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Aldose reductase inhibition in the treatment of diabetic neuropathy: Where are we in 2004?

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Abstract

Diabetic neuropathy is a major complication of poorly controlled diabetes mellitus. Aldose reductase, the first enzyme of the polyol pathway, is thought to play a role in initiating the metabolic damage to peripheral nerves during hyperglycemia. Aldose reductase inhibitors (ARIs) have been proposed to dampen the flux of glucose through the pathway during hyperglycemia; however, clinical trials in diabetic patients to demonstrate efficacy in the prevention or amelioration of diabetic neuropathy have failed thus far. Recent improved understanding of the pitfalls of past trials and some improved ARIs and clinical evaluation instruments show promise that success in the 20-plus year search for efficacious ARIs may soon be at hand.

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References and Recommended Reading

  1. Kinoshita JH: A thirty year journey in the polyol pathway. Exp Eye Res 1990, 50:567–573.

    Article  PubMed  CAS  Google Scholar 

  2. Buzney SM, Frank RN, Varma SD, et al.: Aldose reductase in retinal mural cells. Invest Ophthalmol Vis Sci 1977, 16:392–396.

    PubMed  CAS  Google Scholar 

  3. Robison WG, Nagata M, Laver N, et al.: Diabetic-like retinopathy in rats prevented with an aldose reductase inhibitor. Invest Ophthalmol Vis Sci 1989, 30:2285–2292.

    PubMed  Google Scholar 

  4. Gabbay KH: Role of sorbitol pathway in neuropathy. Adv Metab Disord 1973, 2(suppl 2):417–432.

    PubMed  CAS  Google Scholar 

  5. Gabbay KH, Snider J: Nerve conduction defect in galactosefed rats. Diabetes 1972, 21:295–300.

    CAS  Google Scholar 

  6. Judzewitsch RG, Jaspan JB, Polonsky K, et al.: Aldose reductase inhibition improves nerve conduction velocity in diabetic patients. N Engl J Med 1983, 308:119–125.

    Article  PubMed  CAS  Google Scholar 

  7. Mogensen CE: The effect of blood pressure intervention on renal function in insulin-dependent diabetes. Diabete Metab 1989, 15(5 Pt 2):343–351.

    PubMed  CAS  Google Scholar 

  8. Schleicher ED, Olgemoller B: Glomerular changes in diabetes mellitus. Eur J Clin Chem Clin Biochem 1992, 30:635–640.

    PubMed  CAS  Google Scholar 

  9. Pedersen MM, Christiansen JS, Mogensen CE: Reduction of glomerular hyperfiltration in normoalbuminuric IDDM patients by six months of aldose reductase inhibition. Diabetes 1991, 40:527–531.

    Article  PubMed  CAS  Google Scholar 

  10. Williamson JR, Chang K, Tilton RG, et al.: Increased vascular permeability in spontaneously diabetic BB/W rats and in rats with mild versus severe streptozocin-induced diabetes. Prevention by aldose reductase inhibitors and castration. Diabetes 1987, 36:813–821.

    Article  PubMed  CAS  Google Scholar 

  11. Ramasamy R, Oates PJ, Schaefer S: Aldose reductase inhibition protects diabetic and nondiabetic rat hearts from ischemic injury. Diabetes 1997, 46:292–300.

    Article  PubMed  CAS  Google Scholar 

  12. Hwang YC, Sato S, Tsai JY, et al.: Aldose reductase activation is a key component of myocardial response to ischemia. FASEB J 2001, 16:243–245.

    PubMed  Google Scholar 

  13. Johnson BF, Nesto RW, Pfeifer MA, et al.: Cardiac abnormalities in diabetic patients with neuropathy: effects of aldose reductase inhibitor administration. Diabetes Care 2004, 27:448–454. Presents a significant study of the effects of a 1-year study of zopolrestat on improving or preventing the deterioration of cardiac function in diabetic patients.

    Article  PubMed  CAS  Google Scholar 

  14. Effect of intensive diabetes treatment on nerve conduction in the Diabetes Control and Complications Trial. The Diabetes Control and Complications (DCCT) Research Group [no authors listed]. Ann Neurol 1995, 38:869–880.

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

    Article  PubMed  CAS  Google Scholar 

  16. Pfeifer MA, Schumer MP, Gelber DA: Aldose reductase inhibitors: the end of an era or the need for different trial designs? Diabetes 1997, 46(suppl):S82-S89.

    PubMed  CAS  Google Scholar 

  17. Hotta N, Toyota T, Matsuoka K, et al.: Clinical efficacy of fidarestat, a novel aldose reductase inhibitor, for diabetic peripheral neuropathy: a 52-week multicenter placebocontrolled double-blind parallel group study. Diabetes Care 2001, 24:1776–1782.

    Article  PubMed  CAS  Google Scholar 

  18. Bril V, Buchanan RA: Aldose reductase inhibition by AS-3201 in sural nerve from patients with diabetic sensorimotor polyneuropathy. Diabetes Care 2004, 27:2369–2375. Presents preliminary data for AS-3201 phase II trial.

    Article  PubMed  CAS  Google Scholar 

  19. Hamada Y, Kitoh R, Raskin P: Crucial role of aldose reductase activity and plasma glucose level in sorbitol accumulation in erythrocytes from diabetic patients. Diabetes 1991, 40:1233–1240.

    Article  PubMed  CAS  Google Scholar 

  20. Hamada Y, Kitoh R, Raskin P: Association of erythrocyte aldose reductase activity with diabetic complications in type 1 diabetes mellitus. Diabet Med 1993, 10:33–38. [Published erratum appears in Diabet Med 1993, 10:197.]

    Article  PubMed  CAS  Google Scholar 

  21. Hamada Y, Hammon K, Raskin P: No correlation between glycemic control and an increase in erythrocyte aldose reductase activity in type I and type II diabetic patients. J Diabetes Complications 1992, 6:111–115.

    Article  PubMed  CAS  Google Scholar 

  22. Nishimura C, Furue M, Ito T, et al.: Quantitative determination of human aldose reductase by enzyme-linked immunosorbent assay. Immunoassay of human aldose reductase. Biochem Pharmacol 1993, 46:21–28.

    Article  PubMed  CAS  Google Scholar 

  23. Nishimura C, Hamada Y, Tachikawa T, et al.: Enzyme immunoassay for erythrocyte aldose reductase. Clin Chem 1994, 40:889–894.

    PubMed  CAS  Google Scholar 

  24. Gabbay KH, Cathcart ES: Purification and immunologic identification of aldose reductases. Diabetes 1974, 23:460–468.

    PubMed  CAS  Google Scholar 

  25. Bril V, Perkins BA: Validation of the Toronto Clinical Scoring System for diabetic polyneuropathy. Diabetes Care 2002, 25:2048–2052. Presents data validating the CSS and review of current diagnostic methods for neuropathy.

    Article  PubMed  Google Scholar 

  26. Perkins BA, Bril V: Diabetic neuropathy: a review emphasizing diagnostic methods. Clin Neurophysiol 2003, 114:1167–1175.

    Article  PubMed  Google Scholar 

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Gabbay, K.H. Aldose reductase inhibition in the treatment of diabetic neuropathy: Where are we in 2004?. Curr Diab Rep 4, 405–408 (2004). https://doi.org/10.1007/s11892-004-0047-z

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