Portal de Periódicos da CAPES

Aldose reductase inhibitors: An approach to the treatment of diabetic nerve damage

1993; Wiley; Volume: 9; Issue: 3 Linguagem: Inglês

10.1002/dmr.5610090304

1099-0895

D. A. Greene, Anders A. F. Sima, M. J. Stevens, Eva L. Feldman, Paul D. Killen, D N Henry, T. Thomas, J. Dananberg, S. A. Lattimer,

Pain Management and Opioid Use

Diabetes/Metabolism ReviewsVolume 9, Issue 3 p. 189-217 Article Aldose reductase inhibitors: An approach to the treatment of diabetic nerve damage D. A. Greene MD, Corresponding Author D. A. Greene MD Departments of Internal Medicine, Pathology, Neurology and Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, U.S.A.3920 Taubman Box 0354, 1500 E. Medical Center Dr., Ann Arbor, MI 48109, U.S.A.Search for more papers by this authorA. A. F. Sima, A. A. F. Sima Departments of Internal Medicine, Pathology, Neurology and Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, U.S.A.Search for more papers by this authorM. J. Stevens, M. J. Stevens Departments of Internal Medicine, Pathology, Neurology and Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, U.S.A.Search for more papers by this authorE. L. Feldman, E. L. Feldman Departments of Internal Medicine, Pathology, Neurology and Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, U.S.A.Search for more papers by this authorP. D. Killen, P. D. Killen Departments of Internal Medicine, Pathology, Neurology and Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, U.S.A.Search for more papers by this authorD. N. Henry, D. N. Henry Departments of Internal Medicine, Pathology, Neurology and Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, U.S.A.Search for more papers by this authorT. Thomas, T. Thomas Departments of Internal Medicine, Pathology, Neurology and Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, U.S.A.Search for more papers by this authorJ. Dananberg, J. Dananberg Departments of Internal Medicine, Pathology, Neurology and Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, U.S.A.Search for more papers by this authorS. A. Lattimer, S. A. Lattimer Departments of Internal Medicine, Pathology, Neurology and Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, U.S.A.Search for more papers by this author D. A. Greene MD, Corresponding Author D. A. Greene MD Departments of Internal Medicine, Pathology, Neurology and Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, U.S.A.3920 Taubman Box 0354, 1500 E. Medical Center Dr., Ann Arbor, MI 48109, U.S.A.Search for more papers by this authorA. A. F. Sima, A. A. F. Sima Departments of Internal Medicine, Pathology, Neurology and Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, U.S.A.Search for more papers by this authorM. J. Stevens, M. J. Stevens Departments of Internal Medicine, Pathology, Neurology and Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, U.S.A.Search for more papers by this authorE. L. Feldman, E. L. Feldman Departments of Internal Medicine, Pathology, Neurology and Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, U.S.A.Search for more papers by this authorP. D. Killen, P. D. Killen Departments of Internal Medicine, Pathology, Neurology and Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, U.S.A.Search for more papers by this authorD. N. Henry, D. N. Henry Departments of Internal Medicine, Pathology, Neurology and Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, U.S.A.Search for more papers by this authorT. Thomas, T. Thomas Departments of Internal Medicine, Pathology, Neurology and Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, U.S.A.Search for more papers by this authorJ. Dananberg, J. Dananberg Departments of Internal Medicine, Pathology, Neurology and Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, U.S.A.Search for more papers by this authorS. A. Lattimer, S. A. Lattimer Departments of Internal Medicine, Pathology, Neurology and Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, U.S.A.Search for more papers by this author First published: October 1993 https://doi.org/10.1002/dmr.5610090304Citations: 51AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat References 1 Greene DA, Sima AAF, Stevens MJ, Feldman EL, and Lattimer SA: Complications: neuropathy, pathogenetic considerations. Diabetes Care 15: 1902–1925, 1992. 10.2337/diacare.15.12.1902 CASPubMedWeb of Science®Google Scholar 2 Judzewitsch RG, Jaspan JB, Polonsky KS, Weinberg CR, Halter JB, Halar E, Pfeifer MA, Vukadinovic C, Bernstein L, Schneider M, Liang KY, Gabbay KH, Rubenstein AG, and Porte D: Aldose reductase inhibition improves nerve conduction velocity in diabetic patients. N Engl J Med 308: 119–125, 1983. 10.1056/NEJM198301203080302 CASPubMedWeb of Science®Google Scholar 3 Greene DA, and Sima AAF: Aldose reductase inhibitor (ARI) treatment normalizes axo-glial dysjunction and improves nerve fiber pathology in advanced diabetic neuropathy. Diabetes 40 (Suppl 1): 9A, 1991. Google Scholar 4 Sima AAF, Bril V, Nathanial V, McEwen TA, Brown M, Lattimer SA, and Greene DA: Regeneration and repair of myelinated fibers in sural nerve biopsies from patients with diabetic neuropathy treated with an ARI. N Engl J Med 319: 548–555, 1988. 10.1056/NEJM198809013190905 PubMedWeb of Science®Google Scholar 5 Report and recommendations of the San Antonio Conference on Diabetic Neuropathy. Diabetes 37: 1000–1004, 1988. 10.2337/diab.37.7.1000 CASPubMedWeb of Science®Google Scholar 6 Feldman EL, Stevens MJ, Thomas PK, Brown MB, Canal N, and Greene DA: A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy. (submitted). Google Scholar 7 Dyck PJ, Karnes J and O'Brien PC: Diagnosis, staging, and classification of diabetic neuropathy and associations with other complications. In Diabetic Neuropathy, PJ Dyck, PK Thomas, AK Asbury, AI Winegrad and D Porte, Eds. W.B. Saunders, Philadelphia, 1987, pp 36–44. The figure appears on page 40. Google Scholar 8 Greene DA, Sima AAF, Albers JW, and Pfeifer MA: Diabetic neuropathy. In Diabetes Mellitus, 4th ed., H Rifkin, and D Porte, Eds. Elsevier, New York, 1990, pp 710–755. Google Scholar 9 Dyck PJ, Karnes JL, Daube J, O'Brien P, and Service FJ: Clinical and neuropathological criteria for the diagnosis and staging of diabetic polyneuropathy. Brain 108: 861–880, 1985. 10.1093/brain/108.4.861 PubMedWeb of Science®Google Scholar 10 Britland ST, Young RJ, Sharma AK, and Clarke BF: Association of painful and painless diabetic polyneuropathy with different patterns of nerve fiber degeneration and regeneration. Diabetes 39: 898–908, 1990. 10.2337/diab.39.8.898 CASPubMedWeb of Science®Google Scholar 11 Pirart J: Diabetes mellitus and its degenerative complications: a prospective study of 4,400 patients observed between 1947 and 1973. Diabetes Care 1: 168–188, 252–263, 1978. 10.2337/diacare.1.3.168 Google Scholar 12 Thomas PK, and Lascelles RG: Schwann-cell abnormalities in diabetic neuropathy. Lancet 1: 1355–1357, 1965. 10.1016/S0140-6736(65)92154-9 CASPubMedWeb of Science®Google Scholar 13 Maser RE, Steenkiste AR, Dorman JS, Nielsen VK, Bass EB, Manjoo Q, Drash AL, Becker DJ, Kuller LH, Greene DA, and Orchard TJ: Epidemiological correlates of diabetic neuropathy. Diabetes 38: 1456–1461, 1989. CASPubMedWeb of Science®Google Scholar 14 Ellenburg M: Diabetic neuropathy: clinical aspects. Metabolism 25: 1627–1655, 1976. 10.1016/0026-0495(76)90115-3 PubMedWeb of Science®Google Scholar 15 The DCCT Research Group: Factors in the development of diabetic neuropathy: baseline analysis of neuropathy in the feasibility phase of the Diabetes Control and Complication Trial (DCCT). Diabetes 37: 476–481, 1988. PubMedGoogle Scholar 16 Graf RJ, Halter JB, Halar E, and Porte D: Nerve conduction abnormalities in untreated maturity-onset diabetes: relation to levels of fasting plasma glucose and glycosylated hemoglobin. Ann Intern Med 90: 298–303, 1979. 10.7326/0003-4819-90-3-298 CASPubMedWeb of Science®Google Scholar 17 Gregersen G: Variations in motor conduction velocity produced by acute changes of the metabolic state in diabetic patients. Diabetologia 4: 273–277, 1968. 10.1007/BF01309900 Google Scholar 18 Ward JD, Bowes CG, Fisher DJ, Jessop JD, and Boher WR: Improvement in nerve conduction following treatment in newly diagnosed diabetics. Lancet 1: 428–430, 1971. 10.1016/S0140-6736(71)92415-9 PubMedWeb of Science®Google Scholar 19 Terkidsen AB, and Christensen NJ: Reversible nervous abnormalities in juvenile diabetics with recently diagnosed diabetes. Diabetologia 7: 113–117, 1971. 10.1007/BF00443891 PubMedWeb of Science®Google Scholar 20 Eng GD, Nellington H, and August GP: Nerve conduction velocity determination in juvenile diabetes. Mod Probl Paediatr 12: 213–219, 1975. Google Scholar 21 Gregersen G: Diabetic neuropathy: influence of age, sex, metabolic control and duration of diabetes on motor conduction velocity. Neurology 17: 972–998, 1967. 10.1212/WNL.17.10.972 CASPubMedWeb of Science®Google Scholar 22 Graf RJ, Halter JB, Pfeifer MD, Halar E, Brozovich F, and Porte D: Glycemic control and nerve conduction abnormalities in noninsulin-dependent diabetic subjects. Ann Intern Med 94: 307–311, 1981. 10.7326/0003-4819-94-3-307 CASPubMedWeb of Science®Google Scholar 23 Holman RR, White VM, Orde-Peckar C, Steemson J, Smith B, McPherson K, Rizza C, Knight AH, Dorman TL, Howard-Williams J, Jenkins L, Rolfe R, Barbour D, Poon P, Mann JI, Bron AJ, and Turner RC: Prevention of deterioration of renal and sensory-nerve function by more intensive management of insulin-dependent diabetic patients. A two-year randomized prospective study. Lancet 1: 204–208, 1983. 10.1016/S0140-6736(83)92586-2 CASPubMedWeb of Science®Google Scholar 24 Pietri A, Ehle A, and Raskin P: Changes in nerve conduction velocity after six weeks of glyco-regulation with portable insulin infusion pumps. Diabetes 29: 668–671, 1980. CASPubMedWeb of Science®Google Scholar 25 Service FJ, Rizza RA, Daube JR, O'Brien PC, and Dyck PJ: Near normoglycaemia improved nerve conduction and vibration sensation in diabetic neuropathy. Diabetologia 28: 722–727, 1985. CASPubMedWeb of Science®Google Scholar 26 Steno Study Group: Effect of 6 months strict metabolic control on eye and kidney function in insulin-dependent diabetes with background retinopathy. Lancet 1: 121–123, 1982. 10.1016/S0140-6736(82)90377-4 PubMedGoogle Scholar 27 Gallai V, Agostini L, Rossi A, Massi-Benedetti M, Calabrese G, Puxeddu and Brunetti P: Evaluation of the motor and sensory conduction velocity (MCV, SCV) in diabetic patients before and after a three days treatment with the artificial beta cell (biostator). In Peripheral Neuropathies, N Canal, and G Pozza, Eds. Elsevier, North Holland Biomedical Press, Amsterdam, 1978, pp 287–289. 10.1016/B978-0-444-80079-4.50032-6 Google Scholar 28 Service FJ, Daube JR, O-Brien PC, and Dyck PJ: Effect of artificial pancreas treatment on peripheral nerve function in diabetes. Neurology 31: 1375–1380, 1981. 10.1212/WNL.31.11.1375 CASPubMedWeb of Science®Google Scholar 29 Troni W, Carta Q, Cantello R, Caselle MT, and Rainero I: Peripheral nerve function and metabolic control in diabetes mellitus. Ann Neurol 16: 178–183, 1984. 10.1002/ana.410160204 CASPubMedWeb of Science®Google Scholar 30 Committee on Health Care Issues, American Neurological Association: Does improved control of glycemia prevent or ameliorate diabetic neuropathy? Ann Neurol 19: 288–290, 1986. 10.1002/ana.410190311 PubMedWeb of Science®Google Scholar 31 Dyck PJ, Lais A, Karnes JL, O'Brien P, and Rizza R: Fiber loss is primary and multifocal in sural nerves in diabetic polyneuropathy. Ann Neurol 19: 425–439, 1986. 10.1002/ana.410190503 CASPubMedWeb of Science®Google Scholar 32 Vracko R: A comparison of the microvascular lesions in diabetes mellitus with those of normal aging. J Am Geriatr Soc 30: 201–205, 1982. 10.1111/j.1532-5415.1982.tb01304.x CASPubMedWeb of Science®Google Scholar 33 Behse J, Buchtal F, and Carlsen F: Nerve biopsy and conduction studies in diabetic neuropathy. J Neurol Neurosurg Psychiatry 40: 1072–1082, 1977. 10.1136/jnnp.40.11.1072 CASPubMedWeb of Science®Google Scholar 34 Chopra JS, Hurwitz LJ, and Montgomery DAD: The pathogenesis of sural nerve changes in diabetes mellitus. Brain 92: 391–418, 1969. 10.1093/brain/92.2.391 CASPubMedWeb of Science®Google Scholar 35 Thomas PK, and Lascelles RG: The pathology of diabetic neuropathy. Q J Med 35: 489–909, 1966. Web of Science®Google Scholar 36 Bischoff A: Diabetic neuropathy. Pathologic anatomy, pathophysiology and pathogenesis on the basis of electron microscopic studies. Dtsch Med Wochenschr 93: 237–241, 1968. 10.1055/s-0028-1105047 CASPubMedWeb of Science®Google Scholar 37 Sima AAF, Nathaniel V, Bril V, McEwen TAJ, and Greene DA: 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 81: 349–364, 1988. 10.1172/JCI113327 PubMedWeb of Science®Google Scholar 38 Yagihasi S, and Matsumaja M: Ultrastructural pathology of peripheral nerves in patients with diabetic neuropathy. Tohoku J Exp Med 129: 357–366, 1979. 10.1620/tjem.129.357 PubMedWeb of Science®Google Scholar 39 Appenzeller O, and Ogin G: Myelinated fibres in human paravertebral sympathetic chain: white rami communicantes in alcoholic and diabetic patients. J Neurol Neurosurg Psychiatry 37: 1155–1161, 1974. 10.1136/jnnp.37.10.1155 CASPubMedWeb of Science®Google Scholar 40 Smith B: Neuropathology of the oesophagus in diabetes mellitus. J Neurol Neurosurg Psychiatry 37: 1151–1154, 1974. 10.1136/jnnp.37.10.1151 CASPubMedWeb of Science®Google Scholar 41 Sima AAF, Nathaniel V, Prashar A, Bril V, and Greene DA: Endoneurial microvessels in human diabetic neuropathy: endothelial cell dysjunction and lack of treatment effect by ARI. Diabetes 40: 1090–1099, 1991. 10.2337/diabetes.40.9.1090 CASPubMedWeb of Science®Google Scholar 42 Appenzeller O, and Richardson EP Jr.: The sympathetic chain in patients with diabetic and alcoholic polyneuropathy. Neurology 16: 1205–1209, 1966. 10.1212/WNL.16.12.1205 CASPubMedWeb of Science®Google Scholar 43 Fagerberg SE: Diabetic neuropathy, a clinical and histological study on the significance of vascular affection. Acta Med Scand Suppl 345: 1–97, 1959. CASPubMedGoogle Scholar 44 Williams E, Timperley WR, Ward JD, and Duckworth T: Electron microscopic studies of vessels in diabetic peripheral neuropathy. J Clin Pathol 33: 462–470, 1980. 10.1136/jcp.33.5.462 CASPubMedWeb of Science®Google Scholar 45 Dyck PJ, Karnes JL, O'Brien P, Okazaki H, Lais A, and Engelstad J: The spatial distribution of fiber loss of diabetic polyneuropathy suggests ischemia. Ann Neurol 19: 440–449, 1986. 10.1002/ana.410190504 CASPubMedWeb of Science®Google Scholar 46 Johnson PC, Doll SC, and Cromey DW: Pathogenesis of diabetic neuropathy. Ann Neurol 19: 450–457, 1986. 10.1002/ana.410190505 CASPubMedWeb of Science®Google Scholar 47 Sima AAF, and Brismar T: Reversible diabetic nerve dysfunction. Structural correlates to electrophysiological abnormalities. Ann Neurol 18: 21–29, 1985. 10.1002/ana.410180105 PubMedWeb of Science®Google Scholar 48 Sima AAF: Can the BB-rat help to unravel diabetic neuropathy? Annotation. Neuropathol Appl Neurobiol 11: 253–264, 1985. 10.1111/j.1365-2990.1985.tb00023.x CASPubMedWeb of Science®Google Scholar 49 Greene DA, Chakrabarti S, Lattimer SA, and Sima AAF: Role of sorbitol accumulation and myoinositol depletion in paranodal swelling of large myelinated nerve fibers in the insulin-deficient spontaneously diabetic Biobreeding rat. J Clin Invest 79: 1479–1485, 1987. 10.1172/JCI112977 CASPubMedWeb of Science®Google Scholar 50 Sima AAF, Lattimer SA, Yagihashi S, and Greene DA: "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 77: 474–484, 1986. 10.1172/JCI112326 CASPubMedWeb of Science®Google Scholar 51 Robertson DM, and Sima AAF: Diabetic neuropathy in the mutant mouse [C57/BL/Ks(db/db)]. A morphometric study. Diabetes 29: 60–67, 1980. 10.2337/diabetes.29.1.60 CASPubMedWeb of Science®Google Scholar 52 Brismar T, Sima AAF, and Greene DA: Reversible and irreversible nodal dysfunction in diabetic neuropathy. Ann Neurol 21: 504–507, 1987. 10.1002/ana.410210515 CASPubMedWeb of Science®Google Scholar 53 Sima AAF, Prashar A, Zhang W-X, Chakrabarti S, and Greene DA: Preventive effect of long term aldose reductase inhibition (Ponalrestat) on nerve conduction and sural nerve structure in the spontaneously diabetic BB-rat. J Clin Invest 85: 1410–1420, 1990. 10.1172/JCI114585 CASPubMedWeb of Science®Google Scholar 54 Sima AAF, Zhang W-X, Tai J, Tze WJ, and Nathaniel V: Diabetic neuropathy in STZ-induced diabetic rat and effect of allogenic islet cell transplantation. Morphometric analysis. Diabetes 37: 1129–1136, 1988. 10.2337/diabetes.37.8.1129 CASPubMedWeb of Science®Google Scholar 55 Sima AAF, Nathaniel V, and Greene DA: Peripheral nerve repair following ARI-treatment. In Fuel Homeostasis and the Nervous System. Advances in Experimental Medicine and Biology, Vol. 291, M Vranic, S Efendic, and CH Hollenberg, Eds. Plenum, New York, 1991, pp 265–270. 10.1007/978-1-4684-5931-9_21 Web of Science®Google Scholar 56 Sima AAF: Peripheral neuropathy in the spontaneous diabetic BB–Wistar rat. An ultrastructural study. Acta Neuropathol (Berlin) 50: 223–227, 1980. 10.1007/BF00687389 Web of Science®Google Scholar 57 Sima AAF, and Robertson DM: Peripheral neuropathy in the diabetic mutant mouse [C57/BL/Ks(db/db)]. An ultrastructural study. Lab Invest 40: 627–632, 1979. CASPubMedWeb of Science®Google Scholar 58 Jakobsen J, and Sidenius P: Decreased axonal transport of structural proteins in streptozotocin diabetic rats. J Clin Invest 66: 292–297, 1980. 10.1172/JCI109856 CASPubMedWeb of Science®Google Scholar 59 Williams SK, Howarth NL, Devenny JJ, and Britensky NW: Structural and functional consequences of increased tubulin glycosylation in diabetes mellitus. Proc Natl Acad Sci USA 72: 6546–6550, 1982. 10.1073/pnas.79.21.6546 Web of Science®Google Scholar 60 Medori R, Jemich H, Antilio-Gambetti L, and Gambetti P: Experimental diabetic neuropathy: similar changes of slow axonal transport and axonal size in different animal models. J Neurosci 8: 1814–1821, 1988. CASPubMedWeb of Science®Google Scholar 61 Chakrabarti S, Ma N, and Sima AAF: Anionic sites in diabetic basement membranes and their possible role in diffusion barrier abnormalities in the BB-rat. Diabetologia 34: 301–306, 1991. 10.1007/BF00405000 PubMedWeb of Science®Google Scholar 62 Thomas PK, Wright DW, and Tzebelikos E: Amino acid uptake by dorsal root ganglia from streptozotocin-diabetic rats. J Neurol Neurosurg Psychiatry 47: 912–916, 1984. 10.1136/jnnp.47.9.912 CASPubMedWeb of Science®Google Scholar 63 Greene DA, and Mackway AM: Decreased myo-inositol content and Na+–K+-ATPase activity in superior cervical ganglion of STZ-diabetic rat and prevention by aldose reductase inhibition. Diabetes 35: 1106–1108, 1986. 10.2337/diabetes.35.10.1106 CASPubMedWeb of Science®Google Scholar 64 Sima AAF, Bouchier M, and Christensen H: Axonal atrophy in sensory nerves of the diabetic BB–Wistar rat, a possible early correlate of human diabetic neuropathy. Ann Neurol 13: 264–272, 1983. 10.1002/ana.410130307 CASPubMedWeb of Science®Google Scholar 65 Schmidt RE, and Scharp DW: Axonal dystrophy in experimental diabetic autonomic neuropathy. Diabetes 31: 761–770, 1982. 10.2337/diabetes.31.9.761 CASPubMedWeb of Science®Google Scholar 66 Schmidt RE, Plurad SB, Olack BJ, and Scharp DW: The effect of pancreatic islet transplantation and insulin therapy on experimental diabetic autonomic neuropathy. Diabetes 32: 532–540, 1983. CASPubMedWeb of Science®Google Scholar 67 Yagihashi S, and Sima AAF: Diabetic autonomic neuropathy in the BB-rat. Ultrastructural and morphometric changes in sympathetic nerves. Diabetes 34: 558–564, 1985. 10.2337/diabetes.34.6.558 CASPubMedWeb of Science®Google Scholar 68 Yagihashi S, and Sima AAF: Neuroaxonal and dendritic dystrophy in diabetic autonomic neuropathy. J Neuropathol Exp Neurol 45: 545–565, 1986. 10.1097/00005072-198609000-00005 PubMedWeb of Science®Google Scholar 69 Yagihashi S, and Sima AAF: The distribution of structural changes in sympathetic nerves in the diabetic BB-rat. Am J Pathol 121: 138–147, 1985. PubMedWeb of Science®Google Scholar 70 Yagihashi S, and Sima AAF: Diabetic autonomic neuropathy in the BB-rat. Ultrastructural and morphometric changes in parasympathetic nerves. Diabetes 35: 733–743, 1986. PubMedWeb of Science®Google Scholar 71 Greene DA, Winegrad AI, Carpentier JL, Brown MJ, Fukuma M, and Orci L: Rabbit sciatic nerve fascicle and endoneurial preparations for in vitro studies of peripheral nerve glucose metabolism. J Neurochem 33: 1007–1018, 1979. 10.1111/j.1471-4159.1979.tb05237.x CASPubMedWeb of Science®Google Scholar 72 Greene DA, and Winegrad AL: In vitro studies of the substrates for energy production and the effects of insulin on glucose utilization in the neural compartments of peripheral nerve. Diabetes 28: 878–887, 1979. Google Scholar 73 Greene DA, Lattimer SA, Carroll PB, Fernstrom JD, and Finegold DN: A defect in sodium-dependent amino acid uptake in diabetic rabbit peripheral nerve: correction by an ARI or myo-inositol administration. J Clin Invest 85: 1657–1665, 1990. 10.1172/JCI114617 CASPubMedWeb of Science®Google Scholar 74 Greene DA, and Winegrad AI: Effects of acute experimental diabetes on composite energy metabolism in peripheral nerve axons and Schwann cells. Diabetes 30: 967–974, 1981. 10.2337/diab.30.11.967 CASPubMedWeb of Science®Google Scholar 75 Greene DA: Metabolic abnormalities in diabetic peripheral nerve: relation to impaired function. Metabolism 32: 118–125, 1983. 10.1016/S0026-0495(83)80024-9 CASPubMedWeb of Science®Google Scholar 76 Greene DA, and Lattimer SA: Impaired energy utilization and Na–K-ATPase in diabetic peripheral nerve. Am J Physiol 246: E311–E318, 1984. CASPubMedWeb of Science®Google Scholar 77 Mayer JH, and Tomlinson DR: Prevention of defects of axonal transport and nerve conduction velocity by oral administration of myo-inositol or an ARI in streptozotocin-diabetic rats. Diabetologia 25: 433–438, 1983. 10.1007/BF00282524 CASPubMedWeb of Science®Google Scholar 78 Greene DA, Lewis RA, Lattimer SA, and Brown MJ: Selective effects of myo-inositol administration on sciatic and tibial motor nerve conduction parameters in the streptozotocin diabetic rat. Diabetes 31: 573–578, 1982. CASPubMedWeb of Science®Google Scholar 79 Greene DA, DeJesus PV, and Winegrad AI: Effects of insulin and dietary myo-inositol on impaired motor nerve conduction velocity in acute streptozotocin diabetes. J Clin Invest 55: 1326–1336, 1975. 10.1172/JCI108052 CASPubMedWeb of Science®Google Scholar 80 Greene DA, and Lattimer SA: Impaired rat sciatic nerve sodium–potassium adenosine trisphosphatase in acute streptozotocin diabetes and its correction by dietary myo-inositol supplementation. J Clin Invest 72: 1058–1063, 1983. 10.1172/JCI111030 CASPubMedWeb of Science®Google Scholar 81 Gabbay KH: Role of polyol pathway in neuropathy. Adv Metab Disord Suppl 2: 417, 1973. CASPubMedGoogle Scholar 82 Greene DA, Lattimer-Greene SA, and Sima AAF: Pathogenesis of diabetic neuropathy: role of altered phosphoinositide metabolism. Crit Rev Neurobiol 5: 143–219, 1989. CASPubMedWeb of Science®Google Scholar 83 Winegrad AI: Banting Lecture 1986. Does a common mechanism induce the diverse complications of diabetes? Diabetes 36: 396–406, 1987. 10.2337/diab.36.3.396 CASPubMedWeb of Science®Google Scholar 84 Palmano KP, Whiting PH, and Hawthorne JN: Free and lipid myo-inositol in tissues from rats with acute and less severe streptozotocin-induced diabetes. Biochem J 167: 229–235, 1977. 10.1042/bj1670229 CASPubMedWeb of Science®Google Scholar 85 Dvornik D, In Aldose Reductase Inhibition—An Approach to the Prevention of Diabetic Complications, D Porte, Ed. MacGraw-Hill, New York, 1987. Google Scholar 86 Tomlinson DR, Sidenius P, and Larsen JR: Slow component-a of axonal transport, nerve myo-inositol and aldose reductase inhibition in streptozotocin-diabetic rats. Diabetes 34: 398–402, 1986. 10.2337/diabetes.35.4.398 Web of Science®Google Scholar 87 Finegold D, Lattimer S, Nolle S, Bernstein M, and Greene DA: Polyol pathway activity and myo-inositol metabolism. Diabetes 32: 988–992, 1983. 10.2337/diabetes.32.11.988 CASPubMedWeb of Science®Google Scholar 88 Mayer JH, and Tomlinson DR: The influence of aldose reductase inhibition and nerve myoinositol on axonal transport and nerve conduction velocity in rats with experimental diabetes. J Physiol (London) 340: 25P–26P, 1983. Google Scholar 89 Greene DA, and Lattimer SA: Action of sorbinil in diabetic peripheral nerve. Relationship of polyol (sorbitol) pathway inhibition to a myo-inositol-mediated defect in sodium–potassium ATPase activity. Diabetes 33: 712–716, 1984. CASPubMedWeb of Science®Google Scholar 90 Tomlinson DR, and Mayer JH: Reversal of deficits in axonal transport and nerve conduction velocity by treatment of streptozotocin diabetic rats with myo-inositol. Exp Neurol 89: 420–427, 1985. 10.1016/0014-4886(85)90101-3 CASPubMedWeb of Science®Google Scholar 91 Gillon KRW, and Hawthorne JN: Sorbitol, inositol and nerve conduction in diabetes. Life Sci 32: 1943–1947, 1983. 10.1016/0024-3205(83)90045-0 CASPubMedWeb of Science®Google Scholar 92 Greene DA, Lattimer S, Ulbrecht J, and Carroll P: Glucose-induced alterations in nerve metabolism: current perspective on the pathogenesis of diabetic neuropathy and future directions for research and therapy. Diabetes Care 8: 290–299, 1985. 10.2337/diacare.8.3.290 CASPubMedWeb of Science®Google Scholar 93 Sharma AK, and Thomas PK: Peripheral nerve structure and function in experimental diabetes. J Neurol Sci 23: 1–15, 1974. 10.1016/0022-510X(74)90136-1 CASPubMedWeb of Science®Google Scholar 94 Fukuma M, Carpentier JL, Orci L, Greene DA, and Winegrad AI: An alteration in internodal myelin membrane structure in large sciatic nerve fibers in rats with acute streptozotocin diabetes and impaired nerve conduction velocity. Diabetologia 15: 65–72, 1978. 10.1007/BF01219331 CASPubMedWeb of Science®Google Scholar 95 Das PK, Bray GM, Aguayo AJ, and Rasminsky M: Diminished ouabain sensitive, sodium–potassium ATPase activity in sciatic nerves of rats with streptozotocin induced diabetes. Exp Neurol 53: 285–288, 1976. 10.1016/0014-4886(76)90299-5 CASPubMedWeb of Science®Google Scholar 96 Lattimer SA, Sima AAF, and Greene DA: In vitro correction of impaired Na+–K+-ATPase in diabetic nerve by protein kinase C agonists. Am J Physiol 256: E264–E269, 1989. 10.1152/ajpendo.1989.256.2.E264 CASPubMedWeb of Science®Google Scholar 97 Simpson CMF, and Hawthorne JN: Reduced Na+–K+-ATPase activity in peripheral nerve of streptozotocin-diabetic rats: a role for protein kinase C? Diabetologia 31: 297–303, 1988. CASPubMedWeb of Science®Google Scholar 98 Bianchi R, Marini P, Merlini S, Fabris M, Triban C, Mussini E, and Fiori MG: ATPase activity defects in alloxan-induced diabetic sciatic nerve recovered by ganglioside treatment. Diabetes 37: 1340–1345, 1988. 10.2337/diabetes.37.10.1340 CASPubMedWeb of Science®Google Scholar 99 Brismar Y, and Sima AAF: Changes in nodal function in nerve fibers of the spontaneously diabetic BB–Wistar rat: potential clamp analysis. Acta Physiol Scand 113: 499–506, 1981.