Aldose reductase inhibitors: therapeutic implications for diabetic complications

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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 ...