; 15: 414–9Google Scholar
  73. 73.
    Taglialatela G, Angelucci L, Ramacci MT, et al. Stimulation of nerve growth factor receptors in PC12 by acetyl-L-carnitine. Biochem Pharmacol 1992; 44: 577–85PubMedCrossRefGoogle Scholar
  74. 74.
    Chiecho S, Caricasole A, Barletta E, et al. L-Acetyl-carnitine induces analgesia by selectively up-regulating mGlu2 metabotropic glucamate receptors. Molecul Pharm 2002; 61: 1–8CrossRefGoogle Scholar
  75. 75.
    Nakamura J, Koh N, Sakakibara F, et al. Polyol pathway hyperactivity is closely related to carnitine deficiency in the pathogenesis of diabetic neuropathy of streptozotocin-diabetic rats. J Pharmacol Exp Therap 1998; 287: 897–902Google Scholar
  76. 76.
    Giudice PL, Careddu A, Magni G, et al. Autonomic neuropathy in streptozotocin diabetic rats: effect of acetyl-L-carnitine. Diab Res Clin Pract 2002; 56: 173–80CrossRefGoogle Scholar
  77. 77.
    Kano M, Kawakann T, Hori H, et al. Effect of ALCAR on the fast axoplasmic transport in cultured sensory neurons of streptozotocin-induced diabetic rats. Neurosci Res 1999; 33: 207–13PubMedCrossRefGoogle Scholar
  78. 78.
    DeGrandis D, Minardi C. Acetyl-L-carnitine (levacecarnine) in the treatment of diabetic neuropathy: a long-term, randomized, double-blind, placebo controlled study. Drugs RD 2002; 3: 223–31CrossRefGoogle Scholar
  79. 79.
    Sima AAF, Calvani M, Mehra M, et al. Acetyl-L-carnitine improves pain, vibratory perception and nerve morphology in patients with chronic diabetic peripheral neuropathy: an analysis of two randomized, placebo-controlled trials. Diabetes Care 2005; 28: 96–101CrossRefGoogle Scholar
  80. 80.
    Amato A, Sima AAF. The protective effect of acetyl-L-carnitine on symptoms, particularly pain, in diabetic neuropathy [abstract]. Diabetes 2006; 55: A506CrossRefGoogle Scholar
  81. 81.
    Turpeinen AK, Kuikka JT, Vannineu E, et al. Long-term effect of acetyl-L-carnitine on myocardial 123I-MIBG uptake in patients with diabetes. Clin Autonom Res 2000; 10: 13–6CrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2007

Authors and Affiliations

  1. 1.Departments of Pathology and Neurology, School of MedicineWayne State University and Detroit Medical CenterDetroitUSA

Personalised recommendations