Aldose Reductase - Role in Diabetes

Role in Diabetes

Diabetes mellitus is recognized as a leading cause of new cases of blindness, and is associated with increased risk for painful neuropathy, heart disease and kidney failure. Many theories have been advanced to explain mechanisms leading to diabetic complications, including stimulation of glucose metabolism by the polyol pathway. Additionally, the enzyme is located in the eye (cornea, retina, lens), kidney, and the myelin sheath–tissues that are often involved in diabetic complications. Under normal glycemic conditions, only a small fraction of glucose is metabolized through the polyol pathway, as the majority is phosphorylated by hexokinase, and the resulting product, glucose-6-phosphate, is utilized as a substrate for glycolysis or pentose phosphate metabolism. However, in response to the chronic hyperglycemia found in diabetics, glucose flux through the polyol pathway is significantly increased. Up to 33% of total glucose utilization in some tissues can be through the polyol pathway. Glucose concentrations are often elevated in diabetics and aldose reductase has long been believed to be responsible for diabetic complications involving a number of organs. Many aldose reductase inhibitors have been developed as drug candidates but virtually all have failed although some such as epalrestat are commercially available in several countries. Additional reductase inhibitors such as ranirestat, ponalrestat, rinalrestat, risarestat, sorbinil, and berberine are currently in clinical trials.