Treatments targeting the ARpolyol pathway

Aldose reductase inhibitors

Aldose reductase inhibitors (ARI) block the flux of glucose through the polyol pathway, have no effect on plasma glucose levels and hence do not pose the risk of hypoglycaemia.73 Addition of HOE 843, a specific ARI, to glomerular explants in vitro prevents the high-glucose-induced increases in flux of glucose through the pentose phosphate pathway, DAG synthesis, membrane PKC activity, PLA2 activity, and PGE2 production. These in vitro data suggest a link between increased polyol pathway activity and increased prostaglandin production, as observed in diabetes of recent onset.74 Orally administered HOE 483 has been evaluated in a double-blind, placebocontrolled, clinical trial. HOE 843, is well tolerated and decreases red blood cell sorbitol concentrations, a biochemical marker of pharmacologic activity, in a dose-related fashion in diabetic patients.75

Numerous experimental and clinical studies with different ARI have implicated the diabetes-induced increased flux of glucose through the polyol pathway in the development of diabetic retinopathy and neuropathy; however, only a few studies have investigated the influence of ARI in diabetic kidney. Sorbinil, tolrestat and ponalrestat have been withdrawn from clinical trials due to toxicity or a lack of efficacy in human diabetic neuropathy,76 although ponalrestat has a positive effect on renal hyperfiltration in type 1 diabetic patients.77

Others

Oral administration of vanadate, a nutritional trace element, to alloxan diabetic rats prevents the increase in kidney growth and restores the renal changes in AR and SDH activities and sorbitol content.78 This may be partially due to the normalization of blood and renal glucose by vanadate. The vanadium level of kidney is much higher than the plasma level, probably due to greater accumulation in the kidney during administration.78

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