Aldose reductase inhibitors: therapeutic implications for diabetic complications.

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.