Aldose reductase inhibitors in the prevention of diabetic complications
- Eli A Friedman, MD
Eli A Friedman, MD
- Distinguished Teaching Professor of Medicine
- Downstate Medical Center, Brooklyn, New York
- Section Editors
- Gary C Curhan, MD, ScD
Gary C Curhan, MD, ScD
- Section Editor — Chronic Kidney Disease
- Editor-in-Chief emeritus
- Harvard Medical School
- David M Nathan, MD
David M Nathan, MD
- Editor-in-Chief — Endocrinology
- Section Editor — Diabetes Mellitus
- Professor of Medicine
- Harvard Medical School
The Diabetes Control and Complications Trial (DCCT), the United Kingdom Prospective Diabetes Study (UKPDS) , and other studies have demonstrated the central role of hyperglycemia in the pathogenesis of diabetic microvascular complications such as retinopathy, nephropathy, and neuropathy. In addition to degree of hyperglycemia as a risk factor, mounting evidence suggests that both the incidence and severity of diabetic microvasculopathy are modulated by individual genotypes . Although the molecular basis of how hyperglycemia causes tissue injury is still being defined, two proposed mechanisms, both linked to what has been termed "oxidative stress," are the downstream impact of accumulation of sorbitol and advanced glycosylation end products. (See "Glycemic control and vascular complications in type 1 diabetes mellitus".)
Oxidative stress is strongly implicated as a mediator of multiple diabetes-induced microvascular complications, including nephropathy, retinopathy, and distal symmetric polyneuropathy. Key mediators of glucose-induced oxidative injury are superoxide anions and nitric oxide (NO). One proposed sequence of how hyperglycemia leads to oxidative stress is that high ambient glucose levels increase mitochondrial synthesis of reactive oxygen species, activate protein kinase C (PKC), and overexpress sorbitol. Superoxides are believed to underlie many of the oxidative changes in hyperglycemic conditions, including increases in aldose reductase and protein kinase C activity.
Clinical trials of agents that quench the effects of formed reactive oxygen species in rodents, including vitamin E, C, and alpha-lipoic acid have had limited success in improving cardiovascular outcomes. Statins, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and thiazolidinediones may improve cardiovascular outcomes among patients with diabetes by reducing production of reactive oxygen species at a more proximal part of the cascade, thereby more effectively decreasing the oxidative stress burden. Statins and ACE inhibitors/ARBs appear synergistic in reducing oxidative stress and vascular disease .
However, despite strong evidence that oxidative stress is associated with diabetic complications including nephropathy, retinopathy, and neuropathy, clinical trials of several antioxidants (such as aldose reductase inhibitors, alpha-lipoic acid, vitamins C and E, and growth factors) in diabetic neuropathy and retinopathy, although strongly positive in rodents (with several exceptions ), have not established therapeutic efficacy .
The possible role of the sorbitol pathway in this process remains controversial [6-8]. Glucose that enters cells is metabolized in part to sorbitol via the enzyme aldose reductase. Aldose reductase has a low affinity for glucose, and little substrate is processed under physiologic conditions. However, glucose conversion to sorbitol is more pronounced with chronic hyperglycemia. The accumulation of sorbitol within the cells results in a rise in cell osmolality and a decrease in intracellular myoinositol; these changes in turn lead to a decrease in Na-K-ATPase activity and a possible shift in the redox potential within cells. Hyperglycemia may also contribute directly to the decline in cell myoinositol levels by competitively interfering with myoinositol uptake from the extracellular fluid via a sodium-myoinositol cotransporter .
- Leslie RD. United Kingdom prospective diabetes study (UKPDS): what now or so what? Diabetes Metab Res Rev 1999; 15:65.
- Szaflik JP, Majsterek I, Kowalski M, et al. Association between sorbitol dehydrogenase gene polymorphisms and type 2 diabetic retinopathy. Exp Eye Res 2008; 86:647.
- Rahangdale S, Yeh SY, Malhotra A, Veves A. Therapeutic interventions and oxidative stress in diabetes. Front Biosci (Landmark Ed) 2009; 14:192.
- Paravicini TM, Touyz RM. NADPH oxidases, reactive oxygen species, and hypertension: clinical implications and therapeutic possibilities. Diabetes Care 2008; 31 Suppl 2:S170.
- Cowell RM, Russell JW. Nitrosative injury and antioxidant therapy in the management of diabetic neuropathy. J Investig Med 2004; 52:33.
- Frank RN. The aldose reductase controversy. Diabetes 1994; 43:169.
- Greene DA, Lattimer SA, Sima AA. Sorbitol, phosphoinositides, and sodium-potassium-ATPase in the pathogenesis of diabetic complications. N Engl J Med 1987; 316:599.
- Hotta N. New concepts and insights on pathogenesis and treatment of diabetic complications: polyol pathway and its inhibition. Nagoya J Med Sci 1997; 60:89.
- Tomlinson DR, Stevens EJ, Diemel LT. Aldose reductase inhibitors and their potential for the treatment of diabetic complications. Trends Pharmacol Sci 1994; 15:293.
- Nishimura C, Saito T, Ito T, et al. High levels of erythrocyte aldose reductase and diabetic retinopathy in NIDDM patients. Diabetologia 1994; 37:328.
- Nishimura C, Hotta Y, Gui T, et al. The level of erythrocyte aldose reductase is associated with the severity of diabetic retinopathy. Diabetes Res Clin Pract 1997; 37:173.
- Yoshikawa M, Shimada H, Nishida N, et al. Antidiabetic principles of natural medicines. II. Aldose reductase and alpha-glucosidase inhibitors from Brazilian natural medicine, the leaves of Myrcia multiflora DC. (Myrtaceae): structures of myrciacitrins I and II and myrciaphenones A and B. Chem Pharm Bull (Tokyo) 1998; 46:113.
- Oates PJ. Aldose reductase, still a compelling target for diabetic neuropathy. Curr Drug Targets 2008; 9:14.
- Robison WG Jr, Tillis TN, Laver N, Kinoshita JH. Diabetes-related histopathologies of the rat retina prevented with an aldose reductase inhibitor. Exp Eye Res 1990; 50:355.
- Sun W, Oates PJ, Coutcher JB, et al. A selective aldose reductase inhibitor of a new structural class prevents or reverses early retinal abnormalities in experimental diabetic retinopathy. Diabetes 2006; 55:2757.
- Kassab JP, Guillot R, Andre J, et al. Renal and microvascular effects of an aldose reductase inhibitor in experimental diabetes. Biochemical, functional and ultrastructural studies. Biochem Pharmacol 1994; 48:1003.
- Obrosova IG, Van Huysen C, Fathallah L, et al. An aldose reductase inhibitor reverses early diabetes-induced changes in peripheral nerve function, metabolism, and antioxidative defense. FASEB J 2002; 16:123.
- Ramana KV, Friedrich B, Tammali R, et al. Requirement of aldose reductase for the hyperglycemic activation of protein kinase C and formation of diacylglycerol in vascular smooth muscle cells. Diabetes 2005; 54:818.
- Stevens MJ, Dananberg J, Feldman EL, et al. The linked roles of nitric oxide, aldose reductase and, (Na+,K+)-ATPase in the slowing of nerve conduction in the streptozotocin diabetic rat. J Clin Invest 1994; 94:853.
- Kador PF, Robison WG Jr, Kinoshita JH. The pharmacology of aldose reductase inhibitors. Annu Rev Pharmacol Toxicol 1985; 25:691.
- Suzuki H, Shimosegawa T, Ohara S, Toyota T. Epalrestat prevents the decrease in gastric mucosal blood flow and protects the gastric mucosa in streptozotocin diabetic rats. J Gastroenterol 1999; 34:172.
- Kern, TS, Engerman, RL. Development of complications in diabetic dogs and galactosemic dogs: effect of aldose reductase inhibitors. In: Proceedings of a workshop on aldose reductase inhibitors, NIH publication, 1991. p.81–3114.
- Engerman RL, Kern TS, Garment MB. Capillary basement membrane in retina, kidney, and muscle of diabetic dogs and galactosemic dogs and its response to 5 years aldose reductase inhibition. J Diabetes Complications 1993; 7:241.
- Ohmura C, Watada H, Azuma K, et al. Aldose reductase inhibitor, epalrestat, reduces lipid hydroperoxides in type 2 diabetes. Endocr J 2009; 56:149.
- Ramana KV. ALDOSE REDUCTASE: New Insights for an Old Enzyme. Biomol Concepts 2011; 2:103.
- WHO Pharmaceutical Newsletter Nº 3-4, 12;1997.
- A randomized trial of sorbinil, an aldose reductase inhibitor, in diabetic retinopathy. Sorbinil Retinopathy Trial Research Group. Arch Ophthalmol 1990; 108:1234.
- Tromp A, Hooymans JM, Barendsen BC, van Doormaal JJ. The effects of an aldose reductase inhibitor on the progression of diabetic retinopathy. Doc Ophthalmol 1991; 78:153.
- Nakahara M, Miyata K, Otani S, et al. A randomised, placebo controlled clinical trial of the aldose reductase inhibitor CT-112 as management of corneal epithelial disorders in diabetic patients. Br J Ophthalmol 2005; 89:266.
- Lajer M, Tarnow L, Fleckner J, et al. Association of aldose reductase gene Z+2 polymorphism with reduced susceptibility to diabetic nephropathy in Caucasian Type 1 diabetic patients. Diabet Med 2004; 21:867.
- Zhao HL, Tong PC, Lai FM, et al. Association of glomerulopathy with the 5'-end polymorphism of the aldose reductase gene and renal insufficiency in type 2 diabetic patients. Diabetes 2004; 53:2984.
- Passariello N, Sepe J, Marrazzo G, et al. Effect of aldose reductase inhibitor (tolrestat) on urinary albumin excretion rate and glomerular filtration rate in IDDM subjects with nephropathy. Diabetes Care 1993; 16:789.
- Pedersen MM, Christiansen JS, Mogensen CE. Reduction of glomerular hyperfiltration in normoalbuminuric IDDM patients by 6 mo of aldose reductase inhibition. Diabetes 1991; 40:527.
- McAuliffe AV, Brooks BA, Fisher EJ, et al. Administration of ascorbic acid and an aldose reductase inhibitor (tolrestat) in diabetes: effect on urinary albumin excretion. Nephron 1998; 80:277.
- Iso K, Tada H, Kuboki K, Inokuchi T. Long-term effect of epalrestat, an aldose reductase inhibitor, on the development of incipient diabetic nephropathy in Type 2 diabetic patients. J Diabetes Complications 2001; 15:241.
- Santiago JV, Snksen PH, Boulton AJ, et al. Withdrawal of the aldose reductase inhibitor tolrestat in patients with diabetic neuropathy: effect on nerve function. The Tolrestat Study Group. J Diabetes Complications 1993; 7:170.
- Giugliano D, Acampora R, Marfella R, et al. Tolrestat in the primary prevention of diabetic neuropathy. Diabetes Care 1995; 18:536.
- Boulton AJ, Levin S, Comstock J. A multicentre trial of the aldose-reductase inhibitor, tolrestat, in patients with symptomatic diabetic neuropathy. Diabetologia 1990; 33:431.
- Macleod AF, Boulton AJ, Owens DR, et al. A multicentre trial of the aldose-reductase inhibitor tolrestat, in patients with symptomatic diabetic peripheral neuropathy. North European Tolrestat Study Group. Diabete Metab 1992; 18:14.
- Giugliano D, Marfella R, Quatraro A, et al. Tolrestat for mild diabetic neuropathy. A 52-week, randomized, placebo-controlled trial. Ann Intern Med 1993; 118:7.
- Greene DA, Arezzo JC, Brown MB. Effect of aldose reductase inhibition on nerve conduction and morphometry in diabetic neuropathy. Zenarestat Study Group. Neurology 1999; 53:580.
- Giannoukakis N. Ranirestat as a therapeutic aldose reductase inhibitor for diabetic complications. Expert Opin Investig Drugs 2008; 17:575.
- Bril V, Hirose T, Tomioka S, et al. Ranirestat for the management of diabetic sensorimotor polyneuropathy. Diabetes Care 2009; 32:1256.
- The sorbinil retinopathy trial: neuropathy results. Sorbinil Retinopathy Trial Research Group. Neurology 1993; 43:1141.
- Utsunomiya K, Narabayashi I, Tamura K, et al. Effects of aldose reductase inhibitor and vitamin B12 on myocardial uptake of iodine-123 metaiodobenzylguanidine in patients with non-insulin-dependent diabetes mellitus. Eur J Nucl Med 1998; 25:1643.
- Zhao HT, Hazemann I, Mitschler A, et al. Unusual binding mode of the 2S4R stereoisomer of the potent aldose reductase cyclic imide inhibitor fidarestat (2S4S) in the 15 K crystal structure of the ternary complex refined at 0.78 A resolution: implications for the inhibition mechanism. J Med Chem 2008; 51:1478.
- Obrosova IG, Pacher P, Szabó C, et al. Aldose reductase inhibition counteracts oxidative-nitrosative stress and poly(ADP-ribose) polymerase activation in tissue sites for diabetes complications. Diabetes 2005; 54:234.
- 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 placebo-controlled double-blind parallel group study. Diabetes Care 2001; 24:1776.
- Hotta N, Akanuma Y, Kawamori R, et al. Long-term clinical effects of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy: the 3-year, multicenter, comparative Aldose Reductase Inhibitor-Diabetes Complications Trial. Diabetes Care 2006; 29:1538.
- Sima AA, Greene DA, Brown MB, et al. Effect of hyperglycemia and the aldose reductase inhibitor tolrestat on sural nerve biochemistry and morphometry in advanced diabetic peripheral polyneuropathy. The Tolrestat Study Group. J Diabetes Complications 1993; 7:157.
- Bril V, Buchanan RA. Aldose reductase inhibition by AS-3201 in sural nerve from patients with diabetic sensorimotor polyneuropathy. Diabetes Care 2004; 27:2369.
- Rakowitz D, Piccolruaz G, Pirker C, Matuszczak B. Novel aldose reductase inhibitors derived from 6-[[(diphenylmethylene)amino]oxy]hexanoic acid. Arch Pharm (Weinheim) 2007; 340:202.
- Bradley J, Ju M, Robinson GS. Combination therapy for the treatment of ocular neovascularization. Angiogenesis 2007; 10:141.
- Tammali R, Reddy AB, Srivastava SK, Ramana KV. Inhibition of aldose reductase prevents angiogenesis in vitro and in vivo. Angiogenesis 2011; 14:209.