Aldose reductase: a window to the treatment of diabetic complications?

Medical treatment of diabetic retinopathy

“…Increases in nerve conduction rates, blood flow, and vasodilation have been demonstated with ADIs. 13 With regard to retinal studies, the rate of new microaneurysm formation was slightly reduced in a single long-term study of sorbinil 5 but the preventative effects on retinopathy seem less strong than in normoglycaemic trials of similar duration. A 6-month randomised study of tolrestat involving 31 patients with retinopathy showed a significant decrease in the rate of leakage from focal lesions on fluorescein angiography.…”

“…In a major review of the role of aldose reductase in diabetes, Crabbe and Goode showed that the rat model for cataract formation is inappropriate for human comparison, because of much higher ratio of polyol dehydrogenase to aldose reductase in the human lens. 13 They concluded that based on current knowledge it was difficult to see any role for osmotic damage as an initiating factor in human diabetic complications. Aldose reductase appears to be part of a cellular osmotic defense system with accumulation of sorbitol occurring intracellularly in tissues, which are challenged by increased osmotic load.…”

“…Excess utilisation of NADPH by aldose reductase in conditions of hyperglycaemia may limit access to this cofactor by NO synthetase and glutathione peroxidase and provide a rationale for the development of diabetic complications on the basis that competition for NADPH may stress antioxidant defences. 13 Despite the doubt that now surrounds the theory of osmotic stress, clinical trials of aldose reductase inhibitors (ADI) have shown benefits and have been approved for use in some countries. There are nine aldose reductase inhibitors that have undergone clinical assessment and these are tolrestat, ponalrestat, zenarestat, epalrestat, sorbinil, zopolrestat, symmetristat, and ADN138.…”

“…It is worth noting that vitamin C can inhibit aldose reductase and that red blood cell sorbitol levels were normalised after 3 months of vitamin C (100-600 mg) in a study group of type I diabetics. 13 …”

“…88 It has been postulated that the reduction in antioxidant reserve in diabetic patients may be because of competition for NADPH, from the sorbitol pathway. 13 While this appeared a promising mechanism to manipulate with well-tolerated vitamin supplements, the results of clinical studies of antioxidant supplementation have been, by and large, disappointing. The largest randomised controlled study to investigate this approach was the HOPE study.…”