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September 1990, Vol 108, No. 9 >
ARTICLE | September 1990

Aldose Reductase Inhibition: Title and subTitle BreakThe Chemical Key to the Control of Diabetic Retinopathy? FREE

Robert N. Frank, MD
Arch Ophthalmol. 1990;108(9):1229-1231. doi:10.1001/archopht.1990.01070110045022
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In 1959, the British biochemist Ruth van Heyningen1 reported that the cataractous lenses of diabetic rats contain high concentrations of the sugar alcohol sorbitol, which is produced by reduction of the aldehyde group of glucose. Later work by Kinoshita2,3 demonstrated that the sorbitol is produced by the action of an enzyme, aldose reductase. Cataractogenesis by sugar alcohols was demonstrated more strikingly in nondiabetic animals fed galactose whose sugar alcohol, galactitol, unlike sorbitol, cannot be further oxidized to a keto sugar by sorbitol dehydrogenase. Hence, galactitol builds to high levels intracellularly faster than sorbitol, producing the same effects, but more rapidly.

See also pp 1234 and 1301.

Cataracts were the first complication of diabetes to be attributed to the "sorbitol pathway." As more investigators began to explore this pathway, the complexity of the chemical reactions affected by sugar alcohols was found to be greater than anticipated, as was the

REFERENCES

1 +
Van Heyningen R.  Formation of polyols by the lens of the rat with 'sugar' cataract . Nature . 1959;;184:194-195.
2 +
Kinoshita JH.  Cataracts in galactosemia . Invest Ophthalmol . 1965;;5:786-789.
3 +
Kinoshita JH.  Mechanisms initiating cataract formation . Invest Ophthalmol . 1974;;13:713-724.
4 +
Gabbay KH.  The sorbitol pathway and the complications of diabetes . N Engl J Med . 1973;;288:831-836.
5 +
Kador PF, Kinoshita JH.  Role of aldose reductase in the development of diabetes-associated complications . Am J Med . 1985;;79( (suppl 5A) ):8-12.
6 +
Greene DA, Lattimer SA, Sima AAF.  Sorbitol, phosphoinositides, and sodium-potassium-ATPase in the pathogenesis of diabetic complications . N Engl J Med . 1987;;316:599-606.
7 +
Gabbay KH.  Purification and immunological identification of bovine retinal aldose reductase . Isr J Med Sci . 1972;;8:1626-1630.
8 +
Buzney SM, Frank RN, Varma SD, Tanishima T, Gabbay KH.  Aldose reductase in retinal mural cells . Invest Ophthalmol Vis Sci . 1977;;16:292-296.
9 +
Cogan DG, Toussaint D, Kuwabara T.  Retinal vascular patterns, IV: diabetic retinopathy . Arch Ophthalmol . 1961;;66:366-378.
10 +
Frank RN, Keirn RJ, Kennedy A, Frank KW.  Galactose-induced retinal capillary basement membrane thickening: prevention by Sorbinil . Invest Ophthalmol Vis Sci . 1983;;24:1519-1524.
11 +
Robison WG Jr, Kador PF, Kinoshita JH.  Retinal capillaries: basement membrane thickening by galactosemia prevented with aldose reductase inhibitor . Science . 1983;;221:1177-1179.
12 +
Caird FI, Pirie A, Ramsell TG. Diabetes and the Eye . Boston, Mass: Blackwell Scientific Publications Inc; 1969;:37-58.
13 +
Robison WG Jr, Kador PF, Akagi Y, Kinoshita JH, Gonzalez R, Dvornik D.  Prevention of basement membrane thickening in retinal capillaries by a novel inhibitor of aldose reductase, tolrestat . Diabetes . 1986;;35:295-299.
14 +
Friedenwald JS.  A new approach to some problems of retinal vascular disease . Am J Ophthalmol . 1949;;32:487-498.
15 +
Engerman RL, Bloodworth JM.  Experimental diabetic retinopathy in dogs . Arch Ophthalmol . 1965;;73:205-210.
16 +
Engerman RL, Bloodworth JMB Jr, Nelson S.  Relationship of microvascular disease in diabetes to metabolic control . Diabetes . 1977;;26:760-769.
17 +
Patz A, Maumenee AE.  Studies in diabetic retinopathy, I: retinopathy in a dog with spontaneous diabetes mellitus . Am J Ophthalmol . 1962;;54:532-541.
18 +
Hausler HR, Sibay TM, Campbell J.  Retinopathy in a dog following diabetes induced by growth hormone . Diabetes . 1964;;13:122-126.
19 +
Engerman RL, Kern T.  Experimental galactosemia produces diabetic-like retinopathy . Diabetes . 1984;;33:97-100.
20 +
Kador PF, Akagi Y, Terubayashi H, Wyman M, Kinoshita JH.  Prevention of pericyte ghost formation in retinal capillaries of galactose-fed dogs by aldose reductase inhibitors . Arch Ophthalmol . 1988;;106:1099-1102.
21 +
Kador PF, Akagi Y, Takahashi Y, et al.  Prevention of retinal vessel changes associated with diabetic retinopathy in galactose-fed dogs by aldose reductase inhibitors . Arch Ophthalmol . 1990;;108:1301-1309.
22 +
Sorbinil Retinopathy Trial Research Group.  A randomized trial of sorbinil, an aldose reductase inhibitor, in diabetic retinopathy . Arch Ophthalmol . 1990;;108:1234-1244.
23 +
Robison WG Jr, Nagata M, Laver N, Hohman TC, Kinoshita JH.  Diabetic-like retinopathy in rats prevented with an aldose reductase inhibitor . Invest Ophthalmol Vis Sci . 1989;;30:2285-2292.
24 +
Frank RN, Hoffman WH, Podgor MJ, et al.  Retinopathy in juvenile-onset diabetes of short duration . Ophthalmology . 1980;;87:1-9.
25 +
Palmberg P, Smith M, Waltman S, et al.  The natural history of retinopathy in insulin-dependent juvenile-onset diabetes . Ophthalmology . 1981;;88:613-618.
26 +
Klein R, Klein BEK, Moss SE, Davis MD, DeMets DL.  The Wisconsin epidemiologic study of diabetic retinopathy, II: prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years . Arch Ophthalmol . 1984;;102:520-526.
27 +
Lauritzen T, Frost-Larsen K, Larsen HW, Deckert T, Steno Study Group.  Two-year experience with continuous subcutaneous insulin infusion in relation to retinopathy and neuropathy . Diabetes . 1985;;34( (suppl 3) ):74-79.
28 +
Dahl-Jørgensen K, Brinchmann-Hansen O, Hanssen KF, Sandvik I, Aagenaes 0, Aker Diabetes Group.  Rapid tightening of blood glucose control leads to transient deterioration of retinopathy in insulin dependent diabetes mellitus: the Oslo study . BMJ . 1985;;290:811-815.
29 +
The Kroc Collaborative Study Group.  Diabetic retinopathy after two years of intensified insulin treatment: follow-up of the Kroc collaborative study . JAMA . 1988;;260:37-41.
30 +
The DCCT Research Group.  Diabetes Control and Complications Trial (DCCT): results of feasibility study . Diabetes Care . 1987;;10:1-19.
31 +
Diabetic Retinopathy Study Research Group.  Preliminary report on effects of photocoagulation therapy . Am J Ophthalmol . 1976;;81:383-396.
32 +
Early Treatment Diabetic Retinopathy Study Research Group.  Photocoagulation for diabetic macular edema: Early Treatment Diabetic Retinopathy Study Report number 1 . Arch Ophthalmol . 1985;;103:1796-1806.
33 +
Engerman RL, Kern TS.  Retinal vasculature in sorbinil-treated galactosemic dogs . Invest Ophthalmol Vis Sci . 1989;;30( (suppl) ):139.

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1 +
Van Heyningen R.  Formation of polyols by the lens of the rat with 'sugar' cataract . Nature . 1959;;184:194-195.
2 +
Kinoshita JH.  Cataracts in galactosemia . Invest Ophthalmol . 1965;;5:786-789.
3 +
Kinoshita JH.  Mechanisms initiating cataract formation . Invest Ophthalmol . 1974;;13:713-724.
4 +
Gabbay KH.  The sorbitol pathway and the complications of diabetes . N Engl J Med . 1973;;288:831-836.
5 +
Kador PF, Kinoshita JH.  Role of aldose reductase in the development of diabetes-associated complications . Am J Med . 1985;;79( (suppl 5A) ):8-12.
6 +
Greene DA, Lattimer SA, Sima AAF.  Sorbitol, phosphoinositides, and sodium-potassium-ATPase in the pathogenesis of diabetic complications . N Engl J Med . 1987;;316:599-606.
7 +
Gabbay KH.  Purification and immunological identification of bovine retinal aldose reductase . Isr J Med Sci . 1972;;8:1626-1630.
8 +
Buzney SM, Frank RN, Varma SD, Tanishima T, Gabbay KH.  Aldose reductase in retinal mural cells . Invest Ophthalmol Vis Sci . 1977;;16:292-296.
9 +
Cogan DG, Toussaint D, Kuwabara T.  Retinal vascular patterns, IV: diabetic retinopathy . Arch Ophthalmol . 1961;;66:366-378.
10 +
Frank RN, Keirn RJ, Kennedy A, Frank KW.  Galactose-induced retinal capillary basement membrane thickening: prevention by Sorbinil . Invest Ophthalmol Vis Sci . 1983;;24:1519-1524.
11 +
Robison WG Jr, Kador PF, Kinoshita JH.  Retinal capillaries: basement membrane thickening by galactosemia prevented with aldose reductase inhibitor . Science . 1983;;221:1177-1179.
12 +
Caird FI, Pirie A, Ramsell TG. Diabetes and the Eye . Boston, Mass: Blackwell Scientific Publications Inc; 1969;:37-58.
13 +
Robison WG Jr, Kador PF, Akagi Y, Kinoshita JH, Gonzalez R, Dvornik D.  Prevention of basement membrane thickening in retinal capillaries by a novel inhibitor of aldose reductase, tolrestat . Diabetes . 1986;;35:295-299.
14 +
Friedenwald JS.  A new approach to some problems of retinal vascular disease . Am J Ophthalmol . 1949;;32:487-498.
15 +
Engerman RL, Bloodworth JM.  Experimental diabetic retinopathy in dogs . Arch Ophthalmol . 1965;;73:205-210.
16 +
Engerman RL, Bloodworth JMB Jr, Nelson S.  Relationship of microvascular disease in diabetes to metabolic control . Diabetes . 1977;;26:760-769.
17 +
Patz A, Maumenee AE.  Studies in diabetic retinopathy, I: retinopathy in a dog with spontaneous diabetes mellitus . Am J Ophthalmol . 1962;;54:532-541.
18 +
Hausler HR, Sibay TM, Campbell J.  Retinopathy in a dog following diabetes induced by growth hormone . Diabetes . 1964;;13:122-126.
19 +
Engerman RL, Kern T.  Experimental galactosemia produces diabetic-like retinopathy . Diabetes . 1984;;33:97-100.
20 +
Kador PF, Akagi Y, Terubayashi H, Wyman M, Kinoshita JH.  Prevention of pericyte ghost formation in retinal capillaries of galactose-fed dogs by aldose reductase inhibitors . Arch Ophthalmol . 1988;;106:1099-1102.
21 +
Kador PF, Akagi Y, Takahashi Y, et al.  Prevention of retinal vessel changes associated with diabetic retinopathy in galactose-fed dogs by aldose reductase inhibitors . Arch Ophthalmol . 1990;;108:1301-1309.
22 +
Sorbinil Retinopathy Trial Research Group.  A randomized trial of sorbinil, an aldose reductase inhibitor, in diabetic retinopathy . Arch Ophthalmol . 1990;;108:1234-1244.
23 +
Robison WG Jr, Nagata M, Laver N, Hohman TC, Kinoshita JH.  Diabetic-like retinopathy in rats prevented with an aldose reductase inhibitor . Invest Ophthalmol Vis Sci . 1989;;30:2285-2292.
24 +
Frank RN, Hoffman WH, Podgor MJ, et al.  Retinopathy in juvenile-onset diabetes of short duration . Ophthalmology . 1980;;87:1-9.
25 +
Palmberg P, Smith M, Waltman S, et al.  The natural history of retinopathy in insulin-dependent juvenile-onset diabetes . Ophthalmology . 1981;;88:613-618.
26 +
Klein R, Klein BEK, Moss SE, Davis MD, DeMets DL.  The Wisconsin epidemiologic study of diabetic retinopathy, II: prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years . Arch Ophthalmol . 1984;;102:520-526.
27 +
Lauritzen T, Frost-Larsen K, Larsen HW, Deckert T, Steno Study Group.  Two-year experience with continuous subcutaneous insulin infusion in relation to retinopathy and neuropathy . Diabetes . 1985;;34( (suppl 3) ):74-79.
28 +
Dahl-Jørgensen K, Brinchmann-Hansen O, Hanssen KF, Sandvik I, Aagenaes 0, Aker Diabetes Group.  Rapid tightening of blood glucose control leads to transient deterioration of retinopathy in insulin dependent diabetes mellitus: the Oslo study . BMJ . 1985;;290:811-815.
29 +
The Kroc Collaborative Study Group.  Diabetic retinopathy after two years of intensified insulin treatment: follow-up of the Kroc collaborative study . JAMA . 1988;;260:37-41.
30 +
The DCCT Research Group.  Diabetes Control and Complications Trial (DCCT): results of feasibility study . Diabetes Care . 1987;;10:1-19.
31 +
Diabetic Retinopathy Study Research Group.  Preliminary report on effects of photocoagulation therapy . Am J Ophthalmol . 1976;;81:383-396.
32 +
Early Treatment Diabetic Retinopathy Study Research Group.  Photocoagulation for diabetic macular edema: Early Treatment Diabetic Retinopathy Study Report number 1 . Arch Ophthalmol . 1985;;103:1796-1806.
33 +
Engerman RL, Kern TS.  Retinal vasculature in sorbinil-treated galactosemic dogs . Invest Ophthalmol Vis Sci . 1989;;30( (suppl) ):139.

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