Abstract
The efficacy of treatment with an aldose reductase inhibitor (1,3-dioxo-1 H-benz-de-isoquinoline-2(3H)-acetic acid, AY-22,284, Alrestatin) on peripheral nerve function in diabetic polyneuropathy was assessed. Thirty patients with long-standing diabetes and slight to moderate neuropathy participated in the double-blind placebo trial. Clinical examination, sensory threshold determinations for vibratory, tactile and thermal stimuli, conduction velocity measurements and studies of automatic function were performed to evaluate the treatment. Significant differences favouring Alrestatin over placebo were found for many of the measured variables, whereas no changes occurred on placebo. The apparent improvement of neuropathy occurred despite persisting hyperglycaemia. The results indicate that aldose reductase inhibitor treatment may be of value in diabetic polyneuropathy, and provide support for the sorbitol pathway hypothesis of diabetic polyneuropathy.
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Selected References
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- Bergström J., Lindblom U., Norée L. O. Preservation of peripheral nerve function in severe uremia during treatment with low protein high calorie diet and surplus of essential amino acids. Acta Neurol Scand. 1975 Feb;51(2):99–109. doi: 10.1111/j.1600-0404.1975.tb01363.x. [DOI] [PubMed] [Google Scholar]
- Bischoff A. Diabetische Neuropathie. PathologischeAnatomie, Pathophysiologie und Pathogenese auf Grund elektronenmikroskopischer Untersuchungen. Dtsch Med Wochenschr. 1968 Feb 9;93(6):237–passim. doi: 10.1055/s-0028-1105047. [DOI] [PubMed] [Google Scholar]
- Brown M. J., Martin J. R., Asbury A. K. Painful diabetic neuropathy. A morphometric study. Arch Neurol. 1976 Mar;33(3):164–171. doi: 10.1001/archneur.1976.00500030020004. [DOI] [PubMed] [Google Scholar]
- Clements R. S., Jr Diabetic neuropathy--new concepts of its etiology. Diabetes. 1979 Jun;28(6):604–611. doi: 10.2337/diab.28.6.604. [DOI] [PubMed] [Google Scholar]
- Clements R. S., Jr, Vourganti B., Kuba T., Oh S. J., Darnell B. Dietary myo-inositol intake and peripheral nerve function in diabetic neuropathy. Metabolism. 1979 Apr;28(4 Suppl 1):477–483. doi: 10.1016/0026-0495(79)90060-x. [DOI] [PubMed] [Google Scholar]
- Culebras A., Alió J., Herrera J. L., López-Fraile M. I. Effect of an aldose reductase inhibitor on diabetic peripheral neuropathy. Preliminary report. Arch Neurol. 1981 Feb;38(2):133–134. doi: 10.1001/archneur.1981.00510020091017. [DOI] [PubMed] [Google Scholar]
- Dvornik E., Simard-Duquesne N., Krami M., Sestanj K., Gabbay K. H., Kinoshita J. H., Varma S. D., Merola L. O. Polyol accumulation in galactosemic and diabetic rats: control by an aldose reductase inhibitor. Science. 1973 Dec 14;182(4117):1146–1148. doi: 10.1126/science.182.4117.1146. [DOI] [PubMed] [Google Scholar]
- Ewing D. J., Campbell I. W., Clarke B. F. Mortality in diabetic autonomic neuropathy. Lancet. 1976 Mar 20;1(7960):601–603. doi: 10.1016/s0140-6736(76)90413-x. [DOI] [PubMed] [Google Scholar]
- FRY I. K., HARDWICK C., SCOTT G. W. Diabetic neuropathy: A survey and follow-up of 66 cases. Guys Hosp Rep. 1962;111:113–129. [PubMed] [Google Scholar]
- Fagius J., Wahren L. K. Variability of sensory threshold determination in clinical use. J Neurol Sci. 1981 Jul;51(1):11–27. doi: 10.1016/0022-510x(81)90056-3. [DOI] [PubMed] [Google Scholar]
- Fagius J., Wallin B. G. Sympathetic reflex latencies and conduction velocities in patients with polyneuropathy. J Neurol Sci. 1980 Sep;47(3):449–461. doi: 10.1016/0022-510x(80)90099-4. [DOI] [PubMed] [Google Scholar]
- Field R. A., Adams L. C. Insulin response of peripheral nerve. II. Effects on lipid metabolism. Biochim Biophys Acta. 1965 Dec 2;106(3):474–479. [PubMed] [Google Scholar]
- Fraser D. M., Campbell I. W., Ewing D. J., Murray A., Neilson J. M., Clarke B. F. Peripheral and autonomic nerve function in newly diagnosed diabetes mellitus. Diabetes. 1977 Jun;26(6):546–550. doi: 10.2337/diab.26.6.546. [DOI] [PubMed] [Google Scholar]
- Fruhstorfer H., Lindblom U., Schmidt W. C. Method for quantitative estimation of thermal thresholds in patients. J Neurol Neurosurg Psychiatry. 1976 Nov;39(11):1071–1075. doi: 10.1136/jnnp.39.11.1071. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gabbay K. H., Merola L. O., Field R. A. Sorbitol pathway: presence in nerve and cord with substrate accumulation in diabetes. Science. 1966 Jan 14;151(3707):209–210. doi: 10.1126/science.151.3707.209. [DOI] [PubMed] [Google Scholar]
- Gabbay K. H., O'Sullivan J. B. The sorbitol pathway. Enzyme localization and content in normal and diabetic nerve and cord. Diabetes. 1968 May;17(5):239–243. doi: 10.2337/diab.17.5.239. [DOI] [PubMed] [Google Scholar]
- Gabbay K. H., Spack N., Loo S., Hirsch H. J., Ackil A. A. Aldose reductase inhibition: studies with alrestatin. Metabolism. 1979 Apr;28(4 Suppl 1):471–476. doi: 10.1016/0026-0495(79)90059-3. [DOI] [PubMed] [Google Scholar]
- Gabbay K. H. The sorbitol pathway and the complications of diabetes. N Engl J Med. 1973 Apr 19;288(16):831–836. doi: 10.1056/NEJM197304192881609. [DOI] [PubMed] [Google Scholar]
- Goldberg J. M., Lindblom U. Standardised method of determining vibratory perception thresholds for diagnosis and screening in neurological investigation. J Neurol Neurosurg Psychiatry. 1979 Sep;42(9):793–803. doi: 10.1136/jnnp.42.9.793. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Graf R. J., Halter J. B., Halar E., Porte D., Jr Nerve conduction abnormalities in untreated maturity-onset diabetes: relation to levels of fasting plasma glucose and glycosylated hemoglobin. Ann Intern Med. 1979 Mar;90(3):298–303. doi: 10.7326/0003-4819-90-3-298. [DOI] [PubMed] [Google Scholar]
- Greene D. A., De Jesus P. V., Jr, Winegrad A. I. Effects of insulin and dietary myoinositol on impaired peripheral motor nerve conduction velocity in acute streptozotocin diabetes. J Clin Invest. 1975 Jun;55(6):1326–1336. doi: 10.1172/JCI108052. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gregersen G., Børsting H., Theil P., Servo C. Myoinositol and function of peripheral nerves in human diabetics. A controlled clinical trial. Acta Neurol Scand. 1978 Oct;58(4):241–248. doi: 10.1111/j.1600-0404.1978.tb02884.x. [DOI] [PubMed] [Google Scholar]
- Gregersen G. Diabetic neuropathy: influence of age, sex, metabolic control, and duration of diabetes on motor conduction velocity. Neurology. 1967 Oct;17(10):972–980. doi: 10.1212/wnl.17.10.972. [DOI] [PubMed] [Google Scholar]
- Gregersen G. Variations in motor conduction velocity produced by acute changes of the metabolic state in diabetic patients. Diabetologia. 1968 Nov;4(5):273–277. doi: 10.1007/BF01309900. [DOI] [PubMed] [Google Scholar]
- Jefferys J. G., Palmano K. P., Sharma A. K., Thomas P. K. Influence of dietary myoinositol on nerve conduction and inositol phospholipids in normal and diabetic rats. J Neurol Neurosurg Psychiatry. 1978 Apr;41(4):333–339. doi: 10.1136/jnnp.41.4.333. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lichtenfeld P. Autonomic dysfunction in the Guillain-Barré syndrome. Am J Med. 1971 Jun;50(6):772–780. doi: 10.1016/0002-9343(71)90185-9. [DOI] [PubMed] [Google Scholar]
- Lindblom U. Touch perception threshold in human glabrous skin in terms of displacement amplitude on stimulation with single mechanical pulses. Brain Res. 1974 Dec 27;82(2):205–210. doi: 10.1016/0006-8993(74)90599-x. [DOI] [PubMed] [Google Scholar]
- Lizana J., Hellsing K. Polymer enhancement of automated immunological nephelometric analysis, as illustrated by determination of urinary albumin. Clin Chem. 1974 Apr;20(4):415–420. [PubMed] [Google Scholar]
- MARTIN M. M. Diabetic neuropathy; a clinical study of 150 cases. Brain. 1953;76(4):594–624. doi: 10.1093/brain/76.4.594. [DOI] [PubMed] [Google Scholar]
- Myers R. R., Costello M. L., Powell H. C. Increased endoneurial fluid pressure in galactose neuropathy. Muscle Nerve. 1979 Jul-Aug;2(4):299–303. doi: 10.1002/mus.880020410. [DOI] [PubMed] [Google Scholar]
- Palmano K. P., Whiting P. H., Hawthorne J. N. Free and lipid myo-inositol in tissues from rats with acute and less severe streptozotocin-induced diabetes. Biochem J. 1977 Oct 1;167(1):229–235. doi: 10.1042/bj1670229. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pirart J. Diabète et complications dégénératives présentation d'une étude prospective portant sur 4400 cas observés entre 1947 et 1973. (Première partie). Diabete Metab. 1977 Jun;3(2):97–107. [PubMed] [Google Scholar]
- Powell H., Knox D., Lee S., Charters A. C., Orloff M., Garrett R., Lampert P. Alloxan diabetic neuropathy: electron microscopic studies. Neurology. 1977 Jan;27(1):60–66. doi: 10.1212/wnl.27.1.60. [DOI] [PubMed] [Google Scholar]
- RUSHTON W. A. H. A theory of the effects of fibre size in medullated nerve. J Physiol. 1951 Sep;115(1):101–122. doi: 10.1113/jphysiol.1951.sp004655. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Robertson D. M., Sima A. A. Diabetic neuropathy in the mutant mouse [C57BL/ks(db/db)]: a morphometric study. Diabetes. 1980 Jan;29(1):60–67. doi: 10.2337/diab.29.1.60. [DOI] [PubMed] [Google Scholar]
- Salway J. G., Whitehead L., Finnegan J. A., Karunanayaka A., Barnett D., Payne R. B. Effect of myo-inositol on peripheral-nerve function in diabetes. Lancet. 1978 Dec 16;2(8103):1282–1284. doi: 10.1016/s0140-6736(78)92043-3. [DOI] [PubMed] [Google Scholar]
- Sharma A. K., Thomas P. K., De Molina A. F. Peripheral nerve fiber size in experimental diabetes. Diabetes. 1977 Jul;26(7):689–692. doi: 10.2337/diab.26.7.689. [DOI] [PubMed] [Google Scholar]
- Sharma A. K., Thomas P. K. Peripheral nerve structure and function in experimental diabetes. J Neurol Sci. 1974 Sep;23(1):1–15. doi: 10.1016/0022-510x(74)90136-1. [DOI] [PubMed] [Google Scholar]
- Smith R. S., Koles Z. J. Myelinated nerve fibers: computed effect of myelin thickness on conduction velocity. Am J Physiol. 1970 Nov;219(5):1256–1258. doi: 10.1152/ajplegacy.1970.219.5.1256. [DOI] [PubMed] [Google Scholar]
- Stewart M. A., Sherman W. R., Kurien M. M., Moonsammy G. I., Wisgerhof M. Polyol accumulations in nervous tissue of rats with experimental diabetes and galactosaemia. J Neurochem. 1967 Nov;14(11):1057–1066. doi: 10.1111/j.1471-4159.1967.tb09516.x. [DOI] [PubMed] [Google Scholar]
- Ward J. D., Baker R. W., Davis B. H. Effect of blood sugar control on the accumulation of sorbitol and fructose in nervous tissues. Diabetes. 1972 Dec;21(12):1173–1178. doi: 10.2337/diab.21.12.1173. [DOI] [PubMed] [Google Scholar]
- Ward J. D., Barnes C. G., Fisher D. J., Jessop J. D., Baker R. W. Improvement in nerve conduction following treatment in newly diagnosed diabetics. Lancet. 1971 Feb 27;1(7696):428–430. doi: 10.1016/s0140-6736(71)92415-9. [DOI] [PubMed] [Google Scholar]
- Young R. R., Asbury A. K., Corbett J. L., Adams R. D. Pure pan-dysautonomia with recovery. Description and discussion of diagnostic criteria. Brain. 1975 Dec;98(4):613–636. doi: 10.1093/brain/98.4.613. [DOI] [PubMed] [Google Scholar]