Pharmacological approaches to the treatment of diabetic complications

Diabetes is often accompanied by several long-tt rm complications such as n europathy, nephropathy, retinopathy, cataract and angiopathy; their occurre nce has been linked to the modification of the physiological levels of glyc aemia. Several interrelated metabolic pathways have been implicated in the toxic effects of glucose; the polyol pathway was one of the first considere d. I However, while in diabetic animal models the: inhibitors of aldose red uctase (ALR2, the First enzyme of this pathway) seem to be active,, 16 year s of clinical trials, based mainly on neuropathy, have been inconclusive; o nly one drug currently being marketed. Newer potent and selective aldose re ductase inhibitors have been discovered in the last few years, but the lack of commercial success has probably led to the very rapid decrease in the n umber of patents relating to newer aldose reductase inhibitors. Inhibition of the second enzyme of this pathway, sorbitol dehydrogenase (SDII), has be en shown to be detrimental. Other approaches for the prevention and the del ay of progression of diabetic complications seem to be more promising, name ly, the inhibition of the formation of advanced glycated end products (AGEs ) or protein kinase C (PE;C) beta(2) inhibition; compounds acting on these two pathways have proved effective in retarding the development of diabetic complications in animal models and some products are in clinical trials at the moment. Renewed attention has been paid to vascular involvement in the pathogenesis of diabetic neuropathy; the biological activity of C-peptide and the role of endothelin-l (ET-1) in diabetic vascular disease are emergi ng as a new research area for the treatment of diabetic complications.