Summary
This review considers the definition of clinical diabetic neuropathy and the theoretical basis for the use of aldose reductase inhibitors in the treatment of distal sensorimotor neuropathy, the most common clinical problem. Myoinositol depletion is related to hyperglycaemia-induced polyol activity, changes which are associated with early functional deficits in acute experimental diabetes. These changes are reversible by the administration of aldose reductase inhibitors, and this provides the rationale for the treatment of human diabetic neuropathy with these agents. Many early trials of these drugs have produced some evidence of clinical benefit in patients with diabetic neuropathy, but interpretation of data is difficult as patient selection and neuropathy definition are not yet standardised. In addition, it is possible that once the neuropathic process is initiated, there is a point where it becomes irreversible, and treatment with aldose reductase inhibitors may therefore be of more relevance in early neuropathy. Long term double-blind multicentre trials are in progress, and preliminary data from some of these are reasonably encouraging. In conclusion, the results from clinical trials of the aldose reductase inhibitors in this difficult area are sufficiently encouraging to lead us to be optimistic about their future development, and continuing work should clarify their potential role with respect to the prophylaxis and treatment of diabetic neuropathy.
Similar content being viewed by others
References
Archer AG, Watkins PJ, Thomas PK, Sharma AK, Payan J. The natural history of acute painful neuropathy in diabetes mellitus. Journal of Neurology, Neurosurgery and Psychiatry 46: 491–499, 1983
Bloom S, Till S, Sonksen P, Smith S. Use of a biothesiometer to measure individual vibration thresholds and their variation in 519 non-diabetic subjects. British Medical Journal 288: 1793–1795, 1984
Boulton AJM, Atiea J, DeLeeuw IH, et al. The efficacy and safety of the aldose reductase inhibitor tolrestat in the treatment of chronic sensori motor diabetic neuropathy. Abstract. Diabetologia 32: 469A, 1989
Boulton AJM, Knight G, Drury J, Ward JD. The prevalence of symptomatic, diabetic neuropathy in an insulin-treated population. Diabetes Care 8: 125–128, 1985
Boulton AJM, the Tolrestat in Neuropathy Study Group. Effect of tolrestat, a new aldose reductase inhibitor, on nerve conduction and parasthetic symptoms in diabetic neuropathy. Abstract no. 61. Diabetologia 29: 521A, 1986
Boulton AJM, Ward JD. Diabetic neuropathies and pain. Clinics in Endocrinology and Metabolism 15(4): 917–931, 1986
Brownlee M, Cerami A, Vlassara H. Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. New England Journal of Medicine 318: 1315–1321, 1988
Bruyn GW, Garland H. Neuropathies of endocrine origin. In Vinken PJ & Bruyn GW (Eds) Handbook of clinical neurology, Vol. 8, pp. 29–71, North Holland Publishing Company, Amsterdam, 1970
Christiensen JE, Varnek L, Gregersen G. The effect of an aldose reductase inhibitor (sorbinil) on diabetic neuropathy and neural function of the retina: a double-blind study. Acta Neurologica Scandinavica 71: 164–167, 1985
Clements RS, Bell DSH. Diagnostic, pathogenic and therapeutic aspects of diabetic neuropathy. Special Topics in Endocrinology and Metabolism 3: 1–43, 1982
Consensus Statement. Report and recommendations of the San Antonio Conference on Diabetic Neuropathy. Diabetes 37: 1000–1004, 1988
Culebras A, Alio J, Herrera J-L, Lopez-Fraile IP. Effect of an aldose reductase inhibitor on diabetic peripheral neuropathy. Archives of Neurology 38: 133–134, 1981
Dyck PJ. Detection, characterisation and staging of polyneuropathy, assessed in diabetics. Muscle and Nerve 11: 21–32, 1988
Dyck PJ, Bushek W, Spring EM, Karnes JL, Litchy WJ, et al. Vibratory and cooling detection thresholds compared with other tests in diagnosing and staging diabetic neuropathy. Diabetes Care 10: 432–440, 1987
Dyck PJ, Karnes JL, O’Brien P, Okazaki H, Lais A, et al. The spatial pattern of fibre loss in diabetic neuropathy suggests ischaemia. Annals of Neurology 19: 440–449, 1986
Dyck PJ, Sherman WS, Hallcher LM, Service FJ, O’Brien PC, et al. Human diabetic endoneurial sorbitol, fructose and myoinositol related to sural nerve morphometry. Annals of Neurology 8: 590–596, 1980
Dyck PJ, Zimmerman BR, Vilen TH, Minnerath SR, Karnes JL, et al. Nerve glucose, fructose, sorbitol, myoinositol, and fiber degeneration and regeneration in diabetic neuropathy. New England Journal of Medicine 319: 542–548, 1988
Fagius J, Brattberg A, Jameson S, Berne C. Limited benefit of treatment of diabetic polyneuropathy with an aldose reductase inhibitor: a 24 week controlled trial. Diabetologia 28: 323–329, 1985
Fagius J, Jameson S. Effect of aldose reductase inhibitor treatment in diabetic polyneuropathy: a clinical and neurophysiological study. Journal of Neurology, Neurosurgery and Psychiatry 44: 991–1001, 1981
Florkowski CM, Rowe BR, Nightingale S, Barnett AH. A six month randomised placebo-controlled trial of the aldose reductase inhibitor ‘statil’ in chronic symptomatic peripheral neuropathy. In Ward JD (Ed.) Proceedings of the 1988 IDF Satellite Symposium on Diabetic Neuropathy, John Wiley & Sons Ltd, Chichester, in press, 1989
Flynn TG. The aldehyde reductase family of enzymes. Bulletin of the Canadian Biochemical Society 20: 38–44, 1983
Gabbay KH. The sorbinil pathway and complications of diabetes. New England Journal of Medicine 194: 1085–1087, 1973
Gabbay KH, Merola LO, Field RA. Sorbitol pathway: presence in nerve and cord with substrate accumulation in diabetes. Science 151: 209–210, 1966
Goto Y, Shigeta Y, Sakamoto N, Kito S, Matsuoka K. Clinical effect of aldose reductase inhibitor (ONO-2235) on diabetic neuropathy: multi-institutional studies. Abstracts of the International Symposium on the Polyol Pathway and its Role in Diabetic Complications, p. 15, Kashikojima, October 28–30, 1986
Greene DA, DeJesus PV, Winegrad AI. Effects of insulin and dietary myoinositol on impaired motor nerve conduction velocity in acute streptozotocin diabetes. Journal of Clinical Investigation 55: 1326–1336, 1975
Greene DA, Lattimer SA. Action of sorbinil in diabetic peripheral nerve: relationship of polyol (sorbitol) pathway inhibition to a myoinositol mediated defect in sodium-potassium ATPase activity. Diabetes 33: 712–716, 1984
Greene DA, Lattimer SA, Sima AAF. Are disturbances of Sorbitol, Phosphoinositide, and Na+-K+-ATPase regulation involved in the pathogenesis of diabetic neuropathy? Diabetes 37: 688–693, 1988
Gregerson G, Bertelsen B, Harbo H, Larsen E, Anderson JR, et al. Oral supplementation of myoinositol: effects on peripheral nerve function in human diabetes and on the concentration in plasma, erythrocytes, urine, and muscle tissue in human diabetics and normals. Acta Neurologica Scandinavica 67: 164–172, 1983
Guy RJC, Gilbey SG, Sheehy M, Asselman P, Watkins PJ. Diabetic neuropathy in the upper limb and the effect of twelve months sorbinil treatment. Diabetologia 31: 214–220, 1988
Hale PJ, Nattrass M, Silverman SH, Sennit C, Perkins CM, et al. Peripheral nerve concentrations of glucose, fructose, sorbitol and myoinositol in diabetic and non-diabetic patients. Diabetologia 30: 464–467, 1987
Handelsman DJ, Turtle JR. Clinical trial of an aldose reductase inhibitor in diabetic neuropathy. Diabetes 30: 459–464, 1981
Hotta N, Kakuta H, Koh N, Sakakibara F, Nakamura J, et al. A long-term experimental and clinical study of an aldose reductase inhibitor, ONO-2235 on diabetic neuropathy. In Ward JD (Ed.) Proceedings of the 1988 IDF Satellite Symposium on Diabetic Neuropathy, John Wiley & Sons Ltd, Chichester, in press, 1989
Jamal GA, Hansen S, Weir AI, Ballantync JP. An improved automated method for the measurement of thermal thresholds. 1. Normal subjects. Journal of Neurology, Neurosurgery and Psychiatry 48: 354–360, 1985
Jaspan J, Herold K, Maselli R, Bartkus C. Treatment of severely painful diabetic neuropathy with an aldose reductase inhibitor: relief of pain and improved somatic and autonomie function. Lancet 2: 758–762, 1983
Judzewitsch RG, Jaspan JB, Polonsky KS, Weinberg CR, Halter JB, et al. Aldose reductase inhibition improves nerve conduction velocity in diabetic patients. New England Journal of Medicine 308: 119–125, 1983
Lewin IG, O’Brien IAD, Morgan MH, Corrall RJM. Clinical and neurophysiological studies with the aldose reductase inhibitor, sorbinil, in symptomatic diabetic neuropathy. Diabetologia 26: 445–448,1984
Llewelyn JG, Thomas PK, Gilbey SG, Watkins PJ, Muddle JR. Pattern of myelinated fibre loss in the sural nerve in neuropathy related to Type 1 (insulin-dependent) diabetes. Diabetologia 31: 162–167, 1988
Low PA. Recent advances in the pathogenesis of diabetic neuropathy. Muscle and Nerve 10: 121–128, 1987
Low PA, Schmelzer JD, Ward KK, Yao JK. Experimental chronic hypoxic neuropathy: relevance to diabetic neuropathy. American Journal of Physiology 250: E94–99, 1986
Malik RA, Newrick PG, Sharma AK, Tomlinson DR, Ward JD. Pathogenesis of human diabetic neuropathy. In Ward JD (Ed.) Proceedings of the 1988 IDF Satellite Symposium on Diabetic Neuropathy, John Wiley & Sons Ltd, Chichester, in press, 1989
Masson EA, Church SE, Woodcock AA, Hanley SP, Boulton AJM. Is resistance to ischaemic conduction failure induced by hypoxia? Diabetologia 31: 762–765, 1988
Masson EA, Gem J, Hunt L, Boulton AJM. A novel approach to diagnosis and assessment of symptomatic diabetic neuropathy. Pain 38: 25–28, 1989
Mayer JH, Tomlinson DR. Prevention of defects of axonal transport and nerve conduction velocity by oral administration of myoinositol or an aldose reductase inhibitor in streptozotocin-diabetic rats. Diabetologia 25: 433–438, 1983
Mayhew JA, Grillon KRW, Hawthorne JN. Free and lipid inositol, sorbitol, and sugars in sciatic nerve obtained post-mortem from diabetic patients and control subjects. Diabetologia 24: 13–15, 1983
Mulder DW, Lambert EH, Bastron JA, Sprague RG. The neuropathies associated with diabetes mellitus: a clinical and electromyographic study of 103 unselected diabetic patients. Neurology 11: 275–284, 1961
Nakuda H. Increased susceptibility to ischaemia in diabetic nerve. Abstract ORA-014-005. Diabetes Research and Clinical Practice 5 (Suppl. 1): S57, 1988
Newrick PG, Wilson AJ, Jakubowski J, Boulton AJM, Ward JD. Sural nerve oxygen tension in diabetes. British Medical Journal 293: 1053–1054, 1986
O’Hare JP, Morgan MH, Alden P, Chissel S, O’Brien IAD, et al. Aldose reductase inhibition in diabetic neuropathy: clinical and neurophysiological studies of one year’s treatment with sorbinol. Diabetic Medicine 5: 537–542, 1988
Pavy FW. Address on diabetes, Washington International Congress. Medical News (Philadelphia) September 24: 357, 1887
Pirart J. Diabetes mellitus and its degenerative complications: a prospective study of 4,400 patients between 1947 and 1973. Diabetes Care 1: 168–188, 252–263, 1978
Pitts NE, Gundersen K, Mehta DJ, Vreeland F, Shaw GL, et al. Clinical experience with sorbinil: an aldose reductase inhibitor. Metabolism 35 (Suppl. 1): 96–100, 1986
Ryder S, Sarokhan B, Shand DG, Mullane JF. Human safety profile of tolrestat: an aldose reductase inhibitor. Drug Development Research 11: 131–143, 1987
Ryder S, the Tolrestat in Painful Neuropathy Study Group. Objective (nerve conduction) and subjective (painful symptom) improvement following administration of tolrestat, a new aldose reductase inhibitor. Abstract No. 436, Diabetologia 29: 588A, 1986
Salway JG, Finnegan JA, Barnett D, Whitehead L, Karunanyaka A, et al. Effect of myoinositol on peripheral nerve function in diabetes. Lancet 2: 1282–1284, 1978
Sima AAF, Bril V, Nathaniel V, McEwen TA, Brown MB, et al. Regeneration and repair of myelinated fibres in sural nerve biopsy specimens from patients with diabetic neuropathy treated with sorbinil. New England Journal of Medicine 319: 548–555, 1988
Sima AAF, Lattimer SA, Yagihashi S, Greene DA. Axo-glial dysjunction: a novel structural lesion that accounts for poorly reversible slowing of nerve conduction in the spontaneously diabetic bio-breeding rat. Journal of Clinical Investigation 77: 474–484, 1986
Simard-Dequesne N, Greslin E, Dubuc J, Dvornik D. The effect of a new aldose reductase inhibitor (tolrestat) in galactosacmic and diabetic rats. Metabolism 33: 885–892, 1985
Solders G. Gunnarsson R. Persson A, Wilczek H, Tyden G, et al. Effects of combined pancreatic and renal transplantation on diabetic neuropathy: a two-year follow-up study. Lancet 2: 1232–1235. 1987
Sredy J. Millen J. McCaleb ML, Tutwiler GF. Inhibition of polyol accumulation in lens, sciatic nerve, and RBC in vitro by the aldose reductase inhibitor, tolrestat. Federation Proceedings 45: 902. 1986
Stewart MA, Sherman WR, Kurien MM, Moonsammy GI, Wisgerhof M. Polyol accumulation in nervous tissue of rats with experimental diabetes and galactosaemia. Journal of Neurochemistry 14: 1057–1066, 1967
Terkildsen AB, Christensen NJ. Reversible nervous abnormalities in juvenile diabetics with recently diagnosed diabetes. Diabetologia 7: 113–117. 1971
Thomas PK, Eliasson SG. Diabetic neuropathy. In Dyck PJ et al. (Eds) Peripheral neuropathy, pp. 956–981, Saunders, Philadelphia, 1975
Timperley WR, Boulton AJM, Davies-Jones GAB, Jarratt JA, Ward JD. Small vessel disease in progressive diabetic neuropathy associated with good metabolic control. Journal of Clinical Pathology 38: 1030–1038, 1985
Tomlinson DR, Moriarty RJ, Mayer JH. Prevention and reversal of defective axonal transport and motor nerve conduction velocity in rats with experimental diabetes by treatment with the aldose reductase inhibitor Sorbinil. Diabetes 33: 470–476, 1984
Tuck RR, Schmelzer JD, Low PA. Endoneurial blood flow and oxygen tension in the sciatic nerves of rats with experimental diabetic neuropathy. Brain 107: 935–950, 1984
Turtle JR. Aldose reductase in the pathophysiological aspects of diabetic neuropathy. Abstracts of the International Symposium on the Polyol Pathway and its Role in Diabetic Complications, p. 10; Kashikojima, October 28–30, 1986
Van Heyningen R. Formation of polyols in the lens of the rat with ‘sugar’ cataract. Nature 184: 194–195, 1959
Ward JD, Barnes CG, Fisher DJ, Jessop JD. Improvement in nerve conduction following treatment in newly diagnosed diabetics. Lancet 1: 428–431, 1971
Williams G, Gills JS, Aber V, Mather HM. Variability in vibration perception threshold among sites: a potential source of error in biothesiometry. British Medical Journal 296: 233–235, 1988
Winegrad AI, Simmons DA, Martin DB. Pathogenesis of diabetic neuropathy. Correspondence. New England Journal of Medicine 320: 58–59, 1989
Yasuda H, Dyck PJ. Abnormalities of endoneurial microvessels and sural nerve pathology in diabetic neuropathy. Neurology 37: 20–28, 1987
Young RJ, Ewing DJ, Clarke BP. A controlled trial of sorbinil, an aldose reductase inhibitor, in chronic painful diabetic neuropathy. Diabetes 32: 938–942, 1983
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Masson, E.A., Boulton, A.J.M. Aldose Reductase Inhibitors in the Treatment of Diabetic Neuropathy. Drugs 39, 190–202 (1990). https://doi.org/10.2165/00003495-199039020-00003
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003495-199039020-00003