Aldose reductase inhibitors: therapeutic implications for diabetic complications

Abstract

The 'late complications' of diabetes mellitus, i.e., nephropathy, neuropathy and retinopathy are firmly rooted in inadequate control of blood glucose: hyperglycaemia. Hyperglycaemia causes elevated cytosolic glucose and/or rates of glucose metabolism, i.e., 'hyperglysolia,' within cells of vulnerable tissues. Although the molecular basis for the pathogenic effects of hyperglysolia remains to be proven, substantial evidence points to a key role for increased glucose metabolism through a cytosolic enzyme, aldose reductase (AR). Recent human genetic and biochemical data link polymorphisms of the AR gene (technically called the AR2 gene) and elevated tissue levels of AR with strongly altered risks for diabetic complications. Despite several genetic reports failing to confirm such an association, there are now ten concordant reports from five continents that certain polymorphisms of the AR gene are associated with an ~ 3- to 20-fold higher risk for diabetic complications. Moreover, in US and European diabetic study populations the principle allele of the AR gene associated with elevated disease risk, the Z-2 allele, correlates with an ~ 2- to 3-fold increase in AR expression. These results, together with recent clinical, experimental and pharmacological data, provide powerful new support for the rationale for research and development of aldose reductase inhibitors (ARIs) targeted at slowing the progression of diabetic complications. Although past clinical trials of ARIs have been disappointing, this has stemmed from overly optimistic expectations, inadequate trial designs and lack of pharmacological robustness and/or acceptable systemic toleration of the agents tested. However, a more realistic and encouraging perspective for therapeutic expectations for ARIs has arisen from recent data revealing that the seemingly modest short-term effects of intensified glycaemic control and of pancreatic transplantation are followed by substantial long-term benefits on diabetic complications. In addition, robust inhibition of AR in human nerve has recently yielded dose-dependent efficacy on nerve structure and function. Thus, the quest for well-tolerated, potent ARIs continues to be a worthy and more urgent objective than ever before.

Aldose reductase inhibition counteracts nitrosative stress and poly(ADP-ribose) polymerase activation in diabetic rat kidney and high-glucose-exposed human mesangial cells

“…However, this contradicts numerous reports of (1) alleviation, rather than aggravation, of oxidative-nitrosative stress by AR inhibitors in other tissues of diabetic animals as discussed above, and (2) beneficial effects of both AR inhibitors and antioxidants on experimental DN [4,5,14,15]. Furthermore, several groups demonstrated that prevalence of DN depends on (1) erythrocyte AR content, and/or (2) frequency of the z-2 allele of the AR gene, in human subjects with diabetes mellitus [4,67,68]. Homozygosity for the z-2 allele in Type 1 (insulin-dependent) diabetes is associated with an increased expression of the AR gene and DN [67].…”

“…Prospective Diabetes Study [3] strongly suggest the importance of hyperglycemia in the pathogenesis of chronic complications of diabetes mellitus including diabetic renal disease. Hyperglycemia leads to diabetic nephropathy (DN) via multiple mechanisms, and among them increased aldose reductase (AR) activity [4,5], nonenzymatic glycation and glycooxidation [6,7], activation of protein kinase C (PKC) and hexosamine pathway [8][9][10], arachidonic acid metabolism via 12/15-lipoxygenase pathway [11,12], and triose phosphate accumulation [13] are the best studied. Growing evidence obtained in diabetic animals (primarily, STZ (streptozotocin)-diabetic rats and mice) [14][15][16][17] as well as cell culture models [18][19][20] implicates free radicals and the potent oxidant peroxynitrite (a product of superoxide anion radical reaction with nitric oxide) in both hemodynamic and metabolic abnormalities leading to DN.…”

A Role for the Polyol Pathway in the Early Neuroretinal Apoptosis and Glial Changes Induced by Diabetes in the Rat

“…On the one hand, sorbinil has been found not to prevent the development of diabetic retinopathy in dogs (29) or lessen its progression in patients (30). On the other hand, the frequency of an allelic variant of aldose reductase that confers increased expression of the gene (measured in white blood cells) is found to be significantly greater in diabetic patients with retinopathy than in those without retinopathy (31). Because retinal sorbitol levels in diabetic dogs were only minimally increased (in keeping with GHb elevated to only 8%) (29), one may speculate that the modest hyperglycemia did not lead to a degree of polyol pathway activation that would burden cells, and therefore there was little room for sorbinil to show a beneficial effect.…”

Molecular mechanisms of Diabetic Retinopathy, general preventive strategies and novel therapeutic targets

“…Aldose reductase (AR) reduces glucose to sorbitol with the aid of its cofactor NADPH, and sorbitol dehydrogenase (SDH), with its cofactor NAD + , converts sorbitol to fructose. In animal models, treatment with AR inhibitors (ARI) was shown to be effective in preventing the development of various diabetic complications, including diabetic retinopathy [108]. Although the exact mechanism is unknown, AR appears to be the possible link between increased polyol pathway activity and the development of some diabetic complications.…”